CN116847882A - HIV vaccine and how to use it - Google Patents
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Abstract
本发明提供了HIV‑1融合多肽、编码此类融合多肽的多核苷酸、表达此类融合多肽的载体,用于引发针对HIV‑1的免疫应答;包含此类融合多肽、多核苷酸或载体的药物和免疫原性组合物和试剂盒,以及用于治疗和/或预防HIV‑1的方法。本发明还提供了用于设计抗病毒疫苗包括引发对HIV‑1的免疫应答的疫苗的方法。
The invention provides HIV-1 fusion polypeptides, polynucleotides encoding such fusion polypeptides, and vectors expressing such fusion polypeptides for inducing immune responses against HIV-1; including such fusion polypeptides, polynucleotides or vectors Pharmaceutical and immunogenic compositions and kits, and methods for treating and/or preventing HIV‑1. The present invention also provides methods for designing antiviral vaccines, including vaccines that elicit an immune response to HIV-1.
Description
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本申请根据35 U.S.C.§119(e)要求2021年1月14日提交的美国临时申请号63/137,521;2021年2月16日提交的美国临时申请号63/149,820和2021年4月5日提交的美国临时申请号63/170,900的权益,这些临时申请据此全文以引用方式并入本文以用于所有目的。This application claims the benefit of U.S. Provisional Application No. 63/137,521, filed on January 14, 2021; U.S. Provisional Application No. 63/149,820, filed on February 16, 2021, and U.S. Provisional Application No. 63/170,900, filed on April 5, 2021, under 35 U.S.C. §119(e), which are hereby incorporated by reference in their entirety for all purposes.
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本申请包含序列表,该序列表以ASCII格式以电子方式提交并且据此全文以引用方式并入。所述ASCII副本创建于2021年12月12日,名称为1355-WO-PCT.txt,并且大小为512,244字节。This application contains a sequence listing, which is submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy was created on December 12, 2021, is named 1355-WO-PCT.txt, and is 512,244 bytes in size.
背景技术Background Art
HIV仍然是全球人口流动和死亡率的主要原因之一,2019年全球有超过3800万人感染,并且有69万人死亡(UNAIDS.Fact Sheet-World AIDS Day 2020.unaidsorg/en/resources/fact-sheet.2020)。在过去三十年里,HIV的治疗取得了显著改善。高活性抗逆转录病毒治疗的发展提高了HIV患者的存活率,并降低了HIV相关免疫抑制和机会性感染的发病率(Johnson等人,PLoS Med.2013;10(4):e1001418;May等人,AIDS.(2014)28(8):1193-202;Rodger等人,AIDS.(2013)27(6):973-9;Samji等人,PLoS One.(2013)8(12):e81355)。近年来,抗逆转录病毒治疗(ART)方案已被简化为每天一次药丸,并即将推出长效口服和注射治疗(Swindells等人,N Engl J Med.(2020)382(12):1112-23;Orkin等人,NEngl J Med.(2020)382(12):1124-35;Link等人,Nature.(2020)584(7822):614-8)。尽管在治疗方面取得了这些进展,但迄今为止仅有两个有据可查的治愈示例,这两个示例都需要严格的免疫抑制和骨髓移植(Gupta等人,Lancet HIV.(2020)7(5):e340-e7;Hutter等人,N Engl J Med.(2009)360(7):692-8)。与许多自我限制的感染性疾病不同,HIV病毒将自身整合到其宿主基因组中,并且在静息记忆CD4+T细胞中建立潜伏期(Eisele等人,Immunity.(2012)37(3):377-88)。这些细胞形成无法通过标准抗逆转录病毒治疗清除的HIV潜伏库。储库细胞也受到保护免于免疫监视和清除机制的影响,因为这些细胞不表达病毒抗原,使得这些细胞能够逃避细胞毒性T细胞的识别和清除。该储库是长期存在的,并且尽管可检测到储库尺寸的减小,但在停止ART后观察到病毒反弹(Henrich等人,Ann InternMed.(2014)161(5):319-27;Henrich等人,J Infect Dis.(2013)207(11):1694-702)。用潜伏期逆转剂激活储库将需要与有效机制结合,以刺激细胞毒性T细胞和消除受感染的储库细胞(Ait-Ammar等人,Front Microbiol.(2019)10:3060;Mothe等人,Front Immunol.(2020)11:823;Fidler等人,Lancet.(2020)395(10227):888-98)。被设计用于产生抗原特异性效应T细胞应答的治疗性疫苗可以是HIV治疗策略的附加组分。HIV remains one of the leading causes of global population mobility and mortality, with more than 38 million infections and 690,000 deaths worldwide in 2019 (UNAIDS.Fact Sheet-World AIDS Day 2020.unaidsorg/en/resources/fact-sheet.2020). In the past three decades, HIV treatment has improved significantly. The development of highly active antiretroviral therapy has improved the survival rate of HIV patients and reduced the incidence of HIV-related immunosuppression and opportunistic infections (Johnson et al., PLoS Med. 2013; 10(4): e1001418; May et al., AIDS. (2014) 28(8): 1193-202; Rodger et al., AIDS. (2013) 27(6): 973-9; Samji et al., PLoS One. (2013) 8(12): e81355). In recent years, antiretroviral therapy (ART) regimens have been simplified to a once-daily pill, with long-acting oral and injectable treatments on the horizon (Swindells et al., N Engl J Med. (2020) 382(12):1112-23; Orkin et al., N Engl J Med. (2020) 382(12):1124-35; Link et al., Nature. (2020) 584(7822):614-8). Despite these advances in treatment, there have been only two documented cures to date, both of which required strict immunosuppression and bone marrow transplantation (Gupta et al., Lancet HIV. (2020) 7(5):e340-e7; Hutter et al., N Engl J Med. (2009) 360(7):692-8). Unlike many self-limiting infectious diseases, HIV virus integrates itself into its host genome and establishes latency in resting memory CD4+T cells (Eisele et al., Immunity. (2012) 37 (3): 377-88). These cells form HIV latent reservoirs that cannot be removed by standard antiretroviral therapy. Reservoir cells are also protected from immune surveillance and clearance mechanisms because these cells do not express viral antigens, allowing these cells to escape recognition and clearance of cytotoxic T cells. The reservoir is long-term, and although a decrease in reservoir size can be detected, viral rebound is observed after stopping ART (Henrich et al., Ann Intern Med. (2014) 161 (5): 319-27; Henrich et al., J Infect Dis. (2013) 207 (11): 1694-702). Activation of the reservoir with latency reversal agents will need to be combined with effective mechanisms to stimulate cytotoxic T cells and eliminate infected reservoir cells (Ait-Ammar et al., Front Microbiol. (2019) 10: 3060; Mothe et al., Front Immunol. (2020) 11: 823; Fidler et al., Lancet. (2020) 395 (10227): 888-98). Therapeutic vaccines designed to generate antigen-specific effector T cell responses can be an additional component of HIV treatment strategies.
T细胞疫苗在治疗领域诸如肿瘤学中具有重要的前景。在一些癌症中,高水平的肿瘤浸润CD8+淋巴细胞与较好的预后相关,这使得人们对开发能够诱导肿瘤特异性细胞毒性CD8+ T细胞的疫苗产生了极大兴趣。尽管先前的方法已取得了有限的成功(Rosenberg等人,Nature Medicine.(2004)10(9):909-15),但新型递送平台的使用、抗原发现和免疫调节的改进技术带来了一些希望(Ott等人,Nature.(2017)547(7662):217-21)。类似地,T细胞在HIV病毒血症的控制中发挥重要作用。在急性HIV感染中出现的抗原特异性T细胞负责驱动病毒血症的最初下降(Borrow等人,J Virol.(1994)68(9):6103-10;Koup等人,JVirol.(1994)68(7):4650-5)。受HIV感染的人中的长期不进展者或精英控制者的特征在于具有强有效的抗原特异性T细胞应答。在SIV感染(人HIV感染的非人灵长类动物模型)中,天然产生的或通过疫苗接种产生的抗原特异性T细胞与病毒控制相关(Schmitz等人,Science.(1999)283(5403):857-60;Jin等人,J Exp Med.(1999)189(6):991-8)。尽管有这些数据,但用于预防的T细胞疫苗在诱导有限广度或功效的T细胞应答方面具有有限的成功(Buchbinder等人,Lancet.(2008)372(9653):1881-93;Janes等人,J Infect Dis.(2013)208(8):1231-9;Excler等人,Curr Opin HIV AIDS.(2016)11(6):607-13)。用T细胞疫苗进行的治疗性疫苗试验也显示出有限的功效(Mothe等人,Front Immunol.(2020)11:823;Colby等人,Nature Medicine.(2020)26(4):498-501)。这些试验使用病毒载体诸如腺病毒(人和黑猩猩)以及改良安卡拉痘苗病毒(MVA)和全长病毒抗原或更短的构建体(Barouch等人,Lancet.(2018)392(10143):232-43;Mothe等人,EClinicalMedicine.(2019)11:65-80)。来自这些研究的数据表明,疫苗接种后产生的抗原特异性T细胞的广度较低。尽管这些疫苗诱导的T细胞在标准ELISpot测定中分泌IFN-γ,但所证实的功效缺乏表明这些T细胞可能不具有完全的细胞毒性活性。T cell vaccines have important prospects in therapeutic areas such as oncology. In some cancers, high levels of tumor-infiltrating CD8+ lymphocytes are associated with better prognosis, which has led to great interest in developing vaccines that can induce tumor-specific cytotoxic CD8+ T cells. Although previous methods have achieved limited success (Rosenberg et al., Nature Medicine. (2004) 10 (9): 909-15), the use of novel delivery platforms, antigen discovery and improved techniques for immunomodulation have brought some hope (Ott et al., Nature. (2017) 547 (7662): 217-21). Similarly, T cells play an important role in the control of HIV viremia. Antigen-specific T cells that appear in acute HIV infection are responsible for driving the initial decline in viremia (Borrow et al., J Virol. (1994) 68 (9): 6103-10; Koup et al., J Virol. (1994) 68 (7): 4650-5). Long-term non-progressors or elite controllers in HIV-infected people are characterized by strong and effective antigen-specific T cell responses. In SIV infection (a non-human primate model of human HIV infection), antigen-specific T cells produced naturally or by vaccination are associated with viral control (Schmitz et al., Science. (1999) 283 (5403): 857-60; Jin et al., J Exp Med. (1999) 189 (6): 991-8). Despite these data, T cell vaccines used for prevention have limited success in inducing T cell responses of limited breadth or efficacy (Buchbinder et al., Lancet. (2008) 372 (9653): 1881-93; Janes et al., J Infect Dis. (2013) 208 (8): 1231-9; Excler et al., Curr Opin HIV AIDS. (2016) 11 (6): 607-13). Therapeutic vaccine trials with T cell vaccines have also shown limited efficacy (Mothe et al., Front Immunol. (2020) 11: 823; Colby et al., Nature Medicine. (2020) 26 (4): 498-501). These trials use viral vectors such as adenovirus (human and chimpanzee) and modified vaccinia virus Ankara (MVA) and full-length viral antigens or shorter constructs (Barouch et al., Lancet. (2018) 392 (10143): 232-43; Mothe et al., EClinical Medicine. (2019) 11: 65-80). Data from these studies suggest that the breadth of antigen-specific T cells generated after vaccination is low. Although these vaccine-induced T cells secrete IFN-γ in standard ELISpot assays, the lack of efficacy demonstrated suggests that these T cells may not have full cytotoxic activity.
免疫原设计是任何治疗性HIV疫苗的组成部分,以产生正确的抗原特异性应答、靶向保守区并具有细胞毒性活性。自然感染已经证实,免疫应答将倾向于集中在HIV内的高度免疫显性可变区,例如HIV包膜或Nef中的可变区,或HIV Gag中的可变区(Addo等人,JVirol.(2003)77(3):2081-92;Betts等人,J Virol.2001;75(24):11983-91)。这些应答产生T细胞,病毒可从这些T细胞中快速逃逸而无需付出适应性代价(Liu等人,J Virol.(2006)80(19):9519-29)。有效的HIV疫苗将需要避开这些区域并驱动从头应答的建立,这些从头应答将免疫应答集中在病毒的保守区,其中要求该保守区是保守的以维持病毒功能。Immunogen design is an integral part of any therapeutic HIV vaccine to generate the correct antigen-specific response, target conserved regions, and have cytotoxic activity. Natural infection has demonstrated that immune responses tend to focus on highly immunodominant variable regions within HIV, such as variable regions in HIV envelope or Nef, or variable regions in HIV Gag (Addo et al., J Virol. (2003) 77 (3): 2081-92; Betts et al., J Virol. 2001; 75 (24): 11983-91). These responses generate T cells from which the virus can quickly escape without paying an adaptive cost (Liu et al., J Virol. (2006) 80 (19): 9519-29). Effective HIV vaccines will need to avoid these regions and drive the establishment of de novo responses, which focus immune responses on conserved regions of the virus, where the conserved regions are required to be conserved to maintain viral function.
先前的HIV疫苗主要侧重于通过解决全球HIV病毒多样性而提供通用覆盖来设计免疫原,并且已经产生全长序列或已经适应算法以产生保守区的构建体(Korber等人,HumVaccin Immunother.(2020)16(3):713-722;Fischer等人,Nature Medicine.(2007)13(1):100-6)。所有这些方法主要评估了共有序列,这些共有序列评估患者间的变异性以确定保守区,并连接这些保守区以提供总序列覆盖。然而,受HIV感染的个体内存在几种循环的准种。这些病毒准种中的一些准种是由于T细胞驱动压力而产生的,并且反映了在针对其的T细胞应答出现时病毒的预先存在的逃逸途径(Liu等人,J Virol.(2006)80(19):9519-29;Korber等人,2020,出处同上;Price等人,Proc Natl Acad Sci U S A.(1997)94(5):1890-5)。先前的疫苗对保守区的靶向未考虑到准种以及对高度保守的免疫原性区域的鉴定,这可能部分解释了它们有限的功效(Hanke等人,Expert Rev Vaccines.(2019)18(10):1029-41)。Previous HIV vaccines have focused primarily on designing immunogens by addressing global HIV viral diversity and providing universal coverage, and have generated full-length sequences or have adapted algorithms to generate constructs of conserved regions (Korber et al., Hum Vaccin Immunother. (2020) 16 (3): 713-722; Fischer et al., Nature Medicine. (2007) 13 (1): 100-6). All of these methods have primarily evaluated consensus sequences, which evaluate inter-patient variability to determine conserved regions, and connect these conserved regions to provide total sequence coverage. However, there are several circulating quasispecies in HIV-infected individuals. Some of these viral quasispecies are generated due to T cell-driven pressure and reflect the pre-existing escape pathways of the virus when T cell responses against it appear (Liu et al., J Virol. (2006) 80 (19): 9519-29; Korber et al., 2020, supra; Price et al., Proc Natl Acad Sci U S A. (1997) 94 (5): 1890-5). Previous vaccines targeting conserved regions did not take into account quasispecies and the identification of highly conserved immunogenic regions, which may partly explain their limited efficacy (Hanke et al., Expert Rev Vaccines. (2019) 18 (10): 1029-41).
发明内容Summary of the invention
本发明提供了融合多肽,其包含由选自gag、pol和nef的两种或更多种HIV基因编码的一种或多种人类免疫缺陷病毒-1(HIV-1)蛋白的多个多肽片段。在一些实施方案中,该多个多肽片段包含由HIV-1基因Pol和Nef编码的多肽片段或者由这些多肽片段组成,例如不包含由HIV-1基因env、tat、rev、vpr、vif和/或vpu编码的多肽片段。在一些实施方案中,该多个多肽片段包含由HIV-1基因Gag、Pol和Nef编码的多肽片段或者由这些多肽片段组成,例如不包含由HIV-1基因env、tat、rev、vpr、vif和/或vpu编码的多肽片段。在一些实施方案中,该多个多肽片段来源于病毒蛋白质组序列群体中的保守区。在一些实施方案中,保守区在患者间群体中的HIV-1种类中的保守性大于80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。在一些实施方案中,保守区在HIV-1进化枝A-K中的一者或多者例如进化枝A、B、C、D和G中的一者或多者或HIV-1进化枝A-K中的一者或多者的重组形式以及它们的组合之间是保守的。在一些实施方案中,融合多肽包含至少4个以及至多6个多肽片段,例如,4、5或6个多肽片段。在一些实施方案中,每个多肽片段的长度为至少10个氨基酸,以及长度为至多约225个氨基酸,例如长度为至少10个氨基酸以及长度为至多11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、215、220或225个氨基酸。在一些实施方案中,融合多肽的全长包含至少约330个氨基酸以及至多约505个氨基酸(不含信号肽)或至多约550个氨基酸(包含信号肽),例如至少约330个氨基酸以及至多约335、340、345、350、355、360、365、370、375、380、385、390、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495、500、505、510、515、520、525、530、535、540、545或550个氨基酸。在一些实施方案中,融合多肽的全长不长于550个氨基酸(含信号肽)或不长于505个氨基酸(不含信号肽),例如不长于545、540、535、530、525、520、515、510、505、500、495、490、485、480、475、470、465、460、455、450、445、440、435、430、425、420、415、410、405、400、390、385、380、375、370、365、360、355、350、345、340、335或330个氨基酸。在一些实施方案中,融合多肽的全长包含至少350个氨基酸以及至多385个氨基酸,例如至少350个氨基酸以及至多365个氨基酸。在一些实施方案中,融合多肽的全长包含至少390个氨基酸以及至多395个氨基酸。在一些实施方案中,每个多肽片段包含一个或多个预测的T细胞表位或者由这些表位组成。在一些实施方案中,融合多肽包含三个或更多个预测的T细胞表位,例如四个、五个、六个或更多个预测的T细胞表位。在一些实施方案中,融合多肽包含一个或多个多肽片段,这些多肽片段与例如单个受试者内或多名患者之间的一个或多个人HLA I类等位基因(例如,1、2、3、4、5或6个等位基因)结合或者由这些等位基因呈递。在一些实施方案中,融合多肽包含一个或多个多肽片段,这些多肽片段至少与人A*0201 HLA I类分子结合或者由该分子呈递。在一些实施方案中,融合多肽包含一个或多个多肽片段,这些多肽片段在细胞内加工并由例如单个受试者内的一个或多个人HLA II类等位基因(例如,1、2、3、4、5或6个等位基因)呈递。在一些实施方案中,这些多肽片段中的一个或多个多肽片段与相邻片段邻接或融合。在一些实施方案中,这些多肽片段中的一个或多个多肽片段通过一个或多个肽接头结合到相邻片段。在一些实施方案中,一个或多个肽接头选自聚丙氨酸、聚甘氨酸、Gln-Glu-Glu(QEE)、赖氨酸(L)、异亮氨酸(I)、Leu-Ile(LI)、Lys-Ile-Leu(KIL)、Leu-Ile-Lys(LIK)、Pro-Pro-Val(PPV)、Ser-Glu-Gly(SEG)、可切割接头、柔性接头、刚性接头以及它们的组合中的一者或多者。在一些实施方案中,柔性接头选自Gln-Glu-Glu(QEE)(SEQ ID NO:51)、赖氨酸(L)、异亮氨酸(I)、Leu-Ile(LI)、Lys-Ile-Leu(KIL)(SEQ ID NO:52)、Leu-Ile-Lys(LIK)(SEQID NO:53)、Pro-Pro-Val(PPV)(SEQ ID NO:54)、Ser-Glu-Gly(SEG)(SEQ ID NO:55)。在一些实施方案中,柔性接头包括聚丙氨酸接头或聚甘氨酸接头,例如包含2或3个连续丙氨酸残基,例如AA、AAA(SEQ ID NO:48)、AAY(SEQ ID NO:49)或AAX或者由这些连续丙氨酸残基组成,其中X是任何氨基酸(例如,A、C、D、E、F、G、H、I、K、L、M、N、P、Q、R、S、T、V、Y)(SEQ ID NO:50)。在一些实施方案中,柔性接头包含GG、GGS(SEQ ID NO:57)、GSG(SEQ ID NO:58)或GGGS(SEQ ID NO:59)或者由所述项组成。在一些实施方案中,可切割接头选自2A可切割肽(例如,口蹄疫病毒(F2A)、马鼻炎A病毒(E2A)、猪捷申病毒-1(P2A)和明脉扁刺蛾病毒(T2A))、弗林蛋白酶识别/切割序列(例如,RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)和RRKR(SEQID NO:62))以及它们的组合、衍生物或变体。在一些实施方案中,可切割接头包含选自RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)和RRKR(SEQ ID NO:62)的弗林蛋白酶识别/切割位点或由其组成。在一些实施方案中,可切割接头包含与ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQID NO:65)、QCTNYALLKLAGDVESNPGP(SEQ ID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67)至少90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%相同的氨基酸序列或者由这些氨基酸序列组成,或者包含ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ IDNO:65)、QCTNYALLKLAGDVESNPGP(SEQ ID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67)的氨基酸序列或者由这些氨基酸序列组成。在一些实施方案中,融合多肽包含两个、三个、四个、五个、六个或更多个多肽片段,这些多肽片段包含对应于Gag 1-53、Gag 147-369、Pol56-117、Pol 129-320、Pol 367-431、Pol 542-606、Pol 586-606、Pol683-708、Pol 747-827、Pol 840-909、Pol 840-920、Pol 932-1003、Nef 64-76、Nef 64-99或Nef 117-148的氨基酸残基或者由这些氨基酸残基组成,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQID NO:1、2和3。在一些实施方案中,融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol 607-682、Pol 709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在一些实施方案中,融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47中的任一项或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含选自SEQ IDNO:4-33的两个、三个、四个、五个、六个或更多个多肽片段。在一些实施方案中,融合多肽包含以下多肽片段或者由以下多肽片段组成,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3:(a)对应于以下的氨基酸残基:Gag 1-53、Gag 147-369、Pol 683-708和Nef 117-148;(b)对应于以下的氨基酸残基:Pol 56-117、Pol 129-320、Pol 367-431和Nef64-99;(c)对应于以下的氨基酸残基:Pol542-606、Pol 747-827、Pol 840-920、Pol 932-1003和Nef 64-99;(d)对应于以下的氨基酸残基:Gag 1-53、Gag 147-369、Pol 683-708、Pol 747-827、Pol 840-920和Nef 117-148;(e)对应于以下的氨基酸残基:Pol 56-117、Pol129-320、Pol 367-431、Pol 542-606、Pol 932-1003和Nef 64-99;(f)对应于以下的氨基酸残基:Gag 147-369、Pol 586-606、Pol 683-708和Pol 840-920;(g)对应于以下的氨基酸残基:Pol 129-320、Pol 747-827、Pol 932-1003和Nef 64-76;或(h)对应于以下的氨基酸残基:Gag:147-369、Pol 747-827、Pol 840-909和Nef 64-76。在一些实施方案中,融合多肽包含以下多肽片段或者由以下多肽片段组成:(a)SEQ ID NO:4、6、18和32,或分别与SEQID NO:4、6、18和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(b)SEQ ID NO:5、7、19和33,或分别与SEQ ID NO:5、7、19和33至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(c)SEQ ID NO:8、10、12和30,或分别与SEQ ID NO:8、10、12和30至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(d)SEQ ID NO:9、11、13和31,或分别与SEQ ID NO:9、11、13和31至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(e)SEQ ID NO:14、20、24、26和30,或分别与SEQ ID NO:14、20、24、26和30至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(f)SEQ ID NO:15、21、25、27和31,或分别与SEQ ID NO:15、21、25、27和31至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(g)SEQ ID NO:4、6、18、20、24和32,或分别与SEQ IDNO:4、6、18、20、24和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(h)SEQ IDNO:5、7、19、21、25和33,或分别与SEQ ID NO:5、7、19、21、25和33至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(i)SEQ ID NO:8、10、12、14、26和30,或分别与SEQ ID NO:8、10、12、14、26和30至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(j)SEQ ID NO:9、11、13、15、27和31,或分别与SEQ ID NO:9、11、13、15、27和31至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(k)SEQ ID NO:6、16、18和24,或分别与SEQ ID NO:6、16、18和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(l)SEQ ID NO:7、17、19和25,或分别与SEQID NO:7、17、19和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(m)SEQ ID NO:10、20、26和28,或分别与SEQ ID NO:10、20、26和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(n)SEQ ID NO:11、21、27和29,或分别与SEQ ID NO:11、21、27和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(o)SEQ ID NO:6、20、22和28,或分别与SEQ IDNO:6、20、22和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(p)SEQ ID NO:7、21、23和29,或分别与SEQ ID NO:7、21、23和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(q)SEQ ID NO:6、16、18和24,或分别与SEQ ID NO:6、16、18和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(r)SEQ ID NO:7、17、19和25,或分别与SEQ ID NO:7、17、19和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;(s)SEQ ID NO:10、20、26和28,或分别与SEQ ID NO:10、20、26和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;或(t)SEQ ID NO:11、21、27和29,或分别与SEQ ID NO:11、21、27和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段。在一些实施方案中,融合多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段或者由以下多肽片段组成:SEQID NO:6、4、18和32,或分别与SEQ ID NO:6、4、18和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:7、5、33和19,或分别与SEQ ID NO:7、5、33和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:12、30、8和10,或分别与SEQ ID NO:12、30、8和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:9、31、13和11,或分别与SEQ ID NO:9、31、13和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ IDNO:14、26、20、30和24,或分别与SEQ ID NO:14、26、20、30和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:15、31、21、27和25,或分别与SEQ ID NO:15、31、21、27和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:32、18、4和6,或分别与SEQID NO:32、18、4和6至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:7、33、5和19,或分别与SEQ ID NO:7、33、5和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:8、30、12和10,或分别与SEQ ID NO:8、30、12和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:13、31、9和11,或分别与SEQ ID NO:13、31、9和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:26、30、14、20和24,或分别与SEQID NO:26、30、14、20和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:31、27、15、25和21,或分别与SEQ ID NO:31、27、15、25和21至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:24、6、4、20、18和32,或分别与SEQ ID NO:24、6、4、20、18和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:6、20、4、24、32和18,或分别与SEQ ID NO:6、20、4、24、32和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:7、21、5、25、33和19,或分别与SEQ ID NO:7、21、5、25、33和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:8、30、14、12、26和10,或分别与SEQ IDNO:8、30、14、12、26和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:8、12、30、26、14和10,或分别与SEQ ID NO:8、12、30、26、14和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:9、13、31、27、15和11,或分别与SEQ ID NO:9、13、31、27、15和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:20、32、24、4、6和18,或分别与SEQ ID NO:20、32、24、4、6和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:7、25、19、5、33和21,或分别与SEQ ID NO:7、25、19、5、33和21至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:26、30、12、14、8和10,或分别与SEQ IDNO:26、30、12、14、8和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:15、31、9、27、13和11,或分别与SEQ ID NO:15、31、9、27、13和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:24、6、16和18,或分别与SEQ ID NO:24、6、16和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:7、19、17和25,或分别与SEQ IDNO:7、19、17和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:24、16、6和18,或分别与SEQ ID NO:24、16、6和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:7、25、17和19,或分别与SEQ ID NO:7、25、17和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:26、20、10和28,或分别与SEQ ID NO:26、20、10和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:21、27、11和29,或分别与SEQ ID NO:21、27、11和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:26、10、20和28,或分别与SEQ ID NO:26、10、20和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:11、27、21和29,或分别与SEQ ID NO:11、27、21和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:22、6、20和28,或分别与SEQ ID NO:22、6、20和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ ID NO:23、7、21和29,或分别与SEQ ID NO:23、7、21和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;SEQ IDNO:22、20、6和28,或分别与SEQ ID NO:22、20、6和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;或SEQ ID NO:7、21、23和29,或分别与SEQ ID NO:7、21、23和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。 The present invention provides fusion polypeptides comprising multiple polypeptide fragments of one or more human immunodeficiency virus-1 (HIV-1) proteins encoded by two or more HIV genes selected from gag, pol and nef. In some embodiments, the multiple polypeptide fragments comprise or consist of polypeptide fragments encoded by HIV-1 genes Pol and Nef, for example, polypeptide fragments encoded by HIV-1 genes env, tat, rev, vpr, vif and/or vpu are not included. In some embodiments, the multiple polypeptide fragments comprise or consist of polypeptide fragments encoded by HIV-1 genes Gag, Pol and Nef, for example, polypeptide fragments encoded by HIV-1 genes env, tat, rev, vpr, vif and/or vpu are not included. In some embodiments, the multiple polypeptide fragments are derived from conserved regions in a viral proteome sequence population. In some embodiments, the conserved region is more than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% conservative among HIV-1 species in the interpatient population. In some embodiments, the conserved region is conserved between one or more of HIV-1 clades A-K, such as one or more of clades A, B, C, D and G, or recombinant forms of one or more of HIV-1 clades A-K, and combinations thereof. In some embodiments, the fusion polypeptide comprises at least 4 and at most 6 polypeptide fragments, for example, 4, 5 or 6 polypeptide fragments. In some embodiments, each polypeptide fragment is at least 10 amino acids in length and at most about 225 amino acids in length, for example, at least 10 amino acids in length and at most 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 , 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220 or 225 amino acids. In some embodiments, the full length of the fusion polypeptide comprises at least about 330 amino acids and at most about 505 amino acids (without the signal peptide) or at most about 550 amino acids (including the signal peptide), such as at least about 330 amino acids and at most about 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, or 550 amino acids. In some embodiments, the total length of the fusion polypeptide is no longer than 550 amino acids (including the signal peptide) or no longer than 505 amino acids (without the signal peptide), e.g., no longer than 545, 540, 535, 530, 525, 520, 515, 510, 505, 500, 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 390, 385, 380, 375, 370, 365, 360, 355, 350, 345, 340, 335, or 330 amino acids. In some embodiments, the full length of the fusion polypeptide comprises at least 350 amino acids and at most 385 amino acids, for example, at least 350 amino acids and at most 365 amino acids. In some embodiments, the full length of the fusion polypeptide comprises at least 390 amino acids and at most 395 amino acids. In some embodiments, each polypeptide fragment comprises one or more predicted T cell epitopes or consists of these epitopes. In some embodiments, the fusion polypeptide comprises three or more predicted T cell epitopes, for example, four, five, six or more predicted T cell epitopes. In some embodiments, the fusion polypeptide comprises one or more polypeptide fragments, which are combined with one or more human HLA class I alleles (e.g., 1, 2, 3, 4, 5 or 6 alleles) within a single subject or between multiple patients or presented by these alleles. In some embodiments, the fusion polypeptide comprises one or more polypeptide fragments, which are at least combined with human A*0201 HLA class I molecules or presented by the molecule. In some embodiments, the fusion polypeptide comprises one or more polypeptide fragments, which are processed in the cell and presented by one or more human HLA class II alleles (e.g., 1, 2, 3, 4, 5 or 6 alleles) in, for example, a single subject. In some embodiments, one or more of these polypeptide fragments are adjacent to or fused to adjacent fragments. In some embodiments, one or more of these polypeptide fragments are bound to adjacent fragments by one or more peptide linkers. In some embodiments, one or more peptide linkers are selected from polyalanine, polyglycine, Gln-Glu-Glu (QEE), lysine (L), isoleucine (I), Leu-Ile (LI), Lys-Ile-Leu (KIL), Leu-Ile-Lys (LIK), Pro-Pro-Val (PPV), Ser-Glu-Gly (SEG), cleavable linkers, flexible linkers, rigid linkers, and combinations thereof. In some embodiments, the flexible linker is selected from Gln-Glu-Glu (QEE) (SEQ ID NO: 51), Lysine (L), Isoleucine (I), Leu-Ile (LI), Lys-Ile-Leu (KIL) (SEQ ID NO: 52), Leu-Ile-Lys (LIK) (SEQ ID NO: 53), Pro-Pro-Val (PPV) (SEQ ID NO: 54), Ser-Glu-Gly (SEG) (SEQ ID NO: 55). In some embodiments, the flexible linker comprises a polyalanine linker or a polyglycine linker, for example, comprising 2 or 3 consecutive alanine residues, for example, AA, AAA (SEQ ID NO: 48), AAY (SEQ ID NO: 49) or AAX or consisting of these consecutive alanine residues, wherein X is any amino acid (e.g., A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, Y) (SEQ ID NO: 50). In some embodiments, the flexible linker comprises or consists of GG, GGS (SEQ ID NO: 57), GSG (SEQ ID NO: 58) or GGGS (SEQ ID NO: 59). In some embodiments, the cleavable linker is selected from 2A cleavable peptides (e.g., foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and sphenotype virus (T2A)), furin recognition/cleavage sequences (e.g., RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61) and RRKR (SEQ ID NO: 62)), and combinations, derivatives or variants thereof. In some embodiments, the cleavable linker comprises or consists of a furin recognition/cleavage site selected from RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61) and RRKR (SEQ ID NO: 62). In some embodiments, the cleavable linker comprises or consists of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to ATNFSLLKQAGDVEENPGP (SEQ ID NO:63), APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:64), RAKRAPVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:65), QCTNYALLKLAGDVESNPGP (SEQ ID NO:66), or EGRGSLLTCGDVEENPGP (SEQ ID NO:67). The amino acid sequence of the peptide sequence of SEQ ID NO: 65), QCTNYALLKLAGDVESNPGP (SEQ ID NO: 66) or EGRGSLLTCGDVEENPGP (SEQ ID NO: 67) may also be present in the peptide sequence of SEQ ID NO: 68 or may consist of the amino acid sequence of SEQ ID NO: 69. In some embodiments, the fusion polypeptide comprises two, three, four, five, six or more polypeptide fragments comprising or consisting of amino acid residues corresponding to Gag 1-53, Gag 147-369, Pol56-117, Pol 129-320, Pol 367-431, Pol 542-606, Pol 586-606, Pol683-708, Pol 747-827, Pol 840-909, Pol 840-920, Pol 932-1003, Nef 64-76, Nef 64-99, or Nef 117-148, wherein the Gag, Pol, and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively. In some embodiments, the fusion polypeptide does not include any polypeptide fragment corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol 607-682, Pol 709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116 and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2 and 3, respectively. In some embodiments, the fusion polypeptide does not comprise any polypeptide fragment having an amino acid sequence of any one of SEQ ID NOs: 35-47 or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 35-47 or a fragment or subsequence thereof. In some embodiments, the fusion polypeptide comprises two, three, four, five, six, or more polypeptide fragments selected from SEQ ID NOs: 4-33. In some embodiments, the fusion polypeptide comprises or consists of the following polypeptide fragments, wherein the Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2 and 3, respectively: (a) corresponding to the following amino acid residues: Gag 1-53, Gag 147-369, Pol 683-708 and Nef 117-148; (b) corresponding to the following amino acid residues: Pol 56-117, Pol 129-320, Pol 367-431 and Nef64-99; (c) corresponding to the following amino acid residues: Pol542-606, Pol 747-827, Pol 840-920, Pol 932-1003 and Nef 64-99; (d) corresponding to the following amino acid residues: Gag 1-53, Gag 147-369, Pol 683-708, Pol 747-827, Pol 840-920 and Nef 117-148; (e) corresponding to the following amino acid residues: Pol 56-117, Pol 129-320, Pol 367-431, Pol 542-606, Pol 932-1003 and Nef 64-99; (f) corresponding to the following amino acid residues: Gag 147-369, Pol 586-606, Pol 683-708 and Pol 840-920; (g) corresponding to the following amino acid residues: Pol 129-320, Pol 747-827, Pol 932-1003 and Nef 64-76; or (h) corresponding to the following amino acid residues: Gag: 147-369, Pol 747-827, Pol 840-909 and Nef 64-76. In some embodiments, the fusion polypeptide comprises or consists of the following polypeptide fragments: (a) SEQ ID NO: 4, 6, 18 and 32, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4, 6, 18 and 32, respectively; (b) SEQ ID NO: 5, 7, 19 and 33, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5, 7, 19 and 33, respectively. %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 5, 7, 19 and 33; (c) SEQ ID NOs: 8, 10, 12 and 30, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 10, 12 and 30, respectively; (d) SEQ ID NOs: 9, 11, 13 and 31, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 20, 24, 26 and 30, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 20, 24, 26 and 30, respectively; (f) SEQ ID NOs: 1 NO:15, 21, 25, 27 and 31, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:15, 21, 25, 27 and 31, respectively; (g) SEQ ID NO:4, 6, 18, 20, 24 and 32, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4, 6, 18, 20, 24 and 32, respectively. %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4, 6, 18, 20, 24 and 32; (h) SEQ ID NO:5, 7, 19, 21, 25 and 33, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:5, 7, 19, 21, 25 and 33, respectively; (i) SEQ ID NO: NO:8, 10, 12, 14, 26 and 30, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:8, 10, 12, 14, 26 and 30, respectively; (j) SEQ ID NO:9, 11, 13, 15, 27 and 31, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:8, 10, 12, 14, 26 and 30, respectively; %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 9, 11, 13, 15, 27 and 31; (k) SEQ ID NOs: 6, 16, 18 and 24, or sequence fragments at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 16, 18 and 24, respectively; (l) SEQ ID NOs: 7, 17, 19 and 25, or sequence fragments at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 17, 19 and 25; (m) SEQ ID NOs: 10, 20, 26 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 10, 20, 26 and 28, respectively; (n) SEQ ID NOs: 11, 21, 27 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 21, 27 and 29; (o) SEQ ID NOs: 6, 20, 22 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 20, 22 and 28, respectively; (p) SEQ ID NOs: 7, 21, 23 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 23 and 29; (q) SEQ ID NOs: 6, 16, 18 and 24, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 16, 18 and 24, respectively; (r) SEQ ID NOs: 7, 17, 19 and 25, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 17, 19 and 25; (s) SEQ ID NOs: 10, 20, 26 and 28, or fragments of sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 10, 20, 26 and 28, respectively; or (t) SEQ ID NOs: 11, 21, 27 and 29, or fragments of sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: NO:11, 21, 27 and 29 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical sequence fragments. In some embodiments, the fusion polypeptide comprises or consists of the following polypeptide fragments, optionally bound or linked by one or more linkers, in order from N-terminus to C-terminus: SEQ ID NOs: 6, 4, 18, and 32, or sequence fragments at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 7, 5, 33, and 19, or sequence fragments at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 7, 5, 33, and 19, respectively. %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 5, 33 and 19; SEQ ID NOs: 12, 30, 8 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 12, 30, 8 and 10, respectively; SEQ ID NOs: 9, 31, 13 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 26, 20, 30 and 24, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 26, 20, 30 and 24, respectively; SEQ ID NOs: 15, 31, 21, 27 and 25, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 26, 20, 30 and 24, respectively; 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 12, 14, 16, 18, 19, 20, 21, 27 and 25, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 12, 14, 16, 18, 19, 20, 21, 27 and 25, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 12, 14, 16, 18, 19, 20, 21, 27 and 25, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 33, 5 and 19; SEQ ID NOs: 8, 30, 12 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 30, 12 and 10, respectively; SEQ ID NOs: 13, 31, 9 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 13, 31, 9 and 11; or fragments of sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 30, 14, 20 and 24, respectively; or fragments of sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 30, 14, 20 and 24, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 4, 20, 18 and 32, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 4, 20, 18 and 32, respectively; NO:6, 20, 4, 24, 32 and 18, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:6, 20, 4, 24, 32 and 18, respectively; SEQ ID NO:7, 21, 5, 25, 33 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, 21, 5, 25, 33 and 19, respectively. %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 5, 25, 33 and 19; SEQ ID NOs: 8, 30, 14, 12, 26 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 30, 14, 12, 26 and 10, respectively; NO:8, 12, 30, 26, 14 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:8, 12, 30, 26, 14 and 10, respectively; SEQ ID NO:9, 13, 31, 27, 15 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:9, 13, 31, 27, 15 and 11, respectively. %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 9, 13, 31, 27, 15 and 11; SEQ ID NOs: 20, 32, 24, 4, 6 and 18, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 20, 32, 24, 4, 6 and 18, respectively; NO:7, 25, 19, 5, 33 and 21, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, 25, 19, 5, 33 and 21, respectively; SEQ ID NO:26, 30, 12, 14, 8 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:26, 30, 12, 14, 8 and 10, respectively 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 15, 31, 9, 27, 13 and 11, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 15, 31, 9, 27, 13 and 11, respectively; NO:24, 6, 16 and 18, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24, 6, 16 and 18, respectively; SEQ ID NO:7, 19, 17 and 25, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, 19, 17 and 25, respectively; NO:24, 16, 6 and 18, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24, 16, 6 and 18, respectively; SEQ ID NO:7, 25, 17 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, 25, 17 and 19, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 21, 27, 11 and 29, or fragments thereof that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 21, 27, 11 and 29, respectively; NO: 26, 10, 20 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 26, 10, 20 and 28, respectively; SEQ ID NO: 11, 27, 21 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 11, 27, 21 and 29, respectively; NO:22, 6, 20 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:22, 6, 20 and 28, respectively; SEQ ID NO:23, 7, 21 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:23, 7, 21 and 29, respectively; 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 23 and 29, or fragments of sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 23 and 29, respectively. In some embodiments, the fusion polypeptide comprises or consists of an amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the fusion polypeptide comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223.
还提供了包含至少第一融合多肽和第二融合多肽的复合融合多肽,该第一和第二融合多肽独立地选自如上文和本文所述的融合多肽。在一些实施方案中,复合融合多肽包含任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽或者由该第一融合多肽和该第二融合多肽组成:SEQ ID NO:70和71的融合多肽,或分别与SEQ IDNO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ IDNO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ IDNO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ IDNO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ IDNO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,复合融合多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽或者由该第一融合多肽和该第二融合多肽组成:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ IDNO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:77和76的融合多肽,或分别与SEQ IDNO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ IDNO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和86的融合多肽,或分别与SEQ IDNO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和82的融合多肽,或与SEQ ID NO:85和82、SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和82的融合多肽,或与SEQ ID NO:86和82、SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,第一融合多肽和第二融合多肽通过可切割的接头结合或连接。在一些实施方案中,该第一融合多肽和该第二融合多肽通过选自以下项的可切割接头结合或连接:2A可切割肽(例如,口蹄疫病毒(F2A)、马鼻炎A病毒(E2A)、猪捷申病毒-1(P2A)和明脉扁刺蛾病毒(T2A))、弗林蛋白酶识别/切割序列(例如,RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)和RRKR(SEQ ID NO:62))以及它们的组合、衍生物或变体。在一些实施方案中,该第一融合多肽和该第二融合多肽通过选自以下项的弗林蛋白酶识别/切割位点结合或连接:RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)和RRKR(SEQ ID NO:62)。在一些实施方案中,该第一融合多肽和该第二融合多肽通过2A可切割肽结合或连接,该可切割肽包含以下或由以下组成:ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:65)、QCTNYALLKLAGDVESNPGP(SEQ ID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67的氨基酸序列,或与ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:65)、QCTNYALLKLAGDVESNPGP(SEQ IDNO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67至少90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ IDNO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。 Also provided are composite fusion polypeptides comprising at least a first fusion polypeptide and a second fusion polypeptide, the first and second fusion polypeptides being independently selected from the fusion polypeptides described above and herein. In some embodiments, the composite fusion polypeptide comprises or consists of the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively. 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:76 and 77; a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:78 and 79, respectively; a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:80 and 81, respectively. 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively. 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively. 88 and 89; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively. 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively. 84 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively; a fusion polypeptide of SEQ ID NOs: 85 and 89, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively. 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively. 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively. 94 and 96; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or a fusion polypeptide of SEQ ID NOs:100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101. In some embodiments, the composite fusion polypeptide comprises or consists of the following first and second fusion polypeptides, optionally bound or linked by one or more linkers, in order from N-terminus to C-terminus: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; 71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 71 and 70; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively; a fusion polypeptide of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72; a fusion polypeptide of SEQ ID NOs: 74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 74 and 75, respectively; a fusion polypeptide of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97%, 98%, 99%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 77 and 76; a fusion polypeptide of SEQ ID NOs: 78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; a fusion polypeptide of SEQ ID NOs: 79 and 80%, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively. 80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80; a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 83, respectively. 83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:8 85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; 87 and 86; a fusion polypeptide of SEQ ID NOs: 87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively; a fusion polypeptide of SEQ ID NOs: 89 and 90, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively; 89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 88; a fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; a fusion polypeptide of SEQ ID NOs: 85 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 82, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 82 and 86, respectively; 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; 88 and 82; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 85; a fusion polypeptide of SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively; a fusion polypeptide of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88; a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively; 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 85; a fusion polypeptide of SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85; a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; 91 and 90; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; 93 and 92; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively. 95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 96; a fusion polypeptide of SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; a fusion polypeptide of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 95; a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively. 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99; a fusion polypeptide of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 98; a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or a fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 101 and 100. In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or connected by a cleavable linker. In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or linked by a cleavable linker selected from the group consisting of: 2A cleavable peptides (e.g., foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A), and sphenotype moth virus (T2A)), furin recognition/cleavage sequences (e.g., RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61), and RRKR (SEQ ID NO: 62)), and combinations, derivatives, or variants thereof. In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or linked by a furin recognition/cleavage site selected from the group consisting of: RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61), and RRKR (SEQ ID NO: 62). In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or linked by a 2A cleavable peptide comprising or consisting of the amino acid sequence of ATNFSLLKQAGDVEENPGP (SEQ ID NO:63), APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:64), RAKRAPVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:65), QCTNYALLKLAGDVESNPGP (SEQ ID NO:66), or EGRGSLLTCGDVEENPGP (SEQ ID NO:67), or a 2A cleavable peptide that is conjugated to or linked to ATNFSLLKQAGDVEENPGP (SEQ ID NO:63), APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:64), RAKRAPVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:65), QCTNYALLKLAGDVESNPGP (SEQ ID NO:66), or EGRGSLLTCGDVEENPGP (SEQ ID NO:67). ID NO:66) or EGRGSLLTCGDVEENPGP (SEQ ID NO:67) or EGRGSLLTCGDVEENPGP (SEQ ID NO:68) or EGRGSLLTCGDVEENPGP (SEQ ID NO:69) or EGRGSLLTCGDVEENPGP (SEQ ID NO:60) or EGRGSLLTCGDVEENPGP (SEQ ID NO:61) or EGRGSLLTCGDVEENPGP (SEQ ID NO:62) or EGRGSLLTCGDVEENPGP (SEQ ID NO:63) or EGRGSLLTCGDVEENPGP (SEQ ID NO:64) or EGRGSLLTCGDVEENPGP (SEQ ID NO:65) or EGRGSLLTCGDVEENPGP (SEQ ID NO:66) or EGRGSLLTCGDVEENPGP (SEQ ID NO:67) or EGRGSLLTCGDVEENPGP (SEQ ID NO:66) or EGRGSLLTCGDVE NO: 105-112, 200-209, 222-223 and 227. In some embodiments, the composite fusion polypeptide comprises or consists of an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 209, 222 and 223, or an amino acid sequence that is identical to any one of SEQ ID NO: 209, 222 and 223. Any of NO:209, 222 and 223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence.
关于融合多肽和复合融合多肽的其他实施方案,在一些实施方案中,融合多肽或复合融合多肽还包含N末端信号肽或前导序列。在一些实施方式中,信号肽或前导序列来自选自以下项的源蛋白:血清蛋白、细胞因子、趋化因子、伴侣蛋白、不变蛋白和将蛋白引导至溶酶体区室的蛋白。在一些实施方案中,信号肽或前导序列来自选自以下项的源蛋白:集落刺激因子2(CSF2、GM-CSF)、组织型纤溶酶原活化剂(PLAT、t-PA)、C-C基序趋化因子配体7(CCL7、MCP-3)、C-X-C基序趋化因子配体10(CXCL10、IP-10)、连环蛋白β1(CTNNB1)、CD74(p33;DHLAG;HLADG;Ia-GAMMA、不变链)、血清白蛋白(ALB)、聚泛素B/C(UBB/UBC)、钙网蛋白(CALR)、水泡性口炎病毒G蛋白(VSV-G)、溶酶体相关膜蛋白1(LAMP-1)和溶酶体相关膜蛋白2(LAMP-2)。在一些实施方案中,信号肽或前导序列选自SEQ ID NO:115-126中的任一项的氨基酸序列,或与SEQ ID NO:115-126中的任一项至少95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽和/或复合融合多肽是重组产生的或化学合成的。在一些实施方案中,融合多肽和/或复合融合多肽能够诱导、促进或刺激人的免疫应答。在一些实施方案中,融合多肽和/或复合融合多肽能够诱导、促进或刺激人针对HIV-1的免疫应答。在一些实施方案中,融合多肽和/或复合融合多肽能够诱导、促进或刺激选自单核细胞来源的树突状细胞(DC)、CD8+ T细胞和CD4+ T细胞的一种或多种细胞类型的增殖和/或活化。Regarding other embodiments of fusion polypeptides and composite fusion polypeptides, in some embodiments, the fusion polypeptide or composite fusion polypeptide further comprises an N-terminal signal peptide or leader sequence. In some embodiments, the signal peptide or leader sequence is from a source protein selected from the group consisting of serum proteins, cytokines, chemokines, chaperone proteins, invariant proteins, and proteins that direct proteins to the lysosomal compartment. In some embodiments, the signal peptide or leader sequence is from a source protein selected from the group consisting of colony stimulating factor 2 (CSF2, GM-CSF), tissue plasminogen activator (PLAT, t-PA), C-C motif chemokine ligand 7 (CCL7, MCP-3), C-X-C motif chemokine ligand 10 (CXCL10, IP-10), catenin β1 (CTNNB1), CD74 (p33; DHLAG; HLADG; Ia-GAMMA, invariant chain), serum albumin (ALB), polyubiquitin B/C (UBB/UBC), calreticulin (CALR), vesicular stomatitis virus G protein (VSV-G), lysosomal associated membrane protein 1 (LAMP-1), and lysosomal associated membrane protein 2 (LAMP-2). In some embodiments, the signal peptide or leader sequence is selected from the amino acid sequence of any one of SEQ ID NO: 115-126, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 115-126. In some embodiments, the fusion polypeptide and/or the composite fusion polypeptide is recombinantly produced or chemically synthesized. In some embodiments, the fusion polypeptide and/or the composite fusion polypeptide can induce, promote or stimulate a human immune response. In some embodiments, the fusion polypeptide and/or the composite fusion polypeptide can induce, promote or stimulate a human immune response against HIV-1. In some embodiments, the fusion polypeptide and/or the composite fusion polypeptide can induce, promote or stimulate the proliferation and/or activation of one or more cell types selected from monocyte-derived dendritic cells (DC), CD8+ T cells and CD4+ T cells.
还提供了编码如上文和本文所述的一种或多种融合多肽或复合融合多肽的多核苷酸。在一些实施方案中,多核苷酸包括cDNA、mRNA、自扩增RNA(SAM、saRNA)、自复制RNA或自扩增复制子RNA(RepRNA)。在一些实施方案中,多核苷酸包括自复制或自扩增的甲病毒复制子。在一些实施方案中,多核苷酸包含SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,多核苷酸包含SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。还提供了表达盒,其包含一种或多种本文所述的多核苷酸,这些多核苷酸可操作地连接到一个或多个调控序列,例如启动子。在一些实施方案中,多核苷酸可操作地连接到组成型启动子并在其控制下。在一些实施方案中,启动子选自CMV启动子、CAG启动子和EF1a启动子。Also provided are polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described above and herein. In some embodiments, the polynucleotides include cDNA, mRNA, self-amplifying RNA (SAM, saRNA), self-replicating RNA or self-amplifying replicon RNA (RepRNA). In some embodiments, the polynucleotides include self-replicating or self-amplifying alphavirus replicons. In some embodiments, the polynucleotides include SEQ ID NO: 130-167, 210-219 and 225-226. Any one of the nucleic acid sequence, or with SEQ ID NO: 130-167, 210-219 and 225-226. Any one of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical nucleic acid sequence. In some embodiments, the polynucleotide comprises a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226. Also provided are expression cassettes comprising one or more polynucleotides described herein, which are operably linked to one or more regulatory sequences, such as promoters. In some embodiments, the polynucleotides are operably linked to and under the control of a constitutive promoter. In some embodiments, the promoter is selected from the group consisting of a CMV promoter, a CAG promoter, and an EF1a promoter.
还提供了脂质体复合物,例如脂质纳米颗粒(LNP),其包含一种或多种本文所述的多核苷酸,例如编码一种或多种多肽的多核苷酸,该一种或多种多肽具有SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列;例如包含以下的一种或多种多核苷酸:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,脂质体复合物,例如脂质纳米颗粒(LNP),其包含一种或多种本文所述的多核苷酸,例如编码一种或多种多肽的多核苷酸,该一种或多种多肽具有SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列;例如包含以下的一种或多种多核苷酸:SEQ IDNO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。Also provided are liposome complexes, such as lipid nanoparticles (LNPs), comprising one or more polynucleotides described herein, such as polynucleotides encoding one or more polypeptides having an amino acid sequence of any one of SEQ ID NOs: 70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70-101, 105-112, 200-209, 222-223, and 227; for example, comprising one or more polynucleotides of SEQ ID NOs: NO:130-167, 210-219 and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:130-167, 210-219 and 225-226. In some embodiments, the liposome complex, such as a lipid nanoparticle (LNP), comprises one or more polynucleotides described herein, such as polynucleotides encoding one or more polypeptides having an amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223; for example, comprising one or more polynucleotides of: SEQ ID NOs: 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225 and 226.
还提供了载体,其包含本文所述的一种或多种多核苷酸或一种或多种表达盒。在一些实施方案中,载体包含一种或多种多核苷酸或者由该一种或多种多核苷酸组成,该一种或多种多核苷酸编码一种或多种融合多肽,该一种或多种融合多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:SEQ ID NO:6、4、16和26,以及SEQ ID NO:7、5、27和17;SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NO:26、16、4和6,以及SEQ ID NO:7、27、5和17;SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQ IDNO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NO:20、6、4、18、16和26,以及SEQ ID NO:7、19、5、21、27和17;SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:24、6、4、20、18和32,以及SEQ IDNO:7、21、5、25、33和19;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ ID NO:7、21、5、25、33和19和SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:20、32、24、4、6和18,以及SEQ ID NO:26、30、12、14、8和10;SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ IDNO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NO:24、6、16和18,以及SEQ IDNO:26、10、20和28;SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQ ID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NO:24、16、6和18,以及SEQ ID NO:27、11、21和29;SEQ ID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NO:7、25、17和19,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO:7、21、19、17、27、25、29和11。在一些实施方案中,载体包含编码一种或多种融合多肽的一种或多种多核苷酸,这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,载体包含编码一种或多种融合多肽的一种或多种多核苷酸,这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ IDNO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ IDNO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ IDNO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ IDNO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ IDNO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ IDNO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码从N末端到C末端按顺序且任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ IDNO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和85的融合多肽,或分别与SEQID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ IDNO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,载体包含编码复合融合多肽的多核苷酸,该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,载体包含编码复合融合多肽的多核苷酸,该复合融合多肽包含以下或由以下组成:SEQID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,第一和第二融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol321-366、Pol432-541、Pol 607-682、Pol 709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在一些实施方案中,第一和第二融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ IDNO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,载体包含多核苷酸,该多核苷酸包含以下或由以下组成:SEQ IDNO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,载体包含多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ IDNO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,以下第一多核苷酸和第二多核苷酸:SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和135的多核苷酸,或分别与SEQID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:130或SEQ ID NO:131的多核苷酸,或分别与SEQ ID NO:130或SEQ ID NO:131至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:134或SEQ ID NO:135的多核苷酸,或与SEQ ID NO:134或SEQ IDNO:135至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:132或SEQ ID NO:133的多核苷酸,或分别与SEQ ID NO:132或SEQ ID NO:133至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:136或SEQ ID NO:137的多核苷酸,或与SEQ ID NO:136或SEQ ID NO:137至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:139的多核苷酸,或分别与SEQ ID NO:139至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:145的多核苷酸,或与SEQ ID NO:145至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:142的多核苷酸,或分别与SEQ ID NO:142至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:148的多核苷酸,或与SEQ ID NO:148至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:140的多核苷酸,或分别与SEQ IDNO:140至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:146的多核苷酸,或与SEQ ID NO:146至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:143的多核苷酸,或分别与SEQ ID NO:143至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:149的多核苷酸,或与SEQ ID NO:149至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:150的多核苷酸,或分别与SEQ ID NO:150至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:152的多核苷酸,或与SEQ ID NO:152至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:151的多核苷酸,或分别与SEQ IDNO:151至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:153的多核苷酸,或与SEQ ID NO:153至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:154的多核苷酸,或分别与SEQ ID NO:154至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:157的多核苷酸,或与SEQ ID NO:157至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:155的多核苷酸,或分别与SEQ ID NO:155至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:158的多核苷酸,或与SEQ ID NO:158至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:156的多核苷酸,或分别与SEQ IDNO:156至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:159的多核苷酸,或与SEQ ID NO:159至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:160的多核苷酸,或分别与SEQ ID NO:160至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:161的多核苷酸,或与SEQ ID NO:161至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:162的多核苷酸,或分别与SEQ ID NO:162至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:163的多核苷酸,或与SEQ ID NO:163至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:164的多核苷酸,或分别与SEQ IDNO:164至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:165的多核苷酸,或与SEQ ID NO:165至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:166的多核苷酸,或分别与SEQ ID NO:166至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:167的多核苷酸,或与SEQ ID NO:167至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:216的多核苷酸,或与SEQ IDNO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:219的多核苷酸,或与SEQID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:(a)第一多核苷酸,其包含:SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二多核苷酸,其包含:SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,编码第一融合多肽的第一多核苷酸和编码第二融合多肽的第二多核苷酸位于单个开放阅读框中。在一些实施方案中,编码第一融合多肽的第一多核苷酸位于第一开放阅读框中,并且编码第二融合多肽的第二多核苷酸位于第二开放阅读框中。在一些实施方案中,编码第一融合多肽的第一多核苷酸和编码第二融合多肽的第二多核苷酸位于单个表达盒中。在一些实施方案中,编码第一融合多肽的第一多核苷酸位于第一表达盒中,并且编码第二融合多肽的第二多核苷酸位于第二表达盒中。在一些实施方案中,载体是质粒载体、细菌载体或病毒载体。在一些实施方案中,载体是病毒载体。在一些实施方案中,病毒载体是DNA病毒或RNA病毒。在一些实施方案中,病毒载体是复制缺陷性、复制缺陷型、复制减毒型或有复制能力的。在一些实施方案中,病毒载体来自选自腺病毒、腺相关病毒、沙粒病毒、甲病毒、痘病毒、巨细胞病毒、弹状病毒、水泡性口炎病毒、黄病毒、马拉巴病毒和痘苗病毒的病毒。在一些实施方案中,病毒载体来自选自腺病毒科、沙粒病毒科、疱疹病毒科(例如巨细胞病毒)、痘病毒科(例如痘苗病毒,例如改良安卡拉痘苗病毒(MVA))、黄病毒科(例如黄热病毒)、弹状病毒科(例如水泡性病毒,例如马拉巴水泡性病毒)、披膜病毒科(例如甲病毒,例如委内瑞拉马脑炎病毒)的分类学家族的病毒。在一些实施方案中,病毒载体是选自以下项的沙粒病毒载体:淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)、卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)、瓜纳瑞托病毒(Guanarito virus)(GTOV)、胡宁病毒(Junin virus)(JUNV)、拉沙病毒(Lassa virus)(LASV)、卢约病毒(Lujo virus)(LUJV)、马丘波病毒(Machupo virus)(MACV)、萨比亚病毒(Sabia virus)(SABV)和怀特沃特阿罗约病毒(Whitewater Arroyo virus)(WWAV)。在一些实施方案中,病毒载体是选自以下项的沙粒病毒载体:淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)或卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)。在一些实施方案中,沙粒病毒载体包含双片段基因组。在一些实施方案中,沙粒病毒载体包含三片段基因组。在一些实施方案中,病毒载体是人腺病毒或猿猴腺病毒(例如,黑猩猩腺病毒、大猩猩腺病毒或恒河猴腺病毒)。在一些实施方案中,病毒载体是选自以下项的腺病毒载体:腺病毒血清型5(Ad5)、腺病毒血清型26(Ad26)、腺病毒血清型34(Ad34)、腺病毒血清型35(Ad35)、腺病毒血清型48(Ad48)、黑猩猩腺病毒(例如ChAd3(AdC3)、ChAd5(AdC5)、ChAd6(AdC6)、ChAd7(AdC7)、ChAd8(AdC8)、ChAd9(AdC9)、ChAd10(AdC10)、ChAd11(AdC11)、ChAd17(AdC17)、ChAd16(AdC16)、ChAd19(AdC19)、ChAd20(AdC20)、ChAd22(AdC22)、ChAd24(AdC24)、ChAdY25、ChAd26(AdC26)、ChAd28(AdC28)、ChAd30(AdC30)、ChAd31(AdC31)、ChAd37(AdC37)、ChAd38(AdC38)、ChAd43(AdC43)、ChAd44(AdC44)、ChAd55(AdC55)、ChAd63(AdC63)、ChAdV63、ChAd68(AdC68)、ChAd73(AdC73)、ChAd82(AdC82)、ChAd83(AdC83)、ChAd143(AdC143)、ChAd144(AdC144)、ChAd145(AdC145)、ChAd147(AdC147))、大猩猩腺病毒(例如GC44、GC45、GC46)和恒河猴腺病毒(例如RhAd51、RhAd52、RhAd53、RhAd54、RhAd55、RhAd56、RhAd57、RhAd58、RhAd59、RhAd60、RhAd61、RhAd62、RhAd63、RhAd64、RhAd65、RhAd66)。 Also provided are vectors comprising one or more polynucleotides or one or more expression cassettes described herein. In some embodiments, the vector comprises or consists of one or more polynucleotides encoding one or more fusion polypeptides comprising, in order from N-terminus to C-terminus, the following polypeptide fragments optionally bound or linked by one or more linkers: SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17; SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11; SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21; SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17; SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11; SEQ ID NOs: 22, 24, 14, 18 and 20, and SEQ ID NOs: NO:25, 23, 15, 21 and 19; SEQ ID NO:20, 6, 4, 18, 16 and 26, and SEQ ID NO:7, 19, 5, 21, 27 and 17; SEQ ID NO:8, 24, 14, 12, 22 and 10, and SEQ ID NO:9, 13, 25, 23, 15 and 11; SEQ ID NO:18, 26, 20, 4, 6 and 16, and SEQ ID NO:7, 21, 17, 5, 27 and 19; SEQ ID NO:22, 24, 12, 14, 8 and 10, and SEQ ID NO:15, 25, 9, 23, 13 and 11; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:7, 21, 5, 25, 33 and 19; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:8, 30, 14, 12, 26 and 10, and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:6, 20, 4, 24, 32 and 18, and SEQ ID NO:8, 12, 30, 26, 14 and 10; SEQ ID NO:7, 21, 5, 25, 33 and 19 and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:20, 32, 24, 4, 6 and 18, and SEQ ID NO:26, 30, 12, 14, 8 and 10; SEQ ID NO:7, 25, 19, 5, 33 and 21, and SEQ ID NO:15, 31, 9, 27, 13 and 11; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 20, 10 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 10, 20 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:7, 25, 17 and 19; SEQ ID NO:7, 19, 17 and 25, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:24, 16, 6 and 18, and SEQ ID NO:27, 11, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:11, 27, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 20 and 28, and SEQ ID NO:23, 7, 21 and 29; SEQ ID NO:22, 20, 6 and 28, and SEQ ID NO:7, 21, 23 and 29; SEQ ID NO:26, 10, 20 and 28, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 16, 20, 18, 28, 26 and 10; or SEQ ID NO:7, 21, 19, 17, 27, 25, 29 and 11. In some embodiments, the vector comprises one or more polynucleotides encoding one or more fusion polypeptides comprising or consisting of the amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the vector comprises one or more polynucleotides encoding one or more fusion polypeptides comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223. In some embodiments, the vector comprises one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 72 and 73; a fusion polypeptide of SEQ ID NOs: 74 and 75, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 74 and 75, respectively; a fusion polypeptide of SEQ ID NOs: 76 and 77, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively. 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:76 and 77; a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:78 and 79, respectively; a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:80 and 81, respectively. 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively. 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively. 88 and 89; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively. 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively. 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89; a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively. 94 and 95; a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 94 and 96; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101. In some embodiments, the vector comprises one or more polynucleotides encoding the following first and second fusion polypeptides, in order from N-terminus to C-terminus and optionally bound or connected by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; 71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 71 and 70; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively; a fusion polypeptide of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72; a fusion polypeptide of SEQ ID NOs: 74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 74 and 75, respectively; a fusion polypeptide of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 77 and 76; a fusion polypeptide of SEQ ID NOs: 78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; a fusion polypeptide of SEQ ID NOs: 79 and 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; 80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80; a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 83, respectively. 83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:8 85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively. 87 and 86; a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:87 and 86; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:88 and 89, respectively; 89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 88; a fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; a fusion polypeptide of SEQ ID NOs: 85 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 82; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; 86 and 82; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; 88 and 82; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 85; a fusion polypeptide of SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively; a fusion polypeptide of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88; a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively; 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 85; a fusion polypeptide of SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85; a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; 91 and 90; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; 93 and 92; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively. 95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 96; a fusion polypeptide of SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; a fusion polypeptide of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 95; a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively. 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99; a fusion polypeptide of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 98; a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or a fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:101 and 100. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 84 and 85, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:86 and 87, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 85, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:83 and 87, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:85 and 87, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 96 and 97, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively. In some embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. In some embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227. In some embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 209, 222, and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 209, 222, and 223. In some embodiments, the first and second fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol321-366, Pol432-541, Pol 607-682, Pol 709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116, and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol, and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively. In some embodiments, the first and second fusion polypeptides do not comprise any polypeptide fragments having an amino acid sequence of SEQ ID NOs:35-47, or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:35-47, or a fragment or subsequence thereof. In some embodiments, the vector comprises a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the vector comprises a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226. In some embodiments, the following first and second polynucleotides: polynucleotides of SEQ ID NOs: 130 and 132, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively; polynucleotides of SEQ ID NOs: 130 and 134, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively; polynucleotides of SEQ ID NOs: 131 and 135, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; polynucleotides of SEQ ID NOs: 132 and 136, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; polynucleotides of SEQ ID NOs: 132 and 136, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136; a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively; a polynucleotide of SEQ ID NOs: 133 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137; a polynucleotide of SEQ ID NOs: 134 and 136, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively; a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137; a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 141, respectively; a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 141, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 144; a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 142, respectively; a polynucleotide of SEQ ID NOs: 139 and 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145; a polynucleotide of SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; a polynucleotide of SEQ ID NOs: 142 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively; a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively; a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148; a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; a polynucleotide of SEQ ID NOs: 150 and 155, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155; a polynucleotide of SEQ ID NOs: 151 and 153, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively; a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156; polynucleotides of SEQ ID NOs: 152 and 158, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively; polynucleotides of SEQ ID NOs: 153 and 159, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 153 and 159, respectively. 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 153 and 159; polynucleotides of SEQ ID NOs: 154 and 157, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, respectively; polynucleotides of SEQ ID NOs: 155 and 158, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively; a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 161 and 162, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161; a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively; a polynucleotide of SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165; a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively; a polynucleotide of SEQ ID NOs: 210 and 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211; polynucleotides of SEQ ID NOs: 212 and 213, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 212 and 213, respectively; polynucleotides of SEQ ID NOs: 214 and 215, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215; polynucleotides of SEQ ID NOs: 216 and 217, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively; polynucleotides of SEQ ID NOs: 218 and 219, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 219 and 220, respectively; 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 218 and 219; a polynucleotide of SEQ ID NOs: 218 and 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 218 and 226, respectively; or a polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively. Any of NO:225 and 226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 130 or SEQ ID NO: 131, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 130 or SEQ ID NO: 131, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 134 or SEQ ID NO: 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 134 or SEQ ID NO: 135. ID NO: 135 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the polynucleotide. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 132 or SEQ ID NO: 133, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 132 or SEQ ID NO: 133, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 136 or SEQ ID NO: 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 136 or SEQ ID NO: 137. NO:137 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 139, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 139, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 145. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 142, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 142, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 148. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 140, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 140, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 143, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 143, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 149. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 150, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 150, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 152. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:151, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:151, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:153, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:153. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 154, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 154, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 157. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:155, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:155, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:158. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:156, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:156, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:159. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 160, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 160, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 161. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 162, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 162, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 163. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 164, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 164, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 165. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 166, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 166, respectively, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 167. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:210, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:21 1, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:21 1. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:212, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:213. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:214, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:215. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:216, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:217. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:218, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:219. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:218, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:226. In some embodiments, the vector comprises the following first and second polynucleotides: (a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:225, and (b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:226. In some embodiments, the first polynucleotide encoding the first fusion polypeptide and the second polynucleotide encoding the second fusion polypeptide are located in a single open reading frame. In some embodiments, the first polynucleotide encoding the first fusion polypeptide is located in the first open reading frame, and the second polynucleotide encoding the second fusion polypeptide is located in the second open reading frame. In some embodiments, the first polynucleotide encoding the first fusion polypeptide and the second polynucleotide encoding the second fusion polypeptide are located in a single expression cassette. In some embodiments, the first polynucleotide encoding the first fusion polypeptide is located in the first expression cassette, and the second polynucleotide encoding the second fusion polypeptide is located in the second expression cassette. In some embodiments, the vector is a plasmid vector, a bacterial vector, or a viral vector. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a DNA virus or an RNA virus. In some embodiments, the viral vector is replication defective, replication defective, replication attenuated, or replication competent. In some embodiments, the viral vector is from a virus selected from adenovirus, adeno-associated virus, arenavirus, alphavirus, poxvirus, cytomegalovirus, rhabdovirus, vesicular stomatitis virus, flavivirus, Maraba virus, and vaccinia virus. In some embodiments, the viral vector is from a virus from a taxonomic family selected from Adenoviridae, Arenaviridae, Herpesviridae (e.g., cytomegalovirus), Poxviridae (e.g., vaccinia virus, e.g., modified vaccinia virus Ankara (MVA)), Flaviviridae (e.g., yellow fever virus), Rhabdoviridae (e.g., vesiculovirus, e.g., Maraba vesiculovirus), Togaviridae (e.g., alphavirus, e.g., Venezuelan equine encephalitis virus). In some embodiments, the viral vector is an arenavirus vector selected from the group consisting of: lymphocytic choriomeningitis mammalian arenavirus (LCMV), Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus), Guanarito virus (GTOV), Junin virus (JUNV), Lassa virus (LASV), Lujo virus (LUJV), Machupo virus (MACV), Sabia virus (SABV), and Whitewater Arroyo virus (WWAV). In some embodiments, the viral vector is an arenavirus vector selected from the group consisting of: lymphocytic choriomeningitis mammalian arenavirus (LCMV) or Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus). In some embodiments, the arenavirus vector comprises a two-segment genome. In some embodiments, the arenavirus vector comprises a three-segment genome. In some embodiments, the viral vector is a human adenovirus or a simian adenovirus (e.g., a chimpanzee adenovirus, a gorilla adenovirus, or a rhesus adenovirus). In some embodiments, the viral vector is an adenovirus vector selected from the following: adenovirus serotype 5 (Ad5), adenovirus serotype 26 (Ad26), adenovirus serotype 34 (Ad34), adenovirus serotype 35 (Ad35), adenovirus serotype 48 (Ad48), chimpanzee adenovirus (e.g., ChAd3 (AdC3), ChAd5 (AdC5), ChAd6 (AdC6), ChAd7 (AdC7), ChAd8 (AdC8), ChAd9 (AdC9) , ChAd10(AdC10), ChAd11(AdC11), ChAd17(AdC17), ChAd16(AdC16), ChAd19(AdC19), ChAd20(AdC20), ChAd22(AdC22), ChAd24(AdC24), ChAdY25, ChAd26(AdC26), ChAd28(AdC28), ChAd30 (AdC30), ChAd31(AdC31), Ch Ad37(AdC37), ChAd38(AdC38), ChAd43(AdC43), ChAd44(AdC44), ChAd55(AdC55), ChAd63(AdC63), ChAdV63, ChAd68(AdC68), ChAd73(AdC73), ChAd82(AdC82), ChAd83(AdC83), ChAd143(Ad C143), ChAd144(AdC144), C hAd145 (AdC145), ChAd147 (AdC147)), gorilla adenovirus (e.g., GC44, GC45, GC46), and rhesus monkey adenovirus (e.g., RhAd51, RhAd52, RhAd53, RhAd54, RhAd55, RhAd56, RhAd57, RhAd58, RhAd59, RhAd60, RhAd61, RhAd62, RhAd63, RhAd64, RhAd65, RhAd66).
还提供了宿主细胞,其包含如本文所述的一种或多种多核苷酸、一个或多个表达盒或一种或多种载体。在一些实施方案中,一种或多种多核苷酸不整合到宿主细胞基因组中,例如是游离的。在一些实施方案中,一种或多种多核苷酸被整合到宿主细胞基因组中。在一些实施方案中,宿主细胞是哺乳动物细胞,例如人细胞。在各种实施方案中,宿主细胞可以是体外或体内的。Also provide host cell, it comprises one or more polynucleotides as described herein, one or more expression cassettes or one or more vectors.In some embodiments, one or more polynucleotides are not integrated into the host cell genome, for example, are free.In some embodiments, one or more polynucleotides are integrated into the host cell genome.In some embodiments, host cell is mammalian cell, for example human cell.In various embodiments, host cell can be in vitro or in vivo.
还提供了免疫原性组合物。在各种实施方案中,免疫原性组合物包含如本文所述的融合多肽或复合融合多肽中的一者或多者、一种或多种多核苷酸或一种或多种载体,以及药学上可接受的载体。在一些实施方案中,免疫原性组合物包含如本文所述的融合多肽或复合融合多肽中的两者或更多者、两种或更多种多核苷酸、两种或更多种载体。在一些实施方案中,该一种或多种多核苷酸是DNA、cDNA、mRNA或自复制RNA。在一些实施方案中,免疫原性组合物包含第一融合多肽和第二融合多肽、或包含编码第一和第二融合多肽的一种或多种多核苷酸的一种或多种载体,第一多肽和第二多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:SEQ ID NO:6、4、16和26,以及SEQ IDNO:7、5、27和17;SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQ ID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NO:26、16、4和6,以及SEQ IDNO:7、27、5和17;SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQ ID NO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NO:20、6、4、18、16和26,以及SEQID NO:7、19、5、21、27和17;SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQ ID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:7、21、5、25、33和19;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ IDNO:7、21、5、25、33和19和SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:20、32、24、4、6和18,以及SEQ ID NO:26、30、12、14、8和10;SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、10、20和28;SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQ ID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NO:24、16、6和18,以及SEQ ID NO:27、11、21和29;SEQID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NO:7、25、17和19,以及SEQ IDNO:21、27、11和29;SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO:7、21、19、17、27、25、29和11。在一些实施方案中,免疫原性组合物包含一种或多种融合多肽、或包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,免疫原性组合物包含一种或多种融合多肽、或包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,免疫原性组合物包含以下第一融合多肽和第二融合多肽、一种或多种多核苷酸、或包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含以下第一融合多肽和第二融合多肽、一种或多种多核苷酸、或包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码从N末端到C末端按顺序且任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ IDNO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该组合物包含含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸、或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ IDNO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ ID NO:200的多肽,或与SEQID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:201的多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ ID NO:202的多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:203的多肽,或与SEQID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ ID NO:203的多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:204的多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ ID NO:105的多肽,或与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:107的多肽,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQID NO:206的多肽,或与SEQ ID NO:206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:207的多肽,或与SEQ ID NO:207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ ID NO:208的多肽,或与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ IDNO:209或SEQ ID NO:227的多肽,或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQID NO:222的多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:209或SEQ ID NO:227的多肽,或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ ID NO:222的多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:223的多肽,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。在一些实施方案中,免疫原性组合物包含多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,免疫原性组合物包含多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,免疫原性组合物包含以下第一多核苷酸和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的一种或多种载体:SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和133的多核苷酸,或分别与SEQID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或第一脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:131和135的多核苷酸,或分别与SEQ IDNO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或第二脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或第一脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或第二脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或第一脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或第二脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,此类免疫原性组合物的第一和第二病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或第一脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或第二脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,此类免疫原性组合物的第一和第二病毒载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或第一脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQID NO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或第二脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:160的多核苷酸,或分别与SEQ ID NO:160至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:161的多核苷酸,或分别与SEQ ID NO:161至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:162的多核苷酸,或分别与SEQ ID NO:162至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:163的多核苷酸,或分别与SEQID NO:163至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:164的多核苷酸,或分别与SEQ ID NO:164至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:165的多核苷酸,或分别与SEQ ID NO:165至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:166的多核苷酸,或分别与SEQ ID NO:166至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:167的多核苷酸,或分别与SEQ ID NO:167至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含第一和第二多核苷酸,或包含一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一病毒载体或第一脂质体复合物(例如,LNP),其包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二病毒载体或第二脂质体复合物(例如,LNP),其包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,免疫原性组合物包含复合融合多肽、包含编码复合融合多肽的多核苷酸的载体或脂质体复合物(例如,LNP),该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,免疫原性组合物包含复合融合多肽、包含编码复合融合多肽的多核苷酸的载体或脂质体复合物(例如,LNP),该复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,该一种或多种融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol607-682、Pol 709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ IDNO:1、2和3。在一些实施方案中,该一种或多种融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在免疫原性组合物的各种实施方案中,第一和第二病毒载体可以是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体、卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体或腺病毒载体,例如黑猩猩腺病毒载体(ChAd)。在一些实施方案中,免疫原性组合物包含单一载体,该载体包含编码第一和第二融合多肽的一种或多种多核苷酸。在一些实施方案中,免疫原性组合物还包含佐剂、洗涤剂、胶束形成剂和油中的一种或多种。在一些实施方案中,免疫原性组合物被配制以用于经由选自以下的途径施用:静脉内、肌内、皮内、皮下、结内和粘膜(例如,颊部、鼻内、直肠内、阴道内)。在一些实施方案中,免疫原性组合物被配制为液体、悬浮液或乳液。在一些实施方案中,免疫原性组合物是冻干的。Immunogenic compositions are also provided. In various embodiments, the immunogenic compositions comprise one or more of a fusion polypeptide or a composite fusion polypeptide as described herein, one or more polynucleotides, or one or more vectors, and a pharmaceutically acceptable carrier. In some embodiments, the immunogenic compositions comprise two or more of a fusion polypeptide or a composite fusion polypeptide as described herein, two or more polynucleotides, two or more vectors. In some embodiments, the one or more polynucleotides are DNA, cDNA, mRNA, or self-replicating RNA. In some embodiments, the immunogenic composition comprises a first fusion polypeptide and a second fusion polypeptide, or one or more vectors comprising one or more polynucleotides encoding the first and second fusion polypeptides, the first polypeptide and the second polypeptide comprising, in order from N-terminus to C-terminus, the following polypeptide fragments optionally bound or linked by one or more linkers: SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17; SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11; SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21; SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17; SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11; SEQ ID NOs: 22, 24, 14, 18 and 20, and SEQ ID NOs: NO:25, 23, 15, 21 and 19; SEQ ID NO:20, 6, 4, 18, 16 and 26, and SEQ ID NO:7, 19, 5, 21, 27 and 17; SEQ ID NO:8, 24, 14, 12, 22 and 10, and SEQ ID NO:9, 13, 25, 23, 15 and 11; SEQ ID NO:18, 26, 20, 4, 6 and 16, and SEQ ID NO:7, 21, 17, 5, 27 and 19; SEQ ID NO:22, 24, 12, 14, 8 and 10, and SEQ ID NO:15, 25, 9, 23, 13 and 11; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:7, 21, 5, 25, 33 and 19; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:8, 30, 14, 12, 26 and 10, and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:6, 20, 4, 24, 32 and 18, and SEQ ID NO:8, 12, 30, 26, 14 and 10; SEQ ID NO:7, 21, 5, 25, 33 and 19 and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:20, 32, 24, 4, 6 and 18, and SEQ ID NO:26, 30, 12, 14, 8 and 10; SEQ ID NO:7, 25, 19, 5, 33 and 21, and SEQ ID NO:15, 31, 9, 27, 13 and 11; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 20, 10 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 10, 20 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:7, 25, 17 and 19; SEQ ID NO:7, 19, 17 and 25, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:24, 16, 6 and 18, and SEQ ID NO:27, 11, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:11, 27, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 20 and 28, and SEQ ID NO:23, 7, 21 and 29; SEQ ID NO:22, 20, 6 and 28, and SEQ ID NO:7, 21, 23 and 29; SEQ ID NO:26, 10, 20 and 28, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 16, 20, 18, 28, 26 and 10; or SEQ ID NO:7, 21, 19, 17, 27, 25, 29 and 11. In some embodiments, the immunogenic composition comprises one or more fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, which fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223 and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223 and 227. In some embodiments, the immunogenic composition comprises one or more fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, which fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209 and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209 and 222-223. In some embodiments, the immunogenic composition comprises the following first and second fusion polypeptides, one or more polynucleotides, or one or more vectors or one or more liposome complexes (e.g., LNPs) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively; 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively. 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:76 and 77; a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:78 and 79, respectively; a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:80 and 81, respectively. 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively. 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively. 88 and 89; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively. 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively. 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively. 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89; a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively. 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 94 and 96; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101. In some embodiments, the immunogenic composition comprises the following first and second fusion polypeptides, one or more polynucleotides, or one or more vectors or one or more liposome complexes (e.g., LNPs) comprising one or more polynucleotides encoding the following first and second fusion polypeptides bound or connected in order from N-terminus to C-terminus and optionally through one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 71 and 70, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; 71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 71 and 70; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively; a fusion polypeptide of SEQ ID NOs: 73 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72; a fusion polypeptide of SEQ ID NOs: 74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 74 and 75, respectively; a fusion polypeptide of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 77 and 76, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 77 and 76; a fusion polypeptide of SEQ ID NOs: 78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; a fusion polypeptide of SEQ ID NOs: 79 and 80%, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80; a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 83, respectively. 83 and 82; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; 85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively. 87 and 86; a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:87 and 86; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:88 and 89, respectively; 89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 88; a fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; a fusion polypeptide of SEQ ID NOs: 85 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 82; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; 86 and 82; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; 88 and 82; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 85; a fusion polypeptide of SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively; a fusion polypeptide of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 88; a fusion polypeptide of SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively; 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 85; a fusion polypeptide of SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively. 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85; a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; 91 and 90; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; 93 and 92; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; 95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 96; a fusion polypeptide of SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; a fusion polypeptide of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 95; a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs: 221 and 220; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs: 98; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively. 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99; a fusion polypeptide of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 98; a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or a fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. NO: 101 and 100 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, a first and a second viral vector comprising one or more polynucleotides, or a first and a second liposome complex (e.g., LNP), the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 82 and 83, or a fusion polypeptide with SEQ ID NO: 84, or a fusion polypeptide with SEQ ID NO: 85, or a fusion polypeptide with SEQ ID NO: 86, or a fusion polypeptide with SEQ ID NO: 87, or a fusion polypeptide with SEQ ID NO: 88, or a fusion polypeptide with SEQ ID NO: 89, or a fusion polypeptide with SEQ ID NO: 90, or a fusion polypeptide with SEQ ID NO: 91, NO:82 and 83 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 83, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising SEQ ID NO:86 and 87, or a fusion polypeptide with SEQ ID NO:87, respectively. NO: 86 and 87 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 86 and 87. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 84 and 85, or a fusion polypeptide with SEQ ID NO: 86 and 87, respectively. NO:84 and 85 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:84 and 85, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:88 and 89, or a fusion polypeptide with SEQ ID NO:89, respectively. NO: 88 and 89 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 88 and 89. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 82 and 86, or a fusion polypeptide with SEQ ID NO: 87, or a fusion polypeptide with SEQ ID NO: 88 and 89, respectively. NO:82 and 86 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 86, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:83 and 87, or a fusion polypeptide with SEQ ID NO:83 and 87, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:83 and 87. In some embodiments, the immunogenic composition comprises a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:88 and 87, respectively. In some embodiments, the immunogenic composition comprises a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 87, respectively. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 87, respectively. NO:84 and 88 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:84 and 88, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 89, or a fusion polypeptide with SEQ ID NO:87, 88, 89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of ... NO: 85 and 89 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 85 and 89. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 98 and 100, or a fusion polypeptide with SEQ ID NO: 101, or a fusion polypeptide with SEQ ID NO: 102, or a fusion polypeptide with SEQ ID NO: 103, or a fusion polypeptide with SEQ ID NO: 104, or a fusion polypeptide with SEQ ID NO: 105, or a fusion polypeptide with SEQ ID NO: 106, or a fusion polypeptide with SEQ ID NO: 107, or a fusion polypeptide with SEQ ID NO: 108, or a fusion polypeptide with SEQ ID NO: 110, or a fusion polypeptide with SEQ ID NO: 111, or a fusion polypeptide with SEQ ID NO: 112, or a fusion polypeptide with SEQ ID NO: 113, or a fusion polypeptide with SEQ ID NO: 114, or a fusion polypeptide with SEQ ID NO: 115, or a fusion polypeptide with SEQ ID NO: 116, or NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 101, or a fusion polypeptide with SEQ ID NO:85 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:85 and 101. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively. In some embodiments, the composition comprises a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively. NO:94 and 96 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:94 and 96, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:95 and 97, or a fusion polypeptide with SEQ ID NO:97, respectively. NO: 95 and 97 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 95 and 97. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 220 and 221, or a fusion polypeptide with SEQ ID NO: 222, respectively. NO: 220 and 221 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 220 and 221, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 95 and 97, or a fusion polypeptide with SEQ ID NO: 97, respectively. NO:95 and 97 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:95 and 97. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:98 and 100, or a fusion polypeptide with SEQ ID NO:99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:99 and 101, or a fusion polypeptide with SEQ ID NO: 102, or a fusion polypeptide with SEQ ID NO: 103, or a fusion polypeptide with SEQ ID NO: 104, or a fusion polypeptide with SEQ ID NO: 105, or a fusion polypeptide with SEQ ID NO: 106, or a fusion polypeptide with SEQ ID NO: 107, or a fusion polypeptide with SEQ ID NO: 108, or a fusion polypeptide with SEQ ID NO: 110, or a fusion polypeptide with SEQ ID NO: 111, or a fusion polypeptide with SEQ ID NO: 112, or a fusion polypeptide with SEQ ID NO: 113, or a fusion polypeptide with SEQ ID NO: 114, or a fusion polypeptide with SEQ ID NO: 115, or a fusion polypeptide with SEQ ID NO: 116, or a fusion polypeptide with SEQ ID NO: 117, or a fusion polypeptide with SEQ ID NO: 118, or a fusion polypeptide with SEQ ID NO: 119, or a fusion polypeptide with SEQ ID NO: 121, or a fusion polypeptide with SEQ ID NO: 122, or a fusion polypeptide with SEQ ID NO: 123, or a fusion polypeptide with A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:99 and 101. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87 and 88, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 97, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively. In some embodiments, the immunogenic composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 200, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 201, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptides. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 202, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 203, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptide. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 203, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 203, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 204, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 205. NO:204 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptide. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 105, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 107, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 107. A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:107. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 206, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 207, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208. A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:207. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 208, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:227. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 222, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: 227. A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:227. In some embodiments, the immunogenic composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 222, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 223, or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223. NO:223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptide. In some embodiments, the immunogenic composition comprises a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the immunogenic composition comprises a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226. In some embodiments, the immunogenic composition comprises the following first and second polynucleotides, or one or more vectors comprising the following first and second polynucleotides: polynucleotides of SEQ ID NOs: 130 and 132, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively; polynucleotides of SEQ ID NOs: 130 and 134, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134; a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively; a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135; a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively; a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135; polynucleotides of SEQ ID NOs: 133 and 137, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively; polynucleotides of SEQ ID NOs: 134 and 136, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136; a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively; a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 142, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 138 and 141; a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively; a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 143, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 142; polynucleotides of SEQ ID NOs: 139 and 145, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; polynucleotides of SEQ ID NOs: 140 and 146, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively; a polynucleotide of SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149; a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively; a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152; polynucleotides of SEQ ID NOs: 150 and 155, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively; polynucleotides of SEQ ID NOs: 151 and 153, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153; a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively; a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157; a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively; a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159; a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively; a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively; a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167; the polynucleotides of SEQ ID NOs: 210 and 211, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively; the polynucleotides of SEQ ID NOs: 212 and 213, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively; a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 216 and 217; a polynucleotide of SEQ ID NOs: 218 and 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively; a polynucleotide of SEQ ID NOs: 218 and 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 218 and 229, respectively; or a polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: (a) a first vector or a first liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively, and (b) a second vector or a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 133 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:133 and 137 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: (a) a first vector or a first liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 139 and 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively, and (b) a second vector or a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 142 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:142 and 148 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: (a) a first vector or a first liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively, and (b) a second vector or a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: NO: any of 143 and 149 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the first and second viral vectors of such immunogenic compositions are lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vectors. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: (a) a first vector or a first liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively, and (b) a second vector or a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: any of ID NOs: 155 and 158. In some embodiments, the first and second viral vectors of such immunogenic compositions are Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vectors. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: (a) a first vector or a first liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 151 and 153, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively, and (b) a second vector or a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 156 and 159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:156 and 159 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 160, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 160, respectively, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 161, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 161, respectively. NO:161 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 162, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 162, respectively, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 164, respectively. NO:163 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 164, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 164, respectively, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 165, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 165, respectively. NO:165 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 166, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 166, respectively, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 167, respectively. NO:167 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 210, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 211. NO:211 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 212, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 213. NO:213 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 215. NO:215 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 216, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 217. NO:217 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 219. NO:219 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a first and a second polynucleotide, or a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising one or more polynucleotides: (a) a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 225, and (b) a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide of SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the immunogenic composition comprises a composite fusion polypeptide, a vector comprising a polynucleotide encoding the composite fusion polypeptide, or a liposome complex (e.g., LNP), which composite fusion polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227. In some embodiments, the immunogenic composition comprises a composite fusion polypeptide, a vector comprising a polynucleotide encoding the composite fusion polypeptide, or a liposome complex (e.g., LNP), wherein the composite fusion polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 209, 222, and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 209, 222, and 223. In some embodiments, the one or more fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol607-682, Pol 709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116, and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol, and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively. In some embodiments, the one or more fusion polypeptides do not comprise any polypeptide fragment having an amino acid sequence of SEQ ID NOs: 35-47 or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 35-47 or a fragment or subsequence thereof. In various embodiments of the immunogenic composition, the first and second viral vectors can be lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vectors, Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vectors, or adenovirus vectors, such as chimpanzee adenovirus vectors (ChAd). In some embodiments, the immunogenic composition comprises a single vector comprising one or more polynucleotides encoding the first and second fusion polypeptides. In some embodiments, the immunogenic composition further comprises one or more of an adjuvant, a detergent, a micelle former, and an oil. In some embodiments, the immunogenic composition is formulated for administration via a route selected from: intravenous, intramuscular, intradermal, subcutaneous, intranodal, and mucosal (e.g., buccal, intranasal, rectal, intravaginal). In some embodiments, the immunogenic composition is formulated as a liquid, a suspension, or an emulsion. In some embodiments, the immunogenic composition is lyophilized.
还提供了试剂盒,其包括一个或多个单位剂量的如本文所述的一种或多种融合多肽、一种或多种复合融合多肽、一种或多种多核苷酸、一种或多种载体,或一种或多种免疫原性组合物。在一些实施方案中,试剂盒包括如本文所述的两种或更多种融合多肽、两种或更多种复合融合多肽、两种或更多种多核苷酸、两种或更多种载体,或两种或更多种免疫原性组合物。在一些实施方案中,一个或多个单位剂量在单个容器中。在一些实施方案中,一个或多个单位剂量在两个或更多个单独的容器中。在一些实施方案中,试剂盒包括一个或多个选自小瓶、安瓿和预载注射器的容器。在一些实施方案中,试剂盒包括一个或多个容器,这些容器包含一种或多种融合多肽、一种或多种多核苷酸或一种或多种载体的水性溶液。在一些实施方案中,一个或多个单位剂量是相同的。在一些实施方案中,一个或多个单位剂量是不同的。在一些实施方案中,试剂盒包括一个或多个单位剂量的一种或多种病毒载体,并且该单位剂量在约103至约1012个病毒病灶形成单位(FFU)或空斑形成单位(PFU)或感染性单位(IU)或病毒颗粒(vp)范围内,例如约104至约107个病毒FFU或PFU或IU或vp,例如约103至约104、105、106、107、108、109、1010、1011、1012、1013、1014或1015个病毒FFU或PFU或IU或vp。在一些实施方案中,试剂盒包括第一融合多肽和第二融合多肽、或包含编码第一和第二融合多肽的一种或多种多核苷酸的一种或多种载体,第一多肽和第二多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:SEQ ID NO:6、4、16和26,以及SEQ ID NO:7、5、27和17;SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQ ID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NO:26、16、4和6,以及SEQ ID NO:7、27、5和17;SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQID NO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NO:20、6、4、18、16和26,以及SEQ ID NO:7、19、5、21、27和17;SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQ ID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:24、6、4、20、18和32,以及SEQID NO:7、21、5、25、33和19;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ ID NO:7、21、5、25、33和19和SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:20、32、24、4、6和18,以及SEQ ID NO:26、30、12、14、8和10;SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ IDNO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NO:24、6、16和18,以及SEQ IDNO:26、10、20和28;SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQ ID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NO:24、16、6和18,以及SEQ ID NO:27、11、21和29;SEQ ID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NO:7、25、17和19,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO:7、21、19、17、27、25、29和11。在一些实施方案中,试剂盒包括一种或多种融合多肽、包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(LNP),这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,试剂盒包括一种或多种融合多肽、包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(LNP),这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ IDNO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,试剂盒包括以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ IDNO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ IDNO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ IDNO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ IDNO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ IDNO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括以下第一融合多肽和第二融合多肽、包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码从N末端到C末端按顺序且任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ IDNO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:86和87的融合多肽,或分别与SEQID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ IDNO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ IDNO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ IDNO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:200的融合多肽,或与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:201的融合多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:202的融合多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQID NO:203的融合多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:204的融合多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:205的融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:105或206的融合多肽,或分别与SEQ ID NO:105或206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:107或207的融合多肽,或分别与SEQ ID NO:107或207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:208的融合多肽,或与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:209或SEQ ID NO:227的融合多肽,或与SEQID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:222的融合多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:209或SEQ ID NO:227的融合多肽,或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:222的融合多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下融合多肽的多核苷酸:包含SEQ ID NO:223的融合多肽,或与SEQ IDNO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ IDNO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ IDNO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:95和97的融合多肽,或分别与SEQID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,试剂盒包括含有一种或多种多核苷酸的第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ IDNO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在试剂盒的各种实施方案中,病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体、卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体或腺病毒载体,例如黑猩猩腺病毒载体(ChAd)。在一些实施方案中,试剂盒包括多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,试剂盒包括多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,试剂盒包括以下第一多核苷酸和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP):SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ IDNO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),每个载体或脂质体复合物(例如,LNP)包含第一和第二多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:131和135,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:133和137,或分别与SEQ IDNO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ IDNO:139和145,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,第一和第二病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体。在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,第一和第二病毒载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体。在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),每个载体或脂质体复合物(例如,LNP)包含第一和第二多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:140和146,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:143和149,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:150和152,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:154和157或SEQ ID NO:155和158,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体或脂质体复合物(例如,LNP),每个载体或脂质体复合物(例如,LNP)包含第一和第二多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:150和152,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:155和158,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;(c)第三病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:151和153,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(d)第四病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:156和159,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在各种实施方案中,第一、第二、第三和第四载体中的一者或多者是腺病毒载体。在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ IDNO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:210的多核苷酸,或与SEQ IDNO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ IDNO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,试剂盒包括复合融合多肽、包含编码复合融合多肽的多核苷酸的载体或脂质体复合物(例如,LNP),该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,试剂盒包括复合融合多肽、包含编码复合融合多肽的多核苷酸的载体或脂质体复合物(例如,LNP),该复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,该一种或多种融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol 607-682、Pol709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在一些实施方案中,该一种或多种融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,试剂盒还包括一个或多个单位剂量的一种或多种附加治疗剂。在一些实施方案中,试剂盒包括一种或多种活化潜伏性HIV的药剂,例如一种或多种潜伏期逆转剂(LRA)。在一些实施方案中,试剂盒包括选自以下项的一种或多种LRA:一种或多种toll样受体(TLR)的激动剂或活化剂、组蛋白脱乙酰酶(HDAC)抑制剂、蛋白酶体抑制剂、蛋白激酶C(PKC)活化剂、Smyd2抑制剂、BET-溴结构域4(BRD4)抑制剂、离子霉素、凋亡蛋白抑制剂(IAP)拮抗剂以及胱天蛋白酶(SMAC)第二线粒体衍生的活化剂模拟物。在一些实施方案中,试剂盒包括一种或多种Toll样受体(TLR)的一种或多种激动剂或活化剂。在一些实施方案中,TLR激动剂或活化剂选自TLR2激动剂、TLR3激动剂、TLR4激动剂、TLR5激动剂、TLR7激动剂、TLR8激动剂和TLR9激动剂。在一些实施方案中,TLR7激动剂选自GS 9620(维沙莫特)、R848(瑞喹莫德)、DS-0509、LHC-165和TMX-101(咪喹莫特),并且/或者其中TLR8激动剂选自GS-9688(赛尔甘托莫德)、R848(瑞喹莫德)和NKTR-262(双TLR7/TLR8激动剂)。在一些实施方案中,试剂盒包括选自IL-2、IL-7、IL-12和IL-15的白介素的一种或多种白介素受体激动剂。在一些实施方案中,试剂盒包括选自IL-2、IL-7、IL-12、IL-15以及它们的变体的一种或多种细胞因子。在一些实施方案中,试剂盒包括一种或多种先天免疫活化剂。在一些实施方案中,该一种或多种先天免疫活化剂包括选自以下的受体的激动剂:fms相关酪氨酸激酶3(FLT3)、干扰素基因刺激剂(STING)受体、DExD/H盒解旋酶58(DDX58;又名RIG-I)、含核苷酸结合寡聚化结构域蛋白2(NOD2)。在一些实施方案中,试剂盒包括fms相关酪氨酸激酶3(FLT3)的激动剂。在一些实施方案中,试剂盒包括抑制性免疫检查点蛋白或受体的一种或多种拮抗剂或抑制剂和/或刺激性免疫检查点蛋白或受体的一种或多种活化剂或激动剂。在一些实施方案中,一种或多种免疫检查点蛋白或受体选自:CD27、CD70;CD40、CD40LG;CD47、CD48(SLAMF2)、含跨膜和免疫球蛋白结构域蛋白2(TMIGD2、CD28H)、CD84(LY9B、SLAMF5)、CD96、CD160、MS4A1(CD20)、CD244(SLAMF4);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);自然杀伤细胞细胞毒性受体3配体1(NCR3LG1、B7H6);HERV-H LTR相关2(HHLA2、B7H7);诱导型T细胞共刺激因子(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF8(CD30)、TNFSF8(CD30L);TNFRSF10A(CD261、DR4、TRAILR1)、TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF10B(CD262、DR5、TRAILR2)、TNFRSF10(TRAIL);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));TNFRSF17(BCMA、CD269)、TNFSF13B(BAFF);TNFRSF18(GITR)、TNFSF18(GITRL);MHC I类多肽相关序列A(MICA);MHC I类多肽相关序列B(MICB);CD274(CD274、PDL1、PD-L1);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155);含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);含T细胞免疫球蛋白和粘蛋白结构域蛋白4(TIMD4;TIM4;甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);淋巴细胞活化3(LAG3、CD223);信号转导淋巴细胞活化分子家族成员1(SLAMF1、SLAM、CD150);淋巴细胞抗原9(LY9、CD229、SLAMF3);SLAM家族成员6(SLAMF6、CD352);SLAM家族成员7(SLAMF7、CD319);UL16结合蛋白1(ULBP1);UL16结合蛋白2(ULBP2);UL16结合蛋白3(ULBP3);视黄酸早期转录物1E(RAET1E;ULBP4);视黄酸早期转录物1G(RAET1G;ULBP5);视黄酸早期转录物1L(RAET1L;ULBP6);淋巴细胞活化3(CD223);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);杀伤细胞凝集素样受体C2(KLRC2、CD159c、NKG2C);杀伤细胞凝集素样受体C3(KLRC3、NKG2E);杀伤细胞凝集素样受体C4(KLRC4、NKG2F);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体D1(KLRD1);以及SLAM家族成员7(SLAMF7)。在一些实施方案中,试剂盒包括一种或多种T细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂。在一些实施方案中,T细胞抑制性免疫检查点蛋白或受体选自:CD274(CD274、PDL1、PD-L1);程序性细胞死亡1配体2(PDCD1LG2、PD-L2、CD273);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);淋巴细胞活化3(LAG3、CD223);甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);以及杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1)。在一些实施方案中,试剂盒包括一种或多种T细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂。在一些实施方案中,T细胞刺激性免疫检查点蛋白或受体选自:CD27、CD70、CD40、CD40LG;诱导型T细胞共刺激物(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF18(GITR)、TNFSF18(GITRL);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155)。在一些实施方案中,试剂盒包括一种或多种NK细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂。在一些实施方案中,NK细胞抑制性免疫检查点蛋白或受体选自:杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A);和杀伤细胞凝集素样受体D1(KLRD1、CD94)。在一些实施方案中,试剂盒包括一种或多种NK细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂。在一些实施方案中,NK细胞刺激性免疫检查点蛋白或受体选自CD16、CD226(DNAM-1);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);以及SLAM家族成员7(SLAMF7)。在一些实施方案中,一种或多种免疫检查点抑制剂包括PD-L1(CD274)、PD-1(PDCD1)或CTLA4的蛋白质抑制剂。在一些实施方案中,试剂盒包括结合CTLA4的抗体。在一些实施方案中,CTLA4的蛋白质或抗体抑制剂选自:伊匹单抗、曲美木单抗、BMS-986218、AGEN1181、AGEN1884、BMS-986249、MK-1308、REGN-4659、ADU-1604、CS-1002、BCD-145、APL-509、JS-007、BA-3071、ONC-392、AGEN-2041、JHL-1155、KN-044、CG-0161、ATOR-1144、PBI-5D3H5、FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、XmAb-20717(PD-1/CTLA4)和AK-104(CTLA4/PD-1)。在一些实施方案中,PD-L1(CD274)或PD-1(PDCD1)的蛋白质抑制剂选自:派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、西米单抗(cemiplimab)、匹地利珠单抗(pidilizumab)、AMP-224、MEDI0680(AMP-514)、斯巴达珠单抗(spartalizumab)、阿替利珠单抗(atezolizumab)、阿维鲁单抗(avelumab)、度伐利尤单抗(durvalumab)、BMS-936559、CK-301、PF-06801591、BGB-A317(替雷利珠单抗(tislelizumab))、GLS-010(WBP-3055)、AK-103(HX-008)、AK-105、CS-1003、HLX-10、MGA-012、BI-754091、AGEN-2034、JS-001(特瑞普利单抗(toripalimab))、JNJ-63723283、杰诺单抗(genolimzumab)(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、SHR-1210(卡瑞利珠单抗(camrelizumab))、Sym-021、ABBV-181、PD1-PIK、BAT-1306(MSB0010718C)、CX-072、CBT-502、TSR-042(多塔利单抗(dostarlimab))、MSB-2311、JTX-4014、BGB-A333、SHR-1316、CS-1001(WBP-3155、KN-035、IBI-308(信迪利单抗(sintilimab))、HLX-20、KL-A167、STI-A1014、STI-A1015(IMC-001)、BCD-135、FAZ-053、TQB-2450、MDX1105-01、FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-013(PD-1/LAG-3)、FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、RO-7121661(PD-1/TIM-3)、XmAb-20717(PD-1/CTLA4)、AK-104(CTLA4/PD-1)、M7824(PD-L1/TGFβ-EC结构域)、CA-170(PD-L1/VISTA)、CDX-527(CD27/PD-L1)、LY-3415244(TIM3/PDL1)和INBRX-105(4-1BB/PDL1)。在一些实施方案中,一种或多种免疫检查点抑制剂包含CD274(PDL1、PD-L1)、程序性细胞死亡1(PDCD1、PD1、PD-1)或CTLA4的小分子抑制剂。在一些实施方案中,CD274或PDCD1的小分子抑制剂选自GS-4224、GS-4416、INCB086550和MAX10181。在一些实施方案中,CTLA4的小分子抑制剂包括BPI-002。在一些实施方案中,试剂盒还包括一种或多种抗病毒剂。在一些实施方案中,该一种或多种抗病毒剂选自:HIV蛋白酶抑制剂、HIV逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或变构)整合酶抑制剂、HIV进入(融合)抑制剂、HIV成熟抑制剂和衣壳抑制剂。Also provided is a kit, which includes one or more unit doses of one or more fusion polypeptides as described herein, one or more composite fusion polypeptides, one or more polynucleotides, one or more carriers, or one or more immunogenic compositions. In some embodiments, the kit includes two or more fusion polypeptides as described herein, two or more composite fusion polypeptides, two or more polynucleotides, two or more carriers, or two or more immunogenic compositions. In some embodiments, one or more unit doses are in a single container. In some embodiments, one or more unit doses are in two or more separate containers. In some embodiments, the kit includes one or more containers selected from vials, ampoules, and preloaded syringes. In some embodiments, the kit includes one or more containers, which contain an aqueous solution of one or more fusion polypeptides, one or more polynucleotides, or one or more carriers. In some embodiments, one or more unit doses are the same. In some embodiments, one or more unit doses are different. In some embodiments, the kit includes one or more unit doses of one or more viral vectors, and the unit dose is in the range of about 10 3 to about 10 12 viral focus forming units (FFU) or plaque forming units (PFU) or infectious units (IU) or viral particles (vp), for example, about 10 4 to about 10 7 viral FFU or PFU or IU or vp, for example, about 10 3 to about 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 or 10 15 viral FFU or PFU or IU or vp. In some embodiments, the kit includes a first fusion polypeptide and a second fusion polypeptide, or one or more vectors comprising one or more polynucleotides encoding the first and second fusion polypeptides, the first polypeptide and the second polypeptide comprising, in order from N-terminus to C-terminus, the following polypeptide fragments optionally bound or connected by one or more linkers: SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17; SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11; SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21; SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17; SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11; SEQ ID NOs: 22, 24, 14, 18 and 20, and SEQ ID NOs: NO:25, 23, 15, 21 and 19; SEQ ID NO:20, 6, 4, 18, 16 and 26, and SEQ ID NO:7, 19, 5, 21, 27 and 17; SEQ ID NO:8, 24, 14, 12, 22 and 10, and SEQ ID NO:9, 13, 25, 23, 15 and 11; SEQ ID NO:18, 26, 20, 4, 6 and 16, and SEQ ID NO:7, 21, 17, 5, 27 and 19; SEQ ID NO:22, 24, 12, 14, 8 and 10, and SEQ ID NO:15, 25, 9, 23, 13 and 11; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:7, 21, 5, 25, 33 and 19; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:8, 30, 14, 12, 26 and 10, and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:6, 20, 4, 24, 32 and 18, and SEQ ID NO:8, 12, 30, 26, 14 and 10; SEQ ID NO:7, 21, 5, 25, 33 and 19 and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:20, 32, 24, 4, 6 and 18, and SEQ ID NO:26, 30, 12, 14, 8 and 10; SEQ ID NO:7, 25, 19, 5, 33 and 21, and SEQ ID NO:15, 31, 9, 27, 13 and 11; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 20, 10 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 10, 20 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:7, 25, 17 and 19; SEQ ID NO:7, 19, 17 and 25, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:24, 16, 6 and 18, and SEQ ID NO:27, 11, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:11, 27, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 20 and 28, and SEQ ID NO:23, 7, 21 and 29; SEQ ID NO:22, 20, 6 and 28, and SEQ ID NO:7, 21, 23 and 29; SEQ ID NO:26, 10, 20 and 28, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 16, 20, 18, 28, 26 and 10; or SEQ ID NO:7, 21, 19, 17, 27, 25, 29 and 11. In some embodiments, the kit includes one or more fusion polypeptides, one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, or one or more liposome complexes (LNPs), wherein the fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the kit includes one or more fusion polypeptides, one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, or one or more liposome complexes (LNPs), wherein the fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223. In some embodiments, the kit includes the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively. 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively. 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:76 and 77; a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:78 and 79, respectively; a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:80 and 81, respectively. 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively. 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively. 88 and 89; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively. 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively. 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively; 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89; a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively. 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 94 and 96; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101. In some embodiments, the kit includes the following first and second fusion polypeptides, one or more vectors or one or more liposome complexes (e.g., LNPs) comprising one or more polynucleotides encoding the following first and second fusion polypeptides bound or connected in order from N-terminus to C-terminus and optionally through one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; 71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 71 and 70; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively; a fusion polypeptide of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72; a fusion polypeptide of SEQ ID NOs: 74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 74 and 75, respectively; a fusion polypeptide of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 77 and 76, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 77 and 76; a fusion polypeptide of SEQ ID NOs: 78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; a fusion polypeptide of SEQ ID NOs: 79 and 80%, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80; a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 83, respectively. 83 and 82; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; 85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively. 87 and 86; a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:87 and 86; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:88 and 89, respectively; 89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 89 and 88; a fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; a fusion polypeptide of SEQ ID NOs: 85 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 82; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; 86 and 82; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; 88 and 82; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87 and 85; a fusion polypeptide of SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively; a fusion polypeptide of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 88; a fusion polypeptide of SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively; 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 85; a fusion polypeptide of SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively. 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85; a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; 91 and 90; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:93 and 93, respectively. 93 and 92; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; 95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 97 and 96; a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:94 and 96, respectively; a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:94 and 96, respectively; 96 and 94; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:97 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 97, respectively. 97 and 95; a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs: 221 and 220; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs: 98; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively. 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99; a fusion polypeptide of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 98; a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or a fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:101 and 100. In some embodiments, the kit includes a first, second, third, and fourth viral vectors or liposome complexes (e.g., LNPs) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively; NO:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:84 and 85, respectively; (c) a third viral vector or liposome complex (e.g., LNP), comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:84 and 85, respectively; NO:86 and 87 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:86 and 87; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:88 and 89, respectively. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:83 and 87. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 88 and 89, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:88 and 87. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 85 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:85 and 87. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 200, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 201, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 202, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 203, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 204, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 205, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 205. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 105 or 206, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105 or 206, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 107 or 207, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: NO:107 or 207 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical fusion polypeptides. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 208, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 222, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 222, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: a polynucleotide encoding the following fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 223, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223. IDNO: 223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; NO:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively; (c) a third viral vector or liposome complex (e.g., LNP), comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively; NO:84 and 88 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:84 and 88; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 89, respectively. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; NO:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively; (c) a third viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively; NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 101, respectively. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; NO:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively; (c) a third viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively; NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:99 and 101, respectively. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 90 and 91, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:92 and 93. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:95 and 97. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively. NO:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 96 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:96 and 97. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively, and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:99 and 101, respectively. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: NO:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively; (c) a third viral vector or liposome complex (e.g., LNP), comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively; NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:99 and 101, respectively. In some embodiments, the kit includes a first, second, third, and fourth viral vectors or liposome complexes (e.g., LNPs) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; NO:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively; (c) a third viral vector or liposome complex (e.g., LNP), comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively; NO:98 and 99 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 99; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:100 and 101, respectively. In various embodiments of the kit, the viral vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vector, a Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vector, or an adenovirus vector, such as a chimpanzee adenovirus vector (ChAd). In some embodiments, the kit includes a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the kit includes a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226. In some embodiments, the kit includes the following first and second polynucleotides, or one or more vectors or one or more liposome complexes (e.g., LNPs) comprising the following first and second polynucleotides: polynucleotides of SEQ ID NOs: 130 and 132, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively; polynucleotides of SEQ ID NOs: 130 and 134, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134; a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively; a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135; a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively; a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135; polynucleotides of SEQ ID NOs: 133 and 137, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively; polynucleotides of SEQ ID NOs: 134 and 136, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136; a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively; a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 142, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 138 and 141; a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively; a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 143, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 142; a polynucleotide of SEQ ID NOs: 139 and 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; a polynucleotide of SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively; a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149; a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively; a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152; polynucleotides of SEQ ID NOs: 150 and 155, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively; polynucleotides of SEQ ID NOs: 151 and 153, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153; a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively; a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, ... 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157; a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively; a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159; a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively; a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively; a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167; the polynucleotides of SEQ ID NOs: 210 and 211, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively; the polynucleotides of SEQ ID NOs: 212 and 213, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 212 and 213, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively; a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217; polynucleotides of SEQ ID NOs: 218 and 219, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively; polynucleotides of SEQ ID NOs: 218 and 226, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 229, respectively; or a polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 133 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:133 and 137 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 139 and 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:139 and 145 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP), each vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide: (a) a first viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 131 and 135, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 133 and 137, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively. any one of SEQ ID NOs: 133 and 137 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; (c) a third viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NOs: 139 and 145, or respectively identical to SEQ ID NOs: 139 and 145. any one of SEQ ID NOs: 139 and 145 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 142 and 148, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: NO: any of 143 and 149 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the first and second viral vectors are lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vectors. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: NO: any of 155 and 158 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the first and second viral vectors are Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vectors. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP), each vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide: (a) a first viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 140 and 146, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 143 and 149, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. any of SEQ ID NOs: 143 and 149 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; (c) a third viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 150 and 152, or respectively identical to SEQ ID NOs: 151 and 152. any of SEQ ID NOs: 150 and 152 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or the same as SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, respectively. Any of NOs: 155 and 158 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the kit includes a first, second, third, and fourth viral vector or liposome complex (e.g., LNP), each vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide: (a) a first viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 150 and 152, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively. any of SEQ ID NOs: 155 and 158 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; (c) a third viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NOs: 151 and 153, or respectively identical to SEQ ID NOs: any one of SEQ ID NOs: 151 and 153 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (d) a fourth viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 156 and 159, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively. In various embodiments, one or more of the first, second, third, and fourth vectors are adenoviral vectors. In some embodiments, the kit includes a first and a second viral vector or liposome complex (e.g., LNP) containing the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 162 and 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively. Any of NO:162 and 163 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the kit includes a first and a second viral vector comprising the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 166 and 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:166 and 167 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 210, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 211. NO:211 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 212, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 213. NO:213 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 215. NO:215 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 216, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 217. NO:217 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 219. NO:219 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 225, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the kit includes a composite fusion polypeptide, a vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding the composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227. In some embodiments, the kit includes a composite fusion polypeptide, a vector or a liposome complex (e.g., LNP) comprising a polynucleotide encoding the composite fusion polypeptide, wherein the composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 209, 222, and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 209, 222, and 223. In some embodiments, the one or more fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol 607-682, Pol709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116, and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol, and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively. In some embodiments, the one or more fusion polypeptides do not comprise any polypeptide fragment having an amino acid sequence of SEQ ID NO:35-47 or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:35-47 or a fragment or subsequence thereof. In some embodiments, the kit further comprises one or more unit doses of one or more additional therapeutic agents. In some embodiments, the kit comprises one or more agents that activate latent HIV, such as one or more latency reversal agents (LRAs). In some embodiments, the kit includes one or more LRAs selected from the following: one or more toll-like receptor (TLR) agonists or activators, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, inhibitor of apoptosis protein (IAP) antagonists, and activator mimics of the second mitochondria derived from caspase (SMAC). In some embodiments, the kit includes one or more agonists or activators of one or more Toll-like receptors (TLR). In some embodiments, TLR agonists or activators are selected from TLR2 agonists, TLR3 agonists, TLR4 agonists, TLR5 agonists, TLR7 agonists, TLR8 agonists, and TLR9 agonists. In some embodiments, the TLR7 agonist is selected from GS 9620 (visamod), R848 (resiquimod), DS-0509, LHC-165 and TMX-101 (imiquimod), and/or wherein the TLR8 agonist is selected from GS-9688 (selgantomod), R848 (resiquimod) and NKTR-262 (dual TLR7/TLR8 agonist). In some embodiments, the kit includes one or more interleukin receptor agonists selected from the interleukins of IL-2, IL-7, IL-12 and IL-15. In some embodiments, the kit includes one or more cytokines selected from IL-2, IL-7, IL-12, IL-15 and their variants. In some embodiments, the kit includes one or more innate immune activators. In some embodiments, the one or more innate immune activators include agonists of receptors selected from the following: fms-associated tyrosine kinase 3 (FLT3), interferon gene stimulator (STING) receptor, DExD/H box helicase 58 (DDX58; also known as RIG-I), nucleotide binding oligomerization domain protein 2 (NOD2). In some embodiments, the kit includes an agonist of fms-associated tyrosine kinase 3 (FLT3). In some embodiments, the kit includes one or more antagonists or inhibitors of inhibitory immune checkpoint proteins or receptors and/or one or more activators or agonists of stimulatory immune checkpoint proteins or receptors. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137 ), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC Class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing protein (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT ); T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4; TIM4; hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signal transducer lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2 ); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, N KG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7). In some embodiments, the kit includes one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the T cell inhibitory immune checkpoint protein or receptor is selected from: CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated Immunoglobulin domain proteins (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the kit includes one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the T cell stimulatory immune checkpoint proteins or receptors are selected from: CD27, CD70, CD40, CD40LG; inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the kit includes one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the NK cell inhibitory immune checkpoint proteins or receptors are selected from: killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In some embodiments, the kit includes one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. In some embodiments, NK cell stimulatory immune checkpoint proteins or receptors are selected from CD16, CD226 (DNAM-1); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, one or more immune checkpoint inhibitors include protein inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the kit includes antibodies that bind to CTLA4. In some embodiments, the protein or antibody inhibitor of CTLA4 is selected from: ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, C G-0161, ATOR-1144, PBI-5D3H5, FPT-155(CTLA4/PD-L1/CD28), PF-06936308(PD-1/CTLA4), MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4) and AK-104(CTLA4/PD-1). In some embodiments, the protein inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from: pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), elizumab), GLS-010(WBP-3055), AK-103(HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001(toripalimab), JNJ-63723283, genolimzumab(CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210(camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306(MSB001 0718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD -013(PD-1/LAG-3), FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-1 04 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1) and INBRX-105 (4-1BB/PDL1). In some embodiments, one or more immune checkpoint inhibitors include small molecule inhibitors of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitors of CTLA4 include BPI-002. In some embodiments, the kit further includes one or more antiviral agents. In some embodiments, the one or more antiviral agents are selected from: HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, and capsid inhibitors.
还提供了用于在对其有需要的受试者中引发针对人类免疫缺陷病毒(HIV)的免疫应答的方法,这些方法包括向受试者施用如本文所述的融合多肽、复合融合多肽、多核苷酸、载体、脂质体复合物(例如,LNP)或免疫原性组合物。还提供了在对其有需要的受试者中治疗或预防人类免疫缺陷病毒(HIV)的方法,这些方法包括向受试者施用如本文所述的融合多肽、复合融合多肽、载体、脂质体复合物(例如,LNP)或免疫原性组合物。在一些实施方案中,该方法需要施用单一载体,该载体包含编码第一融合多肽和第二融合多肽的一种或多种多核苷酸。在一些实施方案中,将如本文所述的两种或更多种融合多肽、两种或更多种复合融合多肽、编码融合多肽的两种或更多种多核苷酸、包含编码融合多肽的多核苷酸的两种或更多种病毒表达载体、两种或更多种脂质体复合物(例如,LNP)或两种或更多种免疫原性组合物同时或并行地施用于受试者。在一些实施方案中,两种或更多种融合多肽、或编码融合多肽的两种或更多种多核苷酸、或两种或更多种病毒表达载体为二价抗原组合物的形式。在一些实施方案中,该方法需要施用第一融合多肽和第二融合多肽、编码第一和第二融合多肽的一种或多种多核苷酸、或包含编码第一和第二融合多肽的一种或多种多核苷酸的一种或多种载体、或一种或多种脂质体复合物(例如,LNP),第一多肽和第二多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:SEQ ID NO:6、4、16和26,以及SEQ ID NO:7、5、27和17;SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQ ID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NO:26、16、4和6,以及SEQ ID NO:7、27、5和17;SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQ ID NO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NO:20、6、4、18、16和26,以及SEQ ID NO:7、19、5、21、27和17;SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQ ID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ IDNO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:7、21、5、25、33和19;SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ ID NO:7、21、5、25、33和19和SEQ ID NO:9、13、31、27、15和11;SEQ ID NO:20、32、24、4、6和18,以及SEQ IDNO:26、30、12、14、8和10;SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、10、20和28;SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NO:24、16、6和18,以及SEQ IDNO:27、11、21和29;SEQ ID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NO:7、25、17和19,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO:7、21、19、17、27、25、29和11。在一些实施方案中,该方法需要施用一种或多种融合多肽、编码一种或多种融合多肽的一种或多种多核苷酸、包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体、一种或多种脂质体复合物(例如,LNP),该一种或多种融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,该方法需要施用一种或多种融合多肽、编码一种或多种融合多肽的一种或多种多核苷酸、包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体、一种或多种脂质体复合物(例如,LNP),该一种或多种融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,该方法需要施用以下第一融合多肽和第二融合多肽、一种或多种多核苷酸、包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用以下第一融合多肽和第二融合多肽、包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码从N末端到C末端按顺序且任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ IDNO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ IDNO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含一种或多种多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二多核苷酸或包含一种或多种多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:200,与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ IDNO:201,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:202,与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:203,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:204,与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:205,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:105,与SEQID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:107,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:206,与SEQ ID NO:206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:207,或与SEQ ID NO:207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:208,与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:209或SEQ ID NO:227,或与SEQ ID NO:209或SEQ IDNO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:222,与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:209或SEQ ID NO:227,或与SEQ ID NO:209或SEQ IDNO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含编码第一融合多肽的多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该第一融合多肽包含SEQ ID NO:222,与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含编码第二融合多肽的多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该第二融合多肽包含SEQ ID NO:223,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,该方法需要施用含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ IDNO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在各种实施方案中,第一和第二病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体、卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体或腺病毒载体,例如黑猩猩腺病毒载体(ChAd)。在一些实施方案中,第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)并行地共同施用。在一些实施方案中,该方法需要施用以下第一多核苷酸和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP):SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ IDNO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,其中第一和第二病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体。在一些实施方案中,该方法需要施用含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP):(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,其中第一和第二病毒载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体。在一些实施方案中,该方法需要施用复合融合多肽、包含编码复合融合多肽的多核苷酸的载体或脂质体复合物(例如,LNP),该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,该方法需要施用复合融合多肽、包含编码复合融合多肽的多核苷酸的载体或脂质体复合物(例如,LNP),该复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,该方法需要施用多核苷酸(例如,在载体中、在脂质体复合物(例如,LNP)中),该多核苷酸包含以下或由以下组成:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,该方法需要施用多核苷酸(例如,在载体中、在脂质体复合物(例如,LNP)中),该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQID NO:211的多核苷酸,或与SEQ ID NO:211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ IDNO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ IDNO:215的多核苷酸,或与SEQ ID NO:215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ IDNO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ IDNO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,该一种或多种融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol321-366、Pol 432-541、Pol 607-682、Pol 709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在一些实施方案中,该一种或多种融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,受试者被HIV-1病毒感染,疑似被HIV-1病毒感染,或有感染HIV-1病毒的风险。在一些实施方案中,受试者被HIV-1慢性感染。在一些实施方案中,受试者被HIV-1急性感染。在一些实施方案中,受试者患有Fiebig IV期或更早,例如Fiebig III期、Fiebig II期或Fiebig I期的HIV-1感染。在一些实施方案中,融合多肽、复合融合多肽、多核苷酸、载体、脂质体复合物(例如,LNP)或免疫原性组合物经由选自以下的途径施用:静脉内、肌肉内、皮内、皮下、结内和粘膜(例如,颊部、鼻内、直肠内、阴道内)。在一些实施方案中,该方法需要每次施用约103至约1012个病毒病灶形成单位(FFU)或噬菌斑形成单位(PFU)或感染单位(IU)或病毒颗粒(vp),例如约104至约107个病毒FFU或PFU或IU或vp,例如约103至约104、105、106、107、108、109、1010、1011、1012、1013、1014或1015个病毒FFU或PFU或IU或vp。在一些实施方案中,该方法包括初免-加强方案,其包括在第一时间点施用初免组合物并在一个或多个后续时间点施用一种或多种加强组合物。在一些实施方案中,该方法包括重复初免-加强方案一次或多次迭代。在一些实施方案中,初免组合物和一种或多种加强组合物的施用间隔至少1周、2周、3周或1个月,例如至少2、3、4、5、6、7、8、9、10、11或12个月。在一些实施方案中,初免组合物和加强组合物包含相同的免疫原性组合物。在一些实施方案中,初免组合物和加强组合物包含不同的免疫原性组合物。在一些实施方案中,初免组合物和加强组合物包含相同的一种或多种融合多肽和相同的病毒表达载体。在一些实施方案中,初免组合物和加强组合物包含不同的融合多肽和/或不同的病毒表达载体。在一些实施方案中,这些方法包括用第一病毒表达载体初免,并用第二病毒表达载体加强。在一些实施方案中,初免-加强方案包括:(a)用一种或多种病毒表达载体初免并用一种或多种多核苷酸加强,其中该一种或多种多核苷酸包含DNA、cDNA、mRNA或自复制RNA;(b)用一种或多种多核苷酸初免,其中该一种或多种多核苷酸包含DNA、cDNA、mRNA或自复制RNA,并用一种或多种病毒表达载体加强;(c)用一种或多种病毒表达载体初免并用一种或多种病毒表达载体加强,其中初免组合物中的一种或多种病毒表达载体和加强组合物中的一种或多种病毒表达载体来自相同、相关或不相关的分类学家族;(d)用一种或多种复制缺陷型病毒表达载体初免并用一种或多种复制缺陷型病毒表达载体加强,其中初免组合物中的一种或多种复制缺陷型病毒表达载体和加强组合物中的一种或多种复制缺陷型病毒表达载体来自相同、相关或不相关的分类学家族;(e)用一种或多种复制减毒型病毒表达载体初免并用一种或多种复制减毒型病毒表达载体加强,其中初免组合物中的一种或多种复制减毒型病毒表达载体和加强组合物中的一种或多种复制减毒型病毒表达载体来自相同、相关或不相关的分类学家族;(f)用一种或多种复制缺陷型病毒表达载体初免并用一种或多种复制减毒型病毒表达载体加强;(g)用一种或多种复制减毒型病毒表达载体初免并用一种或多种复制缺陷型病毒表达载体加强;(h)用一种或多种淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体初免并用一种或多种皮钦德哺乳动物沙粒病毒病毒表达载体加强;(i)用一种或多种皮钦德哺乳动物沙粒病毒病毒表达载体初免并用一种或多种淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体加强;(j)用一种或多种复制缺陷型皮钦德哺乳动物沙粒病毒病毒表达载体初免并用一种或多种复制缺陷型淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体加强;(k)用一种或多种复制缺陷型淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体初免并用一种或多种复制缺陷型皮钦德哺乳动物沙粒病毒病毒表达载体加强;(l)用一种或多种沙粒病毒病毒表达载体初免并用一种或多种腺病毒病毒表达载体加强;(m)用一种或多种腺病毒病毒表达载体初免并用包含一种或多种沙粒病毒病毒表达载体的加强组合物加强;(n)用一种或多种腺病毒病毒表达载体初免并用包含一种或多种RNA分子(例如,mRNA、自扩增或自复制RNA)的加强组合物加强;(o)用一种或多种RNA分子(例如,mRNA、自扩增或自复制RNA)初免并用包含一种或多种腺病毒病毒表达载体的加强组合物加强;(p)用一种或多种黑猩猩腺病毒(ChAd)表达载体初免并用包含一种或多种自扩增或自复制RNA(saRNA或samRNA)的加强组合物加强;(q)用一种或多种自扩增或自复制RNA(saRNA或samRNA)初免并用包含一种或多种黑猩猩腺病毒(ChAd)表达载体的加强组合物加强;(r)用一种或多种痘病毒病毒表达载体初免并用一种或多种沙粒病毒病毒表达载体加强;(s)用一种或多种沙粒病毒病毒表达载体初免并用包含一种或多种痘病毒病毒表达载体的加强组合物加强;(t)用一种或多种痘病毒病毒表达载体初免并用一种或多种腺病毒病毒表达载体加强;或(u)用一种或多种腺病毒病毒表达载体初免并用包含一种或多种痘病毒病毒表达载体的加强组合物加强。在一些实施方案中,初免-加强方案包括:(1)用免疫原性组合物初免,该免疫原性组合物包含以下第一融合多肽和第二融合多肽、包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用免疫原性组合物加强,该免疫原性组合物包含第一融合多肽和第二融合多肽、包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:74和75的融合多肽,或分别与SEQ IDNO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和85的融合多肽,或分别与SEQ IDNO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:82和88的融合多肽,或分别与SEQ IDNO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和89的融合多肽,或分别与SEQ IDNO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:96和97的融合多肽,或分别与SEQ IDNO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;SEQ IDNO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用免疫原性组合物初免,该免疫原性组合物包含以下第一融合多肽和第二融合多肽、包含一种或多种多核苷酸的一种或多种载体、一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(d)SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或(e)SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用免疫原性组合物加强,该免疫原性组合物包含第一融合多肽和第二融合多肽、包含一种或多种多核苷酸的一种或多种载体或一种或多种脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(b)SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;(c)SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或(d)SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,或编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:87和88的融合多肽,或分别与SEQID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。Also provided are methods for eliciting an immune response to human immunodeficiency virus (HIV) in a subject in need thereof, comprising administering to the subject a fusion polypeptide, a composite fusion polypeptide, a polynucleotide, a carrier, a liposome complex (e.g., LNP) or an immunogenic composition as described herein. Also provided are methods for treating or preventing human immunodeficiency virus (HIV) in a subject in need thereof, comprising administering to the subject a fusion polypeptide, a composite fusion polypeptide, a carrier, a liposome complex (e.g., LNP) or an immunogenic composition as described herein. In some embodiments, the method requires administration of a single vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide. In some embodiments, two or more fusion polypeptides, two or more composite fusion polypeptides, two or more polynucleotides encoding fusion polypeptides, two or more viral expression vectors comprising polynucleotides encoding fusion polypeptides, two or more liposome complexes (e.g., LNP) or two or more immunogenic compositions as described herein are administered to the subject simultaneously or in parallel. In some embodiments, two or more fusion polypeptides, or two or more polynucleotides encoding fusion polypeptides, or two or more viral expression vectors are in the form of a bivalent antigenic composition. In some embodiments, the method requires administering a first fusion polypeptide and a second fusion polypeptide, one or more polynucleotides encoding the first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the first and second fusion polypeptides, or one or more liposome complexes (e.g., LNPs), wherein the first polypeptide and the second polypeptide comprise, in order from N-terminus to C-terminus, the following polypeptide fragments optionally bound or linked by one or more linkers: SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17; SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11; SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21; SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17; SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11; SEQ ID NOs: NO:22, 24, 14, 18 and 20, and SEQ ID NO:25, 23, 15, 21 and 19; SEQ ID NO:20, 6, 4, 18, 16 and 26, and SEQ ID NO:7, 19, 5, 21, 27 and 17; SEQ ID NO:8, 24, 14, 12, 22 and 10, and SEQ ID NO:9, 13, 25, 23, 15 and 11; SEQ ID NO:18, 26, 20, 4, 6 and 16, and SEQ ID NO:7, 21, 17, 5, 27 and 19; SEQ ID NO:22, 24, 12, 14, 8 and 10, and SEQ ID NO:15, 25, 9, 23, 13 and 11; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:7, 21, 5, 25, 33 and 19; SEQ ID NO:24, 6, 4, 20, 18 and 32, and SEQ ID NO:8, 30, 14, 12, 26 and 10; SEQ ID NO:8, 30, 14, 12, 26 and 10, and SEQ ID NO:9, 13, 31, 27, 15 and 11; SEQ ID NO:6, 20, 4, 24, 32 and 18, and SEQ ID NO:8, 12, 30, 26, 14 and 10; SEQ ID NO:7, 21, 5, 25, 33 and 19 and SEQ ID NO:9, 13, 31, 27, 15 and 11; NO:20, 32, 24, 4, 6 and 18, and SEQ ID NO:26, 30, 12, 14, 8 and 10; SEQ ID NO:7, 25, 19, 5, 33 and 21, and SEQ ID NO:15, 31, 9, 27, 13 and 11; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 20, 10 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:26, 10, 20 and 28; SEQ ID NO:24, 6, 16 and 18, and SEQ ID NO:7, 25, 17 and 19; SEQ ID NO:7, 19, 17 and 25, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:24, 16, 6 and 18, and SEQ ID NO:27, 11, 21 and 29; SEQ ID NO: NO:7, 25, 17 and 19, and SEQ ID NO:11, 27, 21 and 29; SEQ ID NO:7, 25, 17 and 19, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 20 and 28, and SEQ ID NO:23, 7, 21 and 29; SEQ ID NO:22, 20, 6 and 28, and SEQ ID NO:7, 21, 23 and 29; SEQ ID NO:26, 10, 20 and 28, and SEQ ID NO:21, 27, 11 and 29; SEQ ID NO:22, 6, 16, 20, 18, 28, 26 and 10; or SEQ ID NO:7, 21, 19, 17, 27, 25, 29 and 11. In some embodiments, the method entails administering one or more fusion polypeptides comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the method entails administering one or more fusion polypeptides comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223. In some embodiments, the method entails administering the following first and second fusion polypeptides, one or more polynucleotides, one or more vectors comprising one or more polynucleotides, or one or more liposome complexes (e.g., LNPs), the one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively. 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively. 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:76 and 77; a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:78 and 79, respectively; a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:80 and 81, respectively. 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively. 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively. 88 and 89; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively. 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively. 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively. 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89; a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively. 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 94 and 96; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or a fusion polypeptide of SEQ ID NOs:100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101. In some embodiments, the method entails administering the following first and second fusion polypeptides, one or more vectors or one or more liposome complexes (e.g., LNPs) comprising one or more polynucleotides encoding the following first and second fusion polypeptides bound or linked, in order from N-terminus to C-terminus and optionally via one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; 71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 71 and 70; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 72 and 73, respectively; a fusion polypeptide of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 73 and 72; a fusion polypeptide of SEQ ID NOs: 74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 74 and 75, respectively; a fusion polypeptide of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 77 and 76; a fusion polypeptide of SEQ ID NOs: 78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; a fusion polypeptide of SEQ ID NOs: 79 and 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively; 80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80; a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 83, respectively. 83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:8 85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively. 87 and 86; a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:87 and 86; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:88 and 89, respectively; 89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 88; a fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; a fusion polypeptide of SEQ ID NOs: 85 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 82; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; 86 and 82; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; 88 and 82; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 85; a fusion polypeptide of SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively; a fusion polypeptide of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88; a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively; 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 89 and 85; a fusion polypeptide of SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85; a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; 91 and 90; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; 93 and 92; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively. 95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 96; a fusion polypeptide of SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; a fusion polypeptide of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 97 and 95; a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively; a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively. 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99; a fusion polypeptide of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 98; a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or a fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:101 and 100. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:86 and 87, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 84 and 85, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 88 and 89, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 87, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively. NO:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:88 and 87, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 89, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively. 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:99 and 101, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 101, respectively. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 200 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 201 or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO:202 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:202, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO:203 or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:203. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO:204 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:204, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO:205 or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:205. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 105 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 107 or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 107. NO:107 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO:206 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:206, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO:207 or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:207. NO:207 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO:208 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:208, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO:209 or SEQ ID NO:227, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:209 or SEQ ID NO:227. IDNO: 227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO:222 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:222, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO:209 or SEQ ID NO:227, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:209 or SEQ ID NO:227. IDNO: 227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO:222 and being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:222, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO:223 or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:223. NO: 223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the method requires the administration of a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NO: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 90 and 91, respectively. In some embodiments, the method entails administering a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide of SEQ ID NOs: 92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively. In various embodiments, the first and second viral vectors are lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vectors, Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vectors, or adenovirus vectors, such as chimpanzee adenovirus vectors (ChAd). In some embodiments, the first and second viral vectors or the first and second liposome complexes (e.g., LNPs) are co-administered in parallel. In some embodiments, the method requires administration of the following first and second polynucleotides, or one or more vectors or one or more liposome complexes (e.g., LNPs) comprising the following first and second polynucleotides: polynucleotides of SEQ ID NOs: 130 and 132, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively; polynucleotides of SEQ ID NOs: 130 and 134, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134; a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively; a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135; a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively; a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135; polynucleotides of SEQ ID NOs: 133 and 137, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively; polynucleotides of SEQ ID NOs: 134 and 136, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136; a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively; a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 142, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 138 and 141; a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively; a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 143, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 142; polynucleotides of SEQ ID NOs: 139 and 145, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; polynucleotides of SEQ ID NOs: 140 and 146, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively; a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149; a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively; a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152; polynucleotides of SEQ ID NOs: 150 and 155, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively; polynucleotides of SEQ ID NOs: 151 and 153, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153; a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively; a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, ... 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157; a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively; a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159; a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively; a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively; a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167; the polynucleotides of SEQ ID NOs: 210 and 211, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively; the polynucleotides of SEQ ID NOs: 212 and 213, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively; a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively. 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217; polynucleotides of SEQ ID NOs: 218 and 219, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively; polynucleotides of SEQ ID NOs: 218 and 226, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 229, respectively; or a polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively. In some embodiments, the method entails administering a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: Any of NO:143 and 149 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides, wherein the first and second viral vectors are lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vectors. In some embodiments, the method entails administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing the following first and second polynucleotides: (a) a first vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively, and (b) a second vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: Any of NOs: 155 and 158 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides, wherein the first and second viral vectors are Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vectors. In some embodiments, the method requires administering a composite fusion polypeptide, a vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding the composite fusion polypeptide, which composite fusion polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227. In some embodiments, the method requires administering a composite fusion polypeptide, a vector or a liposome complex (e.g., LNP) comprising a polynucleotide encoding the composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 209, 222, and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 209, 222, and 223. In some embodiments, the method entails administering a polynucleotide (e.g., in a vector, in a liposome complex (e.g., LNP)) comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the method entails administering a polynucleotide (e.g., in a vector, in a liposome complex (e.g., LNP)) comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence of any one of SEQ ID NOs: any one of NO:139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225 and 226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical nucleic acid sequence. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 210, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 211. any one of NO:211 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 212, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 213. any one of NO:213 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 215. Any of NO:215 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the polynucleotide. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 216, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 217. any one of NO:217 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 219. NO:219 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 225, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the one or more fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol321-366, Pol 432-541, Pol 607-682, Pol 709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116, and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol, and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively. In some embodiments, the one or more fusion polypeptides do not comprise any polypeptide fragment having the following amino acid sequence: an amino acid sequence of SEQ ID NO: 35-47 or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 35-47 or a fragment or subsequence thereof. In some embodiments, the subject is infected with HIV-1 virus, suspected of being infected with HIV-1 virus, or at risk of being infected with HIV-1 virus. In some embodiments, the subject is chronically infected with HIV-1. In some embodiments, the subject is acutely infected with HIV-1. In some embodiments, the subject suffers from HIV-1 infection at Fiebig stage IV or earlier, such as Fiebig stage III, Fiebig stage II or Fiebig stage I. In some embodiments, the fusion polypeptide, composite fusion polypeptide, polynucleotide, vector, liposome complex (e.g., LNP) or immunogenic composition is administered via a route selected from: intravenous, intramuscular, intradermal, subcutaneous, intranodal and mucosal (e.g., buccal, intranasal, rectal, vaginal). In some embodiments, the method requires about 10 3 to about 10 12 Virus focus forming units (FFU) or plaque forming units (PFU) or infectious units (IU) or virus particles (vp), for example about 10 4 to about 10 7 Virus FFU or PFU or IU or vp, for example about 10 3 to about 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 or 10 15 In some embodiments, the method includes a primary immunization-boosting scheme, which includes applying a primary immunization composition at a first time point and applying one or more boosting compositions at one or more subsequent time points. In some embodiments, the method includes repeating the primary immunization-boosting scheme once or multiple iterations. In some embodiments, the primary immunization composition and the one or more boosting compositions are administered at intervals of at least 1 week, 2 weeks, 3 weeks or 1 month, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In some embodiments, the primary immunization composition and the boosting composition comprise the same immunogenic composition. In some embodiments, the primary immunization composition and the boosting composition comprise different immunogenic compositions. In some embodiments, the primary immunization composition and the boosting composition comprise the same one or more fusion polypeptides and the same viral expression vector. In some embodiments, the primary immunization composition and the boosting composition comprise different fusion polypeptides and/or different viral expression vectors. In some embodiments, these methods include primary immunization with a first viral expression vector and boosting with a second viral expression vector. In some embodiments, the prime-boost regimen comprises: (a) priming with one or more viral expression vectors and boosting with one or more polynucleotides, wherein the one or more polynucleotides comprise DNA, cDNA, mRNA, or self-replicating RNA; (b) priming with one or more polynucleotides, wherein the one or more polynucleotides comprise DNA, cDNA, mRNA, or self-replicating RNA, and boosting with one or more viral expression vectors; (c) priming with one or more viral expression vectors and boosting with one or more viral expression vectors, wherein the one or more viral expression vectors in the priming composition and the one or more viral expression vectors in the boosting composition are from the same, related, or unrelated taxonomic families; (d) priming with one or more replication-defective viral expression vectors and boosting with one or more replication-defective viral expression vectors, wherein the one or more replication-defective viral expression vectors in the priming composition and the one or more replication-defective viral expression vectors in the boosting composition are from the same, related, or unrelated taxonomic families. unrelated taxonomic families; (e) priming with one or more replication-attenuated viral expression vectors and boosting with one or more replication-attenuated viral expression vectors, wherein the one or more replication-attenuated viral expression vectors in the priming composition and the one or more replication-attenuated viral expression vectors in the boosting composition are from the same, related or unrelated taxonomic families; (f) priming with one or more replication-defective viral expression vectors and boosting with one or more replication-attenuated viral expression vectors; (g) priming with one or more replication-attenuated viral expression vectors and boosting with one or more replication-defective viral expression vectors; (h) priming with one or more lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral expression vectors and boosting with one or more picinder mammalian arenavirus viral expression vectors; (i) priming with one or more picinder mammalian arenavirus viral expression vectors and boosting with one or more lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral expression vectors (j) priming with one or more replication-defective mammalian arenavirus viral expression vectors and boosting with one or more replication-defective mammalian lymphocytic choriomeningitis arenavirus (LCMV) viral expression vectors; (k) priming with one or more replication-defective mammalian lymphocytic choriomeningitis arenavirus (LCMV) viral expression vectors and boosting with one or more replication-defective mammalian arenavirus viral expression vectors; (l) priming with one or more arenavirus viral expression vectors and boosting with one or more adenovirus viral expression vectors; (m) priming with one or more adenovirus viral expression vectors and boosting with a boosting composition comprising one or more arenavirus viral expression vectors; (n) priming with one or more adenovirus viral expression vectors and boosting with a boosting composition comprising one or more RNA molecules (e.g., mRNA, self-amplifying or self-replicating RNA); (o) priming with one or more RNA molecules (e.g., mRNA, self-amplifying or self-replicating RNA ) and boosted with a boosting composition comprising one or more adenovirus expression vectors; (p) primed with one or more chimpanzee adenovirus (ChAd) expression vectors and boosted with a boosting composition comprising one or more self-amplifying or self-replicating RNAs (saRNA or samRNA); (q) primed with one or more self-amplifying or self-replicating RNAs (saRNA or samRNA) and boosted with a boosting composition comprising one or more chimpanzee adenovirus (ChAd) expression vectors; (r) primed with one or more poxvirus expression vectors and boosted with one or more arenavirus expression vectors; (s) primed with one or more arenavirus expression vectors and boosted with a boosting composition comprising one or more poxvirus expression vectors; (t) primed with one or more poxvirus expression vectors and boosted with one or more adenovirus expression vectors; or (u) primed with one or more adenovirus expression vectors and boosted with a boosting composition comprising one or more poxvirus expression vectors. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising the following first and second fusion polypeptides, one or more vectors comprising one or more polynucleotides or one or more liposome complexes (e.g., LNPs), wherein the one or more polynucleotides encode the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 70 and 71, respectively; a fusion polypeptide of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively. 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:76 and 77; a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:78 and 79, respectively; a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:80 and 81, respectively. 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively; a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively. 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85; a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively. 88 and 89; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively. 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively. 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively. 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively; 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89; a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively; a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91; a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively; a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively. 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively; 94 and 96; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221; a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; a fusion polypeptide of SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or a fusion polypeptide of SEQ ID NOs:100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:100 and 101, respectively. NO: 100 and 101 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 100 and 101; and (2) boosted with an immunogenic composition comprising a first fusion polypeptide and a second fusion polypeptide, one or more vectors or one or more liposome complexes (e.g., LNPs) comprising one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked by one or more linkers: SEQ ID NO: 70 and 71, or SEQ ID NO: 72, or SEQ ID NO: 73, or SEQ ID NO: 74, or SEQ ID NO: 75, or SEQ ID NO: 76, or SEQ ID NO: 77, or SEQ ID NO: 78, or SEQ ID NO: 79, or SEQ ID NO: 80, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 100 and 101, or 70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively. 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 74 and 75; a fusion polypeptide of SEQ ID NOs: 76 and 77, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 76 and 77, respectively; a fusion polypeptide of SEQ ID NOs: 78 and 79, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 78 and 79, respectively. 80 and 81, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 80 and 81, respectively; a fusion polypeptide of SEQ ID NOs: 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively. 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively. 86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87; a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively; a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively. 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85; a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively; a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively. 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88; a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively; a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively. 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87; a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively; a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively. 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88; a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively; a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively. 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101; a fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; a fusion polypeptide of SEQ ID NOs: 92 and 93, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively. 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97; a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively; a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively. 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100; a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively; a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively; or a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising the following first and second fusion polypeptides, one or more vectors comprising one or more polynucleotides, one or more liposome complexes (e.g., LNPs), wherein the one or more polynucleotides encode the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a fusion polypeptide of SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; (b) a fusion polypeptide of SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97; (c) a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively; (d) a fusion polypeptide of SEQ ID NOs:220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: NO: 220 and 221 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 220 and 221; and/or (e) a fusion polypeptide of SEQ ID NO: 95 and 97, or a fusion polypeptide of SEQ ID NO: 97, or a fusion polypeptide of SEQ ID NO: 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, NO:95 and 97 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:95 and 97; and (2) boosted with an immunogenic composition comprising the first fusion polypeptide and the second fusion polypeptide, one or more vectors or one or more liposome complexes (e.g., LNPs) comprising one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a fusion polypeptide of SEQ ID NO:98 and 99, or a fusion polypeptide of SEQ ID NO:99, or a fusion polypeptide of SEQ ID NO:91, or a fusion polypeptide of SEQ ID NO:92, or a fusion polypeptide of SEQ ID NO:93, or a fusion polypeptide of SEQ ID NO:94, or a fusion polypeptide of SEQ ID NO:95 and 97, respectively. 98 and 99; (b) a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; (c) a fusion polypeptide of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NOS:98 and 100; and/or (d) a fusion polypeptide of SEQ ID NOS:99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOS:99 and 101, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively, or one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: NO: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 220 and 221, respectively; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: comprising a fusion polypeptide of SEQ ID NO: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 220 and 221, respectively; NO:95 and 97 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NOs:98 and 100, or a fusion polypeptide with SEQ ID NOs: 101 and 102, respectively; NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:99 and 101, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 82 and 85, or a fusion polypeptide comprising SEQ ID NO: 83 and 84, respectively; NO:82 and 85 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 85; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO:87 and 88, or a fusion polypeptide with SEQ ID NO:89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:89, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:81 and 90, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:87 and 88. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively. NO: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 87 and 88, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 87 and 88, respectively. NO:82 and 88 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 88; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO:85 and 87, or a fusion polypeptide with SEQ ID NO:87, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:85 and 87. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, comprising a fusion polypeptide of SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, comprising SEQ ID NOs: 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively. NO:94 and 95 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:94 and 95; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO:96 and 97, or a fusion polypeptide with SEQ ID NO:97, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:96 and 97. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively. NO:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively.
在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ IDNO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:105的复合融合多肽,或分别与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:109的复合融合多肽,或与SEQ ID NO:109至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:105或206的复合融合多肽,或分别与SEQ ID NO:105或206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:107或207的复合融合多肽,或与SEQ IDNO:107或207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:105的融合多肽,或分别与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:107的融合多肽,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:206的融合多肽,或分别与SEQ ID NO:206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:207的融合多肽,或与SEQ ID NO:207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ IDNO:208的复合融合多肽,或分别与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:SEQ ID NO:209或SEQ ID NO:227的复合融合多肽,或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQID NO:222的复合融合多肽,或分别与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:SEQ ID NO:209或SEQ ID NO:227的复合融合多肽,或与SEQ ID NO:209或SEQ IDNO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:222的复合融合多肽,或分别与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:223的复合融合多肽,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:208的融合多肽,或分别与SEQID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:209或SEQ ID NO:227的融合多肽,或分别与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:222的融合多肽,或分别与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:209或SEQ ID NO:227的融合多肽,或分别与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:222的融合多肽,或分别与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:223的融合多肽,或与SEQID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:107的复合融合多肽,或分别与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:111的复合融合多肽,或与SEQ ID NO:111至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:200的复合融合多肽,或分别与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:201的复合融合多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:200的融合多肽,或与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:201的融合多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ IDNO:202的复合融合多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:203的复合融合多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:202的融合多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:203的融合多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ IDNO:204的复合融合多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:205的复合融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:204的融合多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:205的融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:86和87的融合多肽,或分别与SEQ IDNO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ IDNO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及(2)用包含病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:133和137,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ IDNO:139和145,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:143和149,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:150和152,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:154和157或SEQ ID NO:155和158,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ IDNO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:154和157或SEQ ID NO:155和158,或分别与SEQ ID NO:154和157或SEQ IDNO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQID NO:140和146,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:143和149,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:155和158,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:151和153,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:156和159,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免-加强方案包括:(1)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:155和158,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及(2)用包含第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)的免疫原性组合物加强,该第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP)包含以下多核苷酸:(a)第一病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:139和145,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和(b)第二病毒载体或脂质体复合物(例如,LNP),其包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免-加强方案包括:(1)用包含第一病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一和第二多核苷酸:包含SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及(2)用包含第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该第二病毒载体或脂质体复合物(例如,LNP)包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:162和163,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免-加强方案包括:(1)用包含第一病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一和第二多核苷酸:包含SEQ ID NO:164和165的多核苷酸,或分别与SEQ IDNO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及(2)用包含第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物加强,该第二病毒载体或脂质体复合物(例如,LNP)包含第一和第二多核苷酸,该第一和第二多核苷酸包含SEQ ID NO:166和167,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,初免组合物中的病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体,并且加强组合物中的病毒载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体。在各种实施方案中,初免组合物中的病毒载体是卡利哺乳动物沙粒病毒病毒载体(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒),并且加强组合物中的病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ IDNO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:213的多核苷酸,或与SEQ IDNO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含以下第一多核苷酸:包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体或脂质体复合物(例如,LNP)包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,初免组合物中的病毒载体和加强组合物中的病毒载体是腺病毒载体,例如黑猩猩腺病毒载体(ChAd)。在一些实施方案中,初免组合物中的病毒载体和加强组合物中的病毒载体是复制缺陷型的。在一些实施方案中,初免组合物中的病毒载体和加强组合物中的病毒载体是复制减毒型的。在一些实施方案中,受试者未接受抗逆转录病毒治疗(ART),或者在施用一种或多种组合物之前中断ART。在一些实施方案中,在一次或多次施用组合物之后中断ART。在一些实施方案中,这些方法需要向受试者施用一种或多种附加治疗剂,例如两种、三种、四种或更多种附加治疗剂。在一些实施方案中,这些方法需要共同施用一种或多种活化潜伏性HIV的药剂,例如一种或多种潜伏期逆转剂(LRA)。在一些实施方案中,一种或多种LRA选自:一种或多种toll样受体(TLR)的激动剂或活化剂、组蛋白脱乙酰酶(HDAC)抑制剂、蛋白酶体抑制剂、蛋白激酶C(PKC)活化剂、Smyd2抑制剂、BET-溴结构域4(BRD4)抑制剂、离子霉素、凋亡蛋白抑制剂(IAP)拮抗剂以及胱天蛋白酶(SMAC)第二线粒体衍生的活化剂模拟物。在一些实施方案中,这些方法需要共同施用一种或多种Toll样受体(TLR)的一种或多种激动剂或活化剂。在一些实施方案中,TLR激动剂或活化剂选自TLR2激动剂、TLR3激动剂、TLR4激动剂、TLR5激动剂、TLR7激动剂、TLR8激动剂和TLR9激动剂。在一些实施方案中,TLR7激动剂选自GS 9620(维沙莫特)、R848(瑞喹莫德)、DS-0509、LHC-165和TMX-101(咪喹莫特),并且/或者其中TLR8激动剂选自GS-9688(赛尔甘托莫德)、R848(瑞喹莫德)和NKTR-262(双TLR7/TLR8激动剂)。在一些实施方案中,这些方法需要共同施用选自IL-2、IL-7、IL-12和IL-15的白介素的一种或多种白介素受体激动剂。在一些实施方案中,这些方法需要共同施用选自IL-2、IL-7、IL-12、IL-15以及它们的变体的一种或多种细胞因子。在一些实施方案中,这些方法需要共同施用一种或多种先天免疫活化剂。在一些实施方案中,该一种或多种先天免疫活化剂包括选自以下的受体的激动剂:fms相关酪氨酸激酶3(FLT3)、干扰素基因刺激剂(STING)受体、DExD/H盒解旋酶58(DDX58;又名RIG-I)、含核苷酸结合寡聚化结构域蛋白2(NOD2)。在一些实施方案中,方法需要共同施用fms相关酪氨酸激酶3(FLT3)的激动剂。在一些实施方案中,该方法需要共同施用抑制性免疫检查点蛋白或受体的一种或多种拮抗剂或抑制剂和/或刺激性免疫检查点蛋白或受体的一种或多种活化剂或激动剂。在一些实施方案中,一种或多种免疫检查点蛋白或受体选自:CD27、CD70;CD40、CD40LG;CD47、CD48(SLAMF2)、含跨膜和免疫球蛋白结构域蛋白2(TMIGD2、CD28H)、CD84(LY9B、SLAMF5)、CD96、CD160、MS4A1(CD20)、CD244(SLAMF4);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);自然杀伤细胞细胞毒性受体3配体1(NCR3LG1、B7H6);HERV-H LTR相关2(HHLA2、B7H7);诱导型T细胞共刺激因子(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF8(CD30)、TNFSF8(CD30L);TNFRSF10A(CD261、DR4、TRAILR1)、TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF10B(CD262、DR5、TRAILR2)、TNFRSF10(TRAIL);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));TNFRSF17(BCMA、CD269)、TNFSF13B(BAFF);TNFRSF18(GITR)、TNFSF18(GITRL);MHC I类多肽相关序列A(MICA);MHC I类多肽相关序列B(MICB);CD274(CD274、PDL1、PD-L1);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155);含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);含T细胞免疫球蛋白和粘蛋白结构域蛋白4(TIMD4;TIM4;甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);淋巴细胞活化3(LAG3、CD223);信号转导淋巴细胞活化分子家族成员1(SLAMF1、SLAM、CD150);淋巴细胞抗原9(LY9、CD229、SLAMF3);SLAM家族成员6(SLAMF6、CD352);SLAM家族成员7(SLAMF7、CD319);UL16结合蛋白1(ULBP1);UL16结合蛋白2(ULBP2);UL16结合蛋白3(ULBP3);视黄酸早期转录物1E(RAET1E;ULBP4);视黄酸早期转录物1G(RAET1G;ULBP5);视黄酸早期转录物1L(RAET1L;ULBP6);淋巴细胞活化3(CD223);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);杀伤细胞凝集素样受体C2(KLRC2、CD159c、NKG2C);杀伤细胞凝集素样受体C3(KLRC3、NKG2E);杀伤细胞凝集素样受体C4(KLRC4、NKG2F);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体D1(KLRD1);以及SLAM家族成员7(SLAMF7)。在一些实施方案中,该方法需要共同施用一种或多种T细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂。在一些实施方案中,T细胞抑制性免疫检查点蛋白或受体选自:CD274(CD274、PDL1、PD-L1);程序性细胞死亡1配体2(PDCD1LG2、PD-L2、CD273);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);淋巴细胞活化3(LAG3、CD223);甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);以及杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1)。在一些实施方案中,该方法需要共同施用一种或多种T细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂。在一些实施方案中,T细胞刺激性免疫检查点蛋白或受体选自:CD27、CD70、CD40、CD40LG;诱导型T细胞共刺激物(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF18(GITR)、TNFSF18(GITRL);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155)。在一些实施方案中,该方法需要共同施用一种或多种NK细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂。在一些实施方案中,NK细胞抑制性免疫检查点蛋白或受体选自:杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A);和杀伤细胞凝集素样受体D1(KLRD1、CD94)。在一些实施方案中,该方法需要共同施用一种或多种NK细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂。在一些实施方案中,NK细胞刺激性免疫检查点蛋白或受体选自CD16、CD226(DNAM-1);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);以及SLAM家族成员7(SLAMF7)。在一些实施方案中,一种或多种免疫检查点抑制剂包括PD-L1(CD274)、PD-1(PDCD1)或CTLA4的蛋白质抑制剂。在一些实施方案中,这些方法需要共同施用结合CTLA4的抗体。在一些实施方案中,CTLA4的蛋白质或抗体抑制剂选自:伊匹单抗、曲美木单抗、BMS-986218、AGEN1181、AGEN1884、BMS-986249、MK-1308、REGN-4659、ADU-1604、CS-1002、BCD-145、APL-509、JS-007、BA-3071、ONC-392、AGEN-2041、JHL-1155、KN-044、CG-0161、ATOR-1144、PBI-5D3H5、FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、XmAb-20717(PD-1/CTLA4)和AK-104(CTLA4/PD-1)。在一些实施方案中,PD-L1(CD274)或PD-1(PDCD1)的蛋白质抑制剂选自:派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、西米单抗(cemiplimab)、匹地利珠单抗(pidilizumab)、AMP-224、MEDI0680(AMP-514)、斯巴达珠单抗(spartalizumab)、阿替利珠单抗(atezolizumab)、阿维鲁单抗(avelumab)、度伐利尤单抗(durvalumab)、BMS-936559、CK-301、PF-06801591、BGB-A317(替雷利珠单抗(tislelizumab))、GLS-010(WBP-3055)、AK-103(HX-008)、AK-105、CS-1003、HLX-10、MGA-012、BI-754091、AGEN-2034、JS-001(特瑞普利单抗(toripalimab))、JNJ-63723283、杰诺单抗(genolimzumab)(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、SHR-1210(卡瑞利珠单抗(camrelizumab))、Sym-021、ABBV-181、PD1-PIK、BAT-1306(MSB0010718C)、CX-072、CBT-502、TSR-042(多塔利单抗(dostarlimab))、MSB-2311、JTX-4014、BGB-A333、SHR-1316、CS-1001(WBP-3155、KN-035、IBI-308(信迪利单抗(sintilimab))、HLX-20、KL-A167、STI-A1014、STI-A1015(IMC-001)、BCD-135、FAZ-053、TQB-2450、MDX1105-01、FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-013(PD-1/LAG-3)、FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、RO-7121661(PD-1/TIM-3)、XmAb-20717(PD-1/CTLA4)、AK-104(CTLA4/PD-1)、M7824(PD-L1/TGFβ-EC结构域)、CA-170(PD-L1/VISTA)、CDX-527(CD27/PD-L1)、LY-3415244(TIM3/PDL1)和INBRX-105(4-1BB/PDL1)。在一些实施方案中,一种或多种免疫检查点抑制剂包含CD274(PDL1、PD-L1)、程序性细胞死亡1(PDCD1、PD1、PD-1)或CTLA4的小分子抑制剂。在一些实施方案中,CD274或PDCD1的小分子抑制剂选自GS-4224、GS-4416、INCB086550和MAX10181。在一些实施方案中,CTLA4的小分子抑制剂包括BPI-002。在一些实施方案中,该方法还包括向受试者施用一种或多种抗病毒剂。在一些实施方案中,该一种或多种抗病毒剂选自:HIV蛋白酶抑制剂、HIV逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或变构)整合酶抑制剂、HIV进入(融合)抑制剂、HIV成熟抑制剂和衣壳抑制剂。在一些实施方案中,这些方法还包括向受试者施用一种或多种抗HIV抗体或其抗原结合片段。在一些实施方案中,该一种或多种抗HIV抗体或其抗原结合片段与HIV gp120结合。在一些实施方案中,抗HIV抗体或其抗原结合片段包括广谱中和抗体。在一些实施方案中,结合、抑制和/或中和HIV的一种或多种抗HIV抗体或其抗原结合片段与抗HIV的广谱中和抗体(bNAb)的VH和VL可变结构域竞争或者包含这些可变结构域。在一些实施方案中,结合、抑制和/或中和HIV的一种或多种抗HIV抗体或其抗原结合片段与选自以下的gp120的表位或区域结合:(i)第三可变环(V3)和/或包含N332寡甘露糖聚糖的高甘露糖补丁;(ii)CD4结合位点(CD4bs);(iii)第二可变环(V2)和/或Env三聚体顶点;(iv)gp120/gp41交界面;或者(v)gp120的沉默面。在一些实施方案中,结合、抑制和/或中和HIV的抗体或其抗原结合片段与第三可变环(V3)和/或包含N332寡甘露糖聚糖的高甘露糖补丁中的gp120的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:GS-9722、PGT-121、PGT-121.414、PGT-122、PGT-123、PGT-124、PGT-125、PGT-126、PGT-128、PGT-130、PGT-133、PGT-134、PGT-135、PGT-136、PGT-137、PGT-138、PGT-139、10-1074、10-1074-J、GS-2872、VRC24、2G12、BG18、354BG8、354BG18、354BG42、354BG33、354BG129、354BG188、354BG411、354BG426、DH270.1、DH270.6、PGDM12、VRC41.01、PGDM21、PCDN-33A、BF520.1和VRC29.03。在一些实施方案中,该抗体或其抗原结合片段与CD4结合位点(CD4bs)中的gp120的表位或区域结合,并且与选自以下的抗体的VH区域和VL区域竞争或者包含这些区域:b12、F105、VRC01、VRC07、VRC07-523、VRC03、VRC06、VRC06b01VRC08、VRC0801、NIH45-46、GS-9723、GS-5423、3BNC117、3BNC60、VRC-PG04、PGV04;CH103、44-VRC13.01、1NC9、12A12、N6、N49-P7、NC-Cow1、IOMA、CH235和CH235.12、N49P6、N49P7、N49P11、N49P9和N60P25。在一些实施方案中,结合、抑制和/或中和HIV的抗体或其抗原结合片段与第二可变环(V2)和/或Env三聚体顶点中的gp120的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:PG9、PG16、PGC14、PGG14、PGT-142、PGT-143、PGT-144、PGT-145、CH01、CH59、PGDM1400、CAP256、CAP256-VRC26.08、CAP256-VRC26.09、CAP256-VRC26.25、PCT64-24E和VRC38.01。在一些实施方案中,该抗体或其抗原结合片段与gp120/gp41交界面中的gp120的表位或区域结合,并且与选自以下的抗体的VH区域和VL区域竞争或者包含这些区域:PGT-151、CAP248-2B、35O22、8ANC195、ACS202、VRC34和VRC34.01。在一些实施方案中,结合、抑制和/或中和HIV的抗体或其抗原结合片段与gp120沉默面的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:VRC-PG05和SF12。在一些实施方案中,结合、抑制和/或中和HIV的抗体或其抗原结合片段与膜近侧区域(MPER)中的gp41的表位或区域结合。在一些实施方案中,结合、抑制和/或中和HIV的抗体或其抗原结合片段与膜近侧区域(MPER)中的gp41的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:10E8、10E8v4、10E8-5R-100cF、4E10、DH511.11P、2F5、7b2和LN01。在一些实施方案中,结合、抑制和/或中和HIV的抗体或其抗原结合片段与gp41融合肽的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:VRC34和ACS202。在这些方法的一些实施方案中,在任选地与一种或多种附加治疗剂组合一次或多次施用一种或多种融合多肽、复合融合多肽、多核苷酸、载体、脂质体复合物(例如,LNP)或免疫原性组合物之后,受试者在没有抗逆转录病毒治疗(ART)的情况下至少3个月、至少6个月、至少1年、至少2年、至少3年或更长时间未表现出HIV或AIDS的症状。在这些方法的一些实施方案中,在任选地与一种或多种附加治疗剂组合一次或多次施用一种或多种融合多肽、复合融合多肽、多核苷酸、载体、脂质体复合物(例如,LNP)或免疫原性组合物之后,受试者在没有抗逆转录病毒治疗(ART)的情况下至少3个月、至少6个月、至少1年、至少2年、至少3年或更长时间具有小于500(例如小于400、小于300、小于200、小于100、小于50)的病毒载量拷贝/ml血液。 In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 94 and 96, or a fusion polypeptide comprising SEQ ID NO: 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 NO:94 and 96 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:94 and 96; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO:95 and 97, or a fusion polypeptide with SEQ ID NO:97, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide of SEQ ID NOs: 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275 NO: 220 and 221 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 220 and 221; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 95 and 97, or a fusion polypeptide with SEQ ID NO: 97, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:95 and 97. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: NO:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) and a second viral vector or liposome complex (e.g., LNP), the first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively. ID NO: 220 and 221 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of the above-mentioned fusion polypeptides; the second viral vector or liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 95 and 97, or a fusion polypeptide comprising SEQ ID NO: 97, or a fusion polypeptide comprising SEQ ID NO: 98, or a fusion polypeptide comprising SEQ ID NO: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide comprising SEQ ID NOs: 95 and 97, respectively. NO:94 and 95 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:94 and 95; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO:98 and 99, or a fusion polypeptide with SEQ ID NO:99, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NOs:98 and 99. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 109, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 109, respectively. NO:109 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105 or 206, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105 or 206, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105 or 206. NO:107 or 207, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:107 or 207. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 105, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 107, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 107, respectively. NO:107 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 206, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 207, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, respectively. NO:207 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 208, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 228, respectively. NO:209 or SEQ ID NO:227 that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 222, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively. NO:209 or SEQ ID NO:227 that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 222, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 223, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223, respectively. NO:223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 208, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209, respectively. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 222, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: 227, respectively. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 222, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 223, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223, respectively. NO:223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 96 and 97, or a fusion polypeptide comprising SEQ ID NO: 97, or a fusion polypeptide comprising SEQ ID NO: 98, or a fusion polypeptide comprising SEQ ID NO: 99, or a fusion polypeptide comprising SEQ ID NO: 100, or a fusion polypeptide comprising SEQ ID NO: 101, or a fusion polypeptide comprising SEQ ID NO: 102, or a fusion polypeptide comprising SEQ ID NO: 103, or a fusion polypeptide comprising SEQ ID NO: 104, or a fusion polypeptide comprising SEQ ID NO: 105, or a fusion polypeptide comprising SEQ ID NO: 106, or a fusion polypeptide comprising SEQ ID NO: 107, or a fusion polypeptide comprising SEQ ID NO: 108, or a fusion polypeptide comprising SEQ ID NO: 109, or a fusion polypeptide comprising SEQ ID NO: 110, or a fusion polypeptide comprising SEQ ID NO: 111, or a fusion polypeptide comprising SEQ ID NO: 112, or a fusion polypeptide comprising SEQ ID NO: 113, or a fusion polypeptide comprising SEQ ID NO: 114, or a fusion polypeptide comprising SEQ ID NO: 115, or a fusion polypeptide comprising SEQ ID NO: 116, or a fusion polypeptide comprising SEQ ID NO: 117, or a fusion polypeptide comprising SEQ ID NO: 118, or a fusion polypeptide comprising SEQ ID NO: 119 ... NO:96 and 97 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:96 and 97; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 100 and 101, or a fusion polypeptide with SEQ ID NO: 102, or a fusion polypeptide with SEQ ID NO: 103, or a fusion polypeptide with SEQ ID NO: 104, or a fusion polypeptide with SEQ ID NO: 105, or a fusion polypeptide with SEQ ID NO: 106, or a fusion polypeptide with SEQ ID NO: 107, or a fusion polypeptide with SEQ ID NO: 108, or a fusion polypeptide with SEQ ID NO: 110, or a fusion polypeptide with SEQ ID NO: 111, or a fusion polypeptide with SEQ ID NO: 112, or a fusion polypeptide with SEQ ID NO: 113, or a fusion polypeptide with SEQ ID NO: 114, or a fusion polypeptide with SEQ ID NO: 115, or a fusion polypeptide with SEQ ID NO: 116, or a fusion polypeptide with SEQ ID NO: 117, or a fusion polypeptide with SEQ ID NO: 118, or a fusion polypeptide with SEQ ID NO: 119, or a fusion polypeptide with SEQ ID NO: 121, or a fusion polypeptide with SEQ ID NO: 122, or a fusion polypeptide with SEQ ID NO: 123, or a fusion polypeptide with A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 107, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 107, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 111, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 111, respectively. NO:111 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 200, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200, respectively; and (2) boosting with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 201, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201, respectively. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 200, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 201, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 202, or a composite fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202; and (2) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 203, or a composite fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 202, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 203, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 204, or a composite fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204; and (2) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 205, or a composite fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 205. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the composite fusion polypeptide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 204, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 205, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 205. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NO:82 and 83, or a fusion polypeptide comprising SEQ ID NO:84, or a fusion polypeptide comprising SEQ ID NO:85, or a fusion polypeptide comprising SEQ ID NO:86, or a fusion polypeptide comprising SEQ ID NO:87, or a fusion polypeptide comprising SEQ ID NO:88, or a fusion polypeptide comprising SEQ ID NO:89, or a fusion polypeptide comprising SEQ ID NO:90, or a fusion polypeptide comprising SEQ ID NO:91, or a fusion polypeptide comprising SEQ ID NO:92, or a fusion polypeptide comprising SEQ ID NO:93, or a fusion polypeptide comprising SEQ ID NO:94, or a fusion polypeptide comprising SEQ ID NO:95, or a fusion polypeptide comprising SEQ ID NO:96, or a fusion polypeptide comprising SEQ ID NO:97, or a fusion polypeptide comprising SEQ ID NO:98, or a fusion polypeptide comprising SEQ ID NO:99, or a fusion polypeptide comprising SEQ ID NO:100, or a fusion polypeptide comprising SEQ ID NO:82 and 83 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 83; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:86 and 87, or a fusion polypeptide comprising SEQ ID NO:87, or a fusion polypeptide comprising SEQ ID NO:88, or a fusion polypeptide comprising SEQ ID NO:89, or a fusion polypeptide comprising SEQ ID NO:90, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:91, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 86 and 87 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 86 and 87; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NOs: 84 and 85, or a fusion polypeptide comprising SEQ ID NOs: 86 and 87 ... NO:84 and 85 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:84 and 85; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:88 and 89, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:88 and 89, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 82 and 86, or a fusion polypeptide comprising SEQ ID NO: 83 and 84, respectively; NO:82 and 86 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:82 and 86; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:83 and 87, or a fusion polypeptide comprising SEQ ID NO:84 or SEQ ID NO:85, or a fusion polypeptide comprising SEQ ID NO:86, or a fusion polypeptide comprising SEQ ID NO:87, or a fusion polypeptide comprising SEQ ID NO:88, or a fusion polypeptide comprising SEQ ID NO:89, or a fusion polypeptide comprising SEQ ID NO:90, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:91, NO:83 and 87 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs:84 and 88, or a fusion polypeptide comprising SEQ ID NOs:85 and 89, respectively; NO:84 and 88 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:84 and 88; and (b) a second viral vector comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 89, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 82 and 86, or a fusion polypeptide comprising SEQ ID NO: 83 and 84, respectively; NO:82 and 86 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:82 and 86; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:83 and 87, or a fusion polypeptide comprising SEQ ID NO:84 or SEQ ID NO:85, or a fusion polypeptide comprising SEQ ID NO:86, or a fusion polypeptide comprising SEQ ID NO:87, or a fusion polypeptide comprising SEQ ID NO:88, or a fusion polypeptide comprising SEQ ID NO:89, or a fusion polypeptide comprising SEQ ID NO:90, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:91, NO:83 and 87 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs:83 and 87; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NOs:98 and 100, or a fusion polypeptide with SEQ ID NOs:101 and 102, respectively; NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:99 and 101, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 82 and 86, or a fusion polypeptide comprising SEQ ID NO: 83 and 84, respectively; NO:82 and 86 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:82 and 86; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:83 and 87, or a fusion polypeptide comprising SEQ ID NO:84 or SEQ ID NO:85, or a fusion polypeptide comprising SEQ ID NO:86, or a fusion polypeptide comprising SEQ ID NO:87, or a fusion polypeptide comprising SEQ ID NO:88, or a fusion polypeptide comprising SEQ ID NO:89, or a fusion polypeptide comprising SEQ ID NO:90, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:91, NO:83 and 87 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of SEQ ID NOs:83 and 87; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NOs:98 and 100, or a fusion polypeptide with SEQ ID NOs:101 and 102, respectively; NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:98 and 100; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 101, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 98 and 100, or a fusion polypeptide with SEQ ID NO: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:99 and 101, or a fusion polypeptide comprising SEQ ID NO:91 or 102, respectively. 99 and 101 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide comprising SEQ ID NOs: 83 and 87, respectively; NO:82 and 86 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 86; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and the second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO: 98 and 100, or a fusion polypeptide with SEQ ID NO: 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, NO:98 and 100 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:98 and 100; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:85 and 101, or a fusion polypeptide comprising SEQ ID NO:87 and 102, respectively. NO: 85 and 101 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 101; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP), wherein the first and the second viral vector or the first and the second liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: (a) a first viral vector or a liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide comprising SEQ ID NOs: 83 and 87, respectively; NO:82 and 86 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:82 and 86; and (b) a second viral vector or liposome complex (e.g., LNP) comprising: one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: a fusion polypeptide comprising SEQ ID NO:83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:83 and 87, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked via one or more linkers: fusion polypeptides of SEQ ID NOs: 90 and 91, or fusion polypeptides of SEQ ID NOs: 91 and 92, respectively; NO:90 and 91 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:90 and 91; and (2) boosted with an immunogenic composition comprising a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding the following first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: SEQ ID NO:92 and 93, or SEQ ID NO:94, or SEQ ID NO:95, or SEQ ID NO:96, or SEQ ID NO:97, or SEQ ID NO:98, or SEQ ID NO:99, or SEQ ID NO:100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:92 and 93. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; and (b) a second viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 133 and 137, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: any of SEQ ID NOs: 133 and 137 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (2) boosted with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NOs: 139 and 145, or a polynucleotide identical to SEQ ID NOs: 139 and 145, respectively. any one of SEQ ID NOs: 139 and 145 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 142 and 148, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; and (b) a second viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 143 and 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: any of NOs: 143 and 149 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (2) boosted with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NOs: 150 and 152, or SEQ ID NOs: 151 and 152, respectively. any of SEQ ID NOs: 150 and 152 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or the same as SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, respectively. Any of NOs: 155 and 158 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and (b) a second viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 158 and 159. NO: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 154 and 157 or SEQ ID NO: 155 and 158, respectively; and (2) boosting with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NO: 140 and 146, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 154 and 157 or SEQ ID NO: 155 and 158, respectively; any one of SEQ ID NOs: 140 and 146 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 143 and 149, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and (b) a second viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: any of NOs: 155 and 158 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (2) boosted with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NOs: 151 and 153, or SEQ ID NOs: 154 and 155, respectively. any one of SEQ ID NOs: 151 and 153 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 156 and 159, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and (b) a second viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: any of NOs: 155 and 158 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (2) boosted with an immunogenic composition comprising a first and a second viral vector or a first and a second liposome complex (e.g., LNP) comprising the following polynucleotides: (a) a first viral vector or a liposome complex (e.g., LNP) comprising a first and a second polynucleotide, the first and the second polynucleotide comprising SEQ ID NOs: 139 and 145, or a polynucleotide identical to SEQ ID NOs: 139 and 145, respectively. any one of SEQ ID NOs: 139 and 145 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and (b) a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 142 and 148, or being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising a polynucleotide comprising SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively; and (2) boosting with an immunogenic composition comprising a second viral vector or liposome complex (e.g., LNP) comprising a first and a second polynucleotide comprising SEQ ID NOs: 162 and 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively. Any of NO:162 and 163 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the prime-boost regimen comprises: (1) priming with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively; and (2) boosting with an immunogenic composition comprising a second viral vector or liposome complex (e.g., LNP) comprising a first and second polynucleotide comprising SEQ ID NOs: 166 and 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively. Any of NO: 166 and 167 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some embodiments, the viral vector in the priming composition is a lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vector, and the viral vector in the boosting composition is a Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vector. In various embodiments, the viral vector in the priming composition is a Cali mammalian arenavirus viral vector (also known as Pichinde mammalian arenavirus or Pichinde arenavirus), and the viral vector in the boosting composition is a lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vector. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 210; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 211. NO:211 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 212; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214. ID NO: 213 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotide. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 215. NO:215 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 216; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 217. NO:217 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 219. NO:219 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 227. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides. In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 225; and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 227. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides. In some embodiments, the viral vector in the initial immunization composition and the viral vector in the booster composition are adenoviral vectors, such as chimpanzee adenovirus vectors (ChAd). In some embodiments, the viral vector in the initial immunization composition and the viral vector in the booster composition are replication-deficient. In some embodiments, the viral vector in the initial immunization composition and the viral vector in the booster composition are replication-attenuated. In some embodiments, the subject has not received antiretroviral therapy (ART), or ART is interrupted before administering one or more compositions. In some embodiments, ART is interrupted after one or more administrations of the composition. In some embodiments, these methods require administration of one or more additional therapeutic agents, such as two, three, four or more additional therapeutic agents, to the subject. In some embodiments, these methods require co-administration of one or more agents that activate latent HIV, such as one or more latency reversal agents (LRAs). In some embodiments, one or more LRAs are selected from: agonists or activators of one or more toll-like receptors (TLRs), histone deacetylase (HDAC) inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, inhibitor of apoptosis protein (IAP) antagonists, and activator mimics of the second mitochondria derived from caspase (SMAC). In some embodiments, these methods require co-administration of one or more agonists or activators of one or more Toll-like receptors (TLRs). In some embodiments, TLR agonists or activators are selected from TLR2 agonists, TLR3 agonists, TLR4 agonists, TLR5 agonists, TLR7 agonists, TLR8 agonists, and TLR9 agonists. In some embodiments, the TLR7 agonist is selected from GS 9620 (visamod), R848 (resiquimod), DS-0509, LHC-165 and TMX-101 (imiquimod), and/or wherein the TLR8 agonist is selected from GS-9688 (sergantomod), R848 (resiquimod) and NKTR-262 (dual TLR7/TLR8 agonist). In some embodiments, these methods require co-administration of one or more interleukin receptor agonists selected from interleukins selected from IL-2, IL-7, IL-12 and IL-15. In some embodiments, these methods require co-administration of one or more cytokines selected from IL-2, IL-7, IL-12, IL-15 and variants thereof. In some embodiments, these methods require co-administration of one or more innate immune activators. In some embodiments, the one or more innate immune activators include agonists of receptors selected from the following: fms-associated tyrosine kinase 3 (FLT3), interferon gene stimulator (STING) receptor, DExD/H box helicase 58 (DDX58; also known as RIG-I), nucleotide binding oligomerization domain protein 2 (NOD2). In some embodiments, the method requires co-administration of an agonist of fms-associated tyrosine kinase 3 (FLT3). In some embodiments, the method requires co-administration of one or more antagonists or inhibitors of inhibitory immune checkpoint proteins or receptors and/or one or more activators or agonists of stimulatory immune checkpoint proteins or receptors. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137 ), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC Class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing protein (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT ); T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4; TIM4; hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signal transducer lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2 ); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, N KG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7). In some embodiments, the method requires co-administration of one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the T cell inhibitory immune checkpoint protein or receptor is selected from: CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated Immunoglobulin domain proteins (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the method requires co-administration of one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the T cell stimulatory immune checkpoint proteins or receptors are selected from: CD27, CD70, CD40, CD40LG; inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the method requires co-administration of one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the NK cell inhibitory immune checkpoint proteins or receptors are selected from: killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In some embodiments, the method requires co-administration of one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. In some embodiments, NK cell stimulatory immune checkpoint proteins or receptors are selected from CD16, CD226 (DNAM-1); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, one or more immune checkpoint inhibitors include protein inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, these methods require co-administration of antibodies that bind to CTLA4. In some embodiments, the protein or antibody inhibitor of CTLA4 is selected from: ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, C G-0161, ATOR-1144, PBI-5D3H5, FPT-155(CTLA4/PD-L1/CD28), PF-06936308(PD-1/CTLA4), MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4) and AK-104(CTLA4/PD-1). In some embodiments, the protein inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from: pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), elizumab), GLS-010(WBP-3055), AK-103(HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001(toripalimab), JNJ-63723283, genolimzumab(CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210(camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306(MSB001 0718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD -013(PD-1/LAG-3), FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-1 04 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1) and INBRX-105 (4-1BB/PDL1). In some embodiments, one or more immune checkpoint inhibitors include small molecule inhibitors of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, small molecule inhibitors of CD274 or PDCD1 are selected from GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, small molecule inhibitors of CTLA4 include BPI-002. In some embodiments, the method further includes administering one or more antiviral agents to the subject. In some embodiments, the one or more antiviral agents are selected from: HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, and capsid inhibitors. In some embodiments, these methods further include administering one or more anti-HIV antibodies or antigen-binding fragments thereof to the subject. In some embodiments, the one or more anti-HIV antibodies or antigen-binding fragments thereof bind to HIV gp120. In some embodiments, the anti-HIV antibody or antigen-binding fragment thereof comprises a broadly neutralizing antibody. In some embodiments, one or more anti-HIV antibodies or antigen-binding fragments thereof that bind, inhibit and/or neutralize HIV compete with or comprise the VH and VL variable domains of broadly neutralizing antibodies (bNAbs) against HIV. In some embodiments, one or more anti-HIV antibodies or antigen-binding fragments thereof that bind, inhibit and/or neutralize HIV bind to an epitope or region of gp120 selected from the following: (i) the third variable loop (V3) and/or a high mannose patch containing the N332 oligomannosaccharide glycan; (ii) the CD4 binding site (CD4bs); (iii) the second variable loop (V2) and/or the Env trimer vertex; (iv) the gp120/gp41 interface; or (v) the silent face of gp120. In some embodiments, the antibody or antigen-binding fragment thereof that binds, inhibits and/or neutralizes HIV binds to an epitope or region of gp120 in the third variable loop (V3) and/or the high mannose patch comprising the N332 oligomannose glycan, and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PG T-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, GS-2872, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG41 1. 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope or region of gp120 in the CD4 binding site (CD4bs) and competes with or comprises the VH and VL regions of an antibody selected from b12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01VRC08, VRC0801, NIH 45-46, GS-9723, GS-5423, 3BNC117, 3BNC60, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25. In some embodiments, the antibody or antigen-binding fragment thereof that binds to, inhibits and/or neutralizes HIV binds to an epitope or region of gp120 in the second variable loop (V2) and/or the apex of the Env trimer, and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHO1, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01. In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope or region of gp120 in the gp120/gp41 interface and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of PGT-151, CAP248-2B, 35O22, 8ANC195, ACS202, VRC34, and VRC34.01. In some embodiments, the antibody or antigen-binding fragment thereof that binds, inhibits, and/or neutralizes HIV binds to an epitope or region of the silent face of gp120 and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of VRC-PG05 and SF12. In some embodiments, the antibody or antigen-binding fragment thereof that binds, inhibits, and/or neutralizes HIV binds to an epitope or region of gp41 in the membrane proximal region (MPER). In some embodiments, the antibody or antigen-binding fragment thereof that binds, inhibits and/or neutralizes HIV binds to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01. In some embodiments, the antibody or antigen-binding fragment thereof that binds, inhibits and/or neutralizes HIV binds to an epitope or region of the gp41 fusion peptide and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of VRC34 and ACS202. In some embodiments of these methods, after one or more administrations of one or more fusion polypeptides, composite fusion polypeptides, polynucleotides, carriers, liposome complexes (e.g., LNPs), or immunogenic compositions, optionally in combination with one or more additional therapeutic agents, the subject does not exhibit symptoms of HIV or AIDS for at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, or longer without antiretroviral therapy (ART). In some embodiments of these methods, after one or more administrations of one or more fusion polypeptides, composite fusion polypeptides, polynucleotides, carriers, liposome complexes (e.g., LNPs), or immunogenic compositions, optionally in combination with one or more additional therapeutic agents, the subject has less than 500 (e.g., less than 400, less than 300, less than 200, less than 100, less than 50) viral load copies/ml blood for at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, or longer without antiretroviral therapy (ART).
还提供了设计能够引发针对一种或多种病毒靶抗原的免疫应答的融合多肽的方法,该方法包括:(a)计算机鉴定由病毒基因编码的多肽序列群体中的一个或多个序列保守区,该群体来自患者间病毒群体;(b)计算机鉴定来自在步骤a)中鉴定的一个或多个保守区的两个最普遍的多肽序列,并由这些保守区产生多价多肽片段;以及(c)排列这些多肽片段以减少或避免在多肽片段之间的连接部处产生有害表位。在一些实施方案中,步骤(c)包括减少或消除以小于约1000nM的预测IC50值与特定HLA等位基因结合或百分位等级在多肽片段群体中的前5%内的连接9聚体。还提供了设计能够引发针对一种或多种病毒靶抗原的免疫应答的融合多肽的方法,该方法包括:(a)计算机鉴定由病毒基因编码的第一多肽序列群体中的一个或多个序列保守区,该第一群体来自患者间病毒群体;(b)任选地,计算机鉴定来自在步骤a)中鉴定的一个或多个保守区的两个最普遍的多肽序列;以及(c)将保留的多肽片段排列成一个或多个连续融合多肽,使得连接多肽片段的连接部避免或减少产生能够例如以小于约1000nM的预测结合亲和力IC50值结合人MHC I类或人MHC II类分子或百分位等级在多肽片段群体中的前5%内的表位。在一些实施方案中,步骤(c)包括减少或消除与人类蛋白质具有至少55%(9个氨基酸残基中的5个)、例如至少65%(9个氨基酸残基中的6个)、例如至少75%(9个氨基酸残基中的7个)、例如至少85%(9个氨基酸残基中的8个)氨基酸序列同一性的病毒多肽9聚体。在一些实施方案中,多价多肽片段是二价多肽片段。在一些实施方案中,融合多肽设计方法还包括例如使用深度测序数据鉴定由病毒基因编码的多肽序列的患者内群体中的一个或多个序列保守区内的变体亚序列的步骤。在一些实施方案中,融合多肽设计方法还包括鉴定由病毒基因编码的多肽的保守区,使得患者内群体中一个或多个序列保守区内的变体亚序列的至少70%在二价多肽片段内的步骤。在一些实施方案中,融合多肽设计方法还包括将融合多肽的长度例如缩短至少10%、15%、20%、25%、30%或更多,保留包含(i)计算机预测和(ii)体外确认的表位的多肽片段亚序列的步骤。还提供了用于产生多价抗原的方法,该方法包括通过包括以下步骤的方法来计算机构建病毒蛋白质组序列群体的结构保守区内的一组多价氨基酸序列:(a)比对这些病毒蛋白质组序列群体;(b)对于该比对中的每个序列,产生一组从N末端氨基酸开始的9个氨基酸子序列(“9聚体”),每个子序列与前面的子序列重叠八个氨基酸,使得该比对中每个长度为l的序列含有(l-8)个9聚体;(c)计算在该比对的每个序列中从位置i开始的每个独特9聚体的频率,并鉴定每个位置处的两个或更多个最常见的独特9聚体;(c)(1)其中频率计算为该独特9聚体在该比对中在位置i出现的次数除以该比对中的序列总数;(d)通过将该比对中含有两个或更多个最常见的独特9聚体中的任一项的序列的比例相加来计算每个位置的多价保守性;(e)通过提取该比对中具有大于80%或大于90%的多价保守性的序列来产生保守区的比对;(f)确定该保守区的比对中每个位置处每对独特9聚体的频率;(g)将9聚体对连接在该保守区的比对的相邻位置,这些位置共享八个氨基酸的重叠;(h)产生有向无环图,其中每个9聚体对是一个节点,相邻节点之间的边由相邻位置中连接的9聚体对形成,每条边的权重等于下游9聚体对的频率,(h)(1)添加源节点并将其与第一个位置的所有节点连接,(h)(2)添加宿节点并将其与最后一个位置的所有节点连接,以及(h)(3)将所有权重取反;(i)在该有向无环图中找到从源节点到宿节点的最佳路径,其中该最佳路径是根据该有向无环图中所有9聚体对的频率之和来定义的;(j)如果最佳二价9聚体路径内相邻位置的两个或更多个9聚体共享八个氨基酸的重叠,则通过连接它们来构建多价抗原,从而产生连接的9聚体的两个或更多个序列,它们一起形成多价抗原;以及(k)任选地,重新排列多肽片段以减少或避免在多肽片段之间的连接部处产生有害表位。在一些实施方案中,多价保守性是二价保守性,并且其中多价抗原是二价抗原。在一些实施方案中,在步骤(a)中,通过执行以下步骤中的一个或多个步骤进一步限定保守区:(i)去除长度少于35个氨基酸(例如,长度为9个氨基酸至10、15、20、25、30或35个氨基酸)的片段;(ii)去除被确定为具有小于90%多价(例如,二价)保守性的片段;(iii)去除被确定为弱免疫原性或非免疫原性(例如,如体外或体内所证明)的片段;以及/或者(iv)包括被确定为免疫原性(例如,如体外或体内所证明)的另外的片段。在一些实施方案中,重新排列肽片段以减少或避免产生有害表位的步骤是通过包括计算机HLA结合分析和人类蛋白质组交叉识别分析中的一种或多种的方法进行的。在一些实施方案中,融合多肽设计方法还包括在一个或多个相邻片段之间插入接头序列的步骤。在一些实施方案中,融合多肽设计方法还包括通过去除以小于约1000nM的预测IC50值与特定HLA等位基因结合或百分位等级在多肽片段群体中的前5%内的连接9聚体来改进在步骤(h)中产生的多价(例如二价)抗原。在一些实施方案中,该方法还包括通过去除与人类肽具有至少55%(9个氨基酸残基中的5个)、例如至少65%(9个氨基酸残基中的6个)、例如至少75%(9个氨基酸残基中的7个)、例如至少85%(9个氨基酸残基中的8个)氨基酸序列同一性或与人类蛋白质具有相同的面向T细胞受体(TCR)的残基的9聚体来改进在步骤(h)中产生的多价(例如二价)抗原。在一些实施方案中,融合多肽设计方法还包括重新排列多肽片段以减少或避免在多肽片段之间的连接部处产生有害表位的步骤。在一些实施方案中,重新排列肽片段以减少或避免产生有害表位的步骤是通过包括计算机HLA结合分析和人类蛋白质组交叉识别分析中的一种或多种的方法进行的。在一些实施方案中,融合多肽设计方法还包括例如使用深度测序数据鉴定由病毒基因编码的多肽序列的患者内群体中的一个或多个序列保守区内的变体亚序列的步骤。在一些实施方案中,融合多肽设计方法还包括鉴定由病毒基因编码的多肽的保守区,使得患者内群体中一个或多个序列保守区内的变体亚序列的至少70%在二价多肽片段内的步骤。在一些实施方案中,融合多肽设计方法还包括将融合多肽的长度例如缩短至少10%、15%、20%、25%、30%或更多,保留包含(i)计算机预测和(ii)体外确认的表位的多肽片段亚序列的步骤。关于融合多肽设计方法,在一些实施方案中,该一种或多种病毒靶抗原来自哺乳动物病毒,例如人类病毒。在一些实施方案中,该一种或多种病毒靶抗原来自选自以下的病毒:人类免疫缺陷病毒(HIV)、乙型肝炎病毒(HBV)、人乳头瘤病毒(HPV)、单纯疱疹病毒(HSV)、埃博拉病毒、寨卡病毒和基孔肯雅病病毒。在一些实施方案中,患者间病毒群体来自未接受抗逆转录病毒治疗(ART)的患者群。在一些实施方案中,患者间病毒群体来自已接受抗逆转录病毒治疗(ART)的患者群。还提供了根据本文所述的融合多肽设计方法制备的融合多肽,其中该融合多肽引发哺乳动物例如人对病毒的免疫应答。Also provided is a method for designing a fusion polypeptide capable of eliciting an immune response against one or more viral target antigens, the method comprising: (a) computer identification of one or more sequence conserved regions in a population of polypeptide sequences encoded by viral genes, the population being derived from a population of inter-patient viruses; (b) computer identification of the two most common polypeptide sequences from the one or more conserved regions identified in step a), and generating multivalent polypeptide fragments from these conserved regions; and (c) arranging these polypeptide fragments to reduce or avoid the generation of harmful epitopes at the junctions between the polypeptide fragments. In some embodiments, step (c) comprises reducing or eliminating the junction 9-mers that bind to a specific HLA allele with a predicted IC50 value of less than about 1000 nM or a percentile rank within the top 5% in the population of polypeptide fragments. Also provided is a method for designing a fusion polypeptide capable of eliciting an immune response against one or more viral target antigens, the method comprising: (a) computer identification of one or more sequence conserved regions in a first polypeptide sequence population encoded by a viral gene, the first population being derived from an inter-patient viral population; (b) optionally, computer identification of the two most common polypeptide sequences from the one or more conserved regions identified in step a); and (c) arranging the retained polypeptide fragments into one or more continuous fusion polypeptides so that the connecting portion connecting the polypeptide fragments avoids or reduces the generation of epitopes that can bind to human MHC class I or human MHC class II molecules or have a percentile rank within the top 5% of the polypeptide fragment population, for example, with a predicted binding affinity IC50 value of less than about 1000 nM. In some embodiments, step (c) comprises reducing or eliminating viral polypeptide 9-mers having at least 55% (5 of 9 amino acid residues), such as at least 65% (6 of 9 amino acid residues), such as at least 75% (7 of 9 amino acid residues), such as at least 85% (8 of 9 amino acid residues) amino acid sequence identity with human proteins. In some embodiments, the multivalent polypeptide fragment is a bivalent polypeptide fragment. In some embodiments, the fusion polypeptide design method further includes the step of identifying variant subsequences within one or more sequence conserved regions in a patient population of polypeptide sequences encoded by viral genes using deep sequencing data, for example. In some embodiments, the fusion polypeptide design method further includes the step of identifying the conserved regions of polypeptides encoded by viral genes, so that at least 70% of the variant subsequences within one or more sequence conserved regions in the patient population are within the bivalent polypeptide fragment. In some embodiments, the fusion polypeptide design method further includes the step of shortening the length of the fusion polypeptide, for example, by at least 10%, 15%, 20%, 25%, 30% or more, retaining a polypeptide fragment subsequence containing (i) computer-predicted and (ii) in vitro-confirmed epitopes. Also provided is a method for producing a multivalent antigen, the method comprising constructing a set of multivalent amino acid sequences within a structurally conserved region of a population of viral proteome sequences by a method comprising the following steps: (a) aligning the population of viral proteome sequences; (b) for each sequence in the alignment, generating a set of 9 amino acid subsequences ("9-mers") starting from the N-terminal amino acid, each subsequence overlapping the previous subsequence by eight amino acids, such that each sequence of length 1 in the alignment contains (1-8) 9-mers; (c) calculating the number of amino acid sequences in each sequence in the alignment from position (c)(1) wherein the frequency is calculated as the number of times the unique 9-mer occurs at position i in the alignment divided by the total number of sequences in the alignment; (d) calculating the polyvalent conservation at each position by adding the proportion of sequences in the alignment that contain any of the two or more most common unique 9-mers; (e) generating an alignment of conserved regions by extracting sequences in the alignment that have polyvalent conservation greater than 80% or greater than 90%; and (f) determining the polyvalent conservation of the conserved regions. The frequency of each unique 9-mer pair at each position in the alignment; (g) connecting the 9-mer pairs at adjacent positions in the alignment of the conserved region that share an overlap of eight amino acids; (h) generating a directed acyclic graph in which each 9-mer pair is a node, edges between adjacent nodes are formed by connecting 9-mer pairs in adjacent positions, the weight of each edge equal to the frequency of the downstream 9-mer pair, (h)(1) adding the source node and connecting it to all nodes at the first position, (h)(2) adding the sink node and connecting it to all nodes at the last position, and (h)(3) connecting all The weight is negated; (i) finding the best path from the source node to the sink node in the directed acyclic graph, wherein the best path is defined by the sum of the frequencies of all 9-mer pairs in the directed acyclic graph; (j) if two or more 9-mers at adjacent positions in the best bivalent 9-mer path share an overlap of eight amino acids, a multivalent antigen is constructed by connecting them, thereby generating two or more sequences of connected 9-mers, which together form a multivalent antigen; and (k) optionally, rearranging the polypeptide fragments to reduce or avoid the generation of harmful epitopes at the junctions between the polypeptide fragments. In some embodiments, the multivalent conservation is bivalent conservation, and wherein the multivalent antigen is a bivalent antigen. In some embodiments, in step (a), the conserved regions are further defined by performing one or more of the following steps: (i) removing fragments of less than 35 amino acids in length (e.g., 9 amino acids to 10, 15, 20, 25, 30 or 35 amino acids in length); (ii) removing fragments determined to have less than 90% multivalent (e.g., bivalent) conservation; (iii) removing fragments determined to be weakly immunogenic or non-immunogenic (e.g., as demonstrated in vitro or in vivo); and/or (iv) including additional fragments determined to be immunogenic (e.g., as demonstrated in vitro or in vivo). In some embodiments, the step of rearranging the peptide fragments to reduce or avoid the generation of harmful epitopes is performed by a method comprising one or more of a computer HLA binding analysis and a human proteome cross-recognition analysis. In some embodiments, the fusion polypeptide design method further comprises the step of inserting a linker sequence between one or more adjacent fragments. In some embodiments, the fusion polypeptide design method further comprises improving the multivalent (e.g., bivalent) antigen generated in step (h) by removing connected 9-mers that bind to a specific HLA allele with a predicted IC50 value of less than about 1000 nM or a percentile rank within the top 5% of the polypeptide fragment population. In some embodiments, the method further comprises improving the multivalent (e.g., bivalent) antigen generated in step (h) by removing 9-mers that have at least 55% (5 of 9 amino acid residues), such as at least 65% (6 of 9 amino acid residues), such as at least 75% (7 of 9 amino acid residues), such as at least 85% (8 of 9 amino acid residues) amino acid sequence identity with human peptides or residues facing the same T cell receptor (TCR) as human proteins. In some embodiments, the fusion polypeptide design method further comprises the step of rearranging the polypeptide fragments to reduce or avoid the generation of harmful epitopes at the junctions between the polypeptide fragments. In some embodiments, the step of rearranging the peptide fragments to reduce or avoid the generation of harmful epitopes is performed by a method comprising one or more of a computer HLA binding analysis and a human proteome cross-recognition analysis. In some embodiments, the fusion polypeptide design method further includes, for example, using deep sequencing data to identify variant subsequences within one or more sequence conserved regions in a patient population of a polypeptide sequence encoded by a viral gene. In some embodiments, the fusion polypeptide design method further includes identifying a conserved region of a polypeptide encoded by a viral gene, so that at least 70% of the variant subsequences within one or more sequence conserved regions in a patient population are within a bivalent polypeptide fragment. In some embodiments, the fusion polypeptide design method further includes shortening the length of the fusion polypeptide, for example, by at least 10%, 15%, 20%, 25%, 30% or more, retaining a step of a polypeptide fragment subsequence containing (i) computer prediction and (ii) in vitro confirmed epitopes. With regard to the fusion polypeptide design method, in some embodiments, the one or more viral target antigens are from mammalian viruses, such as human viruses. In some embodiments, the one or more viral target antigens are from a virus selected from the group consisting of human immunodeficiency virus (HIV), hepatitis B virus (HBV), human papillomavirus (HPV), herpes simplex virus (HSV), Ebola virus, Zika virus, and chikungunya virus. In some embodiments, the inter-patient viral population is from a patient population that has not received antiretroviral therapy (ART). In some embodiments, the inter-patient viral population is from a patient population that has received antiretroviral therapy (ART). Also provided is a fusion polypeptide prepared according to the fusion polypeptide design method described herein, wherein the fusion polypeptide triggers an immune response of a mammal, such as a human, to the virus.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1示出了用于设计融合多肽以引发抗病毒应答的6步工作流程。FIG1 shows a six-step workflow for designing fusion polypeptides to elicit an antiviral response.
图2示出了基于群体的疫苗构建方法的代表性方法。FIG2 shows a representative method of a population-based vaccine construction approach.
图3示出了如本文所述的保守步行分析(CWA)算法的步骤。FIG3 illustrates the steps of a conservative walking analysis (CWA) algorithm as described herein.
图4A至图4B。图4A示出了能够如何基于群体中所有考虑的病毒序列中两个最常见的9聚体的流行率来确定“二价保守性”。图4A按出现的顺序将对应于患者1至10的序列分别公开为SEQ ID NO 168-169、169-170、169、169、171-172和172-173。图4A还将“QNLQGQMVH”公开为SEQ ID NO:174,将“QNIQGQMVH”公开为SEQ ID NO:175并且将“PNIQGQMVH”公开为SEQ ID NO:176。图4B示出了如何基于9聚体位置中的“二价保守性”分布来鉴定保守区。HIV-1 Gag p24用作代表性蛋白质。Figures 4A to 4B. Figure 4A shows how "bivalent conservation" can be determined based on the prevalence of the two most common 9-mers among all considered viral sequences in a population. Figure 4A discloses the sequences corresponding to patients 1 to 10 as SEQ ID NOs 168-169, 169-170, 169, 169, 171-172, and 172-173, respectively, in order of appearance. Figure 4A also discloses "QNLQGQMVH" as SEQ ID NO: 174, "QNIQGQMVH" as SEQ ID NO: 175, and "PNIQGQMVH" as SEQ ID NO: 176. Figure 4B shows how conserved regions can be identified based on the distribution of "bivalent conservation" in 9-mer positions. HIV-1 Gag p24 is used as a representative protein.
图5A至图5C。图5A示出了从比对的天然序列中提取的独特9聚体。图5A按列的顺序分别公开了SEQ ID NO:177-183。图5B示出了基于9聚体对节点以及它们连接部构建的有向无环图。图5B将“GIIIIIIII”公开为SEQ ID NO:180,将“AIIIIIIII”公开为SEQ ID NO:181,将“IIIIIIIIK”公开为SEQ ID NO:182,将“IIIIIIIIH”公开为SEQ ID NO:183并且将“IIIIIIIIR”公开为SEQ ID NO:184。图5C示出了如何连接连接的9聚体对中的9聚体。当连接有两种选择时,最终连接由每个连接在天然存在的序列中的流行率决定。图5C将“GIIIIIIII”公开为SEQ ID NO:180,将“AIIIIIIII”公开为SEQ ID NO:181,将“IIIIIIIIK”公开为SEQ ID NO:182并且将“IIIIIIIIH”公开为SEQ ID NO:183。Figures 5A to 5C. Figure 5A shows unique 9-mers extracted from aligned natural sequences. Figure 5A discloses SEQ ID NOs: 177-183, respectively, in column order. Figure 5B shows a directed acyclic graph constructed based on 9-mer pair nodes and their connections. Figure 5B discloses "GIIIIIIII" as SEQ ID NO: 180, "AIIIIIIII" as SEQ ID NO: 181, "IIIIIIIIK" as SEQ ID NO: 182, "IIIIIIIIH" as SEQ ID NO: 183 and "IIIIIIIIR" as SEQ ID NO: 184. Figure 5C shows how to connect the 9-mers in the connected 9-mer pairs. When there are two options for connection, the final connection is determined by the prevalence of each connection in the naturally occurring sequence. Figure 5C discloses "GIIIIIIII" as SEQ ID NO:180, "AIIIIIIII" as SEQ ID NO:181, "IIIIIIIIK" as SEQ ID NO:182 and "IIIIIIIIH" as SEQ ID NO:183.
图6示出了人类蛋白质组交叉识别分析的结果。图6按列的顺序分别公开了SEQ IDNO:185-188。Figure 6 shows the results of human proteome cross-recognition analysis. Figure 6 discloses SEQ ID NOs: 185-188 in column order.
图7示出了多肽片段排列分析能够如何减少或消除连接区中有害或不希望的表位的可能呈现。Figure 7 illustrates how polypeptide fragment alignment analysis can reduce or eliminate the potential presentation of deleterious or undesirable epitopes in junction regions.
图8提供了含有免疫原版本1的融合蛋白(例如,SEQ ID NO:94-101)的病毒载体的示意图。免疫原版本1的融合多肽在HIV-1 Gag、Pol和Nef内具有长度在516至527个氨基酸范围内的十二个保守区,这些保守区已被重新排列以减少或最小化总体连接反应。总共四种载体能够实现二价、异源初免/加强疫苗方案。Figure 8 provides a schematic diagram of a viral vector containing a fusion protein (e.g., SEQ ID NO: 94-101) of immunogen version 1. The fusion polypeptide of immunogen version 1 has twelve conserved regions within HIV-1 Gag, Pol, and Nef ranging in length from 516 to 527 amino acids, which have been rearranged to reduce or minimize overall ligation reactions. A total of four vectors enable a bivalent, heterologous prime/boost vaccine regimen.
图9提供了示出用于设计免疫原版本2的融合蛋白(例如,SEQ ID NO:82-89)的方法的基本方法的流程图。从保守区选择一组9聚体,并组合形成免疫原版本2的融合多肽,即免疫原版本1的亚组。表E中提供了免疫原版本2中包含的序列和基因区域。Figure 9 provides a flow chart showing the basic method of the method for designing fusion proteins (e.g., SEQ ID NOs: 82-89) of immunogen version 2. A set of 9-mers are selected from the conserved regions and combined to form the fusion polypeptides of immunogen version 2, a subset of immunogen version 1. The sequences and gene regions included in immunogen version 2 are provided in Table E.
图10A至图10D示出了编码HIV的蛋白质Pol(A-B)、Gag(C)和Nef(D)的区域,这些区域通过组合深度测序数据和免疫原性数据而被选择用于免疫原版本2。实心水平黑线=患者内保守性(通过用二价疫苗覆盖患者内的9聚体变体来评估)。灰色水平线=患者间保守性。实心竖直黑条=LANL应答。白色竖直条=ELISpot应答。水平条(对角线条带)=在免疫原版本2中保持的区域。Figures 10A to 10D show regions encoding HIV proteins Pol (A-B), Gag (C) and Nef (D) that were selected for immunogen version 2 by combining deep sequencing data and immunogenicity data. Solid horizontal black line = intra-patient conservation (assessed by covering 9-mer variants within patients with bivalent vaccines). Gray horizontal line = inter-patient conservation. Solid vertical black bar = LANL response. White vertical bar = ELISpot response. Horizontal bar (diagonal strip) = region maintained in immunogen version 2.
图11提供了含有免疫原版本2的融合蛋白(例如,SEQ ID NO:82-89)的病毒载体的示意图。免疫原版本2的融合多肽在HIV-1 Gag、Pol和Nef内具有长度在351至365个氨基酸范围内的八个保守区,这些保守区已被重新排列以减少或最小化总体连接反应。总共四种载体能够实现二价、异源初免/加强疫苗方案。Figure 11 provides a schematic diagram of a viral vector containing a fusion protein (e.g., SEQ ID NO: 82-89) of immunogen version 2. The fusion polypeptide of immunogen version 2 has eight conserved regions within HIV-1 Gag, Pol and Nef ranging in length from 351 to 365 amino acids, which have been rearranged to reduce or minimize overall ligation reactions. A total of four vectors enable a bivalent, heterologous prime/boost vaccine regimen.
图12A至图12B表明,随着免疫原版本1的融合多肽与免疫原版本2的融合多肽的大小减小,中值应答保持稳定。12A.在体外对总共93个供体PBMC测试了免疫原版本1的融合多肽诱导T细胞应答的能力。虚线表示所识别的应答的中值数目。免疫原版本1在93个参与者中的73个参与者(78.49%)中检测到免疫应答。12B.计算机评估免疫原2的融合多肽在相同参与者中诱导T细胞应答的能力。虚线表示所识别的应答的中值数目。免疫原版本2在93个参与者中的71个参与者(76.34%)中检测到免疫应答。Figures 12A-12B demonstrate that as the size of the fusion polypeptide of immunogen version 1 decreases with the size of the fusion polypeptide of immunogen version 2, the median response remains stable. 12A. The ability of the fusion polypeptide of immunogen version 1 to induce a T cell response was tested in vitro on a total of 93 donor PBMCs. The dotted line represents the median number of responses identified. Immunogen version 1 detected an immune response in 73 of the 93 participants (78.49%). 12B. Computer assessment of the ability of the fusion polypeptide of immunogen 2 to induce a T cell response in the same participants. The dotted line represents the median number of responses identified. Immunogen version 2 detected an immune response in 71 of the 93 participants (76.34%).
图13提供了示出用于设计免疫原版本3的融合蛋白(例如,SEQ ID NO:90-93)的方法的基本方法的流程图。从保守区选择一组9聚体,并组合形成免疫原版本3的融合多肽,即免疫原版本1的亚组。表E中提供了免疫原版本3中包含的序列和基因区域。Figure 13 provides a flow chart showing the basic method of the method for designing fusion proteins (e.g., SEQ ID NOs: 90-93) of immunogen version 3. A set of 9-mers are selected from the conserved regions and combined to form the fusion polypeptides of immunogen version 3, a subset of immunogen version 1. The sequences and gene regions included in immunogen version 3 are provided in Table E.
图14A至图14D示出了编码HIV的蛋白质Pol(A-B)、Gag(C)和Nef(D)的区域,这些区域通过组合深度测序数据和免疫原性数据而被选择用于免疫原版本3。实心水平黑线=患者内保守性(通过用二价疫苗覆盖患者内的9聚体变体来评估)。灰色水平线=患者间保守性。实心竖直黑条=LANL应答。灰色竖直条=ELISpot应答。水平空心柱=在改善的免疫原中保持的区域。Figures 14A to 14D show regions encoding HIV proteins Pol (A-B), Gag (C) and Nef (D) that were selected for immunogen version 3 by combining deep sequencing data and immunogenicity data. Solid horizontal black line = intra-patient conservation (assessed by covering 9-mer variants within patients with bivalent vaccine). Gray horizontal line = inter-patient conservation. Solid vertical black bar = LANL response. Gray vertical bar = ELISpot response. Horizontal open column = region maintained in improved immunogen.
图15提供了含有免疫原版本3的融合蛋白(例如,SEQ ID NO:90-93)的病毒载体的示意图。免疫原3版本构建体的示意图。免疫原版本3的融合多肽在HIV-1 Gag、Pol和Nef内具有长度在391至394个氨基酸范围内的四个保守区,这些保守区已被重新排列以最小化总体连接反应。总共两种载体能够实现二价、异源初免/加强疫苗方案。Figure 15 provides a schematic diagram of a viral vector containing a fusion protein of immunogen version 3 (e.g., SEQ ID NO: 90-93). Schematic diagram of immunogen version 3 construct. The fusion polypeptide of immunogen version 3 has four conserved regions within HIV-1 Gag, Pol and Nef with lengths ranging from 391 to 394 amino acids, which have been rearranged to minimize overall ligation reactions. A total of two vectors enable a bivalent, heterologous prime/boost vaccine regimen.
图16示出了在本文所述的融合多肽构建体中使用的由HIV-1 Gag基因编码的多肽片段。Gag HIV-1 HXB2参考多肽(SEQ ID NO:1)序列用下划线标记。与Gag HIV-1 HXB2参考多肽残基54-146和370-500对应的氨基酸残基及其亚序列和片段未包括在本文所述的多肽片段中。图16按出现的顺序分别公开了SEQ ID NO 1和4-7。FIG. 16 shows polypeptide fragments encoded by the HIV-1 Gag gene used in the fusion polypeptide constructs described herein. The Gag HIV-1 HXB2 reference polypeptide (SEQ ID NO: 1) sequence is underlined. Amino acid residues corresponding to residues 54-146 and 370-500 of the Gag HIV-1 HXB2 reference polypeptide and subsequences and fragments thereof are not included in the polypeptide fragments described herein. FIG. 16 discloses SEQ ID NOs 1 and 4-7, respectively, in the order of appearance.
图17A至图17C示出了在本文所述的融合多肽构建体中使用的由HIV-1Pol基因编码的多肽片段。Pol HIV-1 HXB2参考多肽(SEQ ID NO:2)序列用下划线标记。与Pol HIV-1HXB2参考多肽残基1-55、118-128、321-366、432-541、607-682、709-746、828-839和921-931对应的氨基酸残基及其亚序列和片段未包括在本文所述的多肽片段中。图17A至图17C按出现的顺序分别公开了SEQ ID NO 2、8-21、24-25、189、23和26-27。Figure 17A to Figure 17C show the polypeptide fragments encoded by HIV-1Pol gene used in the fusion polypeptide construct described herein.Pol HIV-1 HXB2 reference polypeptide (SEQ ID NO:2) sequence is underlined.Amino acid residues corresponding to Pol HIV-1HXB2 reference polypeptide residues 1-55, 118-128, 321-366, 432-541, 607-682, 709-746, 828-839 and 921-931 and their subsequences and fragments are not included in the polypeptide fragments described herein.Figure 17A to Figure 17C disclose SEQ ID NO 2, 8-21, 24-25, 189, 23 and 26-27 respectively in the order of appearance.
图18示出了在本文所述的融合多肽构建体中使用的由HIV-1Nef基因编码的多肽片段。在位置124处具有色氨酸(W)的Nef HIV-1 HXB2参考多肽(SEQ ID NO:3)序列用下划线标记。与Nef HIV-1 HXB2参考多肽残基1-63、100-116和149-206对应的氨基酸残基及其亚序列和片段未包括在本文所述的多肽片段中。图18按出现的顺序分别公开了SEQ ID NO3、30-31、28-29和32-33。Figure 18 shows the polypeptide fragments encoded by the HIV-1 Nef gene used in the fusion polypeptide constructs described herein. The Nef HIV-1 HXB2 reference polypeptide (SEQ ID NO:3) sequence with tryptophan (W) at position 124 is underlined. The amino acid residues corresponding to Nef HIV-1 HXB2 reference polypeptide residues 1-63, 100-116 and 149-206 and their subsequences and fragments are not included in the polypeptide fragments described herein. Figure 18 discloses SEQ ID NO3, 30-31, 28-29 and 32-33 in the order of appearance, respectively.
图19示出了含有HIV-1免疫原版本1多肽序列(例如,SEQ ID NO:105、107、109、111和206-209)的复合融合多肽的示意图。所描绘的复合融合多肽在HIV-1 Gag、Pol和Nef内具有12个保守区,这些保守区已被重新排列以最小化总体连接反应。所有四种载体用于在CD8+ T细胞初免测定中转导单核细胞衍生的树突细胞(moDC),并且在对应于这些多肽序列的测定中被共同标记为“疫苗接种后”。图19将“AAA”公开为SEQ ID NO:48并且将“AAY”公开为SEQ ID NO:49。Figure 19 shows a schematic diagram of a composite fusion polypeptide containing HIV-1 immunogen version 1 polypeptide sequences (e.g., SEQ ID NOs: 105, 107, 109, 111, and 206-209). The composite fusion polypeptide depicted has 12 conserved regions within HIV-1 Gag, Pol, and Nef, which have been rearranged to minimize overall ligation reactions. All four vectors are used to transduce monocyte-derived dendritic cells (moDCs) in CD8+ T cell primary immunization assays and are co-labeled as "post-vaccination" in assays corresponding to these polypeptide sequences. Figure 19 discloses "AAA" as SEQ ID NO: 48 and discloses "AAY" as SEQ ID NO: 49.
图20A至图20B。表达SEQ ID NO:105、107、109或111的复合融合多肽的Ad5载体被用于转导moDC,以评估转基因的表达和转导效率。通过Gag p24 ELISA(N=2)评估表达效率(图20A)。y轴表示在用表达SEQ ID NO:105、107、109或111的复合融合多肽的Ad5载体(■)或空载体对照(▲)以500的感染复数(MOI)转导后第3天,在moDC裂解物中检测到的Gag p24浓度(pg/ml)。图20B示出了在N=36个人类供体中使用表达GFP的Ad5病毒载体以500的MOI转导后第3天的代表性moDC转导效率。通过流式细胞术得到的表达GFP的细胞比例在y轴上示出。x轴表示感染复数(MOI)为500时,SEQ ID NO:105、107、109和111(■)或空载体对照(▲)或未转导(·)的保守区的疫苗免疫原构建体。通过流式细胞术评估转导的moDC的GFP表达百分比来确定转导效率(N=36)。氨基酸序列在表F中提供。Figures 20A to 20B. Ad5 vectors expressing composite fusion polypeptides of SEQ ID NO: 105, 107, 109 or 111 were used to transduce moDC to assess transgene expression and transduction efficiency. Expression efficiency was assessed by Gag p24 ELISA (N = 2) (Figure 20A). The y-axis represents the concentration of Gag p24 (pg/ml) detected in moDC lysates on day 3 after transduction with an Ad5 vector (■) expressing a composite fusion polypeptide of SEQ ID NO: 105, 107, 109 or 111 or an empty vector control (▲) at a multiplicity of infection (MOI) of 500. Figure 20B shows representative moDC transduction efficiency on day 3 after transduction with an Ad5 viral vector expressing GFP at an MOI of 500 in N = 36 human donors. The proportion of cells expressing GFP obtained by flow cytometry is shown on the y-axis. The x-axis represents vaccine immunogen constructs of the conserved regions of SEQ ID NO: 105, 107, 109 and 111 (■) or empty vector control (▲) or untransduced (·) at a multiplicity of infection (MOI) of 500. Transduction efficiency was determined by flow cytometry assessment of the percentage of GFP expression of transduced moDCs (N=36). The amino acid sequences are provided in Table F.
图21示出了含有HIV-1免疫原版本2融合多肽(SEQ ID NO:82-89)的融合多肽的示意图。所描绘的复合融合多肽在HIV-1 Gag、Pol和Nef内具有12个保守区,这些保守区已被重新排列以最小化总体连接反应。所有八种载体用于在CD8+ T细胞初免测定中转导moDC,并且在使用这些序列的测定中被共同标记为“疫苗接种后”。图21将“AAA”公开为SEQ IDNO:48,将“QEE”公开为SEQ ID NO:51,将“KILQEE”公开为SEQ ID NO:198并且将“AAQEE”公开为SEQ ID NO:199。Figure 21 shows a schematic diagram of a fusion polypeptide containing HIV-1 immunogen version 2 fusion polypeptide (SEQ ID NO: 82-89). The composite fusion polypeptide depicted has 12 conserved regions within HIV-1 Gag, Pol and Nef that have been rearranged to minimize overall ligation reactions. All eight vectors were used to transduce moDC in a CD8+ T cell priming assay and were collectively labeled "post-vaccination" in assays using these sequences. Figure 21 discloses "AAA" as SEQ ID NO: 48, "QEE" as SEQ ID NO: 51, "KILQEE" as SEQ ID NO: 198 and "AAQEE" as SEQ ID NO: 199.
图22A至图22B。表达SEQ ID NO:82-89的复合融合多肽的Ad5载体被用于转导moDC,以评估转基因的表达和转导效率。通过Gag p24 ELISA(N=2)评估表达效率(图22A)。y轴表示在用表达SEQ ID NO:82-89的复合融合多肽的Ad5载体(■)或空载体对照(▲)以500的感染复数(MOI)转导后第3天,在moDC裂解物中检测到的Gag p24浓度(pg/ml)。图22B示出了在N=3个人类供体中使用表达GFP的Ad5病毒载体以500的MOI转导后第3天的代表性moDC转导效率。通过流式细胞术得到的表达GFP的细胞比例在y轴上示出。x轴表示感染复数(MOI)为500时,SEQ ID NO:82-89(■)或空载体对照(▲)或未转导(·)的保守区的疫苗免疫原构建体。氨基酸序列在表E中提供。Figure 22A to Figure 22B. Ad5 vectors expressing composite fusion polypeptides of SEQ ID NO: 82-89 were used to transduce moDC to assess transgene expression and transduction efficiency. Expression efficiency was assessed by Gag p24 ELISA (N = 2) (Figure 22A). The y-axis represents the concentration of Gag p24 (pg/ml) detected in moDC lysates on the 3rd day after transduction with an Ad5 vector (■) expressing a composite fusion polypeptide of SEQ ID NO: 82-89 or an empty vector control (▲) at a multiplicity of infection (MOI) of 500. Figure 22B shows a representative moDC transduction efficiency on the 3rd day after transduction with an MOI of 500 using an Ad5 viral vector expressing GFP in N = 3 human donors. The proportion of cells expressing GFP obtained by flow cytometry is shown on the y-axis. The x-axis represents vaccine immunogen constructs of the conserved regions of SEQ ID NOs: 82-89 (■) or empty vector control (▲) or untransduced (·) at a multiplicity of infection (MOI) of 500. The amino acid sequences are provided in Table E.
图23示出了含有HIV-1免疫原版本3融合多肽(SEQ ID NO:90-93)的融合多肽的示意图。所有四种载体用于在CD8+ T细胞初免测定中转导moDC,并且在使用这些序列的测定中被共同标记为“疫苗接种后”。图23将“QEE”公开为SEQ ID NO:51,将“AAQEE”公开为SEQID NO:199并且将“AAY”公开为SEQ ID NO:49。Figure 23 shows a schematic diagram of fusion polypeptides containing HIV-1 immunogen version 3 fusion polypeptides (SEQ ID NOs: 90-93). All four vectors were used to transduce moDCs in a CD8+ T cell priming assay and are collectively labeled "post-vaccination" in assays using these sequences. Figure 23 discloses "QEE" as SEQ ID NO: 51, "AAQEE" as SEQ ID NO: 199 and "AAY" as SEQ ID NO: 49.
图24A至图24B。表达SEQ ID NO:90-93的复合融合多肽的Ad5载体被用于转导moDC,以评估转基因的表达和转导效率。通过Gag p24 ELISA(N=2)评估表达效率(图24A)。y轴表示在用表达SEQ ID NO:82-89的复合融合多肽的Ad5载体(■)或空载体对照(▲)以500的感染复数(MOI)转导后第3天,在moDC裂解物中检测到的Gag p24浓度(pg/ml)。图24B示出了在N=3个人类供体中使用表达GFP的Ad5病毒载体以500的MOI转导后第3天的代表性moDC转导效率。通过流式细胞术得到的表达GFP的细胞比例在y轴上示出。x轴表示感染复数(MOI)为500时,SEQ ID NO:90-93(■)或空载体对照(▲)或未转导(·)的保守区的疫苗免疫原构建体。氨基酸序列在表E中提供。Figure 24A to Figure 24B. Ad5 vectors expressing composite fusion polypeptides of SEQ ID NO: 90-93 were used to transduce moDC to evaluate the expression and transduction efficiency of the transgene. The expression efficiency was evaluated by Gag p24 ELISA (N = 2) (Figure 24A). The y-axis represents the concentration of Gag p24 (pg / ml) detected in moDC lysates on the third day after transduction with an Ad5 vector (■) expressing a composite fusion polypeptide of SEQ ID NO: 82-89 or an empty vector control (▲) at an infection multiplicity (MOI) of 500. Figure 24B shows the representative moDC transduction efficiency on the third day after transduction with an Ad5 viral vector expressing GFP at an MOI of 500 in N = 3 human donors. The proportion of cells expressing GFP obtained by flow cytometry is shown on the y-axis. The x-axis represents vaccine immunogen constructs of the conserved regions of SEQ ID NO: 90-93 (■) or empty vector control (▲) or untransduced (·) at a multiplicity of infection (MOI) of 500. The amino acid sequences are provided in Table E.
图25示出了含有HIV-1免疫原版本1融合多肽序列的融合多肽的示意图。SEQ IDNO:94和95的融合多肽表示HIV-1 Gag、Pol和Nef内的二价序列;SEQ ID NO:96和97表示HIV-1Pol和Nef内的二价序列。可组合SEQ ID NO:94-97的融合多肽以形成初免序列。SEQID NO:98和99的融合多肽表示HIV-1 Gag、Pol和Nef内的二价序列。SEQ ID NO:100和101的融合多肽表示HIV-1Pol和Nef内的二价序列。可组合SEQ ID NO:98-101的融合多肽以形成加强序列,该加强序列可在用SEQ ID NO:94-97的融合多肽初免后使用。二价序列被设计用于覆盖病毒序列中>80%的患者间多样性,并且用于生成多肽融合构建体的基因片段被重新排列,从而使与人类蛋白质反应的从头表位的产生最小化并且使初免增强序列中的连接反应的加强最小化。图25将“AAA”公开为SEQ ID NO:48并且将“AAY”公开为SEQ ID NO:49。Figure 25 shows a schematic diagram of fusion polypeptides containing HIV-1 immunogen version 1 fusion polypeptide sequences. The fusion polypeptides of SEQ ID NOs:94 and 95 represent bivalent sequences within HIV-1 Gag, Pol, and Nef; SEQ ID NOs:96 and 97 represent bivalent sequences within HIV-1 Pol and Nef. The fusion polypeptides of SEQ ID NOs:94-97 can be combined to form a prime sequence. The fusion polypeptides of SEQ ID NOs:98 and 99 represent bivalent sequences within HIV-1 Gag, Pol, and Nef. The fusion polypeptides of SEQ ID NOs:100 and 101 represent bivalent sequences within HIV-1 Pol and Nef. The fusion polypeptides of SEQ ID NOs:98-101 can be combined to form a boost sequence that can be used after priming with the fusion polypeptides of SEQ ID NOs:94-97. The bivalent sequence was designed to cover >80% of the inter-patient diversity in viral sequences, and the gene segments used to generate the polypeptide fusion constructs were rearranged to minimize the generation of de novo epitopes reactive with human proteins and to minimize the enhancement of ligation reactions in the prime boost sequence. Figure 25 discloses "AAA" as SEQ ID NO:48 and "AAY" as SEQ ID NO:49.
图26示出了Balb/c小鼠中的免疫方案。如所示,用表达HIV-1融合多肽序列的Ad5载体以1×109PFU在右和左四头肌中通过肌内(IM)对小鼠进行免疫。在免疫后第16天收集脾细胞,并通过IFN-γELISpot测定来测量针对HIV Gag、Pol和Nef抗原的应答。Figure 26 shows the immunization scheme in Balb/c mice. Mice were immunized intramuscularly (IM) with 1×10 9 PFU of Ad5 vector expressing HIV-1 fusion polypeptide sequence in the right and left quadriceps as indicated. Splenocytes were collected on day 16 after immunization and responses to HIV Gag, Pol and Nef antigens were measured by IFN-γ ELISpot assay.
图27A至图27B示出了通过IFN-γELISpot在Balb/c小鼠中进行免疫原性测试的结果,该IFN-γELISpot具有用以下中的任一者刺激的肽:HIV-1Gag(i和ii)、Nef(vii和viii)(图27A)、Pol(蛋白酶/RT)(iii和iv)或Pol(整合酶)(v和vi)(图27B)肽。SEQ ID NO:94-95(Seq 94、Seq95)的融合多肽用作二价初免序列。SEQ ID NO:98-99(Seq 98、Seq 99)的融合多肽用作二价加强序列。Y轴表示对特定肽池刺激的IFN-γ应答的大小,表示为每106个脾细胞的斑点形成集落(SFC)的数量。通过减去无肽刺激的对照以排除非特异性应答来获得肽特异性值。X轴表示用于研究其肽特异性应答的体内初免的单个疫苗构建体。所有载体都是免疫原性的,诱导了对HIV-1 Gag应答的稳健应答、对Pol蛋白(蛋白酶、RT和整合酶)的较弱但可检测的应答。在该模型中没有检测到对HIV-Nef的应答,这可能是由于先前描述的Balb/c小鼠中HIV-1 Gag表位的免疫优势模式,并且反映了可在Balb/c小鼠中呈递的Nef表位的缺乏。Figures 27A to 27B show the results of immunogenicity testing in Balb/c mice by IFN-γ ELISpot with peptides stimulated with any of the following: HIV-1 Gag (i and ii), Nef (vii and viii) (Figure 27A), Pol (Protease/RT) (iii and iv) or Pol (Integrase) (v and vi) (Figure 27B) peptides. The fusion polypeptide of SEQ ID NO: 94-95 (Seq 94, Seq 95) was used as a bivalent priming sequence. The fusion polypeptide of SEQ ID NO: 98-99 (Seq 98, Seq 99) was used as a bivalent boosting sequence. The Y-axis represents the size of the IFN-γ response to stimulation with a specific peptide pool, expressed as the number of spot-forming colonies (SFC) per 106 splenocytes. Peptide-specific values were obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. The X-axis represents the individual vaccine constructs used for in vivo priming to study their peptide-specific responses. All vectors were immunogenic, inducing robust responses to HIV-1 Gag responses, weaker but detectable responses to Pol proteins (protease, RT, and integrase). No responses to HIV-Nef were detected in this model, which may be due to the previously described immunodominant pattern of HIV-1 Gag epitopes in Balb/c mice and reflects the lack of Nef epitopes that can be presented in Balb/c mice.
图28示出了通过IFN-γELISpot在Balb/c小鼠中进行免疫原性测试的结果,该IFN-γELISpot具有用以下中的任一者刺激的肽:HIV-1Pol(蛋白酶和RT)(i和ii)、Pol(整合酶)(iii和iv)或Nef(v和vi)肽。SEQ ID NO:96-97(Seq 96、Seq 97)的融合多肽用作二价初免序列。SEQ ID NO:100-101(Seq 100、Seq 101)的融合多肽用作二价加强序列。Y轴表示对特定肽池刺激的IFN-γ应答的大小,表示为每106个脾细胞的斑点形成集落(SFC)的数量。通过减去无肽刺激的对照以排除非特异性应答来获得肽特异性值。X轴表示用于研究其肽特异性应答的体内初免的单个疫苗构建体。所有载体都是免疫原性的,诱导对HIV-1Pol(特别是蛋白酶和RT肽)的稳健应答、对整合酶肽的能够检测的较弱应答。在该模型中没有检测到对HIV-Nef的应答,这可能是由于先前描述的Balb/c小鼠中HIV-1 Gag表位的免疫优势模式,并且反映了可在Balb/c小鼠中呈递的Nef表位的缺乏。Figure 28 shows the results of immunogenicity testing in Balb/c mice by IFN-γ ELISpot with peptides stimulated with any of the following: HIV-1 Pol (protease and RT) (i and ii), Pol (integrase) (iii and iv) or Nef (v and vi) peptides. The fusion polypeptides of SEQ ID NO: 96-97 (Seq 96, Seq 97) were used as bivalent priming sequences. The fusion polypeptides of SEQ ID NO: 100-101 (Seq 100, Seq 101) were used as bivalent boosting sequences. The Y-axis represents the size of the IFN-γ response to stimulation with a specific peptide pool, expressed as the number of spot-forming colonies (SFC) per 10 6 splenocytes. Peptide-specific values were obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. The X-axis represents individual vaccine constructs used for in vivo priming to study their peptide-specific responses. All vectors were immunogenic, inducing robust responses to HIV-1Pol (particularly protease and RT peptides), weaker responses to integrase peptides that could be detected. No responses to HIV-Nef were detected in this model, which may be due to the previously described immunodominance pattern of HIV-1 Gag epitopes in Balb/c mice and reflects the lack of Nef epitopes that can be presented in Balb/c mice.
图29示出了Balb/c小鼠中的代表性免疫方案。如所示,用表达HIV-1序列的Ad5载体以1×109PFU在右和左四头肌中通过肌内(I.M.)对小鼠进行免疫。测试单个载体(i)作为单剂量的免疫原性,以初免该应答,其中在第16天收获脾以用于分析。按照同源载体初免-加强方案测试组合载体(ii),其中在第29天加强并且在第36天收获脾以用于分析。通过IFN-γELISpot测定和ICS/流式细胞术测定针对Gag、Pol和Nef抗原的应答。Figure 29 shows a representative immunization scheme in Balb/c mice. As shown, mice were immunized intramuscularly (IM) in the right and left quadriceps with Ad5 vectors expressing HIV-1 sequences at 1×10 9 PFU. The immunogenicity of the individual vectors (i) was tested as a single dose to prime the response, with spleens harvested on day 16 for analysis. The combined vectors (ii) were tested according to a homologous vector prime-boost scheme, with boosting on day 29 and spleens harvested on day 36 for analysis. Responses to Gag, Pol and Nef antigens were determined by IFN-γ ELISpot assay and ICS/flow cytometry.
图30A至图30B示出了通过单个Ad5载体单独初免(A)或者同源Ad5载体初免-加强组合(B)中的任一种方式进行免疫而评估的免疫原性。Seq 94-F2A-95(tPA-SEQ ID NO:105)和Seq 98-F2A-99(tPA-SEQ ID NO:109)用作初免-加强对。通过IFN-γELISpot来测试载体在Balb/c小鼠中的免疫原性,该IFN-γELISpot具有用以下中的任一者刺激的肽:HIV-1G ag,(i)和(ii);Pol(蛋白酶/RT,(iii)和(iv);Pol(整合酶,(v)和(vi);或Nef(vii和viii)肽。Y轴表示对特定肽池刺激的IFN-γ应答的大小,表示为每106个脾细胞的斑点形成集落(SFC)的数量。通过减去无肽刺激的对照以排除非特异性应答来获得肽特异性值。X轴表示用于研究其肽特异性应答的体内初免的单个疫苗构建体。所有载体都是免疫原性的,诱导了对HIV-1 Gag应答的稳健应答、对Pol蛋白(蛋白酶、RT和整合酶)的较弱但可检测的应答。在该模型中没有检测到对HIV-Nef的应答,这可能是由于先前描述的Balb/c小鼠中HIV-1 Gag表位的免疫优势模式,并且反映了可在Balb/c小鼠中呈递的Nef表位的缺乏。通过用表达加强序列的Ad5载体进行同源加强来增强应答。Figures 30A-30B show the immunogenicity evaluated by immunization with either a single Ad5 vector alone (A) or a homologous Ad5 vector prime-boost combination (B). Seq 94-F2A-95 (tPA-SEQ ID NO: 105) and Seq 98-F2A-99 (tPA-SEQ ID NO: 109) were used as prime-boost pairs. The immunogenicity of the vectors was tested in Balb/c mice by IFN-γ ELISpot with peptides stimulated with either: HIV-1 Gag, (i) and (ii); Pol (Protease/RT, (iii) and (iv); Pol (Integrase, (v) and (vi); or Nef (vii and viii) peptides. The Y-axis represents the magnitude of the IFN-γ response to stimulation with a specific peptide pool, expressed as the number of spot-forming colonies (SFC) per 106 splenocytes. Peptide-specific values were obtained by subtracting the control without peptide stimulation to exclude nonspecific responses. The X-axis represents the individual vaccine constructs used for in vivo priming to study their peptide-specific responses. All vectors were immunogenic, inducing robust responses to HIV-1 Gag responses, weaker but detectable responses to Pol proteins (Protease, RT and Integrase). No responses to HIV-Nef were detected in this model, which may be due to the previously described HIV-1 in Balb/c mice. The immunodominant pattern of the Gag epitope reflects the lack of Nef epitopes that can be presented in Balb/c mice. The response was enhanced by homologous boosting with an Ad5 vector expressing a booster sequence.
图31A至图31B示出了通过单个Ad5载体单独初免或者同源Ad5载体初免-加强组合中的任一种方式进行免疫而评估的免疫原性。Seq 96-F2A-97(tPA-SEQ ID NO:107)和Seq100-F2A-101(tPA-SEQ ID NO:111)用作初免加强对。通过IFN-γELISpot来测试载体在Balb/c小鼠中的免疫原性,该IFN-γELISpot具有用以下中的任一者刺激的肽:HIV-1Pol(蛋白酶/RT,(i)和(ii);Pol(整合酶,(iii)和(iv);或Nef(v和vi)肽。Y轴表示对特定肽池刺激的IFN-γ应答的大小,表示为每106个脾细胞的斑点形成集落(SFC)的数量。通过减去无肽刺激的对照以排除非特异性应答来获得肽特异性值。X轴表示用于研究其肽特异性应答的体内初免的单个疫苗构建体。所有载体都是免疫原性的,诱导对HIV-1Pol(特别是蛋白酶和RT肽)的稳健应答、对整合酶肽的能够检测的较弱应答。对蛋白酶和RT观察到的应答弱于先前未组合时对Seq 96和Seq 97观察到的应答。然而,在按顺序给药Seq96-F2A-97和Seq100-F2A-101时增强了免疫原性应答。在该模型中没有检测到对HIV-Nef的应答,这可能是由于先前描述的Balb/c小鼠中HIV-1 Gag表位的免疫优势模式,并且反映了可在Balb/c小鼠中呈递的Nef表位的缺乏。Figures 31A-31B show the immunogenicity evaluated by immunization with either a single Ad5 vector prime alone or a homologous Ad5 vector prime-boost combination. Seq 96-F2A-97 (tPA-SEQ ID NO: 107) and Seq100-F2A-101 (tPA-SEQ ID NO: 111) were used as the prime-boost pair. The immunogenicity of the vectors was tested in Balb/c mice by IFN-γ ELISpot with peptides stimulated with either: HIV-1 Pol (protease/RT, (i) and (ii); Pol (integrase, (iii) and (iv); or Nef (v and vi) peptides. The Y-axis represents the magnitude of the IFN-γ response to stimulation with a particular peptide pool, expressed as the number of spot-forming colonies (SFC) per 106 splenocytes. Peptide-specific values were obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. The X-axis represents the individual vaccine constructs used for in vivo priming to study their peptide-specific responses. All vectors were immunogenic, inducing robust responses to HIV-1 Pol (particularly protease and RT peptides), and detectable weaker responses to integrase peptides. The responses observed for protease and RT were weaker than those previously observed for Seq 96 and Seq 96 when not combined. 97. However, the immunogenic response was enhanced when Seq96-F2A-97 and Seq100-F2A-101 were administered sequentially. No response to HIV-Nef was detected in this model, which may be due to the previously described immunodominant pattern of HIV-1 Gag epitopes in Balb/c mice and reflects the lack of Nef epitopes that can be presented in Balb/c mice.
图32A至图32C示出了在用单个载体Seq 94-F2A-95(tPA-SEQ ID NO:105)或Seq98-F2A-99(tPA-SEQ ID NO:109)进行疫苗接种以及同源初免-加强后,通过胞内细胞因子染色(ICS)的HIV-1 Gag免疫原性。Y轴表示CD8+(图32A i、ii和图32C iii)或CD4+(图32Biv、v和图32C vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Gag特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-Gag特异性值。在对疫苗接种的应答中产生了强CD4+和CD8+ T细胞应答,证实了在CD8+ T细胞中最稳健的多功能性。同源初免-加强增强了CD8+ T细胞应答的多功能性。Figures 32A to 32C show HIV-1 Gag immunogenicity by intracellular cytokine staining (ICS) after vaccination with a single vector Seq 94-F2A-95 (tPA-SEQ ID NO: 105) or Seq98-F2A-99 (tPA-SEQ ID NO: 109) and homologous priming-boosting. The Y axis represents the proportion of CD8+ (Figure 32A i, ii and Figure 32C iii) or CD4+ (Figure 32Biv, v and Figure 32C vi) T cells that express HIV-Gag-specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as a single cytokine or a combination of cytokines), as shown on the X axis. HIV-Gag-specific values are obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. Strong CD4+ and CD8+ T cell responses were generated in response to vaccination, confirming the most robust multifunctionality in CD8+ T cells. Homologous prime-boost enhances the polyfunctionality of CD8+ T cell responses.
图33A至图33C示出了在用单个载体Seq 94-F2A-95(tPA-SEQ ID NO:105)或Seq98-F2A-99(tPA-SEQ ID NO:109)进行疫苗接种以及同源初免-加强后,通过ICS的HIV-1Pol(蛋白酶和RT)免疫原性。Y轴表示CD8+(图33A i、ii和图33C iii)或CD4+(图33B iv、v和图33C vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Pol(蛋白酶和RT)特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-Pol(蛋白酶和RT)特异性值。在对疫苗接种的应答中产生了CD4+和CD8+ T细胞应答。这些应答弱于Gag应答并且往往是单官能的,具有有限的加强。Figures 33A to 33C show HIV-1Pol (protease and RT) immunogenicity by ICS after vaccination with single vectors Seq 94-F2A-95 (tPA-SEQ ID NO: 105) or Seq98-F2A-99 (tPA-SEQ ID NO: 109) and homologous priming-boosting. The Y axis represents the proportion of CD8+ (Figure 33A i, ii and Figure 33C iii) or CD4+ (Figure 33B iv, v and Figure 33C vi) T cells that express HIV-Pol (protease and RT) specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as individual cytokines or combinations of cytokines), as shown on the X axis. HIV-Pol (protease and RT) specific values were obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. CD4+ and CD8+ T cell responses were generated in response to vaccination. These responses are weaker than Gag responses and tend to be monofunctional, with limited enhancement.
图34A至图34C示出了在用单个载体Seq 94-F2A-95(tPA-SEQ ID NO:105)或Seq98-F2A-99(tPA-SEQ ID NO:109)进行疫苗接种以及同源初免-加强后,通过ICS的HIV-1Pol(整合酶)免疫原性。Y轴表示CD8+(图34A i、ii和图34C iii)或CD4+(图34B iv、v和图34Cvi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Pol(整合酶)特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-Pol(整合酶)特异性值。在对疫苗接种的应答中产生了CD4+和CD8+ T细胞应答。这些应答弱于Gag应答并且往往是单官能的,具有有限的加强。Figures 34A to 34C show HIV-1Pol (integrase) immunogenicity by ICS after vaccination with a single vector Seq 94-F2A-95 (tPA-SEQ ID NO: 105) or Seq98-F2A-99 (tPA-SEQ ID NO: 109) and homologous priming-boosting. The Y axis represents the proportion of CD8+ (Figure 34A i, ii and Figure 34C iii) or CD4+ (Figure 34B iv, v and Figure 34Cvi) T cells that express HIV-Pol (integrase) specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as individual cytokines or combinations of cytokines), as shown on the X axis. HIV-Pol (integrase) specific values are obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. CD4+ and CD8+ T cell responses were generated in response to vaccination. These responses are weaker than Gag responses and tend to be monofunctional, with limited enhancement.
图35A至图35C示出了在用单个载体Seq 94-F2A-95(tPA-SEQ ID NO:105)或Seq98-F2A-99(tPA-SEQ ID NO:109)进行疫苗接种以及同源初免-加强后,通过ICS的HIV-1Nef免疫原性。Y轴表示CD8+(图35A i、ii和图35C iii)或CD4+(图35B iv、v和图35C vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Nef特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-1Nef特异性值。在对疫苗接种的应答中产生了非常低比例的CD4+和CD8+ T细胞应答。这些应答弱于Gag应答并且往往是单官能的,具有有限的加强。Figures 35A to 35C show HIV-1 Nef immunogenicity by ICS after vaccination with a single vector Seq 94-F2A-95 (tPA-SEQ ID NO: 105) or Seq98-F2A-99 (tPA-SEQ ID NO: 109) and homologous priming-boosting. The Y axis represents the proportion of CD8+ (Figure 35A i, ii and Figure 35C iii) or CD4+ (Figure 35B iv, v and Figure 35C vi) T cells that express HIV-Nef-specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as a combination of individual cytokines or cytokines), as shown on the X axis. HIV-1 Nef-specific values were obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. Very low proportions of CD4+ and CD8+ T cell responses were generated in response to vaccination. These responses are weaker than Gag responses and tend to be monofunctional, with limited enhancement.
图36A至图36C示出了在用单个载体Seq 96-F2A-97(tPA-SEQ ID NO:107)和Seq100-F2A-101(tPA-SEQ ID NO:111)进行疫苗接种以及同源载体初免-加强后,通过ICS的HIV-1Pol(蛋白酶和RT)免疫原性。Y轴表示CD8+(图36A i、ii和图36C iii)或CD4+(图36Biv、v和图36C vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Pol(蛋白酶和RT)特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-1Pol(蛋白酶和RT)特异性值。在对疫苗接种的应答中产生了CD4+和CD8+应答。Seq 100-F2A-101(tPA-SEQ ID NO:111)显示具有多功能性的强免疫原性(产生≥2个细胞因子)。用表达融合多肽的载体进行同源载体初免-加强,增强了CD4+和CD8+ T细胞应答。Figures 36A to 36C show HIV-1Pol (protease and RT) immunogenicity by ICS after vaccination with single vectors Seq 96-F2A-97 (tPA-SEQ ID NO: 107) and Seq100-F2A-101 (tPA-SEQ ID NO: 111) and homologous vector priming-boosting. The Y axis represents the proportion of CD8+ (Figure 36A i, ii and Figure 36C iii) or CD4+ (Figure 36Biv, v and Figure 36C vi) T cells that express HIV-Pol (protease and RT) specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as individual cytokines or combinations of cytokines), as shown on the X axis. HIV-1Pol (protease and RT) specific values were obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. CD4+ and CD8+ responses were generated in response to vaccination. Seq 100-F2A-101 (tPA-SEQ ID NO: 111) showed strong immunogenicity with multifunctionality (production of ≥ 2 cytokines). Homologous vector prime-boost with vector expressing fusion polypeptide enhanced CD4+ and CD8+ T cell responses.
图37A至图37C示出了在用单个载体Seq 96-F2A-97(tPA-SEQ ID NO:107)和Seq100-F2A-101(tPA-SEQ ID NO:111)进行疫苗接种以及同源载体初免-加强后,通过ICS的HIV-1Pol(整合酶)免疫原性。Y轴表示CD8+(图37A i、ii和图37C iii)或CD4+(图37B iv、v和图37C vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Pol(整合酶)特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-1Pol(整合酶)特异性值。在对疫苗接种的应答中产生了CD4+和CD8+应答。Seq 100-F2A-101(tPA-SEQ ID NO:111)显示具有多功能性的强免疫原性(产生≥2个细胞因子)。用表达融合多肽的载体进行同源载体初免-加强,增强了CD4+和CD8+ T细胞应答。Figures 37A to 37C show HIV-1Pol (integrase) immunogenicity by ICS after vaccination with single vectors Seq 96-F2A-97 (tPA-SEQ ID NO: 107) and Seq100-F2A-101 (tPA-SEQ ID NO: 111) and homologous vector priming-boosting. The Y axis represents the proportion of CD8+ (Figure 37A i, ii and Figure 37C iii) or CD4+ (Figure 37B iv, v and Figure 37C vi) T cells that express HIV-Pol (integrase) specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as individual cytokines or combinations of cytokines), as shown on the X axis. HIV-1Pol (integrase) specific values are obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. CD4+ and CD8+ responses were generated in response to vaccination. Seq 100-F2A-101 (tPA-SEQ ID NO: 111) showed strong immunogenicity with multifunctionality (production of ≥ 2 cytokines). Homologous vector prime-boost with vector expressing fusion polypeptide enhanced CD4+ and CD8+ T cell responses.
图38A至图38C示出了在用单个载体Seq 96-F2A-97(tPA-SEQ ID NO:107)和Seq100-F2A-101(tPA-SEQ ID NO:111)进行疫苗接种以及同源载体初免-加强后,通过ICS的HIV-1Nef免疫原性。Y轴表示CD8+(图38A i、ii和图38C iii)或CD4+(图38B iv、v和图38Cvi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独的细胞因子或细胞因子的组合)而表现出HIV-Nef特异性应答,如X轴上所示。通过减去无肽刺激的对照以排除非特异性应答来获得HIV-1Nef特异性值。在对疫苗接种的应答中产生了低水平的CD4+和CD8+ T细胞应答,并且在CD4 T细胞中观察到更多的应答。Seq 100-F2A-101(tPA-SEQ ID NO:111)证实并诱导了主要的单核因子产生。用表达融合多肽的载体进行同源载体初免-加强,增强了CD4+和CD8+ T细胞应答。Figures 38A to 38C show HIV-1 Nef immunogenicity by ICS after vaccination with single vectors Seq 96-F2A-97 (tPA-SEQ ID NO: 107) and Seq100-F2A-101 (tPA-SEQ ID NO: 111) and homologous vector priming-boosting. The Y axis represents the proportion of CD8+ (Figure 38A i, ii and Figure 38C iii) or CD4+ (Figure 38B iv, v and Figure 38Cvi) T cells, which express HIV-Nef-specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as a combination of individual cytokines or cytokines), as shown on the X axis. HIV-1 Nef-specific values are obtained by subtracting controls without peptide stimulation to exclude nonspecific responses. Low levels of CD4+ and CD8+ T cell responses were generated in response to vaccination, and more responses were observed in CD4 T cells. Seq 100-F2A-101 (tPA-SEQ ID NO: 111) demonstrated and induced major monokine production. Homologous vector prime-boost with vector expressing fusion polypeptide enhanced CD4+ and CD8+ T cell responses.
图39提供了为moDC-T细胞初免测定而建立的方案的示意图,这些测定用于测试所有保守区疫苗构建体的免疫原性,随后使用384孔ELISpot测定进行单个表位作图。Figure 39 provides a schematic diagram of the protocol established for the moDC-T cell priming assays used to test the immunogenicity of all conserved region vaccine constructs followed by individual epitope mapping using a 384-well ELISpot assay.
图40提供了在用moDC体外初免后,对来自N=93个参与者的PBMC的离体分析中的应答广度的总结。热图代表在用Ad5-空载体MOI 500(疫苗前)或表达SEQ ID NO:105、107、109和111(各自的MOI=500)的Ad5病毒载体(疫苗后)转导的moDC体外初免后,T细胞对Gag、Pol和Nef保守性抗原的应答广度。热图中的每个匹配行表示来自单个参与者的应答,并且应答广度被分类为0、1-3、4-6、7-9、10-12或13-16。如实施例9中详细描述的,阳性ELISpot应答被定义为>3倍背景水平。Figure 40 provides a summary of the breadth of responses in ex vivo analysis of PBMCs from N = 93 participants after in vitro priming with moDC. The heat map represents the breadth of T cell responses to Gag, Pol and Nef conserved antigens after in vitro priming with Ad5-empty vector MOI 500 (before vaccine) or Ad5 viral vectors expressing SEQ ID NO: 105, 107, 109 and 111 (MOI = 500, respectively). Each matching row in the heat map represents a response from a single participant, and the breadth of the response is classified as 0, 1-3, 4-6, 7-9, 10-12 or 13-16. As described in detail in Example 9, a positive ELISpot response is defined as >3 times the background level.
图41示出了在N=93个参与者中用Ad5病毒载体(其表达空载体(疫苗前)或保守区疫苗(SEQ ID NO:105、107、109和111,各自的MOI=500(疫苗后))转导的moDC初免后,对靶向HIV-1 Gag、Pol和Nef抗原的免疫应答广度的表征。还列举了在用疫苗免疫原序列体外初免后,对每种抗原中的≥3或0个表位表现出应答的参与者的分数。阳性ELISpot应答被定义为>3倍背景水平。每个点代表一个供体。Wilcoxon配对符号秩检验****p<0.0001。Figure 41 shows characterization of the breadth of immune responses targeting HIV-1 Gag, Pol, and Nef antigens following priming with moDC transduced with Ad5 viral vectors expressing either empty vector (pre-vaccine) or conserved region vaccines (SEQ ID NOs: 105, 107, 109, and 111, each at MOI=500 (post-vaccine)) in N=93 participants. Also listed are the fractions of participants that exhibited responses to ≥3 or 0 epitopes in each antigen following in vitro priming with the vaccine immunogen sequences. Positive ELISpot responses were defined as >3 times background levels. Each point represents one donor. Wilcoxon matched pairs signed rank test ****p<0.0001.
图42示出了对Gag(·)、Pol(▲)和Nef(▼)的应答广度,定义为在将PBMC与经Ad5疫苗载体转导的自体moDC(其表达保守区构建体(SEQ ID NO:105、107、109和111,各自的MOI=500))共培养后第10天,通过IFN-γELISpot测定评估的重新识别的肽的数目(不包括预先存在的基线应答)。每个点代表一个供体。示出了具有四分位距的中值。Figure 42 shows the breadth of responses to Gag (·), Pol (▲) and Nef (▼), defined as the number of newly recognized peptides assessed by IFN-γ ELISpot assay (excluding pre-existing baseline responses) at day 10 after co-culturing PBMCs with autologous moDCs transduced with Ad5 vaccine vectors expressing conserved region constructs (SEQ ID NOs: 105, 107, 109 and 111, each at MOI = 500). Each point represents one donor. The median with interquartile range is shown.
图43A至图43B示出了对靶细胞内的Gag-p24进行体外HIV-1病毒抑制测定染色的结果。自体CD4+ T细胞用HIV-1BaL进行体外感染,将其单独培养,或者在存在经疫苗或空载体初免的CFSE标记的CD8+ T细胞的情况下培养3天,并使用流式细胞术分析感染。代表性的流式细胞术图示出了限定靶细胞(CFSE-CD8-细胞)内Gag p24+感染的CD4+ T细胞(具有下调的表面CD4表达的HIV-1 Gag+细胞)的门控策略。Figure 43A to Figure 43B show the results of in vitro HIV-1 virus inhibition assay staining for Gag-p24 in target cells. Autologous CD4+ T cells were infected in vitro with HIV-1BaL, cultured alone, or cultured for 3 days in the presence of CFSE-labeled CD8+ T cells primed with vaccine or empty vector, and analyzed for infection using flow cytometry. Representative flow cytometry diagrams illustrate the gating strategy for CD4+ T cells (HIV-1 Gag+ cells with downregulated surface CD4 expression) infected with Gag p24+ in target cells (CFSE-CD8- cells).
图44A至图44B示出了在与富集的CD8+ T细胞共培养3天后,残留的HIV-1 Gag+CD4-T细胞的分数,这些富集的CD8+T细胞是在用疫苗(SEQ ID NO:105、107、109和111或空载体对照,各自的MOI=500)初免后获得的,其中N=51个参与者被标准化为在没有CD8+ T细胞的情况下感染所培养的CD4+ T细胞。根据细胞可用性,每个条件都以技术重复或一式三份完成。还示出了残留Gag+细胞%(图44A)和总应答广度、Gag应答广度和Pol应答广度(图44B)之间的相关性。在无需Bonferroni调整的情况下通过双侧Spearman秩相关性测试评估相关性。Figures 44A to 44B show the fraction of HIV-1 Gag+CD4-T cells remaining after 3 days of co-culture with enriched CD8+ T cells, which were obtained after primary immunization with vaccines (SEQ ID NO: 105, 107, 109 and 111 or empty vector control, each with MOI = 500), where N = 51 participants were standardized to infect cultured CD4+ T cells in the absence of CD8+ T cells. Depending on cell availability, each condition was completed in technical replicates or triplicates. The correlation between residual Gag+ cell % (Figure 44A) and total response breadth, Gag response breadth and Pol response breadth (Figure 44B) is also shown. Correlation was assessed by a two-sided Spearman rank correlation test without Bonferroni adjustment.
图45A至图45B示出了在将PBMC与经Ad5疫苗载体转导的自体moDC(其表达保守区构建体SEQ ID NO:82-89(图45A)和SEQ ID NO:90-93(图45B),各自的MOI=500)共培养后第10天,通过IFN-γELISpot测定评估的对Gag、Pol和Nef的应答广度。每个点代表一个供体。示出了具有四分位距的中值。Figures 45A-45B show the breadth of responses to Gag, Pol and Nef assessed by IFN-γ ELISpot assay at day 10 after co-culturing PBMCs with autologous moDCs transduced with Ad5 vaccine vectors expressing conserved region constructs SEQ ID NOs: 82-89 (Figure 45A) and SEQ ID NOs: 90-93 (Figure 45B), each at MOI = 500. Each point represents one donor. The median with interquartile range is shown.
图46提供了在非人灵长类动物(NHP)中用沙粒病毒载体进行初免-加强的免疫方案的示意图。用沙粒病毒载体通过肌内(I.M.)途径免疫来自印度的健康恒河猴。将表达Gag和Env的载体(TT2(复制减毒型皮钦德病毒)和TT1(复制减毒型LCMV))施用于左四头肌,而将表达Pol的载体(TT2和TT1)施用于右四头肌。施用剂量如下:1×106TT2 Gag、Env和Pol1/Pol2载体的有复制能力的病毒颗粒(RCV),4×106TT1 Gag、Env的RCV,和2×106TT1 Pol1/Pol2的RCV。在安慰剂组中,对NHP施用由10mM HEPES、150mM NaCl、20mM甘氨酸和0.1%恒河猴血清白蛋白组成的安慰剂缓冲溶液。通过IFN-γELISpot测定来测量针对Gag、Env和Pol抗原的应答。Figure 46 provides a schematic diagram of the prime-boost immunization scheme with arenavirus vectors in non-human primates (NHPs). Healthy rhesus macaques from India were immunized with arenavirus vectors by the intramuscular (IM) route. Vectors expressing Gag and Env (TT2 (replication-attenuated Pichinde virus) and TT1 (replication-attenuated LCMV)) were administered to the left quadriceps, while vectors expressing Pol (TT2 and TT1) were administered to the right quadriceps. The doses administered were as follows: 1×10 6 replication-competent viral particles (RCV) of TT2 Gag, Env, and Pol1/Pol2 vectors, 4×10 6 RCVs of TT1 Gag, Env, and 2×10 6 RCVs of TT1 Pol1/Pol2. In the placebo group, NHPs were administered a placebo buffer solution consisting of 10 mM HEPES, 150 mM NaCl, 20 mM glycine, and 0.1% rhesus serum albumin. Responses to Gag, Env and Pol antigens were measured by IFN-γ ELISpot assay.
图47A至图47B。47A.通过对分离自NHP外周血的PBMC进行IFN-γELISpot来评估对Gag、Env和Pol的总应答的时间过程,其中在第1次疫苗剂量后间隔两个四周直至第32周。示出了具有四分位距的中值。47B.图47A中的NHP应答根据IFN-γ-ELISpot应答峰值大小的大小分别低于或高于1000个SFU/106PBMC而被分类为中度或高度应答者。每条线代表接受沙粒病毒疫苗载体的一只动物。每次免疫后的峰值应答在随后的加强中保持恒定。FIG. 47A-B. 47A. Time course of total responses to Gag, Env and Pol assessed by IFN-γ ELISpot of PBMCs isolated from NHP peripheral blood at two four-week intervals after the first vaccine dose up to week 32. Median values with interquartile ranges are shown. 47B. NHP responses in FIG. 47A were classified as moderate or high responders based on the magnitude of the peak IFN-γ-ELISpot response below or above 1000 SFU/10 6 PBMCs, respectively. Each line represents one animal that received the arenavirus vaccine vector. Peak responses after each immunization remained constant in subsequent boosts.
图48A至图48D示出了在疫苗剂量1、2、3和4后两周,通过对分离自NHP外周血的PBMC进行IFN-γELISpot来评估对Gag(B)、Env(C)和Pol(D)的总应答(A)的大小。阳性应答的阈值用虚线表示,并设定为观察到至少50个SFU/106PBMC的Gag、Env和Pol,以及150个SFU/106PBMC的总SIV特异性应答。每个符号代表一个NHP。示出了具有四分位距的中值。在四次剂量的异源疫苗后,在24个NHP中的至少21个NHP中观察到对Gag、Env和Pol的阳性应答(应答率大于或等于87.5%)。在剂量2(TT1)和剂量3(TT2)后观察到的Gag和Pol应答大小在每次随后的疫苗加强中保持稳定。Figures 48A to 48D show the magnitude of the total response (A) to Gag (B), Env (C) and Pol (D) assessed by IFN-γ ELISpot of PBMCs isolated from peripheral blood of NHPs two weeks after vaccine doses 1, 2, 3 and 4. The threshold for positive responses is indicated by dashed lines and is set to the observation of at least 50 SFU/10 6 PBMCs for Gag, Env and Pol, and 150 SFU/10 6 PBMCs for total SIV-specific responses. Each symbol represents one NHP. The median with interquartile range is shown. After four doses of heterologous vaccine, positive responses to Gag, Env and Pol were observed in at least 21 of 24 NHPs (response rate greater than or equal to 87.5%). The magnitude of the Gag and Pol responses observed after dose 2 (TT1) and dose 3 (TT2) remained stable in each subsequent vaccine boost.
图49A至图49D示出了在疫苗加强剂量2(三角形)、剂量3(正方形)和剂量4(菱形)后2周的总SIV(A)、Gag(B)、Env(C)和Pol(D)特异性IFN-γ应答广度。通过Wilcoxon配对符号秩检验进行统计学分析。数据被表示为中值±四分位距(IQR)。Figure 49A to Figure 49D show the total SIV (A), Gag (B), Env (C) and Pol (D) specific IFN-γ response breadth 2 weeks after vaccine booster dose 2 (triangle), dose 3 (square) and dose 4 (diamond). Statistical analysis was performed by Wilcoxon paired signed rank test. Data are expressed as median ± interquartile range (IQR).
图50A至图50C示出了(A)攻击后第0-40周内的血浆SIV病毒载量的时间过程;(B)攻击后第2周的峰值病毒载量;(C)攻击后第10-40周内测量的设定点病毒载量。安慰剂组显示为实心三角形,并且TT2/TT1疫苗组显示为实心圆形。数据被表示为中值±SEM。通过Mann-Whitney t检验,B和C中*p<0.05并且**p<0.01。中值病毒载量(VL)在图B和图C中示于各组上方。Figure 50A to Figure 50C show the time course of plasma SIV viral load in (A) week 0-40 after attack; (B) peak viral load in week 2 after attack; (C) set point viral load measured in week 10-40 after attack. The placebo group is shown as a solid triangle, and the TT2/TT1 vaccine group is shown as a solid circle. Data are expressed as median ± SEM. By Mann-Whitney t test, *p<0.05 and **p<0.01 in B and C. Median viral load (VL) is shown above each group in Figure B and Figure C.
图51示出了复制减毒型沙粒病毒载体的免疫印迹分析。通过Gag表位p24(mAb抗HIV1 p24;Abcam)的免疫印迹染色,测定来自复制减毒型LCMV和复制减毒型PICV载体的原材料(p1)的Gag/Nef/Pol融合多肽的转基因表达。对三个生物学重复(1、2、3)的全细胞裂解物进行分析。TT1=复制减毒型LCMV;TT2=复制减毒型PICV。GNP=Gag/Nef/Pol;PN=Pol/Nef。TT1-HIV-GNP1/PN1(SEQ ID NO:98和100);TT1-HIV-GNP2/PN2(SEQ ID NO:99和101);TT2-HIV-GNP1/PN1(SEQ ID NO:82和86);TT2-HIV-GNP2/PN2(SEQ ID NO:83和87)。Figure 51 shows immunoblot analysis of replication attenuated arenavirus vectors. Transgenic expression of Gag/Nef/Pol fusion polypeptides from raw materials (p1) of replication attenuated LCMV and replication attenuated PICV vectors was determined by immunoblot staining for Gag epitope p24 (mAb anti-HIV1 p24; Abeam). Whole cell lysates from three biological replicates (1, 2, 3) were analyzed. TT1 = replication attenuated LCMV; TT2 = replication attenuated PICV. GNP = Gag/Nef/Pol; PN = Pol/Nef. TT1-HIV-GNP1/PN1 (SEQ ID NOs: 98 and 100); TT1-HIV-GNP2/PN2 (SEQ ID NOs: 99 and 101); TT2-HIV-GNP1/PN1 (SEQ ID NOs: 82 and 86); TT2-HIV-GNP2/PN2 (SEQ ID NOs: 83 and 87).
图52示出了复制减毒型沙粒病毒载体的免疫印迹分析。通过Gag表位p24(mAb抗HIV1 p24;Abcam)的免疫印迹染色,测定来自复制减毒型LCMV和复制减毒型PICV HIV免疫原1载体的原材料(p1)的Gag/Nef/Pol的转基因表达。对三个生物学重复(1、2、3)的全细胞裂解物进行分析。TT1=复制减毒型LCMV;TT2=复制减毒型PICV。GNP=Gag/Nef/Pol;PN=Pol/Nef。Figure 52 shows immunoblot analysis of replication attenuated arenavirus vectors. Transgenic expression of Gag/Nef/Pol from raw material (p1) of replication attenuated LCMV and replication attenuated PICV HIV Immunogen 1 vectors was determined by immunoblot staining for Gag epitope p24 (mAb anti-HIV1 p24; Abeam). Whole cell lysates from three biological replicates (1, 2, 3) were analyzed. TT1 = replication attenuated LCMV; TT2 = replication attenuated PICV. GNP = Gag/Nef/Pol; PN = Pol/Nef.
图53示出了对TT1-HIV-GNP1/PN1(具有编码SEQ ID NO:98和100的融合多肽的转基因)的转基因稳定性分析。示出了对4个生物学重复(1-4)和所示传代水平的转基因PCR结果。在视觉上评估显示≥50%全长转基因的最后一次传代。Figure 53 shows transgene stability analysis for TT1-HIV-GNP1/PN1 (a transgene encoding a fusion polypeptide of SEQ ID NO: 98 and 100). Transgene PCR results for 4 biological replicates (1-4) and the indicated passage levels are shown. The last passage showing ≥50% full-length transgene was visually assessed.
图54示出了对TT1-HIV-GNP2/PN2(具有编码SEQ ID NO:99和101的融合多肽的转基因)的转基因稳定性分析。示出了对3个生物学重复(1-3)和所示传代水平的转基因PCR结果。在视觉上评估显示≥50%全长转基因的最后一次传代。Figure 54 shows transgene stability analysis of TT1-HIV-GNP2/PN2 (a transgene encoding a fusion polypeptide of SEQ ID NO: 99 and 101). Transgene PCR results for 3 biological replicates (1-3) and the indicated passage levels are shown. The last passage showing ≥50% full-length transgene was visually assessed.
图55示出了对TT2-HIV-GNP1/PN1(具有编码融合多肽SEQ ID NO:94和95的转基因)的转基因稳定性分析。示出了对3个生物学重复(1-3)和所示传代水平的转基因PCR结果。在视觉上评估显示≥50%全长转基因的最后一次传代。Figure 55 shows transgene stability analysis for TT2-HIV-GNP1/PN1 (with transgenes encoding fusion polypeptides SEQ ID NOs: 94 and 95). Transgene PCR results for 3 biological replicates (1-3) and the indicated passage levels are shown. The last passage showing ≥50% full-length transgene was visually assessed.
图56示出了对TT2-HIV-GNP2/PN2(具有编码融合多肽SEQ ID NO:95和97的转基因)的转基因稳定性分析。示出了对3个生物学重复(1-3)和所示传代水平的转基因PCR结果。在传代水平4中断传代。在视觉上评估显示≥50%全长转基因的(大概)最后一次传代。Figure 56 shows transgene stability analysis of TT2-HIV-GNP2/PN2 (with transgenes encoding fusion polypeptides SEQ ID NOs: 95 and 97). Transgene PCR results for 3 biological replicates (1-3) and the indicated passage levels are shown. Passages were interrupted at passage level 4. The (approximately) last passage showing ≥50% full-length transgene was visually assessed.
图57示出了复制减毒型沙粒病毒载体的免疫印迹分析。通过Gag表位p24(mAb抗HIV1 p24;Abcam)的免疫印迹染色,测定来自复制减毒型LCMV和复制减毒型PICV HIV免疫原2载体的原材料(P1)和BDS等同物传代(P4)的Gag/Pol的转基因表达。对生物学重复(TT1-HIV(C2)-GP1/PN1的1、2、3、4;TT1-HIV(C2)-GP2/PN2的1、2)或代表性样品(TT2-HIV(C2)-GP1/PN1和TT2-HIV(C2)-GP2/PN2)的全细胞裂解物进行分析。TT1=复制减毒型LCMV;TT2=复制减毒型PICV。GP=Gag/Pol;PN=Pol/Nef。对照=阳性(+)对照表示受TT1-HIV免疫原2或TT2-HIV免疫原2感染的细胞裂解物;阴性(-)对照表示未感染的细胞。Figure 57 shows immunoblot analysis of replication attenuated arenavirus vectors. Transgenic expression of Gag/Pol from raw materials (P1) and BDS equivalent passages (P4) of replication attenuated LCMV and replication attenuated PICV HIV Immunogen 2 vectors was determined by immunoblot staining for the Gag epitope p24 (mAb anti-HIV1 p24; Abeam). Whole cell lysates of biological replicates (1, 2, 3, 4 of TT1-HIV(C2)-GP1/PN1; 1, 2 of TT1-HIV(C2)-GP2/PN2) or representative samples (TT2-HIV(C2)-GP1/PN1 and TT2-HIV(C2)-GP2/PN2) were analyzed. TT1 = replication attenuated LCMV; TT2 = replication attenuated PICV. GP = Gag/Pol; PN = Pol/Nef. Control = Positive (+) control represents cell lysates infected with TT1-HIV immunogen 2 or TT2-HIV immunogen 2; negative (-) control represents uninfected cells.
图58示出了对TT1-HIV(C2)-GP1/PN1的转基因稳定性分析。A表示对5个生物学重复(1-5)和所示传代水平的转基因PCR结果。全长PCR产物的预期大小分别为1359bp(LCMV-GP1 NP片段)和1366bp(LCMV-PN1GP片段)。在视觉上评估显示≥50%全长转基因的最后一次传代。Figure 58 shows the transgenic stability analysis of TT1-HIV (C2) -GP1 / PN1. A represents the transgenic PCR results of 5 biological replicates (1-5) and the passage levels shown. The expected sizes of the full-length PCR products are 1359bp (LCMV-GP1 NP fragment) and 1366bp (LCMV-PN1 GP fragment) respectively. Visually evaluate the last passage showing ≥ 50% full-length transgenic.
图59示出了对TT1-HIV(C2)-GNP2/PN2的转基因稳定性分析。A表示对4个生物学重复(1-4)和所示传代水平的转基因PCR结果。全长PCR产物的预期大小分别为1344bp(LCMV-GP2 NP片段)和1364bp(LCMV-PN2 GP片段)。在视觉上评估显示≥50%全长转基因的最后一次传代。Figure 59 shows the transgenic stability analysis of TT1-HIV (C2) -GNP2 / PN2. A represents the transgenic PCR results of 4 biological replicates (1-4) and the level of passage shown. The expected size of the full-length PCR product is 1344bp (LCMV-GP2 NP fragment) and 1364bp (LCMV-PN2 GP fragment) respectively. Visually evaluate the last passage showing ≥ 50% full-length transgenic.
图60示出了对TT2-HIV(C2)-GP1/PN1的转基因稳定性分析。A表示对4个生物学重复(1-3和9)和所示传代水平的转基因PCR结果。全长PCR产物的预期大小分别为1456bp(PICV-GP1 NP片段)和1496bp(PICV-PN1GP片段)。在视觉上评估显示≥50%全长转基因的最后一次传代。Figure 60 shows the transgenic stability analysis of TT2-HIV (C2) -GP1/PN1. A represents the transgenic PCR results of 4 biological replicates (1-3 and 9) and the level of passage shown. The expected size of the full-length PCR product is 1456bp (PICV-GP1 NP fragment) and 1496bp (PICV-PN1GP fragment) respectively. Visually evaluate the last passage showing ≥50% full-length transgenic.
图61示出了对TT2-HIV(C2)-GP2/PN2的转基因稳定性分析。示出了对3个生物学重复(1-3)和所示传代水平的转基因PCR结果。全长PCR产物的预期大小分别为1450bp(PICV-GP2 NP片段)和1505bp(PICV-PN2 GP片段)。在传代水平6中断传代。在视觉上评估显示≥50%全长转基因的(大概)最后一次传代。Figure 61 shows the transgenic stability analysis of TT2-HIV (C2) -GP2/PN2. Shown are the transgenic PCR results for 3 biological replicates (1-3) and the level of passage shown. The expected size of the full-length PCR product is 1450bp (PICV-GP2 NP fragment) and 1505bp (PICV-PN2 GP fragment) respectively. The passage is interrupted at level 6 of passage. Visually evaluate the (approximately) last passage showing ≥50% full-length transgenic.
图62示出了评估TT2/TT1疫苗复制减毒型PICV/LCMV沙粒病毒初免-加强方案与免疫调节剂组合的组合的非人灵长类动物研究的示意图。每组有13只恒河猴。疫苗是指TT2(实心圆)和TT1(空心圆)的交替给药。在施用疫苗后,立即施用检查点抑制剂αPD1抗体(三角形)和αCTLA4抗体(正方形)。在每次疫苗剂量前一周施用FLT3L-Fc FLT3激动剂(黑线)。Figure 62 shows a schematic diagram of a non-human primate study evaluating the combination of the attenuated PICV/LCMV arenavirus primary-boost regimen and the combination of immunomodulators in the TT2/TT1 vaccine replication. Each group has 13 rhesus monkeys. The vaccine refers to the alternating administration of TT2 (solid circles) and TT1 (open circles). After the vaccine is administered, the checkpoint inhibitor αPD1 antibody (triangle) and αCTLA4 antibody (square) are immediately administered. FLT3L-Fc FLT3 agonist (black line) is administered one week before each vaccine dose.
图63示出了通过对分离自NHP外周血的PBMC进行IFN-γELISpot来评估对Gag、Env和Pol的总应答动力学,其中在第1次疫苗剂量后间隔两周直至第16周。示出了具有四分位距的中值。通过重复测量的双向ANOVA和Dunnett's后检验进行统计分析。对于组合组与单独疫苗的比较,*p<0.05,**p<0.01,***p<0.001。Figure 63 shows the overall response kinetics to Gag, Env and Pol assessed by IFN-γ ELISpot of PBMCs isolated from NHP peripheral blood at two-week intervals after the first vaccine dose until week 16. Median values with interquartile ranges are shown. Statistical analysis was performed by two-way ANOVA with repeated measures and Dunnett's post-test. *p<0.05, **p<0.01, ***p<0.001 for comparison of the combination group to vaccine alone.
图64A至图64D示出了对PBMC最后一次疫苗剂量后2周的(A)总SIV、(B)Gag、(C)Env和(D)Pol-特异性IFN-γ应答广度。载体(Vx)仅以圆形分组,Vx+αPD1以三角形分组,Vx+αCTLA4以正方形分组,并且Vx+Flt3L以菱形分组。通过Kruskal-Wallis检验和Dunn’s后检验进行统计分析。数据被表示为中值±IQR。*p<0.05,**p<0.01,***p<0.001,****p<0.0001。Figure 64A to Figure 64D show the (A) total SIV, (B) Gag, (C) Env and (D) Pol-specific IFN-γ response breadth 2 weeks after the last vaccine dose of PBMC. Vector (Vx) is grouped in circles only, Vx+αPD1 is grouped in triangles, Vx+αCTLA4 is grouped in squares, and Vx+Flt3L is grouped in diamonds. Statistical analysis was performed by Kruskal-Wallis test and Dunn's post-test. Data are expressed as median ± IQR. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.
具体实施方式DETAILED DESCRIPTION
1.简介1. Introduction
本文描述了一种抗病毒疫苗免疫设计方法,该方法通过使用深度序列数据来评估病毒准种并确定个体内病毒多样性的水平,从而结合了患者内多样性。我们开发了一种算法,该算法在疫苗免疫原以及疫苗序列的免疫原性的设计中考虑了患者间以及患者内病毒多样性。了解宿主病毒多样性和抗原加工和呈递以及T细胞初免不仅确保疫苗免疫原产生大量抗原特异性T细胞,而且确保产生具有细胞毒性活性的抗原特异性T细胞。在抗病毒疫苗免疫原的设计中,我们将病毒序列和结合特异性的经计算的计算机分析与体外实验免疫学相结合。我们建立了体外疫苗试验模型,其使得我们能够鉴定在大量群体中产生最强应答的保守区。该方法使得我们能够在保守区内鉴定先前未被识别的新表位。这种免疫原性数据使得能够开发能够递送给大量群体的高度保守的、高度免疫原性的疫苗免疫原。This article describes an antiviral vaccine immunodesign method that incorporates intra-patient diversity by using deep sequence data to assess viral quasispecies and determine the level of intra-individual viral diversity. We developed an algorithm that takes into account inter-patient and intra-patient viral diversity in the design of vaccine immunogens and the immunogenicity of vaccine sequences. Understanding host viral diversity and antigen processing and presentation as well as T cell priming not only ensures that vaccine immunogens produce a large number of antigen-specific T cells, but also ensures that antigen-specific T cells with cytotoxic activity are produced. In the design of antiviral vaccine immunogens, we combined the calculated computer analysis of viral sequences and binding specificity with in vitro experimental immunology. We established an in vitro vaccine test model that enables us to identify conserved regions that produce the strongest responses in a large population. This method enables us to identify new epitopes that have not been previously recognized within conserved regions. This immunogenicity data enables the development of highly conserved, highly immunogenic vaccine immunogens that can be delivered to a large population.
本文提供了包含多个多肽或肽片段的融合多肽和相关组合物(包括免疫原性组合物和药物组合物),以及用于制备融合多肽的方法和使用它们来引发有需要的受试者对人类免疫缺陷病毒(HIV-1)的免疫原性应答的方法。如本文所用,“免疫原”是引发免疫应答或能够引发免疫应答的物质,诸如抗原。还提供了编码本文所述的融合多肽的多核苷酸,以及包含所述多核苷酸的载体。Provided herein are fusion polypeptides and related compositions (including immunogenic compositions and pharmaceutical compositions) comprising multiple polypeptides or peptide fragments, as well as methods for preparing fusion polypeptides and methods of using them to induce an immunogenic response to human immunodeficiency virus (HIV-1) in a subject in need thereof. As used herein, an "immunogen" is a substance that induces an immune response or is capable of inducing an immune response, such as an antigen. Also provided are polynucleotides encoding the fusion polypeptides described herein, and vectors comprising the polynucleotides.
本文提供了被设计成诱导抗病毒免疫应答的融合多肽。本文所述的疫苗构建体被设计成使用病毒蛋白质组序列源集内最高度保守的预测表位来提供预测T细胞表位(“PTE”)的数学确定的提高覆盖率。作为设计抗病毒免疫原方法的范例,使用由HIV-1基因gag、pol和nef中的至少两者编码的融合多肽。本文所述的融合多肽和方法既保留了PTE在序列源集中的位置信息,又构建了二价序列集以提高保守PTE的覆盖率。因此,本文描述的是多价的(例如二价的)疫苗构建体,其有利地改进或增加了高度保守的PTE,这些PTE最有可能与患者群体中和个体患者内病毒物种表达的蛋白质中天然存在的序列中的保守表位高度相似,因为这两者都保留了位置信息。另外,在患者间群体的HIV-1物种中仅使用高度保守的PTE序列降低了逃逸突变体的可能性,因为高度保守的序列更有可能有助于病毒结构和功能。Provided herein are fusion polypeptides designed to induce antiviral immune responses. Vaccine constructs described herein are designed to provide mathematically determined improved coverage of predicted T cell epitopes ("PTEs") using the most highly conserved predicted epitopes within a viral proteome sequence source set. As an example of a method for designing an antiviral immunogen, a fusion polypeptide encoded by at least two of the HIV-1 genes gag, pol, and nef is used. Fusion polypeptides and methods described herein retain both the positional information of PTEs in the sequence source set and the bivalent sequence set to improve the coverage of conservative PTEs. Therefore, described herein are multivalent (e.g., bivalent) vaccine constructs that advantageously improve or increase highly conservative PTEs that are most likely to be highly similar to conserved epitopes in naturally occurring sequences in proteins expressed by viral species in patient populations and in individual patients, because both retain positional information. In addition, using only highly conserved PTE sequences in HIV-1 species between patient populations reduces the possibility of escape mutants, because highly conserved sequences are more likely to contribute to viral structure and function.
还提供了用于为高度可变的病毒(诸如HIV-1)设计抗病毒疫苗免疫原的计算方法。抗病毒免疫原可以被设计成在个体水平上为具有一组定义的HLA等位基因的一组个体或为广泛的群体覆盖提供覆盖。在本文所述的疫苗免疫原设计方法中,我们定义了一种使用大量群体序列(例如,来自公共数据库和内部开发的数据库)靶向疫苗序列内的保守区的计算方法。此外,使用个体患者深度序列数据,我们定义了保守区内每个潜在T细胞表位的序列变异性。此外,我们基于个体宿主的一组HLA等位基因呈现的可能性鉴定了可用作实际表位的区域。将与由可公开获得和内部开发的数据库定义的宿主HLA结合的可能性用于开发模拟每个等位基因的肽结合的深度学习模型。这可以与可以定义抗原变体在调节TCR识别中的潜在影响或将肽鉴定为逃逸变体的计算机内、已发表和/或实验性体外T细胞引发数据相结合。将该数据用于设计一组含有表位和相关表位变体的肽免疫原。将表位序列串联或串行连接(直接融合或经由接头序列连结)成单个融合多肽。肽片段从N末端到C末端按计算确定的顺序结合,这减少或消除了可能模拟人类自身抗原并且具有不良影响(例如,引发自身免疫反应或耐受原反应)的连接表位的产生。Also provided is a computational method for designing antiviral vaccine immunogens for highly variable viruses (such as HIV-1).Antiviral immunogens can be designed to provide coverage for a group of individuals with a set of defined HLA alleles or for a wide range of population coverage at the individual level.In the vaccine immunogen design method described herein, we define a computational method for using a large number of population sequences (e.g., from public databases and internally developed databases) to target the conserved regions within the vaccine sequence.In addition, using individual patient deep sequence data, we define the sequence variability of each potential T cell epitope in the conserved region.In addition, we identify the region that can be used as the actual epitope based on the possibility of a group of HLA alleles presented by individual hosts.The possibility of combining with the host HLA defined by the publicly available and internally developed database is used to develop a deep learning model that simulates the peptide combination of each allele.This can be combined with the in-computer, published and/or experimental in vitro T cell elicitation data that can define the potential impact of antigen variants in regulating TCR recognition or identify peptides as escape variants.This data is used to design a group of peptide immunogens containing epitopes and related epitope variants. The epitope sequences are linked in series or serially (either directly fused or linked via a linker sequence) into a single fusion polypeptide. The peptide fragments are linked in a computationally determined order from N-terminus to C-terminus, which reduces or eliminates the generation of linked epitopes that may mimic human self-antigens and have adverse effects (e.g., eliciting autoimmune or tolerogenic responses).
与类似的基于图形的疫苗设计方法不同,本文所述的方法仅使用在自然序列中也相邻的相邻PTE来构建连接的PTE片段。另外,本发明方法首先构建由两个匹配的多肽组成的二价构建体,以改进或增加病毒蛋白质组中每个PTE位置的覆盖率。二价构建体本身可用作疫苗,如下文实施例1和2中所述的构建体。通过对基于群体的序列(例如,患者间多样性)进行分析而设计的二价构建体鉴定了可能有助于病毒结构的基于群体的保守序列。Unlike similar graphic-based vaccine design methods, the methods described herein use only adjacent PTEs that are also adjacent in the natural sequence to construct connected PTE fragments. In addition, the method of the present invention first constructs a bivalent construct consisting of two matching polypeptides to improve or increase the coverage of each PTE position in the viral proteome. The bivalent construct itself can be used as a vaccine, such as the constructs described in Examples 1 and 2 below. The bivalent construct designed by analyzing population-based sequences (e.g., diversity between patients) identifies population-based conserved sequences that may contribute to viral structure.
本文所述的方法可以从使用本文称为“保守分析”或“保守算法”的过程鉴定保守区二价序列开始。这些方法还可以包括使用本文称为“保守步行算法”或“CWA”的过程构建具有最大表位覆盖率同时保留来自天然序列的PTE的位置信息的二价疫苗构建体的步骤。The methods described herein may begin with identifying bivalent sequences of conserved regions using a process referred to herein as "conservation analysis" or "conservation algorithm." These methods may also include the step of constructing a bivalent vaccine construct having maximum epitope coverage while retaining positional information of PTEs from natural sequences using a process referred to herein as "conservation walking algorithm" or "CWA."
2.可用于促进对人类免疫缺陷病毒-1(HIV-1)的免疫应答的融合多肽2. Fusion polypeptides that can be used to promote immune responses to human immunodeficiency virus-1 (HIV-1)
本文提供了包含由一种或多种HIV-1基因编码的多个多肽或肽片段的融合多肽。本文所述的融合多肽的“片段”是相对于参考序列(例如,Gag、Pol和Nef多肽的HIV-1 HXB2参考序列,在本文分别提供为SEQ ID NO:1-3)而言至少25个氨基酸的连续序列。本文所述的多肽是“融合”多肽,因为它们由两个或多个HIV-1蛋白(例如,至少Pol和Nef)的连接或串联多肽或肽片段组装而成。关于HIV-1蛋白参考序列,多肽或肽片段可对应于相同HIV-1蛋白或不同HIV-1蛋白的不连续序列。通常,融合多肽是非天然存在的,并且可以是合成的或重组产生的。Provided herein are fusion polypeptides comprising multiple polypeptides or peptide fragments encoded by one or more HIV-1 genes. A "fragment" of a fusion polypeptide as described herein is a continuous sequence of at least 25 amino acids relative to a reference sequence (e.g., HIV-1 HXB2 reference sequences of Gag, Pol and Nef polypeptides, provided herein as SEQ ID NO: 1-3, respectively). Polypeptides as described herein are "fusion" polypeptides because they are assembled from the connection or series polypeptides or peptide fragments of two or more HIV-1 proteins (e.g., at least Pol and Nef). With respect to HIV-1 protein reference sequences, polypeptides or peptide fragments may correspond to discontinuous sequences of the same HIV-1 protein or different HIV-1 proteins. Typically, fusion polypeptides are non-naturally occurring and may be synthetic or recombinantly produced.
在各种实施方案中,本文所述的免疫原性多肽或融合多肽和/或编码此类多肽的多核苷酸以分离的形式提供。这意味着多肽或多核苷酸的纯度通常为至少50重量%的由其生产或纯化产生的干扰蛋白质、细胞和其他污染物,但不排除药剂与过量的药学上可接受的载剂或旨在促进其使用的其他媒介物组合的可能性。如本文所述,当应用于多肽或多核苷酸时,术语“分离的”表示多肽或多核苷酸基本上不含在天然状态下与其缔合的细胞组分。它可例如处于均质状态并且可处于干燥状态或水溶液中。纯度和均质性可使用已知方法确定,例如分析化学技术,诸如聚丙烯酰胺凝胶电泳、柱色谱法、薄层色谱法或高效液相色谱(HPLC)分析。作为制剂中存在的主要种类的蛋白质是基本上纯化的。“分离的”或“纯化的”多肽或多核苷酸当通过重组技术产生时基本上不含其他细胞材料或培养基,或当化学合成时基本上不含化学前体或其他化学品。在各种实施方案中,纯化的多肽和/或多核苷酸为至少60%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%(w/w),从生产或纯化中分离、纯化或不含干扰蛋白质和污染物。通常,本文所述的免疫原性多肽或融合多肽和/或编码此类多肽的多核苷酸是将其纯化后剩余的主要大分子物质。In various embodiments, the immunogenic polypeptides or fusion polypeptides described herein and/or polynucleotides encoding such polypeptides are provided in an isolated form. This means that the purity of the polypeptide or polynucleotide is generally at least 50% by weight of interfering proteins, cells and other contaminants produced by its production or purification, but does not exclude the possibility of combining the medicament with an excess of pharmaceutically acceptable carriers or other vehicles intended to promote its use. As described herein, when applied to polypeptides or polynucleotides, the term "isolated" means that the polypeptide or polynucleotide is substantially free of cellular components associated with it in the natural state. It can be, for example, in a homogeneous state and can be in a dry state or in an aqueous solution. Purity and homogeneity can be determined using known methods, such as analytical chemistry techniques, such as polyacrylamide gel electrophoresis, column chromatography, thin layer chromatography or high performance liquid chromatography (HPLC) analysis. Proteins that are the main species present in the preparation are substantially purified. "Isolated" or "purified" polypeptides or polynucleotides are substantially free of other cell materials or culture media when produced by recombinant technology, or substantially free of chemical precursors or other chemicals when chemically synthesized. In various embodiments, the purified polypeptide and/or polynucleotide is at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% (w/w), isolated, purified or free of interfering proteins and contaminants from production or purification. Typically, the immunogenic polypeptide or fusion polypeptide described herein and/or the polynucleotide encoding such polypeptide is the main macromolecular species remaining after purification.
a.多肽片段a. Peptide fragments
关于编码用于组装本文所述的融合多肽的多肽片段的HIV-1基因,在各种实施方案中,融合多肽包含由选自Gag、Pol和Nef的一种或多种(例如,两种或更多种、三种或更多种)人类免疫缺陷病毒-1(HIV-1)基因编码的一种或多种HIV-1蛋白的多个多肽片段。在一些实施方案中,该多个多肽片段仅由经HIV-1基因pol和nef编码的多肽片段构成,例如不包含由HIV-1基因gag、env、tat、rev、vpr、vif和vpu编码的多肽片段。在一些实施方案中,该多个多肽片段仅由经HIV-1基因gag、pol和nef编码的多肽片段构成,例如不包含由HIV-1基因env、tat、rev、vpr、vif和vpu编码的多肽片段。With regard to HIV-1 genes encoding polypeptide fragments for assembling the fusion polypeptides described herein, in various embodiments, the fusion polypeptide comprises multiple polypeptide fragments of one or more HIV-1 proteins encoded by one or more (e.g., two or more, three or more) human immunodeficiency virus-1 (HIV-1) genes selected from Gag, Pol and Nef. In some embodiments, the multiple polypeptide fragments consist only of polypeptide fragments encoded by HIV-1 genes pol and nef, for example, polypeptide fragments encoded by HIV-1 genes gag, env, tat, rev, vpr, vif and vpu are not included. In some embodiments, the multiple polypeptide fragments consist only of polypeptide fragments encoded by HIV-1 genes gag, pol and nef, for example, polypeptide fragments encoded by HIV-1 genes env, tat, rev, vpr, vif and vpu are not included.
关于组装、连接、连结或串联成单个融合多肽的多肽片段的数量,在各种实施方案中,融合多肽由至少4个以及至多6个多肽片段(例如,4、5或6个多肽片段)构成。视情况而定,多肽片段可以以与天然存在的蛋白质相同或不同的顺序排列。在各种实施方案中,融合多肽包含1至4个Pol多肽片段、1至2个Nef多肽片段和任选的1至3个Gag多肽片段。With respect to the number of polypeptide fragments assembled, linked, connected or concatenated into a single fusion polypeptide, in various embodiments, the fusion polypeptide is composed of at least 4 and at most 6 polypeptide fragments (e.g., 4, 5 or 6 polypeptide fragments). Depending on the circumstances, the polypeptide fragments can be arranged in the same or different order as the naturally occurring protein. In various embodiments, the fusion polypeptide comprises 1 to 4 Pol polypeptide fragments, 1 to 2 Nef polypeptide fragments and optionally 1 to 3 Gag polypeptide fragments.
关于被选择为包含在融合多肽中的多肽片段的由HIV-1基因编码的多肽区,在各种实施方案中,多肽片段来源于病毒蛋白质组序列群体中的保守区。在一些实施方案中,保守区在HIV-1种类中的保守性大于80%,例如大于81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%,例如,如在患者间群体中测定的。如本文所用,由HIV-1基因编码的多肽中的保守区是指含有与预定氨基酸片段或子序列位置中最普遍的一个氨基酸片段或子序列相同的氨基酸片段或子序列(例如,长度为9个氨基酸的片段或9聚体)的序列群体中序列的百分比,其中氨基酸片段或子序列位置是相对于参考序列(例如HIV-1 HXB2多肽序列,例如SEQ ID NO:1-3)确定的。本文中鉴定的HIV多肽的起始和结束位置是相对于HIV-1 HXB2参考多肽,即GenBank登录号K03455(ncbi.nlm.nih.gov/nuccore/K03455)而言的,在本文提供为SEQ ID NO:1-3并在表A中标识。如本文所用,当任何给定聚合物组分(例如,氨基酸、核苷酸,也统称为“残基”)的位置通过参考所选氨基酸或核酸聚合物中的相同或等同位置(例如,基于最佳比对或共有序列),而不是通过给定聚合物中组分的实际数字位置来指定时,给定氨基酸聚合物或核酸聚合物的编号“对应于”、“与...相对应”或“相对于”所选或参考氨基酸聚合物或核酸聚合物的编号。在各种实施方案中,保守区在组M内HIV-1进化枝中的一个或多个(例如HIV-1进化枝A-K中的一个或多个,例如进化枝A、B、C、D和G中的一个或多个)之间(例如在HIV-1组M进化枝B及其重组形式(例如CRF01_AE)之间)是保守的。With respect to the polypeptide region encoded by the HIV-1 gene selected as the polypeptide fragment included in the fusion polypeptide, in various embodiments, the polypeptide fragment is derived from a conserved region in a population of viral proteome sequences. In some embodiments, the conserved region is greater than 80% in HIV-1 species, for example, greater than 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, for example, as determined in a population of patients. As used herein, a conserved region in a polypeptide encoded by an HIV-1 gene refers to the percentage of sequences in a population of sequences containing the same amino acid fragment or subsequence (e.g., a fragment or 9-mer of 9 amino acids in length) as the most common amino acid fragment or subsequence in a predetermined amino acid fragment or subsequence position, wherein the amino acid fragment or subsequence position is determined relative to a reference sequence (e.g., HIV-1 HXB2 polypeptide sequence, e.g., SEQ ID NO: 1-3). The start and end positions of the HIV polypeptides identified herein are relative to the HIV-1 HXB2 reference polypeptide, GenBank Accession No. K03455 (ncbi.nlm.nih.gov/nuccore/K03455), provided herein as SEQ ID NOs: 1-3 and identified in Table A. As used herein, the numbering of a given amino acid polymer or nucleic acid polymer "corresponds to," "corresponds to," or "relative to" the numbering of a selected or reference amino acid polymer or nucleic acid polymer when the position of any given polymer component (e.g., amino acid, nucleotide, also collectively referred to as "residue") is designated by reference to the same or equivalent position in a selected amino acid or nucleic acid polymer (e.g., based on an optimal alignment or consensus sequence), rather than by the actual numerical position of the component in the given polymer. In various embodiments, the conserved region is conserved between one or more of the HIV-1 evolutionary branches within group M (e.g., one or more of the HIV-1 evolutionary branches A-K, such as one or more of the evolutionary branches A, B, C, D and G) (e.g., between HIV-1 group M evolutionary branch B and its recombinant form (e.g., CRF01_AE)).
在一些实施方案中,多个多肽片段包含至少4个多肽片段,例如至少4、5、6或更多个选自SEQ ID NO:4-33的多肽片段,例如表B中鉴定的多肽片段。In some embodiments, the plurality of polypeptide fragments comprises at least 4 polypeptide fragments, such as at least 4, 5, 6, or more polypeptide fragments selected from SEQ ID NOs: 4-33, such as the polypeptide fragments identified in Table B.
在各种实施方案中,融合多肽包含两个、三个、四个、五个、六个或更多个多肽片段,这些多肽片段包含对应于Gag 1-53、Gag 147-369、Pol56-117、Pol 129-320、Pol 367-431、Pol 542-606、Pol 586-606、Pol 683-708、Pol 747-827、Pol 840-909、Pol 840-920、Pol 932-1003、Nef 64-76、Nef 64-99或Nef 117-148的氨基酸残基或者由这些氨基酸残基组成,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3所示的HIV-1 HXB2参考序列。在一些实施方案中,融合多肽包含选自SEQ ID NO:4-33的两个、三个、四个、五个、六个或更多个多肽片段。In various embodiments, the fusion polypeptide comprises two, three, four, five, six or more polypeptide fragments comprising or consisting of amino acid residues corresponding to Gag 1-53, Gag 147-369, Pol56-117, Pol 129-320, Pol 367-431, Pol 542-606, Pol 586-606, Pol 683-708, Pol 747-827, Pol 840-909, Pol 840-920, Pol 932-1003, Nef 64-76, Nef 64-99 or Nef 117-148, wherein the Gag, Pol and Nef amino acid position numbers correspond to the HIV-1 HXB2 reference sequence set forth in SEQ ID NOs: 1, 2 and 3, respectively. In some embodiments, the fusion polypeptide comprises two, three, four, five, six or more polypeptide fragments selected from SEQ ID NOs: 4-33.
在一些实施方案中,融合多肽包含以下多肽片段或者由以下多肽片段组成,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3:In some embodiments, the fusion polypeptide comprises or consists of the following polypeptide fragments, wherein the amino acid position numbers of Gag, Pol, and Nef correspond to SEQ ID NOs: 1, 2, and 3, respectively:
a)对应于以下的氨基酸残基:Gag 1-53、Gag 147-369、Pol 683-708和Nef 117-148;a) amino acid residues corresponding to Gag 1-53, Gag 147-369, Pol 683-708, and Nef 117-148;
b)对应于以下的氨基酸残基:Pol 56-117、Pol 129-320、Pol 367-431和Nef 64-99;b) amino acid residues corresponding to: Pol 56-117, Pol 129-320, Pol 367-431, and Nef 64-99;
c)对应于以下的氨基酸残基:Pol 542-606、Pol 747-827、Pol840-920、Pol 932-1003和Nef 64-99;c) amino acid residues corresponding to Pol 542-606, Pol 747-827, Pol 840-920, Pol 932-1003, and Nef 64-99;
d)对应于以下的氨基酸残基:Gag 1-53、Gag 147-369、Pol 683-708、Pol 747-827、Pol 840-920和Nef 117-148;d) amino acid residues corresponding to Gag 1-53, Gag 147-369, Pol 683-708, Pol 747-827, Pol 840-920, and Nef 117-148;
e)对应于以下的氨基酸残基:Pol 56-117、Pol 129-320、Pol367-431、Pol 542-606、Pol 932-1003和Nef 64-99;e) amino acid residues corresponding to Pol 56-117, Pol 129-320, Pol367-431, Pol 542-606, Pol 932-1003, and Nef 64-99;
f)对应于以下的氨基酸残基:Gag 147-369、Pol 586-606、Pol 683-708和Pol840-920;f) amino acid residues corresponding to Gag 147-369, Pol 586-606, Pol 683-708, and Pol840-920;
g)对应于以下的氨基酸残基:Pol 129-320、Pol 747-827、Pol 932-1003和Nef64-76;或g) amino acid residues corresponding to Pol 129-320, Pol 747-827, Pol 932-1003, and Nef64-76; or
h)对应于以下的氨基酸残基:Gag:147-369、Pol 747-827、Pol 840-909和Nef 64-76。h) Amino acid residues corresponding to: Gag: 147-369, Pol 747-827, Pol 840-909 and Nef 64-76.
在一些实施方案中,融合多肽包含以下多肽片段或者由以下多肽片段组成:In some embodiments, the fusion polypeptide comprises or consists of the following polypeptide fragments:
a)SEQ ID NO:4、6、18和32,或分别与SEQ ID NO:4、6、18和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;a) SEQ ID NOs: 4, 6, 18 and 32, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 4, 6, 18 and 32, respectively;
b)SEQ ID NO:5、7、19和33,或分别与SEQ ID NO:5、7、19和33至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;b) SEQ ID NOs: 5, 7, 19 and 33, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 5, 7, 19 and 33, respectively;
c)SEQ ID NO:8、10、12和30,或分别与SEQ ID NO:8、10、12和30至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;c) SEQ ID NOs: 8, 10, 12 and 30, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 10, 12 and 30, respectively;
d)SEQ ID NO:9、11、13和31,或分别与SEQ ID NO:9、11、13和31至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;d) SEQ ID NOs: 9, 11, 13 and 31, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 9, 11, 13 and 31, respectively;
e)SEQ ID NO:14、20、24、26和30,或分别与SEQ ID NO:14、20、24、26和30至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;e) SEQ ID NOs: 14, 20, 24, 26 and 30, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 20, 24, 26 and 30, respectively;
f)SEQ ID NO:15、21、25、27和31,或分别与SEQ ID NO:15、21、25、27和31至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;f) SEQ ID NOs: 15, 21, 25, 27 and 31, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 15, 21, 25, 27 and 31, respectively;
g)SEQ ID NO:4、6、18、20、24和32,或分别与SEQ ID NO:4、6、18、20、24和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;g) SEQ ID NO:4, 6, 18, 20, 24 and 32, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4, 6, 18, 20, 24 and 32, respectively;
h)SEQ ID NO:5、7、19、21、25和33,或分别与SEQ ID NO:5、7、19、21、25和33至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;h) SEQ ID NO:5, 7, 19, 21, 25 and 33, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:5, 7, 19, 21, 25 and 33, respectively;
i)SEQ ID NO:8、10、12、14、26和30,或分别与SEQ ID NO:8、10、12、14、26和30至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;i) SEQ ID NOs: 8, 10, 12, 14, 26 and 30, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 10, 12, 14, 26 and 30, respectively;
j)SEQ ID NO:9、11、13、15、27和31,或分别与SEQ ID NO:9、11、13、15、27和31至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;j) SEQ ID NO:9, 11, 13, 15, 27 and 31, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:9, 11, 13, 15, 27 and 31, respectively;
k)SEQ ID NO:6、16、18和24,或分别与SEQ ID NO:6、16、18和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;k) SEQ ID NOs: 6, 16, 18 and 24, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 16, 18 and 24, respectively;
l)SEQ ID NO:7、17、19和25,或分别与SEQ ID NO:7、17、19和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;l) SEQ ID NOs:7, 17, 19 and 25, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:7, 17, 19 and 25, respectively;
m)SEQ ID NO:10、20、26和28,或分别与SEQ ID NO:10、20、26和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;m) SEQ ID NOs: 10, 20, 26 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 10, 20, 26 and 28, respectively;
n)SEQ ID NO:11、21、27和29,或分别与SEQ ID NO:11、21、27和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;n) SEQ ID NOs: 11, 21, 27 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 21, 27 and 29, respectively;
o)SEQ ID NO:6、20、22和28,或分别与SEQ ID NO:6、20、22和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;o) SEQ ID NOs: 6, 20, 22 and 28, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 20, 22 and 28, respectively;
p)SEQ ID NO:7、21、23和29,或分别与SEQ ID NO:7、21、23和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;p) SEQ ID NOs: 7, 21, 23 and 29, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 23 and 29, respectively;
q)SEQ ID NO:6、16、18和24,或分别与SEQ ID NO:6、16、18和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;q) SEQ ID NOs: 6, 16, 18 and 24, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 16, 18 and 24, respectively;
r)SEQ ID NO:7、17、19和25,或分别与SEQ ID NO:7、17、19和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;r) SEQ ID NOs:7, 17, 19 and 25, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:7, 17, 19 and 25, respectively;
s)SEQ ID NO:10、20、26和28,或分别与SEQ ID NO:10、20、26和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;或者s) SEQ ID NOs: 10, 20, 26 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 10, 20, 26 and 28, respectively; or
t)SEQ ID NO:11、21、27和29,或分别与SEQ ID NO:11、21、27和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段。t) SEQ ID NOs: 11, 21, 27 and 29, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 21, 27 and 29, respectively.
可在本文所述的融合多肽和编码此类融合多肽的多核苷酸的结构中进行修饰,并且这些修饰仍然获得编码具有期望(例如免疫原性)特征的变体或衍生多肽的功能分子。当期望改变多肽的氨基酸序列以产生本文所述的融合多肽的等同或甚至改善的变体或部分时,本领域技术人员通常将改变编码DNA序列的密码子中的一个或多个。Modifications can be made in the structures of fusion polypeptides described herein and polynucleotides encoding such fusion polypeptides, and these modifications still obtain functional molecules encoding variants or derivative polypeptides with desired (e.g., immunogenic) characteristics. When it is desired to change the amino acid sequence of a polypeptide to produce an equivalent or even improved variant or part of a fusion polypeptide described herein, those skilled in the art will typically change one or more of the codons encoding the DNA sequence.
例如,某些氨基酸可取代蛋白质结构中的其他氨基酸,而不会明显丧失其结合其他多肽(例如抗原)或细胞的能力。由于正是蛋白质的结合能力和性质限定该蛋白质的生物功能活性,因此可以在蛋白质序列中进行某些氨基酸序列取代,当然可以在其基础DNA编码序列中进行某些氨基酸序列取代,但获得具有类似性质的蛋白质。因此可以设想,可在所公开的融合多肽的多肽序列或编码此类融合多肽的对应DNA序列中进行各种改变,而不会明显丧失它们的生物效用或活性。For example, certain amino acids can be substituted for other amino acids in the protein structure without significantly losing its ability to bind to other polypeptides (e.g., antigens) or cells. Since it is the binding ability and properties of a protein that define the biological functional activity of the protein, certain amino acid sequence substitutions can be made in the protein sequence, and of course in its underlying DNA coding sequence, but obtain a protein with similar properties. It is therefore contemplated that various changes can be made in the polypeptide sequences of the disclosed fusion polypeptides or the corresponding DNA sequences encoding such fusion polypeptides without significantly losing their biological utility or activity.
在许多情况下,多肽变体将含有一个或多个保守取代。“保守取代”是其中氨基酸取代具有相似特性的另一个氨基酸,使得肽化学领域技术人员将期望多肽的二级结构和亲水性基本上不变的取代。In many cases, polypeptide variants will contain one or more conservative substitutions. A "conservative substitution" is one in which an amino acid is substituted for another amino acid with similar properties, such that one skilled in the art of peptide chemistry would expect that the secondary structure and hydrophilicity of the polypeptide would remain essentially unchanged.
当比较多核苷酸和多肽序列时,如果两个序列中的核苷酸或氨基酸的序列在如下所述进行最大对应比对时相同,则认为这两个序列是“相同的”。通常通过在比较窗口上比较序列来进行两个序列之间的比较,以鉴别和比较序列相似性的局部区。如本文所用,“比较窗口”是指至少约20个连续位置(通常为30至约75个、40至约50个)的片段,其中在将两个序列进行最佳比对后,可将该序列与具有相同数目的连续位置的参考序列进行比较。When comparing polynucleotide and polypeptide sequences, two sequences are considered "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. As used herein, a "comparison window" refers to a segment of at least about 20 consecutive positions (usually 30 to about 75, 40 to about 50) in which the sequence can be compared to a reference sequence having the same number of consecutive positions after the two sequences have been optimally aligned.
用于比较的序列的最佳比对可使用Lasergene生物信息学软件包(DNASTAR,Inc.,Madison,WI)中的Megalign程序使用默认参数进行。该程序体现了以下参考文献中描述的若干比对方案:Dayhoff,M.O.(1978)A model of evolutionary change in proteins-Matrices for detecting distant relationships.In Dayhoff,M.O.(编辑)Atlas ofProtein Sequence and Structure,National Biomedical Research Foundation,Washington DC第5卷,增刊3,第345-358页;Hein J.(1990)Unified Approach toAlignment and Phylogenes第626-645页Methods in Enzymology第183卷,AcademicPress,Inc.,San Diego,CA;Higgins,D.G.和Sharp,P.M.(1989)CABIOS 5:151-153;Myers,E.W.和Muller W.(1988)CABIOS 4:11-17;Robinson,E.D.(1971)Comb.Theor 77:105;Santou,N.Nes,M.(1987)Mol.Biol.Evol.4:406-425;Sneath,P.H.A.和Sokal,R.R.(1973)Numerical Taxonomy-the Principles and Practice of Numerical Taxonomy,FreemanPress,San Francisco,CA;Wilbur,W.J.and Lipman,D.J.(1983)Proc.Natl.Acad.,Sci.USA 80:726-730。Optimal alignment of sequences for comparison can be performed using the Megalign program in the Lasergene bioinformatics software package (DNASTAR, Inc., Madison, WI) using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins-Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC, Vol. 5, Supplement 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes, pp. 626-645; Methods in Enzymology, Vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M. (1989) CABIOS 5:151-153; Myers, E.W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 77:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P. H. A. and Sokal, R. R. (1973) Numerical Taxonomy-the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W. J. and Lipman, D. J. (1983) ) Proc. Natl. Acad., Sci. USA 80:726-730.
另选地,用于比较的序列的最佳比对可通过以下算法进行:局部同一性算法(Smith and Waterman(1981)Add.APL.Math 2:482)、同一性比对算法(Needleman和Wunsch(1970)J.Mol.Biol.48:443)、相似性搜索方法(Pearson和Lipman(1988)Proc.Natl.Acad.Sci.USA 85:2444)、这些算法的计算机化实施(Wisconsin遗传学软件包中的GAP、BESTFIT、BLAST、FASTA和TFASTA,Genetics Computer Group(GCG),575ScienceDr.,Madison,WI)或检查。Alternatively, optimal alignment of sequences for comparison can be performed by the local identity algorithm (Smith and Waterman (1981) Add. APL. Math 2:482), the identity alignment algorithm (Needleman and Wunsch (1970) J. Mol. Biol. 48:443), the similarity search method (Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444), computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or inspection.
适于确定序列同一性和序列相似性百分比的算法的一个示例是BLAST和BLAST2.0法,它们分别在Altschul等人(1977)Nucl.Acids Res.25:3389-3402以及Altschul等人(1990)J.Mol.Biol.215:403-410中描述。BLAST和BLAST 2.0可以例如与本文所述的参数一起用于确定本文所述的多核苷酸和多肽的序列同一性百分比。进行BLAST分析的软件可通过美国国家生物技术信息中心(blast.ncbi.nlm.nih.gov/Blast.cgi)公开获得。An example of an algorithm suitable for determining sequence identity and sequence similarity percentages is the BLAST and BLAST 2.0 methods, which are described in Altschul et al. (1977) Nucl. Acids Res. 25: 3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215: 403-410, respectively. BLAST and BLAST 2.0 can be used, for example, with the parameters described herein to determine the sequence identity percentages of the polynucleotides and polypeptides described herein. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (blast.ncbi.nlm.nih.gov/Blast.cgi).
在一个例示性示例中,对于核苷酸序列,可以使用参数M(一对匹配残基的奖励分数;总是>0)和N(错配残基的惩罚分数;总是<0)来计算累积分数。字词命中在每个方向上的延伸在以下情况下停止:累积比对分数从其最大实现值下降数量X;累积分数由于一个或多个负分数残基比对的累积而变为零或更低;或到达任一序列的末端。BLAST算法参数W、T和X决定了比对的灵敏度和速度。BLASTN程序(对于核苷酸序列)使用字长(W)11和期望值(E)10作为默认值,以及BLOSUM62评分矩阵(参见Henikoff和Henikoff(1989)Proc.Natl.Acad.Sci.USA 89:10915)比对,(B)为50,期望值(E)为10,M=5,N=-4,以及两条链的比较。In an illustrative example, for nucleotide sequences, the cumulative score can be calculated using the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatched residues; always < 0). Extension of the word hits in each direction stops when: the cumulative alignment score drops by the amount X from its maximum achieved value; the cumulative score becomes zero or lower due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses a word length (W) of 11 and an expectation (E) of 10 as defaults, and a BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignment, (B) of 50, an expectation (E) of 10, M = 5, N = -4, and a comparison of both chains.
对于氨基酸序列,可以使用评分矩阵来计算累积得分。字词命中在每个方向上的延伸在以下情况下停止:累积比对分数从其最大实现值下降数量X;累积分数由于一个或多个负分数残基比对的累积而变为零或更低;或到达任一序列的末端。BLAST算法参数W、T和X决定了比对的灵敏度和速度。For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction stops when: the cumulative alignment score drops by the amount X from its maximum achieved value; the cumulative score goes to zero or lower due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
在一种方法中,通过在至少20个位置的比较窗口内比较两个最佳比对的序列来确定“序列同一性百分比”,其中与用于两个序列的最佳比对的参考序列(不包含添加或缺失)相比,多核苷酸或多肽序列在比较窗口中的部分可包含20%或更少(通常为5%至15%,或10%至12%)的添加或缺失(即空位)。通过确定两个序列中相同核酸碱基或氨基酸残基出现的位置数以产生匹配位置数,将匹配位置数除以参考序列中的总位置数(即窗口大小)并将结果乘以100以产生序列同一性百分比来计算百分比。In one method, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences within a comparison window of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may contain 20% or less (usually 5% to 15%, or 10% to 12%) additions or deletions (i.e., gaps) compared to the reference sequence (not comprising additions or deletions) for the optimal alignment of the two sequences. The percentage is calculated by determining the number of positions where the same nucleic acid base or amino acid residue occurs in the two sequences to generate the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the result by 100 to generate the percentage of sequence identity.
如本文所用,术语多肽“变体”是通常与本文具体公开的多肽在一个或多个取代、缺失、添加和/或插入方面不同的多肽。此类变体可以是天然存在的或可例如通过修饰本文所述的上述多肽序列中的一个或多个并评估如本文所述的多肽的一种或多种生物活性和/或使用本领域熟知的多种技术中的任一种来合成生成。术语“变体”还可指包含一个或多个核苷酸或氨基酸突变的任何天然存在的或工程化的分子。As used herein, the term polypeptide "variant" is a polypeptide that generally differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants may be naturally occurring or may be generated synthetically, for example, by modifying one or more of the above-described polypeptide sequences described herein and evaluating one or more biological activities of the polypeptide as described herein and/or using any of a variety of techniques well known in the art. The term "variant" may also refer to any naturally occurring or engineered molecule comprising one or more nucleotide or amino acid mutations.
在一些实施方案中,融合多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段或者由以下多肽片段组成:In some embodiments, the fusion polypeptide comprises or consists of the following polypeptide fragments, in order from N-terminus to C-terminus, optionally bound or linked by one or more linkers:
a)SEQ ID NO:6、4、18和32,或分别与SEQ ID NO:6、4、18和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;a) SEQ ID NOs: 6, 4, 18 and 32, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 4, 18 and 32, respectively;
b)SEQ ID NO:7、5、33和19,或分别与SEQ ID NO:7、5、33和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;b) SEQ ID NOs: 7, 5, 33 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 5, 33 and 19, respectively;
c)SEQ ID NO:12、30、8和10,或分别与SEQ ID NO:12、30、8和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;c) SEQ ID NOs: 12, 30, 8 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 12, 30, 8 and 10, respectively;
d)SEQ ID NO:9、31、13和11,或分别与SEQ ID NO:9、31、13和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;d) SEQ ID NOs: 9, 31, 13 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 9, 31, 13 and 11, respectively;
e)SEQ ID NO:14、26、20、30和24,或分别与SEQ ID NO:14、26、20、30和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;e) SEQ ID NOs: 14, 26, 20, 30 and 24, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 26, 20, 30 and 24, respectively;
f)SEQ ID NO:15、31、21、27和25,或分别与SEQ ID NO:15、31、21、27和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;f) SEQ ID NOs: 15, 31, 21, 27 and 25, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 15, 31, 21, 27 and 25, respectively;
g)SEQ ID NO:32、18、4和6,或分别与SEQ ID NO:32、18、4和6至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;g) SEQ ID NOs:32, 18, 4 and 6, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:32, 18, 4 and 6, respectively;
h)SEQ ID NO:7、33、5和19,或分别与SEQ ID NO:7、33、5和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;h) SEQ ID NOs: 7, 33, 5 and 19, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 33, 5 and 19, respectively;
i)SEQ ID NO:8、30、12和10,或分别与SEQ ID NO:8、30、12和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;i) SEQ ID NOs: 8, 30, 12 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 30, 12 and 10, respectively;
j)SEQ ID NO:13、31、9和11,或分别与SEQ ID NO:13、31、9和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;j) SEQ ID NOs: 13, 31, 9 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 13, 31, 9 and 11, respectively;
k)SEQ ID NO:26、30、14、20和24,或分别与SEQ ID NO:26、30、14、20和24至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;k) SEQ ID NOs: 26, 30, 14, 20, and 24, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 26, 30, 14, 20, and 24, respectively;
l)SEQ ID NO:31、27、15、25和21,或分别与SEQ ID NO:31、27、15、25和21至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;l) SEQ ID NOs:31, 27, 15, 25 and 21, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:31, 27, 15, 25 and 21, respectively;
m)SEQ ID NO:24、6、4、20、18和32,或分别与SEQ ID NO:24、6、4、20、18和32至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;m) SEQ ID NOs: 24, 6, 4, 20, 18 and 32, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 4, 20, 18 and 32, respectively;
n)SEQ ID NO:6、20、4、24、32和18,或分别与SEQ ID NO:6、20、4、24、32和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;n) SEQ ID NOs: 6, 20, 4, 24, 32 and 18, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 20, 4, 24, 32 and 18, respectively;
o)SEQ ID NO:7、21、5、25、33和19,或分别与SEQ ID NO:7、21、5、25、33和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;o) SEQ ID NOs: 7, 21, 5, 25, 33 and 19, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 5, 25, 33 and 19, respectively;
p)SEQ ID NO:8、30、14、12、26和10,或分别与SEQ ID NO:8、30、14、12、26和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;p) SEQ ID NOs: 8, 30, 14, 12, 26 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 30, 14, 12, 26 and 10, respectively;
q)SEQ ID NO:8、12、30、26、14和10,或分别与SEQ ID NO:8、12、30、26、14和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;q) SEQ ID NOs: 8, 12, 30, 26, 14 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 12, 30, 26, 14 and 10, respectively;
r)SEQ ID NO:9、13、31、27、15和11,或分别与SEQ ID NO:9、13、31、27、15和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;r) SEQ ID NO:9, 13, 31, 27, 15 and 11, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:9, 13, 31, 27, 15 and 11, respectively;
s)SEQ ID NO:20、32、24、4、6和18,或分别与SEQ ID NO:20、32、24、4、6和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;s) SEQ ID NOs: 20, 32, 24, 4, 6, and 18, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 20, 32, 24, 4, 6, and 18, respectively;
t)SEQ ID NO:7、25、19、5、33和21,或分别与SEQ ID NO:7、25、19、5、33和21至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;t) SEQ ID NOs:7, 25, 19, 5, 33 and 21, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:7, 25, 19, 5, 33 and 21, respectively;
u)SEQ ID NO:26、30、12、14、8和10,或分别与SEQ ID NO:26、30、12、14、8和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;u) SEQ ID NOs: 26, 30, 12, 14, 8 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 30, 12, 14, 8 and 10, respectively;
v)SEQ ID NO:15、31、9、27、13和11,或分别与SEQ ID NO:15、31、9、27、13和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;v) SEQ ID NOs: 15, 31, 9, 27, 13 and 11, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 15, 31, 9, 27, 13 and 11, respectively;
w)SEQ ID NO:24、6、16和18,或分别与SEQ ID NO:24、6、16和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;w) SEQ ID NOs: 24, 6, 16 and 18, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 16 and 18, respectively;
x)SEQ ID NO:7、19、17和25,或分别与SEQ ID NO:7、19、17和25至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;x) SEQ ID NOs: 7, 19, 17 and 25, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 19, 17 and 25, respectively;
y)SEQ ID NO:24、16、6和18,或分别与SEQ ID NO:24、16、6和18至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;y) SEQ ID NOs: 24, 16, 6 and 18, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 16, 6 and 18, respectively;
z)SEQ ID NO:7、25、17和19,或分别与SEQ ID NO:7、25、17和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;z) SEQ ID NOs:7, 25, 17 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:7, 25, 17 and 19, respectively;
aa)SEQ ID NO:26、20、10和28,或分别与SEQ ID NO:26、20、10和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;aa) SEQ ID NOs: 26, 20, 10 and 28, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 20, 10 and 28, respectively;
bb)SEQ ID NO:21、27、11和29,或分别与SEQ ID NO:21、27、11和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;bb) SEQ ID NOs: 21, 27, 11 and 29, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 21, 27, 11 and 29, respectively;
cc)SEQ ID NO:26、10、20和28,或分别与SEQ ID NO:26、10、20和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;cc) SEQ ID NOs: 26, 10, 20 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 10, 20 and 28, respectively;
dd)SEQ ID NO:11、27、21和29,或分别与SEQ ID NO:11、27、21和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;dd) SEQ ID NOs: 11, 27, 21 and 29, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 11, 27, 21 and 29, respectively;
ee)SEQ ID NO:22、6、20和28,或分别与SEQ ID NO:22、6、20和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;ee) SEQ ID NOs: 22, 6, 20 and 28, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 22, 6, 20 and 28, respectively;
ff)SEQ ID NO:23、7、21和29,或分别与SEQ ID NO:23、7、21和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;ff) SEQ ID NOs: 23, 7, 21 and 29, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 23, 7, 21 and 29, respectively;
gg)SEQ ID NO:22、20、6和28,或分别与SEQ ID NO:22、20、6和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;或者gg) SEQ ID NOs: 22, 20, 6 and 28, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 22, 20, 6 and 28, respectively; or
hh)SEQ ID NO:7、21、23和29,或分别与SEQ ID NO:7、21、23和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段。hh) SEQ ID NOs: 7, 21, 23 and 29, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 7, 21, 23 and 29, respectively.
通常,融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol 607-682、Pol 709-746、Pol 828-839、Pol 921-931、Nef1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。通常,融合多肽不包含具有以下氨基酸序列的任何多肽片段:表C中提供的SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。Typically, the fusion polypeptide does not comprise any polypeptide fragment corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol 607-682, Pol 709-746, Pol 828-839, Pol 921-931, Nef1-63, Nef 100-116 and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2 and 3, respectively. Typically, the fusion polypeptide does not comprise any polypeptide fragment having an amino acid sequence of SEQ ID NOs: 35-47, or a fragment or subsequence thereof, provided in Table C, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 35-47, or a fragment or subsequence thereof.
关于单个多肽或肽片段的长度范围,在各种实施方案中,每个多肽片段的长度为至少25个氨基酸,并且长度为至多约230个氨基酸,例如长度为至少25个氨基酸并且长度为至多26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、215、220、225或230个氨基酸。With regard to the range of lengths of individual polypeptides or peptide fragments, in various embodiments, each polypeptide fragment is at least 25 amino acids in length and up to about 230 amino acids in length, e.g., at least 25 amino acids in length and up to 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, or 230 amino acids in length.
关于全长融合多肽的长度,在各种实施方案中,在一些实施方案中,融合多肽的全长在长度上包含至少约330个氨基酸和至多约550个氨基酸,例如至少约330个氨基酸和至多约335、340、345、350、355、360、365、370、375、380、385、390、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495、500、505、510、515、520、525、530、535、540、545或550个氨基酸。在一些实施方案中,融合多肽的全长在长度上不长于550个氨基酸,例如不长于545、540、535、530、525、520、515、510、505、500、495、490、485、480、475、470、465、460、455、450、445、440、435、430、425、420、415、410、405、400、390、385、380、375、370、365、360、355、350、345、340、335或330个氨基酸。在各种实施方案中,在不存在信号或前导序列的情况下,融合多肽的全长在长度上包含至少约330个氨基酸和至多约505个氨基酸,例如至少约330个氨基酸和至多约335、340、345、350、355、360、365、370、375、380、385、390、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495、500或505个氨基酸。在各种实施方案中,在不存在信号或前导序列的情况下,融合多肽的全长在长度上不长于505个氨基酸,例如不长于505、500、495、490、485、480、475、470、465、460、455、450、445、440、435、430、425、420、415、410、405、400、390、385、380、375、370、365、360、355、350、345、340、335或330个氨基酸。在各种实施方案中,在不存在信号或前导序列的情况下,融合多肽的全长在长度上包含至少约350个氨基酸和至多约550个氨基酸,例如至少约350个氨基酸和至多约355、360、365、370、375、380、385、390、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495、500、505、510、515、520、525、530、535、540、545或550个氨基酸。在各种实施方案中,在不存在信号或前导序列的情况下,融合多肽的全长在长度上不长于550个氨基酸,例如不长于545、540、535、530、525、520、515、510、505、500、495、490、485、480、475、470、465、460、455、450、445、440、435、430、425、420、415、410、405、400、390、385、380、375、370、365、360、355或350个氨基酸。信号或前导肽序列的包含在下文更详细地描述。With respect to the length of the full-length fusion polypeptide, in various embodiments, in some embodiments, the full length of the fusion polypeptide comprises at least about 330 amino acids and at most about 550 amino acids in length, e.g., at least about 330 amino acids and at most about 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, or 550 amino acids in length. In some embodiments, the full length of the fusion polypeptide is no longer than 550 amino acids in length, e.g., no longer than 545, 540, 535, 530, 525, 520, 515, 510, 505, 500, 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 390, 385, 380, 375, 370, 365, 360, 355, 350, 345, 340, 335, or 330 amino acids in length. In various embodiments, in the absence of a signal or leader sequence, the full length of the fusion polypeptide comprises at least about 330 amino acids and at most about 505 amino acids in length, e.g., at least about 330 amino acids and at most about 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, or 505 amino acids in length. In various embodiments, in the absence of a signal or leader sequence, the full length of the fusion polypeptide is no longer than 505 amino acids in length, e.g., no longer than 505, 500, 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 390, 385, 380, 375, 370, 365, 360, 355, 350, 345, 340, 335, or 330 amino acids in length. In various embodiments, in the absence of a signal or leader sequence, the full length of the fusion polypeptide comprises at least about 350 amino acids and at most about 550 amino acids in length, e.g., at least about 350 amino acids and at most about 355, 360, 365, 370, 375, 380, 385, 390, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, or 550 amino acids in length. In various embodiments, in the absence of a signal or leader sequence, the total length of the fusion polypeptide is no longer than 550 amino acids in length, e.g., no longer than 545, 540, 535, 530, 525, 520, 515, 510, 505, 500, 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 390, 385, 380, 375, 370, 365, 360, 355 or 350 amino acids. The inclusion of a signal or leader sequence is described in more detail below.
通常,融合多肽是免疫原性的,因为它们能够在人体内引发例如对HIV-1的免疫应答。在一些实施方案中,例如如本文所述的融合多肽任选地与一种或多种附加治疗剂组合能够在人体内引发对HIV-1的保护或治疗有效的免疫应答,例如能够在未感染的个体中或在治疗环境中预防HIV-1感染,能够引发足以诱导免疫介导的对HIV-1的控制或根除被感染个体中的HIV-1的免疫应答。融合多肽的免疫原性可以如本文所述在体外和体内测定中评估和证明。例如,融合多肽的免疫原性可以通过体外测定(包括CD4+和/或CD8+ T细胞活化(例如,包括细胞因子表达和靶标杀伤测定)或增殖测定)来证明。T细胞可以通过暴露于已经用编码融合多肽的多核苷酸转染的抗原呈递细胞(APC)(例如树突细胞,例如单核细胞来源的树突细胞)来活化。此类测定是本领域已知的并在本文中描述。融合多肽的免疫原性还可以在体内动物模型中证明,例如通过向小鼠(例如,BALB/c或BL6)或非人灵长类动物施用例如一种或多种人HLA分子的转基因物(可从Jackson Laboratories或Taconic获得),并评估CD4+和/或CD8+ T细胞活化(例如,包括血清细胞因子水平)或增殖。在各种实施方案中,每个多肽片段中的一个、两个、三个或更多个包含一个或多个预测的T细胞表位或由所述表位组成,例如如计算或实验确定的。在一些实施方案中,融合多肽包含一个或多个多肽片段,所述多肽片段与例如单个受试者内或多名受试者之间的一个或多个人HLA I类和/或II类等位基因(例如,1、2、3、4、5或6个等位基因)结合或由所述等位基因呈递。Generally, fusion polypeptides are immunogenic because they can cause, for example, an immune response to HIV-1 in the human body. In some embodiments, for example, fusion polypeptides as described herein optionally combined with one or more additional therapeutic agents can cause protection or effective immune responses to HIV-1 in the human body, for example, can prevent HIV-1 infection in uninfected individuals or in a therapeutic environment, can cause sufficient to induce immune-mediated control of HIV-1 or eradicate the immune response of HIV-1 in infected individuals. The immunogenicity of fusion polypeptides can be assessed and demonstrated in vitro and in vivo assays as described herein. For example, the immunogenicity of fusion polypeptides can be demonstrated by in vitro assays (including CD4+ and/or CD8+ T cell activation (for example, including cytokine expression and target killing assays) or proliferation assays). T cells can be activated by exposure to antigen presenting cells (APCs) (for example dendritic cells, for example monocyte-derived dendritic cells) transfected with polynucleotides encoding fusion polypeptides. Such assays are known in the art and described herein. The immunogenicity of the fusion polypeptide can also be demonstrated in an in vivo animal model, for example, by administering, for example, a transgenic of one or more human HLA molecules (available from Jackson Laboratories or Taconic) to mice (e.g., BALB/c or BL6) or non-human primates, and assessing CD4+ and/or CD8+ T cell activation (e.g., including serum cytokine levels) or proliferation. In various embodiments, one, two, three or more of each polypeptide fragment comprises or consists of one or more predicted T cell epitopes, for example as determined by calculation or experiment. In some embodiments, the fusion polypeptide comprises one or more polypeptide fragments that are bound to or presented by one or more human HLA class I and/or class II alleles (e.g., 1, 2, 3, 4, 5, or 6 alleles), for example, within a single subject or between multiple subjects.
串联多肽片段Tandem peptide fragments
视情况而定,一个或多个多肽片段可以直接与相邻片段邻接或融合,或者可以通过一个或多个肽接头结合、连接或连结到相邻片段。在各种实施方案中,一个或多个肽接头选自以下项中的一种或多种:例如接头内或全长融合多肽内的聚丙氨酸接头、聚甘氨酸接头、可切割接头、柔性接头、刚性接头、Nef连接序列以及它们的组合。可在本发明融合多肽中用于连接一个或多个多肽片段的例示性融合蛋白接头例如在Chen等人,Adv Drug DelivRev.(2013)65(10):1357–1369中描述。在一些实施方案中,聚丙氨酸接头包含2或3个连续丙氨酸残基例如AA、AAA(SEQ ID NO:48)、AAY(SEQ ID NO:49)或AAX或者由这些连续丙氨酸残基组成,其中X是任何氨基酸(例如,A、C、D、E、F、G、H、I、K、L、M、N、P、Q、R、S、T、V、Y)(SEQ IDNO:50)。在一些实施方案中,使用聚甘氨酸接头,例如GGS(SEQ ID NO:57)、GSG(SEQ ID NO:58)或GGGS(SEQ ID NO:59)。在一些实施方案中,可切割接头选自2A可切割肽。可在本发明融合多肽中用于连接一个或多个多肽片段的例示性2A可切割肽例如在Donnelly等人,J.Gen.Virol(2001),82,1027–1041和Chng等人,mAbs(2015)7:2,403-412中有所描述。可用于连接一个或多个多肽片段的例示性可切割肽包括但不限于2A可切割序列(例如,口蹄疫病毒(F2A)、马鼻炎A病毒(E2A)、猪捷申病毒-1(P2A)和明脉扁刺蛾病毒(T2A))和弗林蛋白酶识别/切割序列(例如,RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)、RRKR(SEQ ID NO:62))。在某些实施方案中,弗林蛋白酶识别/切割序列(例如,RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)、RRKR(SEQ ID NO:62))在单个接头中与2A可切割肽(例如口蹄疫病毒(F2A)、马鼻炎A病毒(E2A)、猪捷申病毒-1(P2A)和明脉扁刺蛾病毒(T2A))组合或融合。参见例如,Chng等人,mAbs(2015)7:2,403-412。在各种实施方案中,2A可切割接头包含与ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:65)、QCTNYALLKLAGDVESNPGP(SEQ ID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67)至少90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%相同的氨基酸序列或者由该氨基酸序列组成,或者包含ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:65)、QCTNYALLKLAGDVESNPGP(SEQ ID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67)的氨基酸序列或者由该氨基酸序列组成。视情况而定,在某些实施方案中,弗林蛋白酶识别/切割序列可位于2A接头的N末端或C末端。在一些实施方案中,可切割接头包含选自RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)和RRKR(SEQID NO:62)的弗林蛋白酶识别/切割位点或由其组成。REKR(SEQ ID NO:61)是HIV和SIV包膜糖蛋白前体中的天然存在的可切割接头(Bahbouhi等人,Biochem.J.(2002)366,863-872)。可以用于连结或连接融合多肽中的一个或多个多肽片段的例示性接头在表D中提供。As the case may be, one or more polypeptide fragments may be directly adjacent to or fused to adjacent fragments, or may be bound, connected or linked to adjacent fragments by one or more peptide linkers. In various embodiments, one or more peptide linkers are selected from one or more of the following: for example, polyalanine linkers, polyglycine linkers, cleavable linkers, flexible linkers, rigid linkers, Nef linker sequences, and combinations thereof within a linker or within a full-length fusion polypeptide. Exemplary fusion protein linkers that can be used to connect one or more polypeptide fragments in the fusion polypeptide of the present invention are described, for example, in Chen et al., Adv Drug Deliv Rev. (2013) 65 (10): 1357–1369. In some embodiments, the polyalanine linker comprises 2 or 3 consecutive alanine residues, such as AA, AAA (SEQ ID NO: 48), AAY (SEQ ID NO: 49), or AAX, or is composed of these consecutive alanine residues, wherein X is any amino acid (e.g., A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, Y) (SEQ ID NO: 50). In some embodiments, a polyglycine linker is used, such as GGS (SEQ ID NO: 57), GSG (SEQ ID NO: 58), or GGGS (SEQ ID NO: 59). In some embodiments, the cleavable linker is selected from a 2A cleavable peptide. Exemplary 2A cleavable peptides that can be used to link one or more polypeptide fragments in the fusion polypeptide of the present invention are described, for example, in Donnelly et al., J. Gen. Virol (2001), 82, 1027–1041 and Chng et al., mAbs (2015) 7: 2, 403-412. Exemplary cleavable peptides that can be used to link one or more polypeptide fragments include, but are not limited to, 2A cleavable sequences (e.g., foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A), and lycopodiella virus (T2A)) and furin recognition/cleavage sequences (e.g., RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61), RRKR (SEQ ID NO: 62)). In certain embodiments, furin recognition/cleavage sequences (e.g., RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61), RRKR (SEQ ID NO: 62)) are combined or fused with 2A cleavable peptides (e.g., foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A), and lycopodiella virus (T2A)) in a single linker. See, e.g., Chng et al., mAbs (2015) 7: 2, 403-412. In various embodiments, the 2A cleavable linker comprises or consists of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to ATNFSLLKQAGDVEENPGP (SEQ ID NO:63), APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:64), RAKRAPVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:65), QCTNYALLKLAGDVESNPGP (SEQ ID NO:66), or EGRGSLLTCGDVEENPGP (SEQ ID NO:67). In some embodiments, the cleavable linker comprises or consists of an amino acid sequence selected from RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61) and RRKR (SEQ ID NO: 62). REKR (SEQ ID NO: 61) is a naturally occurring cleavable linker in HIV and SIV envelope glycoprotein precursors (Bahbouhi et al., Biochem. J. (2002) 366, 863-872). Exemplary linkers that can be used to link or connect one or more polypeptide fragments in a fusion polypeptide are provided in Table D.
表E中提供了根据本文所述方法设计和组装的不含信号序列的例示性融合多肽。表E将“AAA”公开为SEQ ID NO:48,将“LIK”公开为SEQ ID NO:53,将“AAY”公开为SEQ IDNO:49,将“SEG”公开为SEQ ID NO:55,将“QEE”公开为SEQ ID NO:51,将“KIL”公开为SEQ IDNO:52并将“PPV”公开为SEQ ID NO:54。Exemplary fusion polypeptides designed and assembled according to the methods described herein without a signal sequence are provided in Table E. Table E discloses "AAA" as SEQ ID NO:48, "LIK" as SEQ ID NO:53, "AAY" as SEQ ID NO:49, "SEG" as SEQ ID NO:55, "QEE" as SEQ ID NO:51, "KIL" as SEQ ID NO:52 and "PPV" as SEQ ID NO:54.
在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:82的氨基酸序列,或与SEQ ID NO:82至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:83的氨基酸序列,或与SEQ ID NO:83至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:85的氨基酸序列,或与SEQ ID NO:85至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:86的氨基酸序列,或与SEQ IDNO:86至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:87的氨基酸序列,或与SEQ ID NO:87至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:98的氨基酸序列,或与SEQ ID NO:98至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:99的氨基酸序列,或与SEQ ID NO:99至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:100的氨基酸序列,或与SEQID NO:100至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:101的氨基酸序列,或与SEQ ID NO:101至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:209的氨基酸序列,或与SEQ ID NO:209至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQID NO:222的氨基酸序列,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:223的氨基酸序列,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,融合多肽包含以下或由以下组成:SEQ ID NO:227的氨基酸序列,或与SEQID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。视情况而定或需要时,融合多肽可具有N末端甲硫氨酸残基。In some embodiments, the fusion polypeptide comprises or consists of an amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the fusion polypeptide comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 82, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 82. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 83, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 83. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 85, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 85. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 86, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 86. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 87, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 87. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 98, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 99, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 99. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 100, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 100. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 101, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 101. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 209, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 222, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223. In some embodiments, the fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 227. Optionally or as needed, the fusion polypeptide may have an N-terminal methionine residue.
复合融合多肽Composite fusion peptide
在各种实施方案中,提供了包含如本文所述的两种或更多种融合多肽的复合融合多肽。此类复合融合多肽可在病毒载体中递送,这些病毒载体可表达具有至少约750个氨基酸长度,例如至少约800、850、900、950、1000、1050、1100个氨基酸长度或更长的多肽。视情况而定,两种或更多种融合多肽可直接融合,或通过一个或多个接头结合或连接。在一些实施方案中,提供了复合融合多肽,其至少包含如本文所述的第一融合多肽和第二融合多肽,该第一和第二融合多肽任选地通过一个或多个如本文所述的接头(例如,可切割接头,诸如2A可切割肽接头)结合或连接。In various embodiments, a composite fusion polypeptide comprising two or more fusion polypeptides as described herein is provided. Such composite fusion polypeptides can be delivered in viral vectors, which can express polypeptides having at least about 750 amino acids in length, for example, at least about 800, 850, 900, 950, 1000, 1050, 1100 amino acids in length or longer. Depending on the circumstances, two or more fusion polypeptides can be directly fused, or combined or connected by one or more joints. In some embodiments, a composite fusion polypeptide is provided, which at least comprises a first fusion polypeptide and a second fusion polypeptide as described herein, and the first and second fusion polypeptides are optionally combined or connected by one or more joints as described herein (e.g., a cleavable joint, such as a 2A cleavable peptide joint).
在各种实施方案中,复合融合多肽中的第一融合多肽和第二融合多肽包含相同的多肽片段,例如相同的氨基酸残基位置范围。在一些实施方案中,复合融合多肽中的第一融合多肽和第二融合多肽是二价的。例如,在一些实施方案中,第一融合多肽和第二融合多肽包含以下多肽片段或由以下多肽片段组成,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3:In various embodiments, the first fusion polypeptide and the second fusion polypeptide in the composite fusion polypeptide comprise the same polypeptide fragment, such as the same amino acid residue position range. In some embodiments, the first fusion polypeptide and the second fusion polypeptide in the composite fusion polypeptide are bivalent. For example, in some embodiments, the first fusion polypeptide and the second fusion polypeptide comprise or consist of the following polypeptide fragments, wherein the Gag, Pol, and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively:
a)对应于以下的氨基酸残基:Gag 1-53、Gag 147-369、Pol 683-708和Nef 117-148;a) amino acid residues corresponding to Gag 1-53, Gag 147-369, Pol 683-708, and Nef 117-148;
b)对应于以下的氨基酸残基:Pol 56-117、Pol 129-320、Pol 367-431和Nef 64-99;b) amino acid residues corresponding to: Pol 56-117, Pol 129-320, Pol 367-431, and Nef 64-99;
c)对应于以下的氨基酸残基:Pol 542-606、Pol 747-827、Pol 840-920、Pol 932-1003和Nef 64-99;c) amino acid residues corresponding to Pol 542-606, Pol 747-827, Pol 840-920, Pol 932-1003, and Nef 64-99;
d)对应于以下的氨基酸残基:Gag 1-53、Gag 147-369、Pol 683-708、Pol 747-827、Pol 840-920和Nef 117-148;d) amino acid residues corresponding to Gag 1-53, Gag 147-369, Pol 683-708, Pol 747-827, Pol 840-920, and Nef 117-148;
e)对应于以下的氨基酸残基:Pol 56-117、Pol 129-320、Pol 367-431、Pol 542-606、Pol 932-1003和Nef 64-99;e) amino acid residues corresponding to Pol 56-117, Pol 129-320, Pol 367-431, Pol 542-606, Pol 932-1003, and Nef 64-99;
f)对应于以下的氨基酸残基:Gag 147-369、Pol 586-606、Pol 683-708和Pol840-920;f) amino acid residues corresponding to Gag 147-369, Pol 586-606, Pol 683-708, and Pol840-920;
g)对应于以下的氨基酸残基:Pol 129-320、Pol 747-827、Pol 932-1003和Nef64-76;或g) amino acid residues corresponding to Pol 129-320, Pol 747-827, Pol 932-1003, and Nef64-76; or
h)对应于以下的氨基酸残基:Gag:147-369、Pol 747-827、Pol 840-909和Nef 64-76。h) Amino acid residues corresponding to: Gag: 147-369, Pol 747-827, Pol 840-909 and Nef 64-76.
在各种实施方案中,复合融合多肽中的第一融合多肽和第二融合多肽包含不同的多肽片段,例如相同的氨基酸残基位置范围。在一些实施方案中,第一融合多肽和第二融合多肽是二价的。例如,在一些实施方案中,复合融合多肽(包括第一融合多肽和第二融合多肽)包含以下多肽片段或者由以下多肽片段组成,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3:In various embodiments, the first fusion polypeptide and the second fusion polypeptide in the composite fusion polypeptide comprise different polypeptide fragments, such as the same amino acid residue position range. In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bivalent. For example, in some embodiments, the composite fusion polypeptide (including the first fusion polypeptide and the second fusion polypeptide) comprises or consists of the following polypeptide fragments, wherein the Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2 and 3, respectively:
a)对应于以下的氨基酸残基:Gag 147-369、Pol 129-320、Pol 586-606、Pol 683-708、Pol 747-827、Pol 840-920、Pol 932-1003和Nef 64-76;或a) amino acid residues corresponding to Gag 147-369, Pol 129-320, Pol 586-606, Pol 683-708, Pol 747-827, Pol 840-920, Pol 932-1003, and Nef 64-76; or
b)Gag 1-53、Gag 147-369、Pol 56-117、Pol 129-320、Pol 367-431、Pol 542-606、Pol 683-708、Pol 747-827、Pol 840-920、Pol 932-1003、Nef 64-99和Nef 117-148。b)Gag 1-53, Gag 147-369, Pol 56-117, Pol 129-320, Pol 367-431, Pol 542-606, Pol 683-708, Pol 747-827, Pol 840-920, Pol 932- 1003, Nef 64-99 and Nef 117-148.
在一些实施方案中,复合融合多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:In some embodiments, the composite fusion polypeptide comprises the following polypeptide fragments in order from N-terminus to C-terminus, optionally bound or linked by one or more linkers:
a)SEQ ID NO:6、4、16和26以及SEQ ID NO:7、5、27和17,或分别与SEQ ID NO:6、4、16和26以及SEQ ID NO:7、5、27和17至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;a) SEQ ID NOs: 6, 4, 16 and 26 and SEQ ID NOs: 7, 5, 27 and 17, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 6, 4, 16 and 26 and SEQ ID NOs: 7, 5, 27 and 17, respectively;
b)SEQ ID NO:12、24、8和10以及SEQ ID NO:9、25、13和11,或分别与SEQ ID NO:12、24、8和10以及SEQ ID NO:9、25、13和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;b) SEQ ID NOs: 12, 24, 8 and 10 and SEQ ID NOs: 9, 25, 13 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 12, 24, 8 and 10 and SEQ ID NOs: 9, 25, 13 and 11, respectively;
c)SEQ ID NO:14、22、18、24和20以及SEQ ID NO:15、25、19、23和21,或分别与SEQID NO:14、22、18、24和20以及SEQ ID NO:15、25、19、23和21至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;c) SEQ ID NOs: 14, 22, 18, 24 and 20 and SEQ ID NOs: 15, 25, 19, 23 and 21, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 14, 22, 18, 24 and 20 and SEQ ID NOs: 15, 25, 19, 23 and 21, respectively;
d)SEQ ID NO:26、16、4和6以及SEQ ID NO:7、27、5和17,或分别与SEQ ID NO:26、16、4和6以及SEQ ID NO:7、27、5和17至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;d) SEQ ID NOs: 26, 16, 4 and 6 and SEQ ID NOs: 7, 27, 5 and 17, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 16, 4 and 6 and SEQ ID NOs: 7, 27, 5 and 17, respectively;
e)SEQ ID NO:8、24、12和10以及SEQ ID NO:13、25、9和11,或分别与SEQ ID NO:8、24、12和10以及SEQ ID NO:13、25、9和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;e) SEQ ID NOs: 8, 24, 12 and 10 and SEQ ID NOs: 13, 25, 9 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 24, 12 and 10 and SEQ ID NOs: 13, 25, 9 and 11, respectively;
f)SEQ ID NO:24、6、16和18以及SEQ ID NO:7、25、17和19,或分别与SEQ ID NO:24、6、16和18以及SEQ ID NO:7、25、17和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;f) SEQ ID NOs: 24, 6, 16 and 18 and SEQ ID NOs: 7, 25, 17 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 16 and 18 and SEQ ID NOs: 7, 25, 17 and 19, respectively;
g)SEQ ID NO:26、10、20和28以及SEQ ID NO:21、27、11和29,或分别与SEQ ID NO:26、10、20和28以及SEQ ID NO:21、27、11和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;g) SEQ ID NOs: 26, 10, 20 and 28 and SEQ ID NOs: 21, 27, 11 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 26, 10, 20 and 28 and SEQ ID NOs: 21, 27, 11 and 29, respectively;
h)SEQ ID NO:24、6、16和18以及SEQ ID NO:26、10、20和28,或分别与SEQ ID NO:24、6、16和18以及SEQ ID NO:26、10、20和28至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;h) SEQ ID NOs: 24, 6, 16 and 18 and SEQ ID NOs: 26, 10, 20 and 28, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 16 and 18 and SEQ ID NOs: 26, 10, 20 and 28, respectively;
i)SEQ ID NO:7、25、17和19以及SEQ ID NO:21、27、11和29,或分别与SEQ ID NO:7、25、17和19以及SEQ ID NO:21、27、11和29至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;i) SEQ ID NOs:7, 25, 17 and 19 and SEQ ID NOs:21, 27, 11 and 29, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:7, 25, 17 and 19 and SEQ ID NOs:21, 27, 11 and 29, respectively;
j)SEQ ID NO:22、6、16、20、18、28、26和10,或分别与SEQ ID NO:22、6、16、20、18、28、26和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;j) SEQ ID NOs: 22, 6, 16, 20, 18, 28, 26 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 22, 6, 16, 20, 18, 28, 26 and 10, respectively;
k)SEQ ID NO:7、21、19、17、27、25、29和11,或分别与SEQ ID NO:7、21、19、17、27、25、29和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;k) SEQ ID NO:7, 21, 19, 17, 27, 25, 29 and 11, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:7, 21, 19, 17, 27, 25, 29 and 11, respectively;
l)SEQ ID NO:22、24、14、18和20以及SEQ ID NO:25、23、15、21和19,或分别与SEQID NO:22、24、14、18和20以及SEQ ID NO:25、23、15、21和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;l) SEQ ID NOs:22, 24, 14, 18 and 20 and SEQ ID NOs:25, 23, 15, 21 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:22, 24, 14, 18 and 20 and SEQ ID NOs:25, 23, 15, 21 and 19, respectively;
m)SEQ ID NO:20、6、4、18、16和26以及SEQ ID NO:7、19、5、21、27和17,或分别与SEQ ID NO:20、6、4、18、16和26以及SEQ ID NO:7、19、5、21、27和17至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;m) SEQ ID NOs: 20, 6, 4, 18, 16 and 26 and SEQ ID NOs: 7, 19, 5, 21, 27 and 17, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 20, 6, 4, 18, 16 and 26 and SEQ ID NOs: 7, 19, 5, 21, 27 and 17, respectively;
n)SEQ ID NO:8、24、14、12、22和10以及SEQ ID NO:9、13、25、23、15和11,或分别与SEQ ID NO:8、24、14、12、22和10以及SEQ ID NO:9、13、25、23、15和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;n) SEQ ID NOs: 8, 24, 14, 12, 22 and 10 and SEQ ID NOs: 9, 13, 25, 23, 15 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 24, 14, 12, 22 and 10 and SEQ ID NOs: 9, 13, 25, 23, 15 and 11, respectively;
o)SEQ ID NO:18、26、20、4、6和16以及SEQ ID NO:7、21、17、5、27和19,或分别与SEQ ID NO:18、26、20、4、6和16、SEQ ID NO:7、21、17、5、27和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;o) SEQ ID NOs: 18, 26, 20, 4, 6 and 16 and SEQ ID NOs: 7, 21, 17, 5, 27 and 19, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 18, 26, 20, 4, 6 and 16, SEQ ID NOs: 7, 21, 17, 5, 27 and 19, respectively;
p)SEQ ID NO:24、6、4、20、18和32以及SEQ ID NO:7、21、5、25、33和19,或分别与SEQ ID NO:24、6、4、20、18和32、SEQ ID NO:7、21、5、25、33和19至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;p) SEQ ID NOs: 24, 6, 4, 20, 18 and 32 and SEQ ID NOs: 7, 21, 5, 25, 33 and 19, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 4, 20, 18 and 32, SEQ ID NOs: 7, 21, 5, 25, 33 and 19, respectively;
q)SEQ ID NO:6、20、4、24、32、18以及SEQ ID NO:8、12、30、26、14和10,或分别与SEQ ID NO:6、20、4、24、32、18以及SEQ ID NO:8、12、30、26、14和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;q) SEQ ID NO:6, 20, 4, 24, 32, 18 and SEQ ID NO:8, 12, 30, 26, 14 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:6, 20, 4, 24, 32, 18 and SEQ ID NO:8, 12, 30, 26, 14 and 10, respectively;
r)SEQ ID NO:8、30、14、12、26和10以及SEQ ID NO:9、13、31、27、15和11,或分别与SEQ ID NO:8、30、14、12、26和10、SEQ ID NO:9、13、31、27、15和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;r) SEQ ID NOs: 8, 30, 14, 12, 26 and 10 and SEQ ID NOs: 9, 13, 31, 27, 15 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 8, 30, 14, 12, 26 and 10, SEQ ID NOs: 9, 13, 31, 27, 15 and 11, respectively;
s)SEQ ID NO:24、6、4、20、18和32以及SEQ ID NO:8、30、14、12、26和10,或分别与SEQ ID NO:24、6、4、20、18和32以及SEQ ID NO:8、30、14、12、26和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;s) SEQ ID NOs: 24, 6, 4, 20, 18 and 32 and SEQ ID NOs: 8, 30, 14, 12, 26 and 10, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs: 24, 6, 4, 20, 18 and 32 and SEQ ID NOs: 8, 30, 14, 12, 26 and 10, respectively;
t)SEQ ID NO:6、20、4、24、32、18以及SEQ ID NO:8、12、30、26、14和10,或分别与SEQ ID NO:6、20、4、24、32、18以及SEQ ID NO:8、12、30、26、14和10至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段;或者t) SEQ ID NO:6, 20, 4, 24, 32, 18 and SEQ ID NO:8, 12, 30, 26, 14 and 10, or a sequence fragment that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:6, 20, 4, 24, 32, 18 and SEQ ID NO:8, 12, 30, 26, 14 and 10, respectively; or
u)SEQ ID NO:7、21、5、25、33和19以及SEQ ID NO:9、13、31、27、15和11,或分别与SEQ ID NO:7、21、5、25、33和19以及SEQ ID NO:9、13、31、27、15和11至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的序列片段。u) SEQ ID NOs:7, 21, 5, 25, 33 and 19 and SEQ ID NOs:9, 13, 31, 27, 15 and 11, or sequence fragments that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NOs:7, 21, 5, 25, 33 and 19 and SEQ ID NOs:9, 13, 31, 27, 15 and 11, respectively.
在各种实施方案中,复合融合多肽包含任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽或由以下融合多肽组成:In various embodiments, the composite fusion polypeptide comprises or consists of the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、· A fusion polypeptide of SEQ ID NOs:74 and 75, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162%, 163%, 164%, 165%, 166%, 167%, 168%, 169%,
98%或99%相同的融合多肽;98% or 99% identical fusion polypeptides;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在各种实施方案中,复合融合多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽或由以下融合多肽组成:In various embodiments, the composite fusion polypeptide comprises or consists of the following first fusion polypeptide and the second fusion polypeptide, optionally bound or linked by one or more linkers, in order from N-terminus to C-terminus:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:71 and 70, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:73 and 72, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:75 and 74, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:77 and 76, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:77 and 76, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:79 and 78, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:79 and 78, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 86, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 88, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 82, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 82, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 82, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 83, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 85, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 85, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:91 and 90, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:91 and 90, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:93 and 92, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 96, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 94, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 95, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 98, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively;
·SEQ ID NO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 98, respectively;
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or
·SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 100, respectively.
在复合融合多肽的一些实施方案中,第一融合多肽和第二融合多肽通过可切割的接头结合或连接。在各种实施方案中,该第一融合多肽和该第二融合多肽通过选自以下项的可切割接头结合或连接:2A可切割肽(例如,口蹄疫病毒(F2A)、马鼻炎A病毒(E2A)、猪捷申病毒-1(P2A)和明脉扁刺蛾病毒(T2A))、弗林蛋白酶识别/切割序列(例如,RAKR(SEQ IDNO:60)、REKR(SEQ ID NO:61)、RRKR(SEQ ID NO:62))以及它们的组合、衍生物或变体。在一些实施方案中,该第一融合多肽和该第二融合多肽通过选自以下项的弗林蛋白酶识别/切割位点结合或连接:RAKR(SEQ ID NO:60)、REKR(SEQ ID NO:61)和RRKR(SEQ ID NO:62)。在一些实施方案中,该第一融合多肽和该第二融合多肽通过2A可切割肽结合或连接,该2A可切割肽包含以下或者由以下组成:ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ IDNO:65)、QCTNYALLKLAGDVESNPGP(SEQ ID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67)的氨基酸序列,或与ATNFSLLKQAGDVEENPGP(SEQ ID NO:63)、APVKQTLNFDLLKLAGDVESNPGP(SEQID NO:64)、RAKRAPVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:65)、QCTNYALLKLAGDVESNPGP(SEQID NO:66)或EGRGSLLTCGDVEENPGP(SEQ ID NO:67)至少90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%相同的氨基酸序列。In some embodiments of the composite fusion polypeptide, the first fusion polypeptide and the second fusion polypeptide are bound or connected by a cleavable linker. In various embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or connected by a cleavable linker selected from the following items: 2A cleavable peptides (e.g., foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine Teschovirus-1 (P2A) and T. punctatus virus (T2A)), furin protease recognition/cleavage sequences (e.g., RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61), RRKR (SEQ ID NO: 62)) and combinations, derivatives or variants thereof. In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or connected by a furin protease recognition/cleavage site selected from the following items: RAKR (SEQ ID NO: 60), REKR (SEQ ID NO: 61) and RRKR (SEQ ID NO: 62). In some embodiments, the first fusion polypeptide and the second fusion polypeptide are bound or linked by a 2A cleavable peptide comprising or consisting of the amino acid sequence of ATNFSLLKQAGDVEENPGP (SEQ ID NO:63), APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:64), RAKRAPVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:65), QCTNYALLKLAGDVESNPGP (SEQ ID NO:66), or EGRGSLLTCGDVEENPGP (SEQ ID NO:67). NO:66) or EGRGSLLTCGDVEENPGP (SEQ ID NO:67) is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to an amino acid sequence.
表F中提供了根据本文所述方法设计和组装的不含信号序列的例示性复合融合多肽。表F将“AAA”公开为SEQ ID NO:48,将“LIK”公开为SEQ ID NO:53,将“AAY”公开为SEQ IDNO:49,将“SEG”公开为SEQ ID NO:55,将“QEE”公开为SEQ ID NO:51,将“RAKR”公开为SEQID NO:60并将“PPV”公开为SEQ ID NO:54。Exemplary composite fusion polypeptides designed and assembled according to the methods described herein without a signal sequence are provided in Table F. Table F discloses "AAA" as SEQ ID NO:48, "LIK" as SEQ ID NO:53, "AAY" as SEQ ID NO:49, "SEG" as SEQ ID NO:55, "QEE" as SEQ ID NO:51, "RAKR" as SEQ ID NO:60 and "PPV" as SEQ ID NO:54.
在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:209的氨基酸序列,或与SEQ ID NO:209至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:222的氨基酸序列,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:223的氨基酸序列,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,复合融合多肽包含以下或由以下组成:SEQ ID NO:227的氨基酸序列,或与SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。视情况而定或需要时,复合融合多肽可具有N末端甲硫氨酸残基。In some embodiments, the composite fusion polypeptide comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227. In some embodiments, the composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 209, 222, and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 209, 222, and 223. In some embodiments, the composite fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 209, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209. In some embodiments, the composite fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 222, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222. In some embodiments, the composite fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223. In some embodiments, the composite fusion polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 227. Optionally or where desired, the composite fusion polypeptide may have an N-terminal methionine residue.
信号或前导序列Signal or leader sequence
在各种实施方案中,融合多肽和/或复合融合多肽包括信号序列或信号肽,例如,以引导融合多肽或复合融合多肽在细胞内运输至蛋白酶体或溶酶体室。在各种实施方案中,融合多肽或复合融合多肽包括N末端和/或C末端处的信号序列。在一些实施方案中,融合多肽复合融合多肽包括N末端信号肽或前导序列。在各种实施方式中,信号肽或前导序列来自选自血清蛋白、细胞因子、趋化因子、伴侣蛋白、不变蛋白和将蛋白引导至溶酶体区室的蛋白的源蛋白。在一些实施方案中,信号肽或前导序列来自选自以下项的源蛋白:集落刺激因子2(CSF2、GM-CSF)、组织型纤溶酶原活化剂(PLAT、t-PA)、C-C基序趋化因子配体7(CCL7、MCP-3)、C-X-C基序趋化因子配体10(CXCL10、IP-10)、连环蛋白β1(CTNNB1)、CD74(p33;DHLAG;HLADG;Ia-GAMMA、不变链)、血清白蛋白(ALB)、聚泛素B/C(UBB/UBC)、钙网蛋白(CALR)、水泡性口炎病毒G蛋白(VSV-G)、溶酶体相关膜蛋白1(LAMP-1)和溶酶体相关膜蛋白2(LAMP-2)。在某些实施方案中,融合多肽包括来自LAMP-1的N末端和C末端信号序列,例如,分别为SEQ ID NO:125和126。在各种实施方案中,信号肽或前导序列选自SEQ ID NO:115-126中的任一项的氨基酸序列,或与SEQ ID NO:115-126中的任一项至少95%、96%、97%、98%或99%相同的核酸序列。可以用于本发明融合多肽和复合融合多肽中的例示性信号序列在表G中提供。In various embodiments, fusion polypeptide and/or composite fusion polypeptide include signal sequence or signal peptide, for example, to guide fusion polypeptide or composite fusion polypeptide to be transported to proteasome or lysosomal compartment in cell. In various embodiments, fusion polypeptide or composite fusion polypeptide include signal sequence at N-terminal and/or C-terminal. In some embodiments, fusion polypeptide composite fusion polypeptide includes N-terminal signal peptide or leader sequence. In various embodiments, signal peptide or leader sequence are from the source protein selected from serum protein, cytokine, chemokine, chaperone, unchanged protein and the protein that protein is directed to lysosomal compartment. In some embodiments, the signal peptide or leader sequence is from a source protein selected from the group consisting of colony stimulating factor 2 (CSF2, GM-CSF), tissue plasminogen activator (PLAT, t-PA), C-C motif chemokine ligand 7 (CCL7, MCP-3), C-X-C motif chemokine ligand 10 (CXCL10, IP-10), catenin beta 1 (CTNNB1), CD74 (p33; DHLAG; HLADG; Ia-GAMMA, invariant chain), serum albumin (ALB), polyubiquitin B/C (UBB/UBC), calreticulin (CALR), vesicular stomatitis virus G protein (VSV-G), lysosomal associated membrane protein 1 (LAMP-1), and lysosomal associated membrane protein 2 (LAMP-2). In certain embodiments, the fusion polypeptide includes N-terminal and C-terminal signal sequences from LAMP-1, e.g., SEQ ID NOs: 125 and 126, respectively. In various embodiments, the signal peptide or leader sequence is selected from the amino acid sequence of any one of SEQ ID NOs: 115-126, or a nucleic acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 115-126. Exemplary signal sequences that can be used in fusion polypeptides and composite fusion polypeptides of the invention are provided in Table G.
3.编码融合多肽或复合融合多肽的多核苷酸3. Polynucleotides encoding fusion polypeptides or composite fusion polypeptides
提供了编码本文所述的融合多肽或复合融合多肽的多核苷酸、包含此类多核苷酸的载体以及包含此类多核苷酸或表达载体的宿主细胞(例如,人类细胞、哺乳动物细胞、酵母细胞、植物细胞、昆虫细胞、细菌细胞(例如,大肠杆菌))。本文提供了包含编码本文所提供的融合多肽或复合融合多肽中的任一者的核苷酸序列的多核苷酸,以及包含此类多核苷酸序列的表达盒和载体,例如,用于在宿主细胞(例如,哺乳动物细胞)中有效表达的表达载体。在各种实施方案中,多核苷酸是DNA、cDNA、mRNA、自扩增RNA(SAM)、自复制RNA或自扩增复制子RNA(RepRNA)。在一些实施方案中,多核苷酸包括甲病毒自复制或自扩增复制子RNA(RepRNA)。作为疫苗递送模式的自复制RNA和自扩增复制子RNA描述于例如以下文献中:Ballesteros-Briones等人,Curr Opin Virol.(2020)44:145-153;Bloom等人,Gene Ther.(2020)22:1-13;Lundstrom,Int.J.Mol.Sci.(2020)21:5130;Moyo等人,Mol Ther MethodsClin Dev.(2018)12:32-46;Tews等人,Methods Mol Biol.(2017)1499:15-35;Démoulins等人,Methods Mol Biol.(2017)1499:37-75;Englezou等人,Mol Ther Nucleic Acids.(2018)12:118-134;McCollough等人,Vaccines(Basel).(2014)2(4):735-54;以及McCollough等人,Mol Ther Nucleic Acids.(2014)3:e173。Provided are polynucleotides encoding fusion polypeptides or composite fusion polypeptides as described herein, vectors comprising such polynucleotides, and host cells (e.g., human cells, mammalian cells, yeast cells, plant cells, insect cells, bacterial cells (e.g., E. coli)) comprising such polynucleotides or expression vectors. Provided herein are polynucleotides comprising a nucleotide sequence encoding any one of the fusion polypeptides or composite fusion polypeptides provided herein, and expression cassettes and vectors comprising such polynucleotide sequences, e.g., expression vectors for effective expression in host cells (e.g., mammalian cells). In various embodiments, the polynucleotides are DNA, cDNA, mRNA, self-amplifying RNA (SAM), self-replicating RNA, or self-amplifying replicon RNA (RepRNA). In some embodiments, the polynucleotides include alphavirus self-replicating or self-amplifying replicon RNA (RepRNA). Self-replicating RNA and self-amplifying replicon RNA as vaccine delivery modes are described in, for example, Ballesteros-Briones et al., Curr Opin Virol. (2020) 44:145-153; Bloom et al., Gene Ther. (2020) 22:1-13; Lundstrom, Int. J. Mol. Sci. (2020) 21:5130; Moyo et al., Mol Ther Methods Clin Dev. (2018) 12:32-46; Tews et al., Methods Mol Biol. (2017) 1499:15-35; Démoulins et al., Methods Mol Biol. (2017) 1499:37-75; Englezou et al., Mol Ther Nucleic Acids. (2018) 12: 118-134; McCollough et al., Vaccines (Basel). (2014) 2(4): 735-54; and McCollough et al., Mol Ther Nucleic Acids. (2014) 3: e173.
术语“多核苷酸”和“核酸分子”可互换地指核苷酸的聚合形式,并且包括RNA、cDNA、基因组DNA的有义链和反义链,以及上述的合成形式和混合聚合物。如本文所用,术语“核酸分子”可与术语“多核苷酸”互换。在一些实施方案中,核苷酸是指核糖核苷酸、脱氧核糖核苷酸或任一类型的核苷酸的修饰形式以及它们的组合。该术语还包括但不限于单链和双链形式的DNA。另外,多核苷酸例如cDNA或mRNA,可包括通过天然存在的和/或非天然存在的核苷酸键连接在一起的天然存在的和修饰的核苷酸中的一者或两者。如本领域技术人员将容易理解的,核酸分子可以是化学修饰或生物化学修饰的,或者可含有非天然或衍生的核苷酸碱基。此类修饰包括例如标记、甲基化、用类似物取代天然存在的核苷酸中的一者或多者、核苷酸间修饰诸如不带电的键(例如,膦酸甲酯、磷酸三酯、氨基磷酸酯、氨基甲酸酯等)、带电的键(例如,硫代磷酸酯、二硫代磷酸酯等)、侧链部分(例如,多肽)、嵌入剂(例如,吖啶、补骨脂素等)、螯合剂、烷基化物和修饰的键(例如,α异头核酸等)。上述术语还旨在包括任何拓扑构象,包括单链构象、双链构象、部分双链构象、三链构象、发夹构象、环状构象和挂锁构象。除非另外指明,否则对核酸序列的提及涵盖其互补序列。因此,对具有特定序列的核酸分子的提及应理解为涵盖其互补链及其互补序列。该术语还包括用于在期望的病毒表达载体或宿主细胞中改善表达的密码子偏好性多核苷酸。The terms "polynucleotide" and "nucleic acid molecule" refer interchangeably to polymeric forms of nucleotides, and include sense and antisense strands of RNA, cDNA, genomic DNA, and synthetic forms and mixed polymers described above. As used herein, the term "nucleic acid molecule" is interchangeable with the term "polynucleotide". In some embodiments, nucleotides refer to modified forms of ribonucleotides, deoxyribonucleotides, or any type of nucleotides, and combinations thereof. The term also includes, but is not limited to, DNA in single-stranded and double-stranded forms. In addition, polynucleotides, such as cDNA or mRNA, may include one or both of naturally occurring and modified nucleotides linked together by naturally occurring and/or non-naturally occurring nucleotide bonds. As will be readily appreciated by those skilled in the art, nucleic acid molecules may be chemically or biochemically modified, or may contain non-natural or derived nucleotide bases. Such modifications include, for example, labeling, methylation, substitution of one or more of the naturally occurring nucleotides with analogs, internucleotide modifications such as uncharged bonds (e.g., methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), side chain moieties (e.g., polypeptides), intercalators (e.g., acridine, psoralens, etc.), chelators, alkylates, and modified bonds (e.g., α-anomeric nucleic acids, etc.). The above terms are also intended to include any topological conformation, including single-stranded conformation, double-stranded conformation, partially double-stranded conformation, triple-stranded conformation, hairpin conformation, circular conformation, and padlock conformation. Unless otherwise indicated, reference to a nucleic acid sequence encompasses its complementary sequence. Therefore, reference to a nucleic acid molecule with a specific sequence should be understood to encompass its complementary chain and its complementary sequence. The term also includes codon preference polynucleotides for improving expression in a desired viral expression vector or host cell.
如本文所用,“取代”表示一个或多个氨基酸或核苷酸分别被不同的氨基酸或核苷酸替换。As used herein, "substitution" means that one or more amino acids or nucleotides are replaced by different amino acids or nucleotides, respectively.
“分离的”核酸是指已与其天然环境的组分分离的核酸分子。分离的核酸包括包含在通常包含核酸分子的细胞中的核酸分子,但该核酸分子存在于染色体外或存在于与其天然染色体位置不同的染色体位置。编码多肽片段或融合多肽或复合融合多肽的“分离的核酸”是指一种或多种编码此类多肽片段或融合多肽或复合融合多肽的核酸分子,包括单个载体或单独载体中的此类核酸分子,以及存在于宿主细胞中一个或多个位置处的此类核酸分子。An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in a cell that normally contains the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. An "isolated nucleic acid" encoding a polypeptide fragment or a fusion polypeptide or a composite fusion polypeptide refers to one or more nucleic acid molecules encoding such a polypeptide fragment or a fusion polypeptide or a composite fusion polypeptide, including such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules present at one or more locations in a host cell.
如本文所用,术语多核苷酸“变体”是通常与本文具体公开的多核苷酸在一个或多个取代、缺失、添加和/或插入方面不同的多核苷酸。此类变体可以是天然存在的或可例如通过修饰本文所述的多核苷酸序列中的一者或多者并评估如本文所述的所编码的多肽的一种或多种生物活性和/或使用本领域熟知的多种技术中的任一种来合成生成。As used herein, the term polynucleotide "variant" is a polynucleotide that typically differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants may be naturally occurring or may be generated synthetically, for example, by modifying one or more of the polynucleotide sequences described herein and evaluating one or more biological activities of the encoded polypeptide as described herein and/or using any of a variety of techniques well known in the art.
在一些实施方案中,核酸分子具有密码子偏好性以增强在所需宿主细胞(例如,人细胞、哺乳动物细胞、酵母细胞、植物细胞、昆虫细胞或细菌细胞,例如大肠杆菌细胞)中的表达。因此,提供了编码本文所述的融合多肽或复合融合多肽的多核苷酸,其中多核苷酸具有密码子偏好性,包含替换异源信号序列,并且/或者消除了mRNA不稳定性元件。产生密码子偏好性核酸的方法可通过调整在以下文献中描述的方法来进行:例如美国专利号5,965,726;6,174,666;6,291,664;6,414,132;和6,794,498。用于从所需病毒表达载体和/或在所需宿主细胞中表达包含HIV-1多肽片段的融合多肽或复合融合多肽的优选密码子使用例如在kazusa.or.jp/codon/和genscript.com/tools/codon-frequency-table中提供。In some embodiments, the nucleic acid molecule has a codon preference to enhance expression in a desired host cell (e.g., a human cell, a mammalian cell, a yeast cell, a plant cell, an insect cell, or a bacterial cell, such as an E. coli cell). Therefore, a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein is provided, wherein the polynucleotide has a codon preference, comprises a replacement heterologous signal sequence, and/or eliminates an mRNA instability element. Methods for generating codon-biased nucleic acids can be performed by adjusting the methods described in the following documents: for example, U.S. Patent Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498. Preferred codon usage for expressing a fusion polypeptide or a composite fusion polypeptide comprising an HIV-1 polypeptide fragment from a desired viral expression vector and/or in a desired host cell is provided, for example, at kazusa.or.jp/codon/ and genscript.com/tools/codon-frequency-table.
在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与选自表H中提供的SEQID NO:130-167、210-219和225-226的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与选自表H中提供的SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同。表H将“AAA”公开为SEQ ID NO:48,将“LIK”公开为SEQ ID NO:53,将“AAY”公开为SEQ ID NO:49,将“SEG”公开为SEQ ID NO:55,将“QEE”公开为SEQ ID NO:51,将“RAKR”公开为SEQ ID NO:60,将“KIL”公开为SEQ ID NO:52,并且将“PPV”公开为SEQ ID NO:54。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:139的核酸序列,或与SEQ ID NO:139至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:142的核酸序列,或与SEQ ID NO:142至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:145的核酸序列,或与SEQ ID NO:145至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:148的核酸序列,或与SEQ ID NO:148至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:150的核酸序列,或与SEQID NO:150至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:152的核酸序列,或与SEQ ID NO:152至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:155的核酸序列,或与SEQ ID NO:155至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:158的核酸序列,或与SEQ ID NO:158至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:225的核酸序列,或与SEQ ID NO:225至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,编码如本文所述的融合多肽或复合融合多肽的多核苷酸具有SEQ ID NO:226的核酸序列,或与SEQ IDNO:226至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to a nucleic acid sequence selected from SEQ ID NOs: 130-167, 210-219, and 225-226 provided in Table H. In some embodiments, the polynucleotide encoding a fusion polypeptide or composite fusion polypeptide as described herein has a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to a nucleic acid sequence selected from SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226 provided in Table H. Table H discloses "AAA" as SEQ ID NO:48, "LIK" as SEQ ID NO:53, "AAY" as SEQ ID NO:49, "SEG" as SEQ ID NO:55, "QEE" as SEQ ID NO:51, "RAKR" as SEQ ID NO:60, "KIL" as SEQ ID NO:52, and "PPV" as SEQ ID NO:54. In some embodiments, a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO:139, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO:139. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 142, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 142. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 145, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 145. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 148, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 148. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 150, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 150. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 152, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 152. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 155, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 155. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 158, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 158. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO: 225, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 225. In some embodiments, the polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein has a nucleic acid sequence of SEQ ID NO:226, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO:226.
视情况而定,在某些实施方案中,编码本文所述的融合多肽或复合融合多肽的多核苷酸的3'端包含一个或多个串联终止密码子,例如两个或更多个串联TAG(“琥珀(amber)”)、TAA(“赭石(ochre)”)或TGA(“乳白(opal)”或“棕土(umber)”)终止密码子。多个串联终止密码子可以相同或不同。As appropriate, in certain embodiments, the 3' end of the polynucleotide encoding the fusion polypeptide or composite fusion polypeptide described herein comprises one or more tandem stop codons, such as two or more tandem TAG ("amber"), TAA ("ochre"), or TGA ("opal" or "umber") stop codons. The multiple tandem stop codons may be the same or different.
视情况而定,在某些实施方案中,编码本文所述的融合多肽或复合融合多肽的多核苷酸的3'端不包含poly A序列。视情况而定,在某些实施方案中,编码本文所述的融合多肽或复合融合多肽的多核苷酸的3'端包含poly A序列。As the case may be, in certain embodiments, the 3' end of the polynucleotide encoding the fusion polypeptide or composite fusion polypeptide described herein does not contain a poly A sequence. As the case may be, in certain embodiments, the 3' end of the polynucleotide encoding the fusion polypeptide or composite fusion polypeptide described herein contains a poly A sequence.
还提供了表达盒,其包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸可操作地连接到一个或多个调控序列,例如,启动子。在一些实施方案中,多核苷酸可操作地连接到组成型启动子或诱导型启动子并在其控制下。在一些实施方案中,启动子选自巨细胞病毒主要立即早期启动子(CMV)、与鸡β-肌动蛋白启动子(CAG)融合的CMV增强子、人延伸因子-1α(HEF-1α)、小鼠巨细胞病毒(小鼠CMV)、中国仓鼠延伸因子-1α(CHEF-1α)和磷酸甘油酸激酶(PGK)。在一些实施方案中,启动子是病毒表达载体的天然启动子,例如,沙粒病毒载体启动子、腺病毒载体启动子等。An expression cassette is also provided, comprising a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, which is operably connected to one or more regulatory sequences, for example, a promoter. In some embodiments, the polynucleotide is operably connected to a constitutive promoter or an inducible promoter and is under its control. In some embodiments, the promoter is selected from the major immediate early promoter of cytomegalovirus (CMV), a CMV enhancer fused to a chicken β-actin promoter (CAG), human elongation factor-1α (HEF-1α), mouse cytomegalovirus (mouse CMV), Chinese hamster elongation factor-1α (CHEF-1α) and phosphoglycerate kinase (PGK). In some embodiments, the promoter is a natural promoter of a viral expression vector, for example, an arenavirus vector promoter, an adenovirus vector promoter, etc.
还提供了用于制备融合多肽或复合融合多肽、药物组合物、免疫原性组合物或包含它们的疫苗组合物的方法。在一些具体实施中,这些方法包括使用肽合成构建融合多肽或复合融合多肽。在一些实施方案中,该方法包括使用合成或重组DNA技术构建编码二价抗原的多肽中的每一者的多核苷酸并从表达载体表达该多肽。在一些实施方案中,该方法还可包括将多核苷酸插入一种或多种载体中,并在细胞中表达编码的多肽。Also provided are methods for preparing fusion polypeptides or composite fusion polypeptides, pharmaceutical compositions, immunogenic compositions, or vaccine compositions comprising them. In some specific implementations, these methods include constructing fusion polypeptides or composite fusion polypeptides using peptide synthesis. In some embodiments, the method includes constructing polynucleotides encoding each of the polypeptides of the bivalent antigen using synthetic or recombinant DNA technology and expressing the polypeptides from expression vectors. In some embodiments, the method may also include inserting the polynucleotides into one or more vectors and expressing the encoded polypeptides in cells.
4.载体和宿主细胞4. Vectors and Host Cells
还提供了包含编码本文所述的融合多肽或复合融合多肽中的一者或多者的一种或多种多核苷酸的载体,或者或包含此类多核苷酸的表达盒。载体可以是任何类型,例如重组载体,诸如表达载体。载体包括但不限于质粒、粘粒、细菌人工染色体(BAC)和酵母人工染色体(YAC)以及衍生自噬菌体或植物或动物(包括人)病毒的载体。载体可以包括被所提出的宿主细胞识别的复制起点,并且就表达载体而言,包括启动子和被宿主细胞识别的其他调控区。在另外的实施方案中,载体包含编码本公开的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸,所述多核苷酸可操作地连接到启动子和任选地另外的调节元件。某些载体能够在它们所引入的宿主中自主复制(例如,具有细菌复制起点的载体可以在细菌中复制)。其他载体可以在引入宿主时整合到宿主的基因组中,由此与宿主基因组一起复制。载体包括但不限于适用于重组产生本文所公开的融合多肽和/或复合融合多肽的那些。Also provided are vectors comprising one or more polynucleotides encoding one or more of the fusion polypeptides or composite fusion polypeptides described herein, or or an expression cassette comprising such polynucleotides. The vector may be of any type, such as a recombinant vector, such as an expression vector. The vector includes, but is not limited to, plasmids, cosmids, bacterial artificial chromosomes (BACs) and yeast artificial chromosomes (YACs) and vectors derived from bacteriophages or plants or animals (including humans) viruses. The vector may include a replication origin recognized by the proposed host cell, and with respect to expression vectors, includes a promoter and other regulatory regions recognized by the host cell. In other embodiments, the vector includes one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides disclosed herein, and the polynucleotides are operably connected to a promoter and optionally other regulatory elements. Certain vectors are capable of autonomous replication in the host into which they are introduced (for example, a vector with a bacterial replication origin can replicate in bacteria). Other vectors may be integrated into the host's genome when introduced into the host, thereby replicating with the host genome. The vector includes, but is not limited to, those suitable for recombinant production of fusion polypeptides and/or composite fusion polypeptides disclosed herein.
如本文所用,术语“载体”是指能够使与其连接的另一个核酸增殖的核酸分子。该术语包括作为自复制核酸结构的载体以及整合到已引入该载体的宿主细胞的基因组中的载体。一些载体适用于递送本申请的核酸分子或多核苷酸。某些载体能够引导与它们有效连接的核酸的表达。此类载体在本文中称为表达载体。As used herein, the term "vector" refers to a nucleic acid molecule that is capable of propagating another nucleic acid connected thereto. The term includes vectors that are self-replicating nucleic acid structures and vectors that are integrated into the genome of a host cell into which the vector has been introduced. Some vectors are suitable for delivering nucleic acid molecules or polynucleotides of the present application. Certain vectors are capable of directing the expression of nucleic acids that are effectively connected thereto. Such vectors are referred to herein as expression vectors.
术语“可操作地连接”是指通常物理连接并且彼此具有功能关系的两个或更多个核酸序列元件。例如,如果启动子能够引发或调控编码序列的转录或表达,则该启动子可操作地连接到编码序列,在这种情况下,该编码序列应理解为“处于该启动子的控制下”。The term "operably linked" refers to two or more nucleic acid sequence elements that are typically physically linked and in a functional relationship with each other. For example, a promoter is operably linked to a coding sequence if it is capable of initiating or regulating the transcription or expression of the coding sequence, in which case the coding sequence is understood to be "under the control of the promoter."
载体的选择取决于随后的重组程序和使用的宿主。载体向宿主细胞中的引入可通过尤其是磷酸钙转染、DEAE-葡聚糖介导的转染、lipofectamine转染、电穿孔、病毒感染或经由如本文所述的向受试者施用来实现。载体可自主复制或可与它们所整合的染色体一起复制。在某些实施方案中,载体含有一种或多种选择标志物。标志物的选择可取决于选择的宿主细胞。这些包括但不限于,卡那霉素、新霉素、嘌呤霉素、潮霉素、zeocin、来自单纯疱疹病毒的胸苷激酶基因(HSV-TK)和来自小鼠的二氢叶酸还原酶基因(dhfr)。本发明还涵盖包含一个或多个编码本文所述融合多肽或复合融合多肽的核酸分子的载体,这些核酸分子可操作地连接到一个或多个编码可用于分离免疫原性多肽的蛋白质或肽的核酸分子。这些蛋白质或肽包括但不限于谷胱甘肽-S-转移酶、麦芽糖结合蛋白、金属结合多组氨酸、绿色荧光蛋白、荧光素酶和β-半乳糖苷酶。The selection of the vector depends on the subsequent recombination procedure and the host used. The introduction of the vector into the host cell can be achieved by calcium phosphate transfection, DEAE-dextran-mediated transfection, lipofectamine transfection, electroporation, viral infection or via administration to the subject as described herein. The vector can replicate autonomously or can replicate together with the chromosome into which they are integrated. In certain embodiments, the vector contains one or more selection markers. The selection of the marker can depend on the host cell selected. These include but are not limited to kanamycin, neomycin, puromycin, hygromycin, zeocin, thymidine kinase gene (HSV-TK) from herpes simplex virus and dihydrofolate reductase gene (dhfr) from mouse. The present invention also encompasses vectors comprising one or more nucleic acid molecules encoding fusion polypeptides or composite fusion polypeptides described herein, which are operably connected to one or more nucleic acid molecules encoding proteins or peptides that can be used to separate immunogenic polypeptides. These proteins or peptides include but are not limited to glutathione-S-transferase, maltose binding protein, metal-binding polyhistidine, green fluorescent protein, luciferase and beta-galactosidase.
在各种实施方案中,载体包含编码一种或多种融合多肽的一种或多种多核苷酸,这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ IDNO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码一种或多种融合多肽的一种或多种多核苷酸,这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ IDNO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In various embodiments, the vector comprises one or more polynucleotides encoding one or more fusion polypeptides comprising or consisting of the amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227. In various embodiments, the vector comprises one or more polynucleotides encoding one or more fusion polypeptides comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223.
在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:82的氨基酸序列,或与SEQ ID NO:82至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:83的氨基酸序列,或与SEQ ID NO:83至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:85的氨基酸序列,或与SEQ IDNO:85至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:86的氨基酸序列,或与SEQ ID NO:86至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ IDNO:87的氨基酸序列,或与SEQ ID NO:87至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,包含编码前述融合多肽中的一种或多种融合多肽的多核苷酸的载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)。In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:82, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:82. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:83, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:83. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:85, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:86, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:86. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 87, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 87. In various embodiments, the vector comprising a polynucleotide encoding one or more of the aforementioned fusion polypeptides is Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus).
在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:85的氨基酸序列,或与SEQ ID NO:85至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:98的氨基酸序列,或与SEQ ID NO:98至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:99的氨基酸序列,或与SEQ IDNO:99至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:100的氨基酸序列,或与SEQ ID NO:100至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ IDNO:101的氨基酸序列,或与SEQ ID NO:101至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,包含编码前述融合多肽中的一种或多种融合多肽的多核苷酸的载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:85, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:98, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:98. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:99, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:99. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:100, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:100. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 101, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 101. In various embodiments, the vector comprising a polynucleotide encoding one or more of the foregoing fusion polypeptides is a lymphocytic choriomeningitis mammalian arenavirus (LCMV).
在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:209的氨基酸序列,或与SEQ ID NO:209至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:222的氨基酸序列,或与SEQ IDNO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:223的氨基酸序列,或与SEQID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在各种实施方案中,载体包含编码融合多肽的多核苷酸,该融合多肽包含以下或由以下组成:SEQ ID NO:227的氨基酸序列,或与SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:209, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:209. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:222, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:222. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:223. In various embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:227.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the vector comprises one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively;
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:84 and 85, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:82 and 85, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:84 and 88, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively.
在各种实施方案中,载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the vector comprises one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:105或206的复合融合多肽,或与SEQ ID NO:105或206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105 or 206, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 105 or 206.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:107或207的复合融合多肽,或与SEQ ID NO:107或207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 107 or 207, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 107 or 207.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:109的复合融合多肽,或与SEQ ID NO:109至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:109, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:109.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:111的复合融合多肽,或与SEQ ID NO:111至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:111, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:111.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:200的复合融合多肽,或与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:200, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:200.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:201的复合融合多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:201, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:201.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:202的复合融合多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:202, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:202.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:203的复合融合多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:203, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:203.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:204的复合融合多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:204, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:204.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:205的复合融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:205, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:205.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:208的复合融合多肽,或与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:208, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:208.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:209的复合融合多肽,或与SEQ ID NO:209至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:209, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:209.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:222的复合融合多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:222, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:222.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:223的复合融合多肽,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:223, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:223.
在各种实施方案中,载体包含编码以下的多核苷酸:包含SEQ ID NO:227的复合融合多肽,或与SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the vector comprises a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:227, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:227.
在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与选自SEQ ID NO:130-167、210-219和225-226的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与选自SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%相同或100%相同的核酸序列。In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, which has a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219 and 225-226, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to a nucleic acid sequence selected from SEQ ID NOs: 130-167, 210-219 and 225-226. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, which has a nucleic acid sequence of any one of SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225 and 226, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to a nucleic acid sequence selected from SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225 and 226.
在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:139的核酸序列,或与SEQ ID NO:139的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:142的核酸序列,或与SEQ ID NO:142的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:145的核酸序列,或与SEQ ID NO:145的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:148的核酸序列,或与SEQ ID NO:148的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在各种实施方案中,包含一种或多种前述多核苷酸的载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 139, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 139. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 142, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 142. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 145, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 145. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 148, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 148. In various embodiments, the vector comprising one or more of the foregoing polynucleotides is a lymphocytic choriomeningitis mammalian arenavirus (LCMV).
在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:150的核酸序列,或与SEQ ID NO:150的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:152的核酸序列,或与SEQ ID NO:152的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:155的核酸序列,或与SEQ ID NO:155的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:158的核酸序列,或与SEQ ID NO:158的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在各种实施方案中,包含一种或多种前述多核苷酸的载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 150, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or 100% identical to the nucleic acid sequence of SEQ ID NO: 150. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 152, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, or 100% identical to the nucleic acid sequence of SEQ ID NO: 152. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 155, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 155. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 158, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 158. In various embodiments, the vector comprising one or more of the aforementioned polynucleotides is a Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus).
在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:225的核酸序列,或与SEQ ID NO:225的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。在一些实施方案中,载体包含编码如本文所述的融合多肽或复合融合多肽的多核苷酸,该多核苷酸具有SEQ ID NO:226的核酸序列,或与SEQ ID NO:226的核酸序列至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%相同或100%相同的核酸序列。In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 225, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 225. In some embodiments, the vector comprises a polynucleotide encoding a fusion polypeptide or a composite fusion polypeptide as described herein, the polynucleotide having a nucleic acid sequence of SEQ ID NO: 226, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical or 100% identical to the nucleic acid sequence of SEQ ID NO: 226.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
·SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 132, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively;
·SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 134, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively;
·SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively;
·SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively;
·SEQ ID NO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively;
·SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively;
·SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively;
·SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 134 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively;
·SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively;
·SEQ ID NO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 141, respectively;
·SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively;
·SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 142, respectively;
·SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 145, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively;
·SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 140 and 146, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively;
·SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 142 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively;
·SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 143 and 149, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively;
·SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively;
·SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively;
·SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 155, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively;
·SEQ ID NO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 153, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively;
·SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively;
·SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively;
·SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 153 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 153 and 159, respectively;
·SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 154 and 157, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, respectively;
·SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively;
·SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively;
·SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively;
·SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively;
·SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 164 and 165, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively;
·SEQ ID NO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively;
·SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 210 and 211, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively;
·SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 212 and 213, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 212 and 213, respectively;
·SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 214 and 215, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively;
·SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively;
·SEQ ID NO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 218 and 219, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively;
·SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或者a polynucleotide of SEQ ID NOs: 218 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 226, respectively; or
·SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively;
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:130或SEQ ID NO:131的多核苷酸,或分别与SEQ ID NO:130或SEQ ID NO:131至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 130 or SEQ ID NO: 131, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 130 or SEQ ID NO: 131, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:134或SEQ ID NO:135的多核苷酸,或分别与SEQ ID NO:134或SEQ ID NO:135至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 134 or SEQ ID NO: 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 134 or SEQ ID NO: 135, respectively.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:132或SEQ ID NO:133的多核苷酸,或分别与SEQ ID NO:132或SEQ ID NO:133至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 132 or SEQ ID NO: 133, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 132 or SEQ ID NO: 133, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:136或SEQ ID NO:137的多核苷酸,或分别与SEQ ID NO:136或SEQ ID NO:137至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 136 or SEQ ID NO: 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 136 or SEQ ID NO: 137, respectively.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:139的多核苷酸,或分别与SEQ ID NO:139至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 139, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 139, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:145的多核苷酸,或与SEQ ID NO:145至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:140的多核苷酸,或分别与SEQ ID NO:140至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 140, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 140, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:146的多核苷酸,或与SEQ ID NO:146至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 146.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:142的多核苷酸,或分别与SEQ ID NO:142至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 142, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 142, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:148的多核苷酸,或与SEQ ID NO:148至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 148, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 148.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:143的多核苷酸,或分别与SEQ ID NO:143至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 143, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 143, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:149的多核苷酸,或与SEQ ID NO:149至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 149, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 149.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:150的多核苷酸,或分别与SEQ ID NO:150至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 150, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 150, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:152的多核苷酸,或与SEQ ID NO:152至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 152.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:151的多核苷酸,或分别与SEQ ID NO:151至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 151, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 151, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:153的多核苷酸,或与SEQ ID NO:153至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 153, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 153.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:154的多核苷酸,或分别与SEQ ID NO:154至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 154, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 154, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:157的多核苷酸,或与SEQ ID NO:157至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 157, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 157.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:155的多核苷酸,或分别与SEQ ID NO:155至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 155, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 155, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:158的多核苷酸,或与SEQ ID NO:158至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 158.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:156的多核苷酸,或分别与SEQ ID NO:156至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 156, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 156, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:159的多核苷酸,或与SEQ ID NO:159至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 159, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 159.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:160的多核苷酸,或分别与SEQ ID NO:160至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 160, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 160, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:161的多核苷酸,或与SEQ ID NO:161至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 161.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:162的多核苷酸,或分别与SEQ ID NO:162至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 162, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 162, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:163的多核苷酸,或与SEQ ID NO:163至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 163, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 163.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:164的多核苷酸,或分别与SEQ ID NO:164至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 164, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 164, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:165的多核苷酸,或与SEQ ID NO:165至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 165.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:166的多核苷酸,或分别与SEQ ID NO:166至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 166, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 166, respectively, and
b)第二多核苷酸,其包含:SEQ ID NO:167的多核苷酸,或与SEQ ID NO:167至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO: 167, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 167.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 210, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 210, and
b)第二多核苷酸,其包含:SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:211.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:212, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:212, and
b)第二多核苷酸,其包含:SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:213.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:214, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:214, and
b)第二多核苷酸,其包含:SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:215.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:216, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:216, and
b)第二多核苷酸,其包含:SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:217.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:218, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:218, and
b)第二多核苷酸,其包含:SEQ ID NO:219的多核苷酸,或与SEQID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:219.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:218的多核苷酸,或与SEQID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO:218, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:218, and
b)第二多核苷酸,其包含:SEQ ID NO:226的多核苷酸,或与SEQID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在各种实施方案中,载体包含以下第一多核苷酸和第二多核苷酸:In various embodiments, the vector comprises the following first and second polynucleotides:
a)第一多核苷酸,其包含:SEQ ID NO:225的多核苷酸,或与SEQID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和a) a first polynucleotide comprising: a polynucleotide of SEQ ID NO: 225, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 225, and
b)第二多核苷酸,其包含:SEQ ID NO:226的多核苷酸,或与SEQID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second polynucleotide comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在各种实施方案中,载体包含包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In various embodiments, the vector comprises a polynucleotide comprising SEQ ID NO:225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:225.
在各种实施方案中,载体包含多核苷酸,该包含:SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In various embodiments, the vector comprises a polynucleotide comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在其他实施方案中,使用的载体是pcDNATM3.1+(赛默飞世尔科技公司(ThermoFisher,MA)。In other embodiments, the vector used is pcDNA ™ 3.1+ (ThermoFisher, MA).
在一些实施方案中,载体是病毒载体。视情况而定,病毒载体可以是DNA病毒或RNA病毒,包括自复制RNA病毒。自复制RNA病毒包括甲病毒,并且例如在Lundstrom,Molecules.(2018)23(12).pii:E3310(PMID:30551668);和Ljungberg等人,Expert Rev Vaccines.(2015)14(2):177-94)。用作病毒载体的另外的甲病毒描述于例如WO 2020/097393和WO2018/208856中。在各种实施方案中,病毒载体来自选自以下的病毒:腺病毒、腺相关病毒、沙粒病毒、甲病毒、自复制甲病毒、痘病毒、巨细胞病毒、弹状病毒、水泡性口炎病毒、黄病毒、马拉巴病毒和痘苗病毒。在一些实施方案中,病毒载体来自选自以下的病毒家族:腺病毒科(例如,腺病毒、腺相关病毒)、沙粒病毒科(例如,淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒、卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒)、痘病毒科(例如,痘苗病毒)、疱疹病毒科(例如,巨细胞病毒、疱疹病毒,例如,HSV-1)、细小病毒科(例如,细小病毒H1)、痘病毒科(例如,痘苗病毒,例如改良安卡拉痘苗病毒(MVA))、黄病毒科(例如,黄热病毒)、呼肠孤病毒(例如,呼肠孤病毒)、小核糖核酸病毒科(例如,柯萨奇病毒(Coxsackievirus)、塞尼卡谷病毒(Seneca Valley Virus)、脊髓灰质炎病毒(Poliovirus))、副粘病毒科(例如麻疹病毒、新城疫病毒(Newcastle disease virus)(NDV))、弹状病毒科(例如水泡性病毒,包括马拉巴水泡性病毒和水泡性口炎病毒(VSV))、披膜病毒科(例如,甲病毒,例如,委内瑞拉马脑炎病毒,例如自复制甲病毒;辛得比斯病毒(Sindbis virus))、肠病毒科(Enteroviridae)(例如埃可病毒(Echovirus))。用于表达本发明融合多肽和/或复合融合多肽的例示性修饰的牛痘病毒载体描述于例如WO 2019/134049中。In some embodiments, the vector is a viral vector. Depending on the circumstances, the viral vector can be a DNA virus or an RNA virus, including a self-replicating RNA virus. Self-replicating RNA viruses include alphaviruses, and are described, for example, in Lundstrom, Molecules. (2018) 23 (12). pii: E3310 (PMID: 30551668); and Ljungberg et al., Expert Rev Vaccines. (2015) 14 (2): 177-94). Additional alphaviruses used as viral vectors are described, for example, in WO 2020/097393 and WO 2018/208856. In various embodiments, the viral vector is from a virus selected from the group consisting of adenovirus, adeno-associated virus, arenavirus, alphavirus, self-replicating alphavirus, poxvirus, cytomegalovirus, rhabdovirus, vesicular stomatitis virus, flavivirus, Maraba virus, and vaccinia virus. In some embodiments, the viral vector is from a virus family selected from the group consisting of Adenoviridae (e.g., adenovirus, adeno-associated virus), Arenaviridae (e.g., lymphocytic choriomeningitis mammalian arenavirus, Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus), Poxviridae (e.g., vaccinia virus), Herpesviridae (e.g., cytomegalovirus, herpes virus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus H1), Poxviridae (e.g., vaccinia virus, e.g., modified vaccinia virus Ankara (MVA)), Flaviviridae (e.g., yellow fever virus), Reovirus (e.g., Reovirus), Picornaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., measles virus, Newcastle disease virus, Virus) (NDV)), Rhabdoviridae (e.g., vesiculoviruses, including Maraba vesiculovirus and vesicular stomatitis virus (VSV)), Togaviridae (e.g., alphaviruses, e.g., Venezuelan equine encephalitis virus, e.g., self-replicating alphaviruses; Sindbis virus), Enteroviridae (e.g., Echovirus). Exemplary modified vaccinia virus vectors for expressing fusion polypeptides and/or composite fusion polypeptides of the present invention are described, e.g., in WO 2019/134049.
在一些实施方案中,病毒表达载体是选自以下的沙粒病毒载体:淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)(NCBI:txid11623)、卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德病毒)(NCBI:txid2169993)、瓜纳瑞托病毒(GTOV)(NCBI:txid45219)、阿根廷哺乳动物沙粒病毒(又名胡宁病毒(JUNV))(NCBI:txid2169991)、拉沙病毒(LASV)(NCBI:txid11620)、卢约病毒(LUJV)(NCBI:txid649188)、马丘波病毒(MACV)(NCBI:txid11628)、巴西哺乳动物沙粒病毒(又名萨比亚病毒(SABV))(NCBI:txid2169992)和怀特沃特阿罗约病毒(WWAV)(NCBI:txid46919)。在一些实施方案中,病毒表达载体是选自以下项的沙粒病毒载体:淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)或卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)。可用作本文描述的融合多肽的递送和表达媒介的例示性沙粒病毒载体描述于例如WO 2009/083210、WO 2015/183895、WO 2016/075250、WO 2017/198726和美国专利号9,943,585中。In some embodiments, the viral expression vector is an arenavirus vector selected from the group consisting of lymphocytic choriomeningitis mammalian arenavirus (LCMV) (NCBI: txid11623), Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde virus) (NCBI: txid2169993), Guanarito virus (GTOV) (NCBI: txid45219), Argentine mammalian arenavirus (also known as Junin virus (JUNV)) (NCBI: txid2169993), and Argentine mammalian arenavirus (also known as Junin virus (JUNV)). txid2169991), Lassa virus (LASV) (NCBI: txid11620), Luyo virus (LUJV) (NCBI: txid649188), Machupo virus (MACV) (NCBI: txid11628), Brazilian mammalian arenavirus (also known as Sabia virus (SABV)) (NCBI: txid2169992) and Whitewater Arroyo virus (WWAV) (NCBI: txid46919). In some embodiments, the viral expression vector is an arenavirus vector selected from the following: lymphocytic choriomeningitis mammalian arenavirus (LCMV) or Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus). Exemplary arenavirus vectors that can be used as delivery and expression vehicles for the fusion polypeptides described herein are described in, e.g., WO 2009/083210, WO 2015/183895, WO 2016/075250, WO 2017/198726, and U.S. Pat. No. 9,943,585.
在一些实施方案中,病毒表达载体是腺病毒载体,例如,来自人腺病毒或猿猴腺病毒(例如,黑猩猩腺病毒、大猩猩腺病毒或恒河猴腺病毒)。在一些实施方案中,腺病毒载体选自血清型5腺病毒(Ad5)、血清型26腺病毒(Ad26)、血清型34腺病毒(Ad34)、血清型35腺病毒(Ad35)、血清型48腺病毒(Ad48)、黑猩猩腺病毒(例如,ChAd3(AdC3)、ChAd5(AdC5)、ChAd6(AdC6)、ChAd7(AdC7)、ChAd8(AdC8)、ChAd9(AdC9)、ChAd10(AdC10)、ChAd11(AdC11)、ChAd17(AdC17)、ChAd16(AdC16)、ChAd19(AdC19)、ChAd20(AdC20)、ChAd22(AdC22)、ChAd24(AdC24)、ChAdY25、ChAd26(AdC26)、ChAd28(AdC28)、ChAd30(AdC30)、ChAd31(AdC31)、ChAd37(AdC37)、ChAd38(AdC38)、ChAd43(AdC43)、ChAd44(AdC44)、ChAd55(AdC55)、ChAd63(AdC63)、ChAdV63、ChAd68(AdC68)、ChAd73(AdC73)、ChAd82(AdC82)、ChAd83(AdC83)、ChAd143(AdC143)、ChAd144(AdC144)、ChAd145(AdC145)、ChAd147(AdC147))、大猩猩腺病毒(例如,GC44、GC45、GC46)和恒河猴腺病毒(例如,RhAd51、RhAd52、RhAd53、RhAd54、RhAd55、RhAd56、RhAd57、RhAd58、RhAd59、RhAd60、RhAd61、RhAd62、RhAd63、RhAd64、RhAd65、RhAd66)。可用作本文描述的融合多肽和/或复合融合多肽的递送和表达媒介物的例示性黑猩猩、大猩猩和猕猴腺病毒载体描述于例如以下文献中:WO 2019/076880;WO 2019/076877;Andrabi等人,(2019)Cell Reports 27:2426-2441;Guo等人,Hum VaccinImmunother.(2018)14(7):1679-1685;Abbink等人,J Virol.(2015)89(3):1512-22;Abbink等人,J Virol.(2018)92(6).pii:e01924-17,以及WO 2020/243719A1和WO 2018/098362A1中。In some embodiments, the viral expression vector is an adenoviral vector, e.g., from a human adenovirus or a simian adenovirus (e.g., a chimpanzee adenovirus, a gorilla adenovirus, or a rhesus monkey adenovirus). In some embodiments, the adenoviral vector is selected from a serotype 5 adenovirus (Ad5), a serotype 26 adenovirus (Ad26), a serotype 34 adenovirus (Ad34), a serotype 35 adenovirus (Ad35), a serotype 48 adenovirus (Ad48), a chimpanzee adenovirus (e.g., ChAd3 (AdC3), ChAd5 (AdC5), ChAd6 (AdC6), ChAd7 (AdC7), ChAd8 (AdC8), ChAd9 (AdC9), ChAd10 (AdC10), ChAd11(AdC11), ChAd17(AdC17), ChAd16(AdC16), ChAd19(AdC19), ChAd20(AdC20), ChAd22(AdC22), ChAd24(AdC24), ChAdY25, ChAd26(AdC26), ChAd28(AdC28), ChAd30(AdC30) ,ChAd31(AdC31),ChAd37( AdC37), ChAd38(AdC38), ChAd43(AdC43), ChAd44(AdC44), ChAd55(AdC55), ChAd63(AdC63), ChAdV63, ChAd68(AdC68), ChAd73(AdC73), ChAd82(AdC82), ChAd83(AdC83), ChAd143(AdC14 3), ChAd144 (AdC144), ChAd 145 (AdC145), ChAd147 (AdC147)), gorilla adenovirus (e.g., GC44, GC45, GC46), and rhesus macaque adenovirus (e.g., RhAd51, RhAd52, RhAd53, RhAd54, RhAd55, RhAd56, RhAd57, RhAd58, RhAd59, RhAd60, RhAd61, RhAd62, RhAd63, RhAd64, RhAd65, RhAd66). Exemplary chimpanzee, gorilla and macaque adenovirus vectors that can be used as delivery and expression vehicles for the fusion polypeptides and/or composite fusion polypeptides described herein are described, for example, in the following documents: WO 2019/076880; WO 2019/076877; Andrabi et al., (2019) Cell Reports 27:2426-2441; Guo et al., Hum Vaccin Immunother. (2018) 14(7):1679-1685; Abbink et al., J Virol. (2015) 89(3):1512-22; Abbink et al., J Virol. (2018) 92(6).pii:e01924-17, and in WO 2020/243719A1 and WO 2018/098362A1.
在各种实施方案中,病毒表达载体不能复制(即复制缺陷型或复制不足型),例如与野生型病毒载体相比具有降低或减弱的复制能力(即,复制减毒型),或者是复制能力型的。In various embodiments, the viral expression vector is unable to replicate (ie, replication-defective or replication-deficient), eg, has reduced or attenuated replication capacity compared to a wild-type viral vector (ie, replication-attenuated), or is replication-competent.
还提供了宿主细胞,其包含编码本文所述的融合多肽或复合融合多肽中的一者或多者的一种或多种多核苷酸或者表达所述融合多肽或复合融合多肽的一种或多种载体。可以使用各种宿主细胞中的任一种。在一个实施方案中,宿主细胞是原核细胞,例如大肠杆菌。在另一个实施方案中,宿主细胞是真核细胞,例如酵母细胞、植物细胞、昆虫细胞、哺乳动物细胞,诸如基于中国仓鼠卵巢(CHO)或CHO来源的细胞系(例如,CHO-S、CHO DG44、ExpiCHOTM、ZFN修饰的GS-/-CHO细胞系、CHO-K1、CHO-K1a)、COS细胞、BHK细胞、NSO细胞或Bowes黑素瘤细胞。人宿主细胞的示例尤其是HeLa、911、AT1080、A549和HEK293(例如,HEK293E、HEK293F、HEK293H、HEK293T、Expi293TM)。另外,融合多肽和/或复合融合多肽可以在酵母细胞(诸如毕赤酵母(参见例如Powers等人,J Immunol Methods.251:123-35(2001))、汉逊酵母(Hanseula)或酿酒酵母(Saccharomyces))中表达。Also provided is a host cell comprising one or more polynucleotides encoding one or more of the fusion polypeptides or composite fusion polypeptides described herein or one or more vectors expressing the fusion polypeptides or composite fusion polypeptides. Any of a variety of host cells can be used. In one embodiment, the host cell is a prokaryotic cell, such as Escherichia coli. In another embodiment, the host cell is a eukaryotic cell, such as a yeast cell, a plant cell, an insect cell, a mammalian cell, such as a cell line based on Chinese hamster ovary (CHO) or CHO-derived (e.g., CHO-S, CHO DG44, ExpiCHO ™ , ZFN-modified GS-/- CHO cell lines, CHO-K1, CHO-K1a), COS cells, BHK cells, NSO cells or Bowes melanoma cells. Examples of human host cells are, inter alia, HeLa, 911, AT1080, A549 and HEK293 (e.g., HEK293E, HEK293F, HEK293H, HEK293T, Expi293 ™ ). In addition, the fusion polypeptide and/or complex fusion polypeptide can be expressed in yeast cells such as Pichia pastoris (see, e.g., Powers et al., J Immunol Methods. 251: 123-35 (2001)), Hanseula or Saccharomyces.
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用,是指已经引入外源核酸的细胞,包括此类细胞的后代。宿主细胞包括“转化体”和“转化细胞”,包括原代转化细胞和由其衍生的后代,不考虑传代数。后代在核酸含量方面可能与亲本细胞不完全相同,而是可含有突变。本文包括与在最初转化的细胞中筛选或选择的具有相同功能或生物活性的突变后代。The terms "host cell", "host cell line" and "host cell culture" are used interchangeably to refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells", including primary transformed cells and progeny derived therefrom, without regard to the number of passages. Progeny may not be completely identical to the parent cell in terms of nucleic acid content, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected in the initially transformed cell are included herein.
视情况而定,宿主细胞可以用编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸稳定或瞬时转染。视情况而定,宿主细胞可以用表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体感染。在一些实施方案中,宿主细胞能够表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种复制减毒型或复制能力型载体被感染或者能够繁殖所述载体。适用于被病毒载体感染和/或繁殖病毒载体的例示性细胞包括但不限于BHK-21、A549、Vero和HEK293(例如,HEK293E、HEK293F、HEK293H、HEK293T、Expi293TM)细胞。在某些实施方案中,宿主细胞表达柯萨奇病毒和腺病毒受体(CAR),例如MDCK、Caco-2或Calu-3宿主细胞。在某些实施方案中,多核苷酸整合到宿主细胞的基因组中。As the case may be, the host cell can be stably or transiently transfected with one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein. As the case may be, the host cell can be infected with one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein. In some embodiments, the host cell can express one or more replication attenuated or replication-capable vectors of one or more fusion polypeptides or composite fusion polypeptides as described herein or can propagate the vector. Exemplary cells suitable for being infected by viral vectors and/or propagating viral vectors include but are not limited to BHK-21, A549, Vero and HEK293 (e.g., HEK293E, HEK293F, HEK293H, HEK293T, Expi293 TM ) cells. In certain embodiments, the host cell expresses Coxsackie virus and adenovirus receptor (CAR), such as MDCK, Caco-2 or Calu-3 host cells. In certain embodiments, the polynucleotides are integrated into the genome of the host cell.
5.药物组合物/免疫原性组合物5. Pharmaceutical compositions/immunogenic compositions
提供了药物组合物或免疫原性组合物,其包含如本文所述的融合多肽或复合融合多肽中的一者或多者,或编码如本文所述的融合多肽或复合融合多肽中的一者或多者的多核苷酸,或包含一种或多种此类多核苷酸的病毒表达载体,以及药学上可接受的稀释剂、载剂或赋形剂。通常,本文所述的药物组合物是免疫原性的。在某些实施方案中,药物组合物包含治疗有效量的一种或多种融合多肽或复合融合多肽,或编码融合多肽或复合融合多肽中的一者或多者的一种或多种多核苷酸,或含有编码融合多肽或复合融合多肽中的一者或多者的一种或多种多核苷酸的一种或多种病毒表达载体。Provided are pharmaceutical compositions or immunogenic compositions, comprising one or more of a fusion polypeptide or a composite fusion polypeptide as described herein, or polynucleotides encoding one or more of a fusion polypeptide or a composite fusion polypeptide as described herein, or a viral expression vector comprising one or more such polynucleotides, and a pharmaceutically acceptable diluent, carrier or excipient. Typically, the pharmaceutical compositions described herein are immunogenic. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more fusion polypeptides or composite fusion polypeptides, or one or more polynucleotides encoding a fusion polypeptide or a composite fusion polypeptide, or one or more viral expression vectors containing one or more polynucleotides encoding a fusion polypeptide or a composite fusion polypeptide.
根据本公开,各种药学上可接受的稀释剂、载体和赋形剂以及用于制备和使用药物组合物或免疫原性组合物的技术将是本领域技术人员已知的。例示性药物组合物和药学上可接受的稀释剂、载体和赋形剂也描述于例如以下文献中:Loyd V.Allen Jr(编辑),“Remington:The Science and Practice of Pharmacy,”第22版,2012,PharmaceuticalPress;Brunton,Knollman and Hilal-Dandan,“Goodman and Gilman's ThePharmacological Basis of Therapeutics,”第13版,2017,McGraw-Hill Education/Medical;McNally and Hastedt(编辑),“Protein Formulation and Delivery,”第2版,2007,CRC Press;Banga,“Therapeutic Peptides and Proteins:Formulation,Processing,and Delivery Systems,”第3版,2015,CRC Press;Lars Hovgaard,Frokjaerand van de Weert(编辑),“Pharmaceutical Formulation Development of Peptidesand Proteins,”第2版,2012,CRC Press;Carpenter and Manning(编辑),“RationalDesign of Stable Protein Formulations:Theory and Practice,”2002,Springer(Pharmaceutical Biotechnology(Book 13));Meyer(编辑),“Therapeutic Protein DrugProducts:Practical Approaches to Formulation in the Laboratory,Manufacturing,and the Clinic,”2012,Woodhead Publishing。Various pharmaceutically acceptable diluents, carriers, and excipients, as well as techniques for preparing and using pharmaceutical compositions or immunogenic compositions will be known to those of skill in the art in light of the present disclosure. Exemplary pharmaceutical compositions and pharmaceutically acceptable diluents, carriers and excipients are also described, for example, in the following literature: Loyd V. Allen Jr (ed.), "Remington: The Science and Practice of Pharmacy," 22nd edition, 2012, Pharmaceutical Press; Brunton, Knollman and Hilal-Dandan, "Goodman and Gilman's The Pharmacological Basis of Therapeutics," 13th edition, 2017, McGraw-Hill Education/Medical; McNally and Hastedt (eds.), "Protein Formulation and Delivery," 2nd edition, 2007, CRC Press; Banga, "Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems," 3rd edition, 2015, CRC Press; Lars Hovgaard, Frokjaer and van de Weert (eds.), "Pharmaceutical Formulation Development of Peptides and Proteins," 2nd edition, 2012, CRC Press Press; Carpenter and Manning (Editors), "Rational Design of Stable Protein Formulations: Theory and Practice," 2002, Springer (Pharmaceutical Biotechnology (Book 13)); Meyer (Editor), "Therapeutic Protein Drug Products: Practical Approaches to Formulation in the Laboratory, Manufacturing, and the Clinic," 2012, Woodhead Publishing.
在某些实施方案中,多核苷酸或载体被配制成脂复合物,例如,脂质纳米颗粒(LNP)。如本文所用,“脂复合物”是指作为一种或多种多核苷酸(例如,RNA、DNA)的非病毒(合成)脂质载剂的阳离子脂质体。例如,在融合多肽和/或复合融合多肽由自复制或自扩增RNA分子表达的一些实施方案中,自复制或自扩增RNA可被配制成LNP。如本文所用,术语“脂质纳米颗粒”是指平均直径介于约10纳米至约1000纳米之间并且包括可以溶解亲脂性分子的固体脂质核基质的一个或多个球形纳米颗粒。在某些实施方案中,脂质核由表面活性剂(例如,乳化剂)稳定,并且可以包含以下项中的一种或多种:甘油三酯(例如,三硬脂精)、甘油二酯(例如,甘油山嵛酸酯)、甘油单酯(例如,单硬脂酸甘油酯)、脂肪酸(例如,硬脂酸)、类固醇(例如,胆固醇)和蜡(例如,鲸蜡醇棕榈酸酯),包括它们的组合。脂质纳米颗粒描述于例如以下文献中:Petrilli等人,Curr Pharm Biotechnol.15:847-55,2014;以及美国专利号6,217,912、6,881,421、7,402,573、7,404,969、7,550,441、7,727,969、8,003,621、8,691,750、8,871,509、9,017,726、9,173,853、9,220,779、9,227,917和9,278,130,这些文献中的每篇文献全文以引用方式并入。在一个实施方案中,编码本文所述的融合多肽或复合融合多肽中的一者或多者的自复制或自扩增RNA(saRNA)分子被配制或缩合到聚乙烯亚胺(PEI)-复合物递送媒介中,例如,如以下文献中所述:Moyo等人,Mol Ther Methods ClinDev.(2018)12:32-46;Blakney等人,Gene Therapy(2019)26:363-372;Démoulins等人,Nanomedicine.(2016)4月;12(3):711-722和Démoulins等人,J Control Release.(2017)266:256-271,其可以是纳米颗粒。In certain embodiments, polynucleotides or carriers are formulated into lipid complexes, for example, lipid nanoparticles (LNPs). As used herein, "lipoplexes" refer to cationic liposomes as non-viral (synthetic) lipid carriers of one or more polynucleotides (e.g., RNA, DNA). For example, in some embodiments in which fusion polypeptides and/or composite fusion polypeptides are expressed by self-replicating or self-amplifying RNA molecules, self-replicating or self-amplifying RNAs can be formulated into LNPs. As used herein, the term "lipid nanoparticles" refers to one or more spherical nanoparticles of a solid lipid core matrix with an average diameter between about 10 nanometers and about 1000 nanometers and including a lipophilic molecule that can dissolve. In certain embodiments, the lipid core is stabilized by a surfactant (e.g., an emulsifier) and may include one or more of the following items: triglycerides (e.g., tristearin), diglycerides (e.g., glyceryl behenate), monoglycerides (e.g., glyceryl monostearate), fatty acids (e.g., stearic acid), steroids (e.g., cholesterol) and waxes (e.g., cetyl palmitate), including combinations thereof. Lipid nanoparticles are described, for example, in Petrilli et al., Curr Pharm Biotechnol. 15:847-55, 2014; and U.S. Pat. Nos. 6,217,912, 6,881,421, 7,402,573, 7,404,969, 7,550,441, 7,727,969, 8,003,621, 8,691,750, 8,871,509, 9,017,726, 9,173,853, 9,220,779, 9,227,917, and 9,278,130, each of which is incorporated by reference in its entirety. In one embodiment, a self-replicating or self-amplifying RNA (saRNA) molecule encoding one or more of the fusion polypeptides or composite fusion polypeptides described herein is formulated or condensed into a polyethyleneimine (PEI)-complex delivery vehicle, e.g., as described in Moyo et al., Mol Ther Methods Clin Dev. (2018) 12:32-46; Blakney et al., Gene Therapy (2019) 26:363-372; Démoulins et al., Nanomedicine. (2016) Apr; 12(3):711-722 and Démoulins et al., J Control Release. (2017) 266:256-271, which may be a nanoparticle.
在融合多肽或复合融合多肽由病毒表达载体表达的实施方案中,病毒表达载体可以被配制用于所需的施用途径,例如,作为等渗药学上可接受的水溶液用于静脉内、肌内、皮下或结内施用。在一些实施方案中,病毒表达载体可被配制用于粘膜(例如,颊部或直肠内)递送。可用于本文所述的药物组合物和方法中的病毒表达载体的例示性制剂描述于例如以下文献中:Manfredsson和Benskey编辑,“Viral Vectors for Gene Therapy:Methodsand Protocols(Methods in Molecular Biology),”2019,Book 1937in Methods inMolecular Biology Series,Humana Press;WO 2017/013169(formulation ofAdenoviral vectors in an aqueous mixture or freeze dried composition in thepresence of amorphous sugar and low salt concentration);和Kumru等人,J PharmSci.(2018)11月;107(11):2764-3374(aqueous formulations buffered in Tris andcontaining proline,lactose,and mannitol as stabilizing additives)。沙粒病毒载体的配制描述于例如WO 2009/083210、WO 2016/075250和WO 2017/198726中。在某些实施方案中,病毒表达载体经由微针介导的递送来递送,例如,如Zaric等人,Expert Opin DrugDeliv.(2017)10月;14(10):1177-1187。mRNA疫苗的结内递送描述于例如以下文献中:Jong等人,Vaccines(Basel).(2019)7(4):209;Leal等人,AIDS.(2018)32(17):2533-2545;Jong等人,Trials.(2019)20(1):361;以及Joe等人,J Transl Med.(2019)17(1):242。In embodiments where the fusion polypeptide or composite fusion polypeptide is expressed by a viral expression vector, the viral expression vector can be formulated for a desired route of administration, e.g., as an isotonic pharmaceutically acceptable aqueous solution for intravenous, intramuscular, subcutaneous, or intranodal administration. In some embodiments, the viral expression vector can be formulated for mucosal (e.g., buccal or intrarectal) delivery. Exemplary formulations of viral expression vectors that can be used in the pharmaceutical compositions and methods described herein are described, for example, in the following literature: Manfredsson and Benskey, eds., "Viral Vectors for Gene Therapy: Methods and Protocols (Methods in Molecular Biology)," 2019, Book 1937 in Methods in Molecular Biology Series, Humana Press; WO 2017/013169 (formulation of Adenoviral vectors in an aqueous mixture or freeze dried composition in the presence of amorphous sugar and low salt concentration); and Kumru et al., J Pharm Sci. (2018) November; 107(11): 2764-3374 (aqueous formulations buffered in Tris and containing proline, lactose, and mannitol as stabilizing additives). The formulation of arenavirus vectors is described, for example, in WO 2009/083210, WO 2016/075250, and WO 2017/198726. In certain embodiments, the viral expression vector is delivered via microneedle-mediated delivery, for example, as described in Zaric et al., Expert Opin Drug Deliv. (2017) October; 14(10): 1177-1187. Intranodal delivery of mRNA vaccines is described, for example, in Jong et al., Vaccines (Basel). (2019) 7(4): 209; Leal et al., AIDS. (2018) 32(17): 2533-2545; Jong et al., Trials. (2019) 20(1): 361; and Joe et al., J Transl Med. (2019) 17(1): 242.
在一些实施方案中,每种载体、稀释剂或赋形剂在与药物组合物/免疫原性组合物和其他成分相容并且对受试者没有伤害的意义上是“可接受的”。通常,药学上可接受的载剂是水性pH缓冲液。可以用作药学上可接受的载剂、稀释剂或赋形剂的材料的一些示例包括:水;缓冲液,例如,pKa在约6.0至约8.0范围内的缓冲液,例如,生理学上可接受的缓冲液,例如,选自磷酸盐、碳酸盐、碳酸氢盐、柠檬酸盐、马来酸盐、甘氨酸-甘氨酸、HEPES、HEPPSO、HEPPS、咪唑、BICINE、TRICINE、Tris和BIS-Tris;糖,诸如乳糖、海藻糖、葡萄糖和蔗糖;淀粉,诸如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉末状黄蓍胶;麦芽;明胶;滑石;赋形剂,诸如可可油和栓剂蜡;油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,诸如丙二醇;多元醇,诸如甘油、山梨糖醇、甘露糖醇和聚乙二醇;酯,诸如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,诸如氢氧化镁和氢氧化铝;藻酸;无热原水;等渗盐水;汉克氏溶液、林格氏溶液;乙醇;磷酸盐缓冲溶液;氨基酸(例如,带电氨基酸,包括但不限于天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、组氨酸、精氨酸、赖氨酸);以及药物制剂中所采用的其他无毒相容物质。润湿剂、乳化剂和润滑剂(诸如月桂基硫酸钠和硬脂酸镁)以及着色剂、释放剂、涂层剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以存在于组合物中。In some embodiments, each carrier, diluent or excipient is "acceptable" in the sense that it is compatible with the pharmaceutical composition/immunogenic composition and the other ingredients and is not injurious to the subject. Typically, a pharmaceutically acceptable carrier is an aqueous pH buffer. Some examples of materials that can be used as pharmaceutically acceptable carriers, diluents or excipients include: water; buffers, e.g., buffers with a pKa in the range of about 6.0 to about 8.0, e.g., physiologically acceptable buffers, e.g., selected from phosphate, carbonate, bicarbonate, citrate, maleate, glycine-glycine, HEPES, HEPPSO, HEPPS, imidazole, BICINE, TRICINE, Tris and BIS-Tris; sugars, such as lactose, trehalose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered Tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Hank's solution, Ringer's solution; ethanol; phosphate buffer solution; amino acids (e.g., charged amino acids, including but not limited to aspartic acid, asparagine, glutamic acid, glutamine, histidine, arginine, lysine); and other nontoxic compatible substances used in pharmaceutical preparations. Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate) as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.
在一种特定制剂中,本文所述的沙粒病毒载体(例如,LCMV或皮钦德哺乳动物沙粒病毒载体(PICV))以如下等渗水溶液形式配制:其包含pH为中性或接近中性、pKa在约6.0至约8.0范围内的生物相容性缓冲液(例如,HEPES和NaCl)以及非离子表面活性剂(例如,F68(又名泊洛沙姆188))。在一种特定制剂中,本文所述的沙粒病毒载体(例如,LCMV或皮钦德哺乳动物沙粒病毒载体)以如下等渗水溶液形式配制:其包含pH为7.4的HEPES缓冲液、NaCl和F68(又名泊洛沙姆188)。Schleiss等人(ClinVaccine Immunol.2017年1月5日;24(1):e00300-16)描述了在pH7.4的25mM HEPES、150mMNaCl、0.01%PLURONIC F68的稀释剂中配制LCMV载体的LCMV,其可用于配制本文所述的沙粒病毒载体。在低于-60℃冷冻之前,添加最终浓度为10%的山梨糖醇。In one particular formulation, an arenavirus vector described herein (e.g., LCMV or a Pichin's mammalian arenavirus vector (PICV)) is formulated in an isotonic aqueous solution comprising a biocompatible buffer (e.g., HEPES and NaCl) at a neutral or near-neutral pH and a pKa in the range of about 6.0 to about 8.0, and a nonionic surfactant (e.g., F68 (also known as Poloxamer 188). In one particular formulation, the arenavirus vector described herein (e.g., LCMV or Pichinde mammalian arenavirus vector) is formulated in an isotonic aqueous solution comprising HEPES buffer at pH 7.4, NaCl and F68 (also known as Poloxamer 188). Schleiss et al. (Clin Vaccine Immunol. 2017 Jan 5; 24(1): e00300-16) describe the formulation of LCMV vectors in a diluent of 25 mM HEPES, 150 mM NaCl, 0.01% PLURONIC F68 at pH 7.4, which can be used to formulate the arenavirus vectors described herein. Sorbitol was added to a final concentration of 10% before freezing below -60°C.
药物组合物或免疫原性组合物的制剂和递送方法通常将根据待治疗的部位和疾病进行调整。示例性制剂包括但不限于适合肠胃外施用(例如,静脉内、动脉内、肌内、皮下或结内施用)的那些,包括封装在胶束、脂质体或药物释放胶囊中的制剂(掺在被设计用于缓慢释放的生物相容性涂层内的活性剂);可摄取制剂;用于局部使用的制剂,诸如乳膏、软膏和凝胶;以及其他制剂,诸如吸入剂、气雾剂和喷雾剂。在一些实施方案中,药物组合物或免疫原性组合物被配制用于肠胃外(例如,静脉内、皮下、结内或口服)施用。在一些实施方案中,药物组合物或免疫原性组合物被配制用于粘膜(例如,颊部、直肠内和/或阴道内)施用。在一些实施方案中,对于直肠内施用,可将药物组合物或免疫原性组合物配制为栓剂或灌肠剂。在一些实施方案中,对于阴道内施用,可将药物组合物或免疫原性组合物配制为阴道栓剂。The preparation and delivery method of the pharmaceutical composition or immunogenic composition will generally be adjusted according to the site and disease to be treated. Exemplary preparations include, but are not limited to, those suitable for parenteral administration (e.g., intravenous, intraarterial, intramuscular, subcutaneous or intranodal administration), including preparations encapsulated in micelles, liposomes or drug release capsules (incorporated in an active agent designed for slow release in a biocompatible coating); ingestible preparations; preparations for topical use, such as creams, ointments and gels; and other preparations, such as inhalants, aerosols and sprays. In some embodiments, the pharmaceutical composition or immunogenic composition is formulated for parenteral (e.g., intravenous, subcutaneous, intranodal or oral) administration. In some embodiments, the pharmaceutical composition or immunogenic composition is formulated for mucosal (e.g., buccal, rectal and/or intravaginal) administration. In some embodiments, for intrarectal administration, the pharmaceutical composition or immunogenic composition may be formulated as a suppository or enema. In some embodiments, for intravaginal administration, the pharmaceutical composition or immunogenic composition may be formulated as a vaginal suppository.
在某些实施方案中,药物组合物/免疫原性组合物是无菌的。在某些实施方案中,药物组合物或免疫原性组合物具有4.5至8.5、4.5至6.5、6.5至8.5范围内的pH,或者约5.0、约5.5、约6.0、约6.5、约7.0、约7.5、约8.0或约8.5的pH。在一个实施方案中,药物组合物/免疫原性组合物具有240mOsmol/L至260mOsmol/L或250mOsmol/L至330mOsmol/L范围内的同渗容摩。在某些实施方案中,药物组合物/免疫原性组合物是等渗或接近等渗的。In certain embodiments, the pharmaceutical composition/immunogenic composition is sterile. In certain embodiments, the pharmaceutical composition or immunogenic composition has a pH in the range of 4.5 to 8.5, 4.5 to 6.5, 6.5 to 8.5, or a pH of about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, or about 8.5. In one embodiment, the pharmaceutical composition/immunogenic composition has an osmotic capacity in the range of 240mOsmol/L to 260mOsmol/L or 250mOsmol/L to 330mOsmol/L. In certain embodiments, the pharmaceutical composition/immunogenic composition is isotonic or nearly isotonic.
在一些实施方案中,药物组合物或免疫原性组合物是液体或固体。在一些实施方案中,药物组合物或免疫原性组合物包含水性溶液。在一些实施方案中,药物组合物或免疫原性组合物是冻干的或者是冷冻液体。In some embodiments, the pharmaceutical composition or immunogenic composition is a liquid or solid. In some embodiments, the pharmaceutical composition or immunogenic composition comprises an aqueous solution. In some embodiments, the pharmaceutical composition or immunogenic composition is lyophilized or is a frozen liquid.
在一些实施方案中,药物组合物或免疫原性组合物还包含一种或多种附加治疗剂,例如第二治疗剂,或第二治疗剂和第三治疗剂,用于如本文所述的组合疗法。In some embodiments, the pharmaceutical composition or immunogenic composition further comprises one or more additional therapeutic agents, such as a second therapeutic agent, or a second therapeutic agent and a third therapeutic agent, for use in combination therapy as described herein.
在某些实施方案中,药物组合物或免疫原性组合物还包含佐剂。可以与本文所述的融合多肽或复合融合多肽、编码此类融合多肽或复合融合多肽的多核苷酸和表达此类融合多肽或复合融合多肽的载体共同配制或共同施用的例示性佐剂包括但不限于细胞因子、趋化因子、免疫共刺激分子、toll样受体激动剂、胱天蛋白酶(SMAC)第二线粒体衍生的活化剂模拟物或免疫抑制途径的抑制剂(例如免疫检查点抑制剂),如本文所述,并且描述于Li等人,Curr Issues Mol Biol.(2017)22:17-40。可以与本文所述的融合多肽或复合融合多肽、编码此类融合多肽或复合融合多肽的多核苷酸和表达此类融合多肽或复合融合多肽的载体共同配制或共同施用的其他佐剂包括但不限于矿物盐(例如铝盐(例如矾)、磷酸钙、不完全弗罗因德佐剂)、脂质颗粒(例如MF59、脂质卷(cochleate)、病毒样颗粒)、微粒(例如病毒体、聚乳酸(PLA)、聚[丙交酯-共乙交酯](PLG))、免疫增效剂(例如dsRNA:Poly(I:C)、Poly-IC:LC、单磷酰基脂质A(MPL)、LPS、鞭毛蛋白、咪唑啉喹啉:咪喹莫特(R837)、瑞喹莫德(848)、CpG寡聚脱氧核苷酸(ODN)、胞壁酰二肽(MDP)、皂苷(QS-21)和粘膜佐剂(例如,霍乱毒素(CT)、不耐热肠毒素(LTK3和LTR72)、壳聚糖)。可以与本文所述的融合多肽、编码此类融合多肽的多核苷酸和表达此类融合多肽的载体共同配制或共同施用的佐剂描述于Apostólico等人,J Immunol Res.(2016)2016:1459394。In certain embodiments, pharmaceutical composition or immunogenic composition also include adjuvant.Exemplary adjuvants that can be co-formulated or co-administered with fusion polypeptide as described herein or composite fusion polypeptide, polynucleotides encoding such fusion polypeptide or composite fusion polypeptide and carriers expressing such fusion polypeptide or composite fusion polypeptide include but are not limited to cytokines, chemokines, immune co-stimulatory molecules, toll-like receptor agonists, activator mimics derived from the second mitochondria of caspase (SMAC) or inhibitors (such as immune checkpoint inhibitors) of immunosuppressive pathways, as described herein, and described in Li et al., Curr Issues Mol Biol. (2017) 22: 17-40. Other adjuvants that can be co-formulated or co-administered with the fusion polypeptides or composite fusion polypeptides described herein, polynucleotides encoding such fusion polypeptides or composite fusion polypeptides, and vectors expressing such fusion polypeptides or composite fusion polypeptides include, but are not limited to, mineral salts (e.g., aluminum salts (e.g., alum), calcium phosphate, incomplete Freund's adjuvant), lipid particles (e.g., MF59, cochleate, virus-like particles), microparticles (e.g., virosomes, polylactic acid (PLA), poly[lactide-co-glycolide] (PLG)), immunopotentiators (e.g., dsRNA:Poly(I:C), P oly-IC: LC, monophosphoryl lipid A (MPL), LPS, flagellin, imidazoline quinoline: imiquimod (R837), resiquimod (848), CpG oligodeoxynucleotide (ODN), muramyl dipeptide (MDP), saponin (QS-21) and mucosal adjuvants (e.g., cholera toxin (CT), heat-labile enterotoxin (LTK3 and LTR72), chitosan). Adjuvants that can be co-formulated or co-administered with the fusion polypeptides described herein, polynucleotides encoding such fusion polypeptides, and vectors expressing such fusion polypeptides are described in Apostólico et al., J Immunol Res. (2016) 2016: 1459394.
在一些实施方案中,药物组合物或免疫原性组合物包含两种或更多种融合多肽和/或复合融合多肽、编码此类融合多肽和/或复合融合多肽的两种或更多种多核苷酸、或表达此类融合多肽和/或复合融合多肽的两种或更多种载体。在各种实施方案中,药物组合物或免疫原性组合物包含二价的第一融合多肽和第二融合多肽、或包含编码二价第一和第二融合多肽的一种或多种多核苷酸的一种或多种载体。在一些实施方案中,药物组合物或免疫原性组合物包含第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码该第一和第二融合多肽,该第一和第二多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:In some embodiments, the pharmaceutical composition or immunogenic composition comprises two or more fusion polypeptides and/or composite fusion polypeptides, two or more polynucleotides encoding such fusion polypeptides and/or composite fusion polypeptides, or two or more vectors expressing such fusion polypeptides and/or composite fusion polypeptides. In various embodiments, the pharmaceutical composition or immunogenic composition comprises a bivalent first fusion polypeptide and a second fusion polypeptide, or one or more vectors comprising one or more polynucleotides encoding a bivalent first and second fusion polypeptide. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a first fusion polypeptide and a second fusion polypeptide, or one or more vectors comprising one or more polynucleotides encoding the first and second fusion polypeptides, and the first and second polypeptides comprise the following polypeptide fragments optionally bound or connected by one or more linkers in order from N-terminus to C-terminus:
·SEQ ID NO:6、4、16和26,以及SEQ ID NO:7、5、27和17;SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17;
·SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11;
·SEQ ID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21;
·SEQ ID NO:26、16、4和6,以及SEQ ID NO:7、27、5和17;SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17;
·SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11;
·SEQ ID NO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NOs: 22, 24, 14, 18 and 20, and SEQ ID NOs: 25, 23, 15, 21 and 19;
·SEQ ID NO:20、6、4、18、16和26,以及SEQ ID NO:7、19、5、21、27和17;SEQ ID NOs: 20, 6, 4, 18, 16 and 26, and SEQ ID NOs: 7, 19, 5, 21, 27 and 17;
·SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NOs: 8, 24, 14, 12, 22 and 10, and SEQ ID NOs: 9, 13, 25, 23, 15 and 11;
·SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQ ID NOs: 18, 26, 20, 4, 6 and 16, and SEQ ID NOs: 7, 21, 17, 5, 27 and 19;
·SEQ ID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ ID NOs: 22, 24, 12, 14, 8 and 10, and SEQ ID NOs: 15, 25, 9, 23, 13 and 11;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 8, 30, 14, 12, 26 and 10;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:7、21、5、25、33和19;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 7, 21, 5, 25, 33 and 19;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 8, 30, 14, 12, 26 and 10;
·SEQ ID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NOs: 8, 30, 14, 12, 26 and 10, and SEQ ID NOs: 9, 13, 31, 27, 15 and 11;
·SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ ID NOs: 6, 20, 4, 24, 32 and 18, and SEQ ID NOs: 8, 12, 30, 26, 14 and 10;
·SEQ ID NO:7、21、5、25、33和19,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NOs: 7, 21, 5, 25, 33 and 19, and SEQ ID NOs: 9, 13, 31, 27, 15 and 11;
·SEQ ID NO:20、32、24、4、6和18,以及SEQ ID NO:26、30、12、14、8和10;SEQ ID NOs: 20, 32, 24, 4, 6 and 18, and SEQ ID NOs: 26, 30, 12, 14, 8 and 10;
·SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ ID NOs: 7, 25, 19, 5, 33 and 21, and SEQ ID NOs: 15, 31, 9, 27, 13 and 11;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 26, 20, 10 and 28;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、10、20和28;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 26, 10, 20 and 28;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 7, 25, 17 and 19;
·SEQ ID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 7, 19, 17 and 25, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:24、16、6和18,以及SEQ ID NO:27、11、21和29;SEQ ID NOs: 24, 16, 6 and 18, and SEQ ID NOs: 27, 11, 21 and 29;
·SEQ ID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NOs: 7, 25, 17 and 19, and SEQ ID NOs: 11, 27, 21 and 29;
·SEQ ID NO:7、25、17和19,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 7, 25, 17 and 19, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NOs: 22, 6, 20 and 28, and SEQ ID NOs: 23, 7, 21 and 29;
·SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NOs: 22, 20, 6 and 28, and SEQ ID NOs: 7, 21, 23 and 29;
·SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 26, 10, 20 and 28, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO: 22, 6, 16, 20, 18, 28, 26 and 10; or
·SEQ ID NO:7、21、19、17、27、25、29和11。· SEQ ID NO: 7, 21, 19, 17, 27, 25, 29 and 11.
在一些实施方案中,药物组合物或免疫原性组合物包含一种或多种(例如,两种或更多种)融合多肽、或包含编码一种或多种(例如,两种或更多种)融合多肽的一种或多种多核苷酸的一种或多种(例如,两种或更多种)载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,药物组合物或免疫原性组合物包含一种或多种(例如,两种或更多种)融合多肽、或包含编码一种或多种(例如,两种或更多种)融合多肽的一种或多种多核苷酸的一种或多种(例如,两种或更多种)载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In some embodiments, the pharmaceutical composition or immunogenic composition comprises one or more (e.g., two or more) fusion polypeptides, or one or more (e.g., two or more) vectors comprising one or more polynucleotides encoding one or more (e.g., two or more) fusion polypeptides, which fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the pharmaceutical composition or immunogenic composition comprises one or more (e.g., two or more) fusion polypeptides, or one or more (e.g., two or more) vectors comprising one or more polynucleotides encoding one or more (e.g., two or more) fusion polypeptides, which fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223.
在一些实施方案中,药物组合物或免疫原性组合物包含以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, a pharmaceutical composition or immunogenic composition comprises the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked via one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、· A fusion polypeptide of SEQ ID NOs:92 and 93, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 1
98%或99%相同的融合多肽;98% or 99% identical fusion polypeptides;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在一些实施方案中,药物组合物或免疫原性组合物包含复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,药物组合物或免疫原性组合物包含复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,药物组合物或免疫原性组合物包含复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:209的氨基酸序列,或与SEQ ID NO:209至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,药物组合物或免疫原性组合物包含复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:222的氨基酸序列,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,药物组合物或免疫原性组合物包含复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQID NO:223的氨基酸序列,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,药物组合物或免疫原性组合物包含复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ IDNO:227的氨基酸序列,或与SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In some embodiments, the pharmaceutical composition or immunogenic composition comprises a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 209, 222 and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 209, 222 and 223. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of SEQ ID NO:209, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:209. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of SEQ ID NO:222, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:222. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: the amino acid sequence of SEQ ID NO:223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:223. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of SEQ ID NO:227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:227.
在一些实施方案中,药物组合物或免疫原性组合物包含以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸从N末端到C末端按顺序编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the pharmaceutical composition or immunogenic composition comprises the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides in order from N-terminus to C-terminus, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:71 and 70, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:73 and 72, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:75 and 74, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:77 and 76, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:77 and 76, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:79 and 78, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:79 and 78, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 86, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 88, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 82, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 82, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 82, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 83, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 85, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 85, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:91 and 90, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:91 and 90, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:93 and 92, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 96, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 94, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 95, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 98, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively;
·SEQ ID NO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 98, respectively;
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or
·SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 100, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 86 and 87, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 85, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 88 and 87, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含含有一种或多种多核苷酸的病毒载体或脂质体复合物(例如,LNP),该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a viral vector or liposome complex (e.g., LNP) containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87 and 88, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含含有一种或多种多核苷酸的病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含含有一种或多种多核苷酸的病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ IDNO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第二病毒载体,该第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第二病毒载体,该第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第二病毒载体,该第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第二病毒载体,该第二病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In various embodiments, the immunogenic or pharmaceutical composition comprises a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:105或206的复合融合多肽,或与SEQ ID NO:105或206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105 or 206, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 105 or 206.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:107或207的复合融合多肽,或与SEQ ID NO:107或207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 107 or 207, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 107 or 207.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:109的复合融合多肽,或与SEQ ID NO:109至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 109, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 109.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:111的复合融合多肽,或与SEQ ID NO:111至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:111, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:111.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:200的复合融合多肽,或与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:200, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:200.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:201的复合融合多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:201, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:201.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:202的复合融合多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:202, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:202.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:203的复合融合多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:203, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:203.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:204的复合融合多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:204, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:204.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:205的复合融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:205, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:205.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:208的复合融合多肽,或与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:208, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:208.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:209的复合融合多肽,或与SEQ ID NO:209至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:209, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:209.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:222的复合融合多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:222, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:222.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:223的复合融合多肽,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:223, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:223.
在各种实施方案中,该免疫原性组合物或药物组合物包含病毒载体,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:227的复合融合多肽,或与SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:227, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:227.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:200的多肽或与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:201的多肽或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) and a second viral vector or liposome complex (e.g., LNP), wherein the first viral vector or liposome complex (e.g., LNP) comprises a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 200 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200, and the second viral vector or liposome complex (e.g., LNP) comprises a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 201 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptides.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:202的多肽或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:203的多肽或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 202 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 203 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptide.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:204的多肽或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:205的多肽或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 204 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 205 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptide.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:105的多肽或与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:107的多肽或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 105 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 107 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 108. A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:107.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:206的多肽或与SEQ ID NO:206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:207的多肽或与SEQ ID NO:207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 206 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 207 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208. A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:207.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:208的多肽或与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:209或SEQ ID NO:227的多肽或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 208 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:227.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:222的多肽或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:209或SEQ ID NO:227的多肽或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 222 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: 227. A polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to NO:227.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP),该第一病毒载体或脂质体复合物(例如,LNP)包含第一多核苷酸,该第一多核苷酸编码以下第一多肽:包含SEQ IDNO:222的多肽或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽,该第二病毒载体或脂质体复合物(例如,LNP)包含第二多核苷酸,该第二多核苷酸编码以下第二多肽:包含SEQ ID NO:223的多肽或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多肽。In various embodiments, the immunogenic composition or pharmaceutical composition comprises a first viral vector or liposome complex (e.g., LNP) comprising a first polynucleotide encoding a first polypeptide comprising a polypeptide comprising SEQ ID NO: 222 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and a second viral vector or liposome complex (e.g., LNP) comprising a second polynucleotide encoding a second polypeptide comprising a polypeptide comprising SEQ ID NO: 223 or a polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 224. NO:223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polypeptide.
在一些实施方案中,该药物组合物或免疫原性组合物包含多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,该药物组合物或免疫原性组合物包含多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。In some embodiments, the pharmaceutical composition or immunogenic composition comprises a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the pharmaceutical composition or immunogenic composition comprises a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226.
在一些实施方案中,该药物组合物或免疫原性组合物包含以下第一多核苷酸和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的一种或多种载体,该第一和第二多核苷酸分别包含以下或由以下组成:In some embodiments, the pharmaceutical composition or immunogenic composition comprises the following first polynucleotide and second polynucleotide, or one or more vectors comprising the following first polynucleotide and second polynucleotide, the first and second polynucleotides respectively comprising or consisting of:
·SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 132, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively;
·SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 134, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively;
·SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively;
·SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively;
·SEQ ID NO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively;
·SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively;
·SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively;
·SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 134 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively;
·SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively;
·SEQ ID NO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 141, respectively;
·SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively;
·SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 142, respectively;
·SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 145, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively;
·SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 140 and 146, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively;
·SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 142 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively;
·SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 143 and 149, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively;
·SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively;
·SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively;
·SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 155, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively;
·SEQ ID NO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 153, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively;
·SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively;
·SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively;
·SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 153 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 153 and 159, respectively;
·SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 154 and 157, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, respectively;
·SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively;
·SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively;
·SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively;
·SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively;
·SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 164 and 165, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively;
·SEQ ID NO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively;
·SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 210 and 211, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively;
·SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 212 and 213, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 212 and 213, respectively;
·SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 214 and 215, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively;
·SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively;
·SEQ ID NO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 218 and 219, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively;
·SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或者a polynucleotide of SEQ ID NOs: 218 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 226, respectively; or
·SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。· A polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:131和135的第一和第二多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸;和a) a first viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 131 and 135, or a first and a second polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:133和137的第一和第二多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸。b) a second viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 133 and 137, or a first and a second polynucleotide that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:139和145的第一和第二多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸;和a) a first viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 139 and 145, or a first and a second polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:142和148的第一和第二多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸。b) a second viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 142 and 148, or a first and a second polynucleotide that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:140和146的第一和第二多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸;和a) a first viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 140 and 146, or a first and a second polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:143和149的第一和第二多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸。b) a second viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 143 and 149, or a first and a second polynucleotide that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:150和152的第一和第二多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸;和a) a first viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 150 and 152, or a first and a second polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:154和157的第一和第二多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸。b) a second viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 154 and 157, or a first and a second polynucleotide that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:150和152的第一和第二多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸;和a) a first viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 150 and 152, or a first and a second polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:155和158的第一和第二多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸。b) a second viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 155 and 158, or a first and a second polynucleotide that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:151和153的第一和第二多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸;和a) a first viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 151 and 153, or a first and a second polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:156和159的第一和第二多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的第一和第二多核苷酸。b) a second viral vector comprising: a first and a second polynucleotide of SEQ ID NOs: 156 and 159, or a first and a second polynucleotide that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:160的多核苷酸,或分别与SEQ ID NO:160至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 160, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 160, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:161的多核苷酸,或分别与SEQ ID NO:161至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO: 161, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 161, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:162的多核苷酸,或分别与SEQ ID NO:162至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 162, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 162, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:163的多核苷酸,或分别与SEQ ID NO:163至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO: 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 163, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:164的多核苷酸,或分别与SEQ ID NO:164至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 164, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 164, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:165的多核苷酸,或分别与SEQ ID NO:165至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO: 165, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 165, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:166的多核苷酸,或分别与SEQ ID NO:166至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 166, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 166, respectively; and
b)第二病毒载体,其包含:SEQ ID NO:167的多核苷酸,或分别与SEQ ID NO:167至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO: 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 167, respectively.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 210, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 210; and
b)第二病毒载体,其包含:SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:211, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:211.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 212; and
b)第二病毒载体,其包含:SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:213, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:213.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:214的多核苷酸、,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 214, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 214; and
b)第二病毒载体,其包含:SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:215, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:215.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 216; and
b)第二病毒载体,其包含:SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:217, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:217.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 218, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 218; and
b)第二病毒载体,其包含:SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:219, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:219.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 218, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 218; and
b)第二病毒载体,其包含:SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在各种实施方案中,该免疫原性组合物或药物组合物包含第一和第二病毒载体,该第一和第二病毒载体包含一种或多种多核苷酸:In various embodiments, the immunogenic or pharmaceutical composition comprises a first and a second viral vector comprising one or more polynucleotides:
a)第一病毒载体,其包含:SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising: a polynucleotide of SEQ ID NO: 225, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 225; and
b)第二病毒载体,其包含:SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising: a polynucleotide of SEQ ID NO:226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在该药物组合物或免疫原性组合物的各种实施方案中,该一种或多种融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol 607-682、Pol 709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在该药物组合物或免疫原性组合物的各种实施方案中,该一种或多种融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In various embodiments of the pharmaceutical composition or immunogenic composition, the one or more fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol 607-682, Pol 709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116 and Nef149-206, or fragments or subsequences thereof, wherein the Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2 and 3, respectively. In various embodiments of the pharmaceutical composition or immunogenic composition, the one or more fusion polypeptides do not comprise any polypeptide fragment having an amino acid sequence of SEQ ID NOs: 35-47 or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 35-47 or a fragment or subsequence thereof.
6.治疗方法6. Treatment Methods
还提供了用于治疗或预防对其有需要的受试者(例如,人类受试者)的HIV感染或相关疾病或障碍的方法,该方法包括向对其有需要的受试者提供有效量的如本文所述的一种或多种融合多肽或复合融合多肽或者编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或者表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体。如本文所用,术语“受试者”是指哺乳动物。哺乳动物可以是任何哺乳动物,例如人、非人灵长类动物、啮齿动物(例如小鼠、大鼠、豚鼠)、狗、猫或家养动物(诸如奶牛、马、山羊、骆驼、绵羊或猪)。术语“患者”是指人类受试者。如本文所用,术语“有效量”在向受试者施用疗法的上下文中是指达到所需预防或治疗效果的疗法的量。多核苷酸可存在于载体(例如,如本文所述的病毒载体)中。在一些实施方案中,相关疾病或障碍是由HIV感染引起的。在其他实施方案中,其是获得性免疫缺陷综合征(AIDS)。在某些实施方案中,受试者是病毒学抑制的HIV感染的哺乳动物,而在其他实施方案中,受试者是治疗初治型的HIV感染的哺乳动物或未经病毒学抑制的经历过治疗的HIV感染的受试者。在某些实施方案中,治疗初治型受试者具有介于<50个拷贝/mL和108个拷贝/ml之间的病毒载量。在某些实施方案中,病毒学抑制的受试者具有<50个拷贝/ml的病毒载量。在另一个实施方案中,受试者是哺乳动物,例如人。在某些实施方案中,受试者已被诊断患有HIV(例如HIV-1或HIV-2)感染或相关疾病或障碍(例如AIDS),或被认为处于发生HIV(例如HIV-1或HIV-2)感染或相关疾病或障碍(例如AIDS)的风险中。处于HIV相关疾病或障碍的风险中的受试者包括已经与被感染的人接触或已经以某种其他方式暴露于HIV的患者。预防剂的施用可以在HIV相关疾病或障碍的特征性症状表现之前发生,使得预防疾病或障碍或者另选地延迟其进展。Also provided is a method for treating or preventing HIV infection or related diseases or disorders in a subject (e.g., a human subject) in need thereof, the method comprising providing an effective amount of one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or expressing one or more fusion polypeptides or composite fusion polypeptides as described herein to a subject in need thereof. As used herein, the term "subject" refers to a mammal. The mammal can be any mammal, such as a human, non-human primate, rodent (e.g., mouse, rat, guinea pig), dog, cat, or domestic animal (such as a cow, horse, goat, camel, sheep, or pig). The term "patient" refers to a human subject. As used herein, the term "effective amount" refers to the amount of therapy to achieve the desired preventive or therapeutic effect in the context of administering therapy to a subject. The polynucleotide may be present in a vector (e.g., a viral vector as described herein). In some embodiments, the related disease or disorder is caused by HIV infection. In other embodiments, it is acquired immunodeficiency syndrome (AIDS). In certain embodiments, the subject is a mammal infected by HIV of virological inhibition, and in other embodiments, the subject is a mammal infected by HIV of treatment naive type or a subject infected by HIV of treatment without virological inhibition. In certain embodiments, the treatment naive type subject has a viral load between <50 copies/mL and 10 8 copies/ml. In certain embodiments, the subject of virological inhibition has a viral load of <50 copies/ml. In another embodiment, the subject is a mammal, such as a person. In certain embodiments, the subject has been diagnosed with HIV (such as HIV-1 or HIV-2) infection or associated disease or disorder (such as AIDS), or is considered to be in the risk of HIV (such as HIV-1 or HIV-2) infection or associated disease or disorder (such as AIDS). Subjects in the risk of HIV related diseases or disorders include patients who have been exposed to HIV in some other way or have been exposed to HIV with infected people. The use of preventive agents can occur before the characteristic symptoms of HIV related diseases or disorders are manifested, so that preventive diseases or disorders or alternatively delay their progress.
在一些实施方案中,受试者被HIV-1慢性感染。在一些实施方案中,受试者被HIV-1急性感染,例如具有Fiebig IV期或更早例如Fiebig III期、Fiebig II期或Fiebig I期的HIV-1感染。在一些实施方案中,受试者未接受抗逆转录病毒治疗(ART),或者在施用一种或多种组合物之前中断ART。在一些实施方案中,在一次或多次施用组合物之后中断ART。在一些实施方案中,与施用如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体同时施用ART。In some embodiments, the subject is chronically infected with HIV-1. In some embodiments, the subject is acutely infected with HIV-1, for example, with Fiebig IV stage or earlier, such as Fiebig III stage, Fiebig II stage or Fiebig I stage HIV-1 infection. In some embodiments, the subject does not receive antiretroviral therapy (ART), or ART is interrupted before applying one or more compositions. In some embodiments, ART is interrupted after one or more administrations of the composition. In some embodiments, ART is administered simultaneously with one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more carriers expressing one or more fusion polypeptides or composite fusion polypeptides as described herein.
还提供了用于预防或抑制受试者(例如,人受试者)中HIV病毒滴度、病毒复制、病毒增殖或HIV病毒DNA、HIV前病毒DNA或HIV病毒蛋白的量增加的方法。在一个实施方案中,该方法需要向对其有需要的受试者提供一定量的如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体以有效防止HIV滴度增加、病毒复制,或者受试者体内的一定量的一种或多种HIV毒株或分离株的HIV蛋白。在某些实施方案中,该方法还包括在一个或多个时间点(例如,在向受试者提供如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体之前或之后)测量HIV病毒或前病毒DNA或蛋白质的量。用于确定受试者中HIV病毒或前病毒DNA或蛋白质的量的方法和生物标记在本领域中是已知的和可获得的,并且例如在以下文献中描述:Siliciano,J.D.等人,Curr Opin.HIV AIDS,5(6):491-7(2010);以及Rouzioux,C.等人,Curr Opin HIV AIDS,8(3):170-5(2013)。Also provided is a method for preventing or inhibiting the increase in the amount of HIV virus titer, virus replication, virus proliferation or HIV virus DNA, HIV proviral DNA or HIV virus protein in a subject (e.g., a human subject). In one embodiment, the method requires providing a certain amount of one or more fusion polypeptides or composite fusion polypeptides as described herein or encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more polynucleotides or expressing one or more fusion polypeptides or composite fusion polypeptides as described herein to a subject in need thereof to effectively prevent HIV titer increase, virus replication, or a certain amount of one or more HIV strains or isolates in the subject. In certain embodiments, the method also includes measuring the amount of HIV virus or proviral DNA or protein at one or more time points (e.g., before or after providing one or more fusion polypeptides or composite fusion polypeptides as described herein or encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or expressing one or more fusion polypeptides or composite fusion polypeptides as described herein) to a subject in need thereof. Methods and biomarkers for determining the amount of HIV viral or proviral DNA or protein in a subject are known and available in the art and are described, for example, in Siliciano, J.D. et al., Curr Opin. HIV AIDS, 5(6):491-7 (2010); and Rouzioux, C. et al., Curr Opin HIV AIDS, 8(3):170-5 (2013).
在一些实施方案中,如本文所述的一种或多种融合多肽或复合融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体可用于例如抑制某些病毒(诸如本文所述的HIV分离株)、预防性抑制或防止某些病毒(诸如本文所述的HIV分离株)的感染、检测样品中的某些病毒(诸如本文所述的HIV分离株)、抑制某些病毒(诸如本文所述的HIV分离株)或诊断某些病毒(诸如本文所述的HIV分离株)的方法中。In some embodiments, one or more fusion polypeptides or composite fusion polypeptides or composite fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein can be used, for example, in methods of inhibiting certain viruses (such as the HIV isolates described herein), prophylactically inhibiting or preventing infection by certain viruses (such as the HIV isolates described herein), detecting certain viruses (such as the HIV isolates described herein) in samples, inhibiting certain viruses (such as the HIV isolates described herein), or diagnosing certain viruses (such as the HIV isolates described herein).
对于哺乳动物受试者(例如人)的体内治疗,可向受试者施用或提供药物组合物,该药物组合物包含如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体。当用于体内疗法中时,如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体通常以治疗有效量(即,消除或减少患者的病毒负荷和/或病毒储库的量)施用或提供给患者。如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体根据已知的方法施用或提供给哺乳动物受试者(例如人),诸如但不限于静脉内施用(例如推注)或通过在一段时间内连续输注、通过肌内、腹膜内、脑脊髓内、皮下、结内、关节内、滑膜内、鞘内、口服、局部或吸入途径。如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体可在靶细胞位点肠胃外施用(在可能的情况下)或静脉内施用。在一个实施方案中,向受试者施用如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体经由静脉内途径进行。在另一个实施方案中,向受试者施用如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体经由皮下途径进行。在另外的实施方案中,本公开的药物组合物全身、肠胃外或局部(例如经粘膜,包括颊部、直肠内和/或阴道内途径)施用给受试者。For in vivo treatment of mammalian subjects (e.g., humans), a pharmaceutical composition may be administered or provided to a subject, the pharmaceutical composition comprising one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein. When used in in vivo therapy, one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein are typically administered or provided to a patient in a therapeutically effective amount (i.e., the amount of viral load and/or viral reservoirs that eliminate or reduce the patient). One or more fusion polypeptides or composite fusion polypeptides as described herein or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein are administered or provided to mammalian subjects (e.g., humans) according to known methods, such as, but not limited to, intravenous administration (e.g., push injection) or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intranodal, intraarticular, intrasynovial, intrathecal, oral, topical or inhalation routes. One or more fusion polypeptides or composite fusion polypeptides as described herein or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein can be administered parenterally (where possible) or intravenously at the target cell site. In one embodiment, administration of one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein to a subject is performed via an intravenous route. In another embodiment, administration to a subject of one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein is performed via a subcutaneous route. In additional embodiments, the pharmaceutical composition of the present disclosure is administered systemically, parenterally, or topically (e.g., via mucosal, including buccal, rectal, and/or vaginal routes) to a subject.
在某些实施方案中,本公开提供了一种用于治疗HIV感染的方法,该方法包括向有对其需要的人类受试者施用治疗有效量的如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体。在一些实施方案中,本公开提供了一种用于预防HIV感染的方法,该方法包括向有对其需要的人类受试者施用治疗有效量的如本文所述的一种或多种融合多肽或复合融合多肽或编码如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽或复合融合多肽的一种或多种载体。In certain embodiments, the present disclosure provides a method for treating HIV infection, the method comprising administering to a human subject in need thereof a therapeutically effective amount of one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein. In some embodiments, the present disclosure provides a method for preventing HIV infection, the method comprising administering to a human subject in need thereof a therapeutically effective amount of one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides or composite fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides or composite fusion polypeptides as described herein.
在各种实施方案中,该方法需要施用第一和第二二价融合多肽,或分别编码第一和第二融合多肽的第一和第二多核苷酸(例如,第一和第二表达盒、第一和第二开放阅读框),或包含分别编码第一和第二融合多肽的第一和第二多核苷酸(例如,第一和第二表达盒、第一和第二开放阅读框)的单个病毒表达载体,其中第一和第二融合多肽是二价融合多肽。在某些实施方案中,单个病毒表达载体具有双片段基因组。在某些实施方案中,单个病毒表达载体具有三片段基因组。在各种实施方案中,该方法需要施用单个复合融合多肽、或编码该复合融合多肽的单个多核苷酸(例如,单个表达盒、单个开放阅读框)、或包含编码该复合融合多肽的多核苷酸的单个病毒表达载体,其中该复合融合多肽包含二价融合多肽。In various embodiments, the method requires administration of a first and a second bivalent fusion polypeptide, or a first and a second polynucleotide encoding a first and a second fusion polypeptide, respectively (e.g., a first and a second expression cassette, a first and a second open reading frame), or a single viral expression vector comprising a first and a second polynucleotide encoding a first and a second fusion polypeptide, respectively (e.g., a first and a second expression cassette, a first and a second open reading frame), wherein the first and the second fusion polypeptide are bivalent fusion polypeptides. In certain embodiments, the single viral expression vector has a two-segment genome. In certain embodiments, the single viral expression vector has a three-segment genome. In various embodiments, the method requires administration of a single composite fusion polypeptide, or a single polynucleotide encoding the composite fusion polypeptide (e.g., a single expression cassette, a single open reading frame), or a single viral expression vector comprising a polynucleotide encoding the composite fusion polypeptide, wherein the composite fusion polypeptide comprises a bivalent fusion polypeptide.
在一些实施方案中,这些方法需要向受试者施用:第一融合多肽和第二融合多肽或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码该第一和第二融合多肽,该第一和第二多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:In some embodiments, the methods entail administering to a subject: a first fusion polypeptide and a second fusion polypeptide or one or more vectors comprising one or more polynucleotides encoding the first and second fusion polypeptides, the first and second polypeptides comprising, in order from N-terminus to C-terminus, the following polypeptide fragments optionally bound or linked by one or more linkers:
·SEQ ID NO:6、4、16和26,以及SEQ ID NO:7、5、27和17;SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17;
·SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11;
·SEQ ID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21;
·SEQ ID NO:26、16、4和6,以及SEQ ID NO:7、27、5和17;SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17;
·SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11;
·SEQ ID NO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NOs: 22, 24, 14, 18 and 20, and SEQ ID NOs: 25, 23, 15, 21 and 19;
·SEQ ID NO:20、6、4、18、16和26,以及SEQ ID NO:7、19、5、21、27和17;SEQ ID NOs: 20, 6, 4, 18, 16 and 26, and SEQ ID NOs: 7, 19, 5, 21, 27 and 17;
·SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NOs: 8, 24, 14, 12, 22 and 10, and SEQ ID NOs: 9, 13, 25, 23, 15 and 11;
·SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQ ID NOs: 18, 26, 20, 4, 6 and 16, and SEQ ID NOs: 7, 21, 17, 5, 27 and 19;
·SEQ ID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ ID NOs: 22, 24, 12, 14, 8 and 10, and SEQ ID NOs: 15, 25, 9, 23, 13 and 11;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 8, 30, 14, 12, 26 and 10;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:7、21、5、25、33和19;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 7, 21, 5, 25, 33 and 19;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 8, 30, 14, 12, 26 and 10;
·SEQ ID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NOs: 8, 30, 14, 12, 26 and 10, and SEQ ID NOs: 9, 13, 31, 27, 15 and 11;
·SEQ ID NO:7、21、5、25、33和19,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NOs: 7, 21, 5, 25, 33 and 19, and SEQ ID NOs: 9, 13, 31, 27, 15 and 11;
·SEQ ID NO:20、32、24、4、6和18,以及SEQ ID NO:26、30、12、14、8和10;SEQ ID NOs: 20, 32, 24, 4, 6 and 18, and SEQ ID NOs: 26, 30, 12, 14, 8 and 10;
·SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ ID NOs: 6, 20, 4, 24, 32 and 18, and SEQ ID NOs: 8, 12, 30, 26, 14 and 10;
·SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ ID NOs: 7, 25, 19, 5, 33 and 21, and SEQ ID NOs: 15, 31, 9, 27, 13 and 11;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 26, 20, 10 and 28;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、10、20和28;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 26, 10, 20 and 28;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 7, 25, 17 and 19;
·SEQ ID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 7, 19, 17 and 25, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:24、16、6和18,以及SEQ ID NO:27、11、21和29;SEQ ID NOs: 24, 16, 6 and 18, and SEQ ID NOs: 27, 11, 21 and 29;
·SEQ ID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NOs: 7, 25, 17 and 19, and SEQ ID NOs: 11, 27, 21 and 29;
·SEQ ID NO:7、25、17和19,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 7, 25, 17 and 19, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NOs: 22, 6, 20 and 28, and SEQ ID NOs: 23, 7, 21 and 29;
·SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NOs: 22, 20, 6 and 28, and SEQ ID NOs: 7, 21, 23 and 29;
·SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 26, 10, 20 and 28, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO: 22, 6, 16, 20, 18, 28, 26 and 10; or
·SEQ ID NO:7、21、19、17、27、25、29和11。· SEQ ID NO: 7, 21, 19, 17, 27, 25, 29 and 11.
在一些实施方案中,这些方法需要向受试者施用:一种或多种融合多肽、或包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,这些方法需要向受试者施用:一种或多种融合多肽、或包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In some embodiments, the methods entail administering to a subject: one or more fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, comprising or consisting of an amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223, and 227. In some embodiments, the methods entail administering to a subject: one or more fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209, and 222-223.
在一些实施方案中,这些方法需要向受试者施用:以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the methods entail administering to a subject: the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ IDNO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 82 and 83, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 86 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:86 and 87.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ IDNO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 84 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 84 and 85, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 88 and 89, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:88 and 89.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ IDNO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 82 and 86, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:83 and 87.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ IDNO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 82 and 88, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 85 and 87, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:85 and 87.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ IDNO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 82 and 85, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 87 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:87 and 88.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ IDNO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector containing one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 84 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 84 and 88, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 85 and 89, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:85 and 89.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ IDNO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 94 and 96, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:95 and 97.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:220和221的融合多肽,或分别与SEQID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 220 and 221, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:95 and 97.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ IDNO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 94 and 95, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 96 and 97, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:96 and 97.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ IDNO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 98 and 100, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:99 and 101.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ IDNO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 98 and 100, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:85 and 101.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的第一和第二病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:(a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:98和99的融合多肽,或分别与SEQ IDNO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽,和(b)第二病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers: (a) a first viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 98 and 99, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 98 and 99, respectively, and (b) a second viral vector comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 100 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 101 and 102, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO:100 and 101.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:200,与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:201,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding the following first fusion polypeptide: comprising SEQ ID NO: 200, being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding the following second fusion polypeptide: comprising SEQ ID NO: 201, being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202. NO:201 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:202,与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:203,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding the following first fusion polypeptide: comprising SEQ ID NO: 202, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding the following second fusion polypeptide: comprising SEQ ID NO: 203, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204. NO:203 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:204,与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:205,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 204 that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 205 or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 205. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:105,与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:107,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding the following first fusion polypeptide: comprising SEQ ID NO: 105, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding the following second fusion polypeptide: comprising SEQ ID NO: 107, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 108. NO:107 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:206,与SEQ ID NO:206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:207,或与SEQ ID NO:207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding the following first fusion polypeptide: comprising SEQ ID NO:206, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:206, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding the following second fusion polypeptide: comprising SEQ ID NO:207, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:208. NO:207 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:208,与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:209或SEQ ID NO:227,或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 208 that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or is identical to SEQ ID NO: 209 or SEQ ID NO: 228. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:222,与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:209或SEQ ID NO:227,或与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 222 that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or is identical to SEQ ID NO: 209 or SEQ ID NO: 228. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要施用含有第一和第二多核苷酸的第一和第二病毒载体或第一和第二脂质体复合物(例如,LNP),该第一和第二多核苷酸编码以下第一融合多肽和第二融合多肽:(a)第一多核苷酸或包含多核苷酸的第一病毒载体或第一脂质体复合物(例如,LNP),该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:222,与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同,和(b)第二多核苷酸或包含多核苷酸的第二病毒载体或第二脂质体复合物(例如,LNP),该多核苷酸编码以下第二融合多肽:包含SEQ IDNO:223,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。In some embodiments, the methods entail administering first and second viral vectors or first and second liposome complexes (e.g., LNPs) containing first and second polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide: (a) a first polynucleotide or a first viral vector or a first liposome complex (e.g., LNP) comprising a polynucleotide encoding the following first fusion polypeptide: comprising SEQ ID NO: 222, being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and (b) a second polynucleotide or a second viral vector or a second liposome complex (e.g., LNP) comprising a polynucleotide encoding the following second fusion polypeptide: comprising SEQ ID NO: 223, being at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223. NO:223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a viral vector containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively.
在一些实施方案中,这些方法需要向受试者施用含有一种或多种多核苷酸的病毒载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the methods entail administering to a subject a viral vector containing one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively.
在一些实施方案中,这些方法需要向受试者施用:以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸从N末端到C末端按顺序编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the methods entail administering to a subject: the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding, in order from N-terminus to C-terminus, the following first and second fusion polypeptides optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:71 and 70, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:73 and 72, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:75 and 74, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:77 and 76, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:77 and 76, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:79 and 78, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:79 and 78, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 86, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 88, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 82, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 82, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 82, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 83, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 85, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 85, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:91 and 90, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:91 and 90, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:93 and 92, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 96, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 94, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 95, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 98, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively;
·SEQ ID NO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 98, respectively;
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or
·SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 100, respectively.
在一些实施方案中,这些方法需要向受试者施用:多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,这些方法需要向受试者施用:多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。In some embodiments, the methods entail administering to a subject a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the methods entail administering to a subject a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226.
在一些实施方案中,这些方法需要向受试者施用:以下第一多核苷酸和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸或由以下第一多核苷酸和第二多核苷酸组成的一种或多种载体:In some embodiments, the methods entail administering to a subject: the following first and second polynucleotides, or one or more vectors comprising or consisting of the following first and second polynucleotides:
·SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 132, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively;
·SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 134, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively;
·SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively;
·SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively;
·SEQ ID NO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively;
·SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively;
·SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively;
·SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 134 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively;
·SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively;
·SEQ ID NO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 141, respectively;
·SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively;
·SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 142, respectively;
·SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 145, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively;
·SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 140 and 146, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively;
·SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 142 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively;
·SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 143 and 149, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively;
·SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively;
·SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively;
·SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 155, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively;
·SEQ ID NO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 153, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively;
·SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively;
·SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively;
·SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 153 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 153 and 159, respectively;
·SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 154 and 157, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, respectively;
·SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively;
·SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively;
·SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively;
·SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively;
·SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 164 and 165, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively;
·SEQ ID NO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively;
·SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 210 and 211, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively;
·SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 212 and 213, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 212 and 213, respectively;
·SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 214 and 215, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively;
·SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively;
·SEQ ID NO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 218 and 219, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively;
·SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或者a polynucleotide of SEQ ID NOs: 218 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 226, respectively; or
·SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。· A polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 210, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 211. any one of NO:211 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 212, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 213. any one of NO:213 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 215. Any of NO:215 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the polynucleotide.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 216, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 217. any one of NO:217 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 219. any one of NO:219 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. any one of NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides.
在一些实施方案中,该方法需要施用:(a)第一载体或脂质体复合物(例如,LNP),其包含以下第一多核苷酸:包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸,和(b)第二载体或脂质体复合物(例如,LNP),其包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the method entails administering: (a) a first carrier or liposome complex (e.g., LNP) comprising a first polynucleotide comprising SEQ ID NO: 225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 225, and (b) a second carrier or liposome complex (e.g., LNP) comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. any one of NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotides.
在一些实施方案中,这些方法需要向受试者施用:复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,这些方法需要向受试者施用:复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In some embodiments, the methods require administering to a subject: a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, the composite fusion polypeptide comprising or consisting of an amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223, and 227. In some embodiments, the methods require administering to a subject: a composite fusion polypeptide or a vector comprising a polynucleotide encoding a composite fusion polypeptide, the composite fusion polypeptide comprising or consisting of: an amino acid sequence of any one of SEQ ID NOs: 209, 222, and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 209, 222, and 223.
在这些方法的各种实施方案中,该一种或多种融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol 607-682、Pol709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在这些方法的各种实施方案中,该一种或多种融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In various embodiments of these methods, the one or more fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol 607-682, Pol709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116, and Nef 149-206, or fragments or subsequences thereof, wherein Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2, and 3, respectively. In various embodiments of these methods, the one or more fusion polypeptides do not comprise any polypeptide fragment having an amino acid sequence of SEQ ID NOs:35-47, or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:35-47, or a fragment or subsequence thereof.
在一些实施方案中,这些方法需要施用表达一种或多种融合多肽的一种或多种病毒表达载体。在各种实施方案中,这些方法需要每次施用施用约103至约1012个病毒病灶形成单位(FFU)或噬菌斑形成单位(PFU)或感染单位(IU)或病毒颗粒(vp),例如约104至约107个病毒FFU或PFU或IU或vp,例如约103至约104、105、106、107、108、109、1010、1011、1012、1013、1014或1015个病毒FFU或PFU或IU或vp。In some embodiments, these methods require administration of one or more viral expression vectors expressing one or more fusion polypeptides. In various embodiments, these methods require administration of about 10 3 to about 10 12 viral focus forming units (FFU) or plaque forming units (PFU) or infectious units (IU) or viral particles (vp) per administration, such as about 10 4 to about 10 7 viral FFU or PFU or IU or vp, such as about 10 3 to about 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 or 10 15 viral FFU or PFU or IU or vp.
在各种实施方案中,这些方法实施初免-加强方案,其包括在第一时间点施用初免组合物并在一个或多个后续时间点施用一种或多种加强组合物。通常,在初免-加强方案中,依次施用初免组合物和加强组合物。例示性的初免-加强方案包括初免-加强-初免-加强和初免-加强-加强-加强。在一些实施方案中,初免组合物和一种或多种加强组合物的施用间隔至少1周、2周、3周或1个月,例如至少2、3、4、5、6、7、8、9、10、11或12个月。在一些实施方案中,初免组合物和加强组合物包含相同的免疫原性组合物。在一些实施方案中,初免组合物和加强组合物包含不同的免疫原性组合物。在一些实施方案中,初免组合物和加强组合物包含相同的一种或多种融合多肽和相同的病毒表达载体。在一些实施方案中,初免组合物和加强组合物包含不同的融合多肽和相同的病毒表达载体。在一些实施方案中,初免组合物和加强组合物包含相同的融合多肽和不同的病毒表达载体。在一些实施方案中,这些方法需要用第一病毒表达载体初免,并用第二病毒表达载体加强。视情况而定,可重复初免-加强方案一次或多次迭代。In various embodiments, these methods implement a primary immunization-boosting scheme, which includes applying a primary immunization composition at a first time point and applying one or more boosting compositions at one or more subsequent time points. Typically, in a primary immunization-boosting scheme, primary immunization compositions and boosting compositions are applied sequentially. Exemplary primary immunization-boosting schemes include primary immunization-boosting-primary immunization-boosting and primary immunization-boosting-boosting-boosting. In some embodiments, the primary immunization composition and one or more boosting compositions are administered at intervals of at least 1 week, 2 weeks, 3 weeks or 1 month, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In some embodiments, the primary immunization composition and the boosting composition comprise the same immunogenic composition. In some embodiments, the primary immunization composition and the boosting composition comprise different immunogenic compositions. In some embodiments, the primary immunization composition and the boosting composition comprise the same one or more fusion polypeptides and the same viral expression vector. In some embodiments, the primary immunization composition and the boosting composition comprise different fusion polypeptides and the same viral expression vector. In some embodiments, the primary immunization composition and the boosting composition comprise the same fusion polypeptide and different viral expression vectors. In some embodiments, these methods require priming with a first viral expression vector and boosting with a second viral expression vector. Depending on the circumstances, the prime-boost regimen can be repeated one or more iterations.
在各种实施方案中,初免-加强方案包括:In various embodiments, the prime-boost regimen includes:
·用一种或多种病毒表达载体初免并用一种或多种多核苷酸加强,其中该一种或多种多核苷酸包含DNA、cDNA、mRNA或自复制RNA;Prime with one or more viral expression vectors and boost with one or more polynucleotides, wherein the one or more polynucleotides comprise DNA, cDNA, mRNA or self-replicating RNA;
·用一种或多种多核苷酸初免,其中该一种或多种多核苷酸包含DNA、cDNA、mRNA、自扩增或自复制RNA,并用一种或多种病毒表达载体加强;priming with one or more polynucleotides, wherein the one or more polynucleotides comprise DNA, cDNA, mRNA, self-amplifying or self-replicating RNA, and boosting with one or more viral expression vectors;
·用一种或多种病毒表达载体初免,并用一种或多种病毒表达载体加强,其中该初免组合物中的该一种或多种病毒表达载体和该加强组合物中的该一种或多种病毒表达载体来自相同、相关或不相关的分类学家族;priming with one or more viral expression vectors and boosting with one or more viral expression vectors, wherein the one or more viral expression vectors in the priming composition and the one or more viral expression vectors in the boosting composition are from the same, related or unrelated taxonomic families;
·用一种或多种复制缺陷型病毒表达载体初免并用一种或多种复制缺陷型病毒表达载体加强,其中该初免组合物中的该一种或多种复制缺陷型病毒表达载体和该加强组合物中的该一种或多种复制缺陷型病毒表达载体来自相同、相关或不相关的分类学家族;priming with one or more replication-defective viral expression vectors and boosting with one or more replication-defective viral expression vectors, wherein the one or more replication-defective viral expression vectors in the priming composition and the one or more replication-defective viral expression vectors in the boosting composition are from the same, related or unrelated taxonomic families;
·用一种或多种复制减毒型病毒表达载体初免并用一种或多种复制减毒型病毒表达载体加强,其中该初免组合物中的该一种或多种复制减毒型病毒表达载体和该加强组合物中的该一种或多种复制减毒型病毒表达载体来自相同、相关或不相关的分类学家族;priming with one or more replication-attenuated viral expression vectors and boosting with one or more replication-attenuated viral expression vectors, wherein the one or more replication-attenuated viral expression vectors in the priming composition and the one or more replication-attenuated viral expression vectors in the boosting composition are from the same, related or unrelated taxonomic families;
·用一种或多种复制缺陷型病毒表达载体初免并用一种或多种复制减毒型病毒表达载体加强;Prime with one or more replication-defective viral expression vectors and boost with one or more replication-attenuated viral expression vectors;
·用一种或多种复制减毒型病毒表达载体初免并用一种或多种复制缺陷型病毒表达载体加强;Prime with one or more replication-attenuated viral expression vectors and boost with one or more replication-defective viral expression vectors;
·用一种或多种淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体初免并用一种或多种皮钦德哺乳动物沙粒病毒病毒表达载体加强;· priming with one or more lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral expression vectors and boosting with one or more picinder mammalian arenavirus viral expression vectors;
·用一种或多种皮钦德哺乳动物沙粒病毒病毒表达载体初免并用一种或多种淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体加强;· priming with one or more picinder mammalian arenavirus viral expression vectors and boosting with one or more lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral expression vectors;
·用一种或多种复制缺陷型皮钦德哺乳动物沙粒病毒病毒表达载体初免并用一种或多种复制缺陷型淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体加强;· priming with one or more replication-defective picinder mammalian arenavirus viral expression vectors and boosting with one or more replication-defective lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral expression vectors;
·用一种或多种复制缺陷型淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒表达载体初免并用一种或多种复制缺陷型皮钦德哺乳动物沙粒病毒病毒表达载体加强;· priming with one or more replication-defective lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral expression vectors and boosting with one or more replication-defective picinder mammalian arenavirus viral expression vectors;
·用一种或多种沙粒病毒病毒表达载体初免并用一种或多种腺病毒病毒表达载体加强;Prime with one or more arenavirus expression vectors and boost with one or more adenovirus expression vectors;
·用一种或多种腺病毒病毒表达载体初免并用包含一种或多种沙粒病毒病毒表达载体的加强组合物加强;priming with one or more adenovirus expression vectors and boosting with a boosting composition comprising one or more arenavirus expression vectors;
·用一种或多种腺病毒病毒表达载体初免并用包含一种或多种RNA分子(例如,mRNA、自扩增或自复制RNA)的加强组合物加强;priming with one or more adenoviral viral expression vectors and boosting with a boosting composition comprising one or more RNA molecules (e.g., mRNA, self-amplifying or self-replicating RNA);
·用一种或多种RNA分子(例如,mRNA、自扩增或自复制RNA)初免并用包含一种或多种腺病毒病毒表达载体的加强组合物加强;Prime with one or more RNA molecules (e.g., mRNA, self-amplifying or self-replicating RNA) and boost with a boosting composition comprising one or more adenoviral viral expression vectors;
·用一种或多种黑猩猩腺病毒(ChAd)表达载体初免并用包含一种或多种自扩增或自复制RNA(saRNA或samRNA)的加强组合物加强;Prime with one or more chimpanzee adenovirus (ChAd) expression vectors and boost with a boosting composition comprising one or more self-amplifying or self-replicating RNAs (saRNA or samRNA);
·用一种或多种自扩增或自复制RNA(saRNA或samRNA)初免并用包含一种或多种黑猩猩腺病毒(ChAd)表达载体的加强组合物加强;Prime with one or more self-amplifying or self-replicating RNAs (saRNA or samRNA) and boost with a boosting composition comprising one or more chimpanzee adenovirus (ChAd) expression vectors;
·用一种或多种痘病毒(例如,牛痘)病毒表达载体初免并用一种或多种沙粒病毒病毒表达载体加强;Prime with one or more poxvirus (e.g., vaccinia) viral expression vectors and boost with one or more arenavirus viral expression vectors;
·用一种或多种沙粒病毒病毒表达载体初免并用包含一种或多种痘病毒(例如,牛痘)病毒表达载体的加强组合物加强;priming with one or more arenavirus viral expression vectors and boosting with a boosting composition comprising one or more poxvirus (e.g., vaccinia) viral expression vectors;
·用一种或多种痘病毒(例如,牛痘)病毒表达载体初免并用一种或多种腺病毒病毒表达载体加强;或者Prime with one or more poxvirus (e.g., vaccinia) viral expression vectors and boost with one or more adenovirus viral expression vectors; or
·用一种或多种腺病毒病毒表达载体初免并用包含一种或多种痘病毒(例如,牛痘)病毒表达载体的加强组合物加强;priming with one or more adenovirus viral expression vectors and boosting with a boosting composition comprising one or more poxvirus (e.g., vaccinia) viral expression vectors;
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及2)用免疫原性组合物加强,该免疫原性组合物包含以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; and 2) boosting with an immunogenic composition comprising the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively;
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a) a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
b)SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
c)SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;c) a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
d)SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或d) a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; and/or
e)SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及e) a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked via one or more linkers:
a)SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a) a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively;
b)SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively;
c)SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或c) a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively; and/or
d)SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。d) a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 86 and 87, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 85, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ IDNO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒),并且加强载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively. In various embodiments of the method, the priming vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus), and the boosting vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒),并且加强载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 101, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively. In various embodiments of the method, the priming vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus), and the boosting vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV),并且加强载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively. In various embodiments of the method, the priming vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV) and the boosting vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV),并且加强载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively. In various embodiments of the method, the priming vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV) and the boosting vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用免疫原性组合物初免,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:1) priming with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides optionally bound or linked via one or more linkers:
a)第一病毒载体,其包含:编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或编码以下第一融合多肽和第二融合多肽的一种或多种多核苷酸:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及a) a first viral vector, comprising: one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; or one or more polynucleotides encoding the following first and second fusion polypeptides: a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 222, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NOs: 220 and 221; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively; and
2)用免疫原性组合物加强,该免疫原性组合物包含第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和/或a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and/or
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和85,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:87和88,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide optionally bound or linked by one or more linkers: SEQ ID NOs: 87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 87 and 88, respectively.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:87和88的融合多肽,或分别与SEQ IDNO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, comprising a fusion polypeptide of SEQ ID NOs: 82 and 85, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 85, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, comprising SEQ ID NOs: NO:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:87 and 88, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 87, respectively.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和87的融合多肽,或分别与SEQ IDNO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 82 and 88, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 82 and 88, respectively. NO:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:85 and 87, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 97, respectively.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ IDNO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively. NO:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:96 and 97, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ IDNO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NOs: NO:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:95 and 97, respectively.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) and a second viral vector or liposome complex (e.g., LNP), wherein the first viral vector or liposome complex (e.g., LNP) comprises one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 220 and 221, or a fusion polypeptide with SEQ ID NO: 221, respectively. NO: 220 and 221 are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of NO: 220 and 221; the second viral vector or liposome complex (e.g., LNP) comprises one or more polynucleotides, the one or more polynucleotides encoding the following first fusion polypeptide and second fusion polypeptide, optionally bound or connected by one or more linkers: a fusion polypeptide comprising SEQ ID NO: 95 and 97, or SEQ ID NO: 97, respectively. A fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any of NO:95 and 97.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers, of SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,所述多核苷酸编码以下复合融合多肽:包含SEQ ID NO:105的复合融合多肽,或与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 105; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,所述多核苷酸编码以下复合融合多肽:包含SEQ ID NO:109的复合融合多肽,或与SEQ ID NO:109至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 109, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 109.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:105或206的复合融合多肽,或与SEQ ID NO:105或206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 105 or 206, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 105 or 206; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:107或207的复合融合多肽,或与SEQ ID NO:107或207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 107 or 207, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 107 or 207.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:105的融合多肽,或分别与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:107的融合多肽,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 105, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 107, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 107, respectively. NO:107 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:206的融合多肽,或分别与SEQ ID NO:206至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:207的融合多肽,或与SEQ ID NO:207至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 206, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 207, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, respectively. NO:207 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,所述多核苷酸编码以下复合融合多肽:包含SEQ ID NO:208的复合融合多肽,或与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 208, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:209或SEQ ID NO:227的复合融合多肽,或分别与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:209 or SEQ ID NO:227, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:209 or SEQ ID NO:227, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,所述多核苷酸编码以下复合融合多肽:包含SEQ ID NO:222的复合融合多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 222, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 222; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:209或SEQ ID NO:227的复合融合多肽,或分别与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:209 or SEQ ID NO:227, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:209 or SEQ ID NO:227, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,所述多核苷酸编码以下复合融合多肽:包含SEQ ID NO:222的复合融合多肽,或与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 222, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 222; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,所述多核苷酸编码以下复合融合多肽:包含SEQ ID NO:223的复合融合多肽,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:223, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:223.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:208的融合多肽,或分别与SEQ ID NO:208至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:209或SEQ ID NO:227的融合多肽,或分别与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免组合物包含一种或多种ChAd载体并且加强组合物包含一种或多种自扩增mRNA分子,例如,类似于NCT04776317和WO 2021/236854中关于SARS-CoV2疫苗、WO2021/203104中关于感染性疾病疫苗和WO 2020/243719中描述的初免-加强方案。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 208, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 208, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209, respectively. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical fusion polypeptide. In various embodiments of the method, the priming composition comprises one or more ChAd vectors and the boosting composition comprises one or more self-amplifying mRNA molecules, for example, similar to the priming-boosting scheme described in NCT04776317 and WO 2021/236854 for SARS-CoV2 vaccines, WO 2021/203104 for infectious disease vaccines, and WO 2020/243719.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:222的融合多肽,或分别与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:209或SEQ ID NO:227的融合多肽,或分别与SEQ ID NO:209或SEQ ID NO:227至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免组合物包含一种或多种ChAd载体并且加强组合物包含一种或多种自扩增mRNA分子,例如,类似于NCT04776317和WO 2021/236854中关于SARS-CoV2疫苗、WO2021/203104中关于感染性疾病疫苗和WO 2020/243719中描述的初免-加强方案。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising SEQ ID NO: 222, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising SEQ ID NO: 209 or SEQ ID NO: 227, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 or SEQ ID NO: 227, respectively. NO:227 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical fusion polypeptide. In various embodiments of the method, the priming composition comprises one or more ChAd vectors and the boosting composition comprises one or more self-amplifying mRNA molecules, for example, similar to the priming-boosting scheme described in NCT04776317 and WO 2021/236854 for SARS-CoV2 vaccines, WO 2021/203104 for infectious disease vaccines, and WO 2020/243719.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:222的融合多肽,或分别与SEQ ID NO:222至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:223的融合多肽,或与SEQ ID NO:223至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。在该方法的各种实施方案中,初免组合物包含一种或多种ChAd载体并且加强组合物包含一种或多种自扩增mRNA分子,例如,类似于NCT04776317和WO 2021/236854中关于SARS-CoV2疫苗、WO 2021/203104中关于感染性疾病疫苗和WO 2020/243719中描述的初免-加强方案。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 222, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 223, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 223, respectively. NO:223 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical fusion polypeptide. In various embodiments of the method, the priming composition comprises one or more ChAd vectors and the boosting composition comprises one or more self-amplifying mRNA molecules, for example, similar to the priming-boosting scheme described in NCT04776317 and WO 2021/236854 for SARS-CoV2 vaccines, WO 2021/203104 for infectious disease vaccines, and WO 2020/243719.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物初免,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first and a second fusion polypeptide of SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 97, respectively; and
2)用包含含有一种或多种多核苷酸的病毒载体的免疫原性组合物加强,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide, optionally bound or linked by one or more linkers: a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:107的复合融合多肽,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 107, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 107; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:111的复合融合多肽,或与SEQ ID NO:111至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:111, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:111.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:200的复合融合多肽,或与SEQ ID NO:200至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 200, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 200; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:201的复合融合多肽,或与SEQ ID NO:201至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:201, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:201.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:202的复合融合多肽,或与SEQ ID NO:202至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 202, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 202; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:203的复合融合多肽,或与SEQ ID NO:203至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:203, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:203.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含病毒载体的免疫原性组合物初免,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:204的复合融合多肽,或与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;以及1) priming with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO: 204, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 204; and
2)用包含病毒载体的免疫原性组合物加强,该病毒载体包含多核苷酸,该多核苷酸编码以下复合融合多肽:包含SEQ ID NO:205的复合融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。2) boosting with an immunogenic composition comprising a viral vector comprising a polynucleotide encoding a composite fusion polypeptide comprising SEQ ID NO:205, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:205.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体或脂质体复合物(例如,LNP)和第二病毒载体或脂质体复合物(例如,LNP)的免疫原性组合物初免和加强,该第一病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第一融合多肽:包含SEQ ID NO:204的融合多肽,或分别与SEQ ID NO:204至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;该第二病毒载体或脂质体复合物(例如,LNP)包含多核苷酸,该多核苷酸编码以下第二融合多肽:包含SEQ ID NO:205的融合多肽,或与SEQ ID NO:205至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a first fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 204, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 204, respectively; and a second viral vector or liposome complex (e.g., LNP) comprising a polynucleotide encoding a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NO: 205, or a fusion polypeptide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 205, respectively. NO:205 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the fusion polypeptide.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一和第二病毒载体的免疫原性组合物初免,该第一和第二病毒载体包含以下多核苷酸:1) priming with an immunogenic composition comprising a first and a second viral vector, the first and the second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 131 and 135, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQID NO:133和137,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。以及b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 133 and 137, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively. And
2)用包含第一和第二病毒载体的免疫原性组合物加强,该第一和第二病毒载体包含以下多核苷酸:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:139和145,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 139 and 145, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 142 and 148, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一和第二病毒载体的免疫原性组合物初免,该第一和第二病毒载体包含以下多核苷酸:1) priming with an immunogenic composition comprising a first and a second viral vector, the first and the second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及a) a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 139 and 145, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。以及b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 142 and 148, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. And
2)用包含第一和第二病毒载体的免疫原性组合物加强,该第一和第二病毒载体包含以下多核苷酸:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:131和135,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 131 and 135, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:133和137,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 133 and 137, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一和第二病毒载体的免疫原性组合物初免,该第一和第二病毒载体包含以下多核苷酸:1) priming with an immunogenic composition comprising a first and a second viral vector, the first and the second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及a) a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 140 and 146, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。以及b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 143 and 149, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. And
2)用包含第一和第二病毒载体的免疫原性组合物加强,该第一和第二病毒载体包含以下多核苷酸:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 150 and 152, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQ ID NO:155和158,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在该方法的各种实施方案中,初免载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒),并且加强载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, respectively. In various embodiments of the method, the priming vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus), and the boosting vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一和第二病毒载体的免疫原性组合物初免,该第一和第二病毒载体包含以下多核苷酸:1) priming with an immunogenic composition comprising a first and a second viral vector, the first and the second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及a) a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQ ID NO:155和158,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, respectively; and
2)用包含第一和第二病毒载体的免疫原性组合物加强,该第一和第二病毒载体包含以下多核苷酸:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 140 and 146, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在该方法的各种实施方案中,初免载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒),并且加强载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 143 and 149, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. In various embodiments of the method, the priming vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus), and the boosting vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一和第二病毒载体的免疫原性组合物初免,该第一和第二病毒载体包含以下多核苷酸:1) priming with an immunogenic composition comprising a first and a second viral vector, the first and the second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及a) a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:155和158,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。以及b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively. And
2)用包含第一和第二病毒载体的免疫原性组合物加强,该第一和第二病毒载体包含以下多核苷酸:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:151和153,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 151 and 153, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:156和159,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 156 and 159, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一和第二病毒载体的免疫原性组合物初免,该第一和第二病毒载体包含以下多核苷酸:1) priming with an immunogenic composition comprising a first and a second viral vector, the first and the second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及a) a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:155和158,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。以及b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively. And
2)用包含第一和第二病毒载体的免疫原性组合物加强,该第一和第二病毒载体包含以下多核苷酸:2) boosting with an immunogenic composition comprising a first and a second viral vector comprising the following polynucleotides:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:139和145,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 139 and 145, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; and
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在该方法的各种实施方案中,初免载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒),并且加强载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)。在该方法的各种实施方案中,初免载体和加强载体是复制减毒型或有复制能力的。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 142 and 148, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. In various embodiments of the method, the priming vector is a Cali mammalian arenavirus (also known as a Pichinde mammalian arenavirus or a Pichinde arenavirus), and the boosting vector is a lymphocytic choriomeningitis mammalian arenavirus (LCMV). In various embodiments of the method, the priming vector and the boosting vector are replication attenuated or replication competent.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一病毒载体的免疫原性组合物初免,该第一病毒载体包含以下第一和第二多核苷酸:包含SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及1) priming with an immunogenic composition comprising a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively; and
2)用包含第二病毒载体的免疫原性组合物加强,该第二病毒载体包含以下第一和第二多核苷酸:包含SEQ ID NO:162和163,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。2) boosting with an immunogenic composition comprising a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 162 and 163, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively.
在一些实施方案中,初免-加强方案包括:In some embodiments, the prime-boost regimen comprises:
1)用包含第一病毒载体的免疫原性组合物初免,该第一病毒载体包含以下第一和第二多核苷酸:包含SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;以及1) priming with an immunogenic composition comprising a first viral vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively; and
2)用包含第二病毒载体的免疫原性组合物加强,该第二病毒载体包含以下第一和第二多核苷酸:包含SEQ ID NO:166和167,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。2) boosting with an immunogenic composition comprising a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 166 and 167, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 210, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 210; and a second viral vector comprising a second polynucleotide comprising SEQ ID NO: 211, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 211. NO:211 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the prime-boost regimen comprises: priming and boosting with an immunogenic composition comprising a first viral vector comprising the following first polynucleotide: a polynucleotide comprising SEQ ID NO: 212, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 212; and a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO: 213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 213. NO:213 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 214, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 214; and a second viral vector comprising a second polynucleotide comprising SEQ ID NO: 215, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 215. NO:215 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 216, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 216; and a second viral vector comprising a second polynucleotide comprising SEQ ID NO: 217, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 217. NO:217 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218; and a second viral vector comprising a second polynucleotide comprising SEQ ID NO: 219, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 219. NO:219 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to polynucleotides.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在该方法的各种实施方案中,初免组合物包含一种或多种ChAd载体并且加强组合物包含一种或多种自扩增mRNA分子,例如,类似于NCT04776317和WO 2021/236854中关于SARS-CoV2疫苗、WO 2021/203104中关于感染性疾病疫苗和WO 2020/243719中描述的初免-加强方案。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218; and a second viral vector comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotide. In various embodiments of the method, the priming composition comprises one or more ChAd vectors and the boosting composition comprises one or more self-amplifying mRNA molecules, for example, similar to the priming-boosting scheme described in NCT04776317 and WO 2021/236854 for SARS-CoV2 vaccines, WO 2021/203104 for infectious disease vaccines, and WO 2020/243719.
在一些实施方案中,初免-加强方案包括:用包含第一病毒载体和第二病毒载体的免疫原性组合物初免和加强,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在该方法的各种实施方案中,初免组合物包含一种或多种ChAd载体并且加强组合物包含一种或多种自扩增mRNA分子,例如,类似于NCT04776317和WO 2021/236854中关于SARS-CoV2疫苗、WO 2021/203104中关于感染性疾病疫苗和WO 2020/243719中描述的初免-加强方案。In some embodiments, the prime-boost regimen comprises priming and boosting with an immunogenic composition comprising a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 225, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 225; and a second viral vector comprising a second polynucleotide comprising SEQ ID NO: 226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226. NO:226 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical polynucleotide. In various embodiments of the method, the priming composition comprises one or more ChAd vectors and the boosting composition comprises one or more self-amplifying mRNA molecules, for example, similar to the priming-boosting scheme described in NCT04776317 and WO 2021/236854 for SARS-CoV2 vaccines, WO 2021/203104 for infectious disease vaccines, and WO 2020/243719.
在一些实施方案中,在任选地与本文所述的一种或多种附加治疗剂一起一次或多次施用如本文所述的一种或多种融合多肽或编码如本文所述的一种或多种融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽的一种或多种载体之后,受试者在没有抗逆转录病毒治疗(ART)的情况下至少3个月、至少6个月、至少1年、至少2年、至少3年或更长时间未表现出HIV或AIDS的症状。在一些实施方案中,在任选地与本文所述的一种或多种附加治疗剂一起一次或多次施用如本文所述的一种或多种融合多肽或编码如本文所述的一种或多种融合多肽的一种或多种多核苷酸或表达如本文所述的一种或多种融合多肽的一种或多种载体之后,受试者在没有抗逆转录病毒治疗(ART)的情况下至少3个月、至少6个月、至少1年、至少2年、至少3年或更长时间具有小于500(例如小于400、小于300、小于200、小于100、小于50)的病毒载量拷贝/ml血液。In some embodiments, after one or more administrations of one or more fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides as described herein, optionally with one or more additional therapeutic agents as described herein, the subject does not show symptoms of HIV or AIDS for at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, or longer without antiretroviral therapy (ART). In some embodiments, after one or more administrations of one or more fusion polypeptides as described herein, or one or more polynucleotides encoding one or more fusion polypeptides as described herein, or one or more vectors expressing one or more fusion polypeptides as described herein, optionally with one or more additional therapeutic agents as described herein, the subject has a viral load of less than 500 (e.g., less than 400, less than 300, less than 200, less than 100, less than 50) copies/ml of blood for at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, or longer without antiretroviral therapy (ART).
7.组合疗法7. Combination therapy
在某些实施方案中,提供了用于治疗或预防患有HIV感染或具有该感染风险的人中的该感染的方法,其包括与治疗有效量的一种或多种(例如,一种、两种、三种、一种或两种或者一种至三种)附加治疗剂组合向该人施用治疗有效量的如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体。在一个实施方案中,提供了一种用于治疗患有HIV感染或处于HIV感染风险的人的HIV感染的方法,该方法包括与治疗有效量的一种或多种(例如,一种、两种、三种、一种或两种或一种至三种)附加治疗剂组合向人施用治疗有效量的本文所公开的化合物或其药学上可接受的盐。In certain embodiments, methods for treating or preventing HIV infection in a person suffering from or at risk of HIV infection are provided, comprising administering to the person a therapeutically effective amount of one or more fusion polypeptides as disclosed herein, or a polynucleotide encoding such a fusion polypeptide, or a vector expressing such a fusion polypeptide, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating HIV infection in a person suffering from or at risk of HIV infection is provided, comprising administering to the person a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
在各种实施方案中,与一种或多种(例如,一种、两种、三种、四种、一种或两种或者一种至三种或者一种至四种)附加治疗剂组合施用如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体,以及药学上可接受的载体、稀释剂或赋形剂。In various embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides, and a pharmaceutically acceptable carrier, diluent, or excipient are administered in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
在某些实施方案中,提供了用于治疗HIV感染的方法,其包括与治疗有效量的适于治疗HIV感染的一种或多种(例如,一种、两种、三种、一种或两种或者一种至三种)附加治疗剂组合,向对其有需要的患者施用治疗有效量的本文所公开的化合物或其药学上可接受的盐。In certain embodiments, a method for treating HIV infection is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents suitable for treating HIV infection.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体与一种、两种、三种、四种或更多种附加治疗剂和药学上可接受的载剂一起共同配制。在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体或其药学上可接受的盐与两种附加治疗剂组合。视情况而定,一种、两种、三种、四种或更多种附加治疗剂可以是选自相同类别的治疗剂的不同治疗剂,并且/或者它们可选自不同类别的治疗剂。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides are co-formulated with one, two, three, four or more additional therapeutic agents and a pharmaceutically acceptable carrier. In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. As appropriate, one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.
HIV组合疗法的施用Administration of HIV combination therapy
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体与一种或多种附加治疗剂一起施用。本文所公开的化合物与一种或多种附加治疗剂的共同施用通常是指同时或并行或顺序施用本文所公开的化合物和一种或多种附加治疗剂,使得治疗有效量的本文所公开的化合物和一种或多种附加治疗剂均存在于患者体内。当顺序施用时,该组合可以两次或更多次施用的方式施用。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides are administered together with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous, parallel, or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more administrations.
共同施用包括在施用单位剂型的一种或多种附加治疗剂之前或之后施用单位剂型的单位剂量的如本文所公开的一种或多种融合多肽、或编码包含此类多核苷酸的脂质体复合物(例如,LNP)的多核苷酸、或表达此类融合多肽的载体。例如,可在施用一种或多种附加治疗剂后数秒、数分钟或数小时内施用如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体。在一些实施方案中,首先施用单位剂量的如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体,然后在数秒或数分钟内施用单位剂量的一种或多种附加治疗剂。另选地,首先施用单位剂量的一种或多种附加治疗剂,然后在数秒或数分钟内施用单位剂量的如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体。在其他实施方案中,首先施用单位剂量的如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体,然后在数小时(例如,1-12小时)后施用单位剂量的一种或多种附加治疗剂。在其他实施方案中,首先施用单位剂量的一种或多种附加治疗剂,然后在数小时(例如,1-12小时)后施用单位剂量的如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体。在一些实施方案中,一种或多种附加治疗剂不共同施用,而是作为组合治疗方案的一部分单独施用。在此类方法中,单位剂量的如本文所公开的一种或多种融合多肽、或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体,以及一种或多种附加治疗剂可以以更长的时间间隔(例如,1、2、3、4、5、6、7、8、9、10天或更长时间间隔)施用。Co-administration includes administering a unit dosage of one or more fusion polypeptides as disclosed herein, or a polynucleotide encoding a liposome complex (e.g., LNP) comprising such a polynucleotide, or a vector expressing such a fusion polypeptide, before or after administering a unit dosage of one or more additional therapeutic agents. For example, one or more fusion polypeptides as disclosed herein, or a polynucleotide encoding such a fusion polypeptide, a liposome complex (e.g., LNP) comprising such a polynucleotide, or a vector expressing such a fusion polypeptide may be administered within seconds, minutes, or hours after administering one or more additional therapeutic agents. In some embodiments, a unit dose of one or more fusion polypeptides as disclosed herein, or a polynucleotide encoding such a fusion polypeptide, or a vector expressing such a fusion polypeptide is administered first, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of one or more fusion polypeptides as disclosed herein, or a polynucleotide encoding such a fusion polypeptide, or a vector expressing such a fusion polypeptide is administered within seconds or minutes. In other embodiments, a unit dose of one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides is first administered, followed by a unit dose of one or more additional therapeutic agents after a few hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is first administered, followed by a unit dose of one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides after a few hours (e.g., 1-12 hours). In some embodiments, one or more additional therapeutic agents are not co-administered, but are administered separately as part of a combined treatment regimen. In such methods, a unit dose of one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides, and one or more additional therapeutic agents can be administered at longer time intervals (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or longer time intervals).
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体与一种或多种附加治疗剂在单一剂型中组合或共同施用,用于向患者同时或并行施用,例如作为用于静脉内、肌内、皮内、结内或皮下施用的水性制剂。在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸或表达此类融合多肽的载体与一种或多种附加治疗剂在单一剂型中组合用于向患者同时或并行施用,例如作为直肠内栓剂。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides, are combined or co-administered with one or more additional therapeutic agents in a single dosage form for simultaneous or concurrent administration to a patient, e.g., as an aqueous formulation for intravenous, intramuscular, intradermal, intranodal, or subcutaneous administration. In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, or vectors expressing such fusion polypeptides, are combined with one or more additional therapeutic agents in a single dosage form for simultaneous or concurrent administration to a patient, e.g., as a rectal suppository.
在某些实施方案中,可以将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与一种或多种用于治疗HIV的其他化合物共同配制或共同施用。在某些实施方案中,共同配制或共同施用可包含用于治疗HIV的另一种活性剂,诸如抗HIV抗体(例如,HIV bNAb)、双特异性抗体和“抗体样”治疗蛋白、toll样受体(TLR)激动剂(例如,TLR7、TLR8和/或TLR9的激动剂)、免疫检查点抑制剂、HIV蛋白酶抑制剂、逆转录酶的HIV非核苷或非核苷酸抑制剂、逆转录酶的HIV核苷或核苷酸抑制剂、HIV整合酶抑制剂、HIV衣壳抑制剂、核衣壳蛋白7(NCp7)抑制剂、HIV Tat或Rev抑制剂、Tat-TAR-P-TEFb的抑制剂、HIV非催化位点(或变构)整合酶抑制剂、HIV进入(融合)抑制剂、HIV成熟抑制剂、潜伏期逆转剂、基于免疫的疗法、PI3K抑制剂、gp41抑制剂、CXCR4抑制剂、gp120抑制剂、CCR5抑制剂、Nef抑制剂、潜伏期逆转剂、HIV疫苗、细胞因子、免疫检查点抑制剂、FLT3激动剂、募集T细胞和NK细胞的双特异性抗体、靶向HIV抗原的嵌合T细胞受体、药代动力学增强剂和用于治疗HIV的其他药物以及它们的组合。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides may be co-formulated or co-administered with one or more other compounds for treating HIV. In certain embodiments, co-formulation or co-administration may include another active agent for treating HIV, such as anti-HIV antibodies (e.g., HIV bNAbs), bispecific antibodies and "antibody-like" therapeutic proteins, toll-like receptor (TLR) agonists (e.g., agonists of TLR7, TLR8, and/or TLR9), immune checkpoint inhibitors, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, immune-based therapies, PI3K inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 agonists, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers and other drugs for the treatment of HIV and their combinations.
在一些实施方案中,一种或多种附加治疗剂选自度鲁特韦、卡博特韦、伊斯拉曲韦、地瑞拉韦、比卡格韦、依斯沙韦林、利匹韦林和来那卡帕韦,以及它们的组合。In some embodiments, the one or more additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bicagavir, esxavirine, rilpivirine, and lenacapasvir, and combinations thereof.
在某些实施方案中,视情况而定,一种或多种活性剂适于每日一次给药、每周一次给药、每月一次给药、每3个月一次给药、每四个月一次给药、两年一次给药或每年一次给药。In certain embodiments, one or more active agents are suitable for daily administration, weekly administration, monthly administration, once every 3 months, once every 4 months, once every two years, or once a year, as appropriate.
在一些实施方案中,如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体以及一种或多种附加治疗剂可以是抗HIV剂。在一些情况下,附加治疗剂可以是HIV蛋白酶抑制剂、HIV逆转录酶的非核苷或非核苷酸抑制剂、HIV逆转录酶的核苷或核苷酸抑制剂、HIV整合酶抑制剂、HIV非催化位点(或变构)整合酶抑制剂、HIV进入抑制剂、HIV成熟抑制剂、HIV衣壳抑制剂、核衣壳蛋白7(NCp7)抑制剂、HIV Tat或Rev抑制剂、Tat-TAR-P-TEFb的抑制剂、免疫调节剂、免疫治疗剂、抗体-药物缀合物、基因修饰剂、基因编辑物(诸如CRISPR/Cas9、锌指核酸酶、归巢核酸酶、合成核酸酶、TALEN)、细胞疗法(诸如嵌合抗原受体T细胞CAR-T和工程化T细胞受体TCR-T、自体T细胞疗法、工程化B细胞、NK细胞)、潜伏期逆转剂、基于免疫的疗法、磷脂酰肌醇3-激酶(PI3K)抑制剂、HIV抗体、双特异性抗体和“抗体样”治疗蛋白、HIV p17基质蛋白抑制剂、IL-13拮抗剂、肽基脯氨酰顺反异构酶A调节剂、蛋白质二硫键异构酶抑制剂、补体C5a受体拮抗剂、DNA甲基转移酶抑制剂、脂肪酸合酶抑制剂、HIV vif基因调节剂、Vif二聚化拮抗剂、HIV-1病毒感染因子抑制剂、HIV-1Nef调节剂、TNFα配体抑制剂、HIV Nef抑制剂、Hck酪氨酸激酶调节剂、混合谱系激酶-3(MLK-3)抑制剂、HIV-1剪接抑制剂、整合素拮抗剂、核蛋白抑制剂、剪接因子调节剂、含COMM结构域蛋白1调节剂、HIV核糖核酸酶H抑制剂、干扰素(IFN)拮抗剂、防御素调节剂、CD3拮抗剂、CDK-4抑制剂、CDK-6抑制剂、CDK-9抑制剂、细胞色素P450 3抑制剂、CXCR4调节剂、树突状ICAM-3抓取非整合素1抑制剂、HIV GAG蛋白抑制剂、HIV POL蛋白抑制剂、补体因子H调节剂、泛素连接酶抑制剂、脱氧胞苷激酶抑制剂、细胞周期素依赖性激酶抑制剂、HPK1(MAP4K1)抑制剂、前蛋白转化酶PC9刺激剂、ATP依赖性RNA解旋酶DDX3X抑制剂、逆转录酶引发复合物抑制剂、G6PD和NADH氧化酶抑制剂、mTOR复合物1抑制剂、mTOR复合物2抑制剂、P-糖蛋白调节剂、RNA聚合酶调节剂、TAT蛋白抑制剂、脯氨酰内肽酶抑制剂、磷脂酶A2抑制剂、药代动力学增强剂、HIV基因疗法、HIV疫苗、抗HIV肽以及它们的组合。In some embodiments, one or more fusion polypeptides or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides as disclosed herein and one or more additional therapeutic agents can be anti-HIV agents. In some cases, the additional therapeutic agent can be an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitor, an inhibitor of Tat-TAR-P-TEFb, an immunomodulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, a gene editor (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), a cell therapy (such as chimeric antigen receptor T cell CAR-T and engineered T cell receptor TCR-T, autologous T cell therapy, engineered B cells, NK cells), a latency reversal agent, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, interferon (IFN) antagonists, defensin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides and combinations thereof.
在一些实施方案中,附加治疗剂选自用于HIV的组合药物、用于治疗HIV的其他药物、HIV蛋白酶抑制剂、HIV逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或变构)整合酶抑制剂、HIV进入(融合)抑制剂、HIV成熟抑制剂、潜伏期逆转剂、衣壳抑制剂、基于免疫的疗法、PI3K抑制剂、HIV抗体和双特异性抗体和“抗体样”治疗蛋白以及它们的组合。In some embodiments, the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.
组合药物Combination drugs
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV组合药物组合或共同施用。可以与本公开的药剂一起使用的组合药物的示例包括(依法韦仑、富马酸替诺福韦二吡呋酯和恩曲他滨);(;利匹韦林、富马酸替诺福韦二吡呋酯和恩曲他滨);(埃替拉韦、可比司他、富马酸替诺福韦二吡呋酯和恩曲他滨);(富马酸替诺福韦二吡呋酯和恩曲他滨;TDF+FTC);(替诺福韦艾拉酚胺和恩曲他滨);(替诺福韦艾拉酚胺、恩曲他滨和利匹韦林);(替诺福韦艾拉酚胺、恩曲他滨、可比司他和埃替拉韦);地瑞拉韦、半富马酸替诺福韦艾拉酚胺、恩曲他滨和可比司他;依法韦仑、拉米夫定和富马酸替诺福韦二吡呋酯;拉米夫定和富马酸替诺福韦二吡呋酯;替诺福韦和拉米夫定;替诺福韦艾拉酚胺和恩曲他滨;半富马酸替诺福韦艾拉酚胺和恩曲他滨;半富马酸替诺福韦艾拉酚胺、恩曲他滨和利匹韦林;半富马酸替诺福韦艾拉酚胺、恩曲他滨、可比司他和埃替拉韦;替诺福韦类似物;(齐多夫定和拉米夫定;AZT+3TC);(;硫酸阿巴卡韦和拉米夫定;ABC+3TC);(;洛匹那韦和利托那韦);(度鲁特韦、阿巴卡韦和拉米夫定);(比卡格韦+恩曲他滨+替诺福韦艾拉酚胺)、(度鲁特韦+拉米夫定)、(硫酸阿巴卡韦、齐多夫定和拉米夫定;ABC+AZT+3TC);阿扎那韦和可比司他;硫酸阿扎那韦和可比司他;硫酸阿扎那韦和利托那韦;地瑞拉韦和可比司他;度鲁特韦和利匹韦林;度鲁特韦和盐酸利匹韦林;度鲁特韦、硫酸阿巴卡韦和拉米夫定;拉米夫定、奈韦拉平和齐多夫定;雷特格韦和拉米夫定;多拉韦林、拉米夫定和富马酸替诺福韦二吡呋酯;多拉韦林、拉米夫定和替诺福韦二吡呋酯;度鲁特韦+拉米夫定、拉米夫定+阿巴卡韦+齐多夫定、拉米夫定+阿巴卡韦、拉米夫定+富马酸替诺福韦二吡呋酯、拉米夫定+齐多夫定+奈韦拉平、洛匹那韦+利托那韦、洛匹那韦+利托那韦+阿巴卡韦+拉米夫定、洛匹那韦+利托那韦+齐多夫定+拉米夫定、替诺福韦+拉米夫定,和富马酸替诺福韦二吡呋酯+恩曲他滨+盐酸利匹韦林、洛匹那韦、利托那韦、齐多夫定、洛匹那韦+利托那韦+阿巴卡韦+拉米夫定、拉米夫定、卡博特韦+利匹韦林、3-BNC117+艾博卫泰、尔必达(依斯沙韦林,VM-1500)和VM-1500A、来那卡帕韦+伊斯拉曲韦(口服、注射)和双靶向HIV-1反转录酶/核衣壳蛋白7抑制剂。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV combination drugs. Examples of combination drugs that can be used with the agents of the present disclosure include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine and cobicistat; efavirenz, lamivudine and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat and elvitegravir; tenofovir analogs; (zidovudine and lamivudine; AZT+3TC); ( ; abacavir sulfate and lamivudine; ABC+3TC); ( ; lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (Bicagevir + Emtricitabine + Tenofovir Alafenamide), (Dolutegravir + Lamivudine), (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; doravirine, lamivudine and tenofovir disoproxil fumarate; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, raltegravir and lamivudine Tenofovir + lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + aboveta, Elpida (essavirin, VM-1500) and VM-1500A, lenacapvir + islatravir (oral, injection) and dual-targeted HIV-1 reverse transcriptase/nucleocapsid protein 7 inhibitors.
可与如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体组合的用于治疗HIV的其他药物的示例包括但不限于:曲霉毒素(aspernigrin)C、醋孟南、阿拉泊韦、BanLec、去铁酮、Gamimune、米特法林(metenkefalin)、纳曲酮、普拉汀(Prolastin)、REP 9、RPI-MN、VSSP、H1viral、SB-728-T、1,5-二咖啡酰奎尼酸、rHIV7-shl-TAR-CCR5RZ、AAV-eCD4-Ig基因疗法、MazF基因疗法、BlockAide、贝韦立马衍生物、ABBV-382、ABX-464、AG-1105、APH-0812、APH0202、苔藓虫素-1、苔藓虫素类似物、BG-HIV、BIT-225、BRII-732、BRII-778、CYT-107、CS-TATI-1、氟-β-D-阿拉伯糖核酸(FANA)修饰的反义寡核苷酸、FX-101、格瑞弗森、GSK-3739937、GSK-3739937(长效)、HGTV-43、HPH-116、HS-10234、羟氯喹、IMB-10035、IMO-3100、IND-02、JL-18008、LADAVRU、MK-1376、MK-2048、MK-4250、MK-8507、MK-8558、MK-8591、伊斯拉曲韦、NOV-205、OB-002H、ODE-Bn-TFV、PA-1050040(PA-040)、PC-707、PGN-007、QF-036、S-648414、SCY-635、SB-9200、SCB-719、TR-452、TEV-90110、TEV-90112、TEV-90111、TEV-90113、RN-18、DIACC-1010、Fasnall、Immuglo、2-CLIPS肽、HRF-4467、凝血栓蛋白类似物、TBL-1004HI、VG-1177、xl-081、AVI-CO-004、rfhSP-D、[18F]-MC-225、URMC-099-C、RES-529、Verdinexor、IMC-M113V、IML-106、抗病毒素fc缀合物(AVC)、WP-1096、WP-1097、Gammora、ISR-CO48、ISR-48、ISR-49、MK-8527、大麻素类、ENOB-HV-32、HiviCide-I、T-1144、VIR-576、尼帕莫韦(nipamovir)、Covimro和ABBV-1882。Examples of other drugs for treating HIV that can be combined with one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides include, but are not limited to, aspernigerin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9. RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimab derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin analogs, BG-HIV, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro- β-D-arabinose nucleic acid (FANA) modified antisense oligonucleotides, FX-101, Grefsen, GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, MK-8591, Islatravir, NOV-205, OB-002H, ODE-Bn-TF V, PA-1050040 (PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analog, TBL-1004HI, VG-1177, xl-081, AVI-CO-0 04, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral Fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, nipamovir, Covimro and ABBV-1882.
HIV蛋白酶抑制剂HIV protease inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV蛋白酶抑制剂组合或共同施用。可共同施用或组合的HIV蛋白酶抑制剂的示例包括安普那韦、阿扎那韦、贝卡那韦(brecanavir)、地瑞拉韦、膦沙那韦、膦沙那韦钙、茚地那韦、硫酸茚地那韦、洛匹那韦、奈非那韦、甲磺酸奈非那韦、利托那韦、沙奎那韦、甲磺酸沙奎那韦、替拉那韦、ASC-09+利托那韦、AEBL-2、DG-17、GS-1156、TMB-657(PPL-100)、T-169、BL-008、MK-8122、TMB-607、GRL-02031和TMC-310911。HIV蛋白酶抑制剂的附加示例描述于例如,美国专利号10,294,234和美国专利公布号US2020030327和US2019210978中。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV protease inhibitors. Examples of HIV protease inhibitors that may be co-administered or combined include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09+ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911. Additional examples of HIV protease inhibitors are described in, for example, U.S. Pat. No. 10,294,234 and U.S. Patent Publication Nos. US2020030327 and US2019210978.
HIV Gag蛋白抑制剂HIV Gag protein inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV Gag蛋白抑制剂组合或共同施用。可组合或共同施用的HIV Gag蛋白抑制剂的示例包括但不限于HRF-10071。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV Gag protein inhibitors. Examples of HIV Gag protein inhibitors that can be combined or co-administered include, but are not limited to, HRF-10071.
HIV核糖核酸酶H抑制剂HIV RNase H Inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV核糖核酸酶H抑制剂组合或共同施用。可组合或共同施用的HIV核糖核酸酶H抑制剂的示例包括但不限于NSC-727447。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with an HIV RNase H inhibitor. Examples of HIV RNase H inhibitors that can be combined or co-administered include, but are not limited to, NSC-727447.
HIV Nef抑制剂HIV Nef inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV Nef抑制剂组合或共同施用。可组合或共同施用的HIV Nef抑制剂的示例包括但不限于FP-1。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV Nef inhibitors. Examples of HIV Nef inhibitors that can be combined or co-administered include, but are not limited to, FP-1.
HIV逆转录酶抑制剂HIV reverse transcriptase inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与非核苷或非核苷酸抑制剂组合或共同施用。可组合或共同施用的逆转录酶的HIV非核苷或非核苷酸抑制剂的示例包括达匹韦林、地拉韦定、甲磺酸地拉韦定、多拉韦林、依法韦仑、依曲韦林、香菇多糖、奈韦拉平、利匹韦林、ACC-007、ACC-008、AIC-292、F-18、KM-023、PC-1005、M1-TFV、M2-TFV、VM-1500A-LAI、PF-3450074、依斯沙韦林(缓释口服,HIV感染)、多拉韦林+伊斯拉曲韦(固定剂量组合/口服片剂制剂,HIV-1感染)、依斯沙韦林(长效可注射纳米混悬剂,HIV感染)和依斯沙韦林(VM-1500)。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a non-nucleoside or non-nucleotide inhibitor. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase that can be combined or co-administered include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, essavirine (extended release oral, HIV infection), doravirine + islatravir (fixed dose combination/oral tablet formulation, HIV-1 infection), essavirine (long-acting injectable nanosuspension, HIV infection) and essavirine (VM-1500).
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV核苷或核苷酸抑制剂组合或共同施用。可组合或共同施用的逆转录酶的HIV核苷或核苷酸抑制剂的示例包括阿德福韦、阿德福韦双特戊酯、阿兹夫定、恩曲他滨、替诺福韦、替诺福韦艾拉酚胺、富马酸替诺福韦艾拉酚胺、半富马酸替诺福韦艾拉酚胺、替诺福韦二吡呋酯、富马酸替诺福韦二吡呋酯、半富马酸替诺福韦二吡呋酯、和VIDEX(地达诺新,ddl)、阿巴卡韦、硫酸阿巴卡韦、阿洛夫定、阿立他滨、西那夫定、地达诺新、艾夫他滨、非替那韦、磷夫定替酯、CMX-157、达匹韦林、多拉韦林、依曲韦林、OCR-5753、乳清酸替诺福韦二吡呋酯、福齐夫定替酯、拉米夫定、叠氮膦、司他夫定、扎西他滨、齐多夫定、罗瓦福韦-依他拉芬酰胺(GS-9131)、GS-9148、MK-8504、MK-8591、MK-858、VM-2500和KP-1461。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV nucleoside or nucleotide inhibitors. Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase that can be combined or co-administered include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, aritibactam, sinavudine, didanosine, efavirenz, fostavirin, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fostavirin, lamivudine, phosphinothricin, stavudine, zalcitabine, zidovudine, rovafovir-etafoetide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461.
HIV整合酶抑制剂HIV integrase inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV整合酶抑制剂组合或共同施用。可组合或共同施用的HIV整合酶抑制剂的示例包括但不限于艾维雷韦、艾维雷韦(延长释放微胶囊)、姜黄素、姜黄素的衍生物、菊苣酸、菊苣酸的衍生物、3,5-二咖啡酰奎尼酸、3,5-二咖啡酰奎尼酸的衍生物、金精三羧酸、金精三羧酸的衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯的衍生物、酪氨酸激酶抑制剂、酪氨酸激酶抑制剂的衍生物、槲皮素、槲皮素的衍生物、雷特格韦、聚乙二醇化雷特格韦、度鲁特韦、JTK-351、比卡格韦、AVX-15567、卡博特韦(长效注射型)、二酮喹啉-4-1衍生物、整合酶-LEDGF抑制剂、莱金(ledgins)、M-522、M-532、MK-0536、NSC-310217、NSC-371056、NSC-48240、NSC-642710、NSC-699171、NSC-699172、NSC-699173、NSC-699174、二苯乙烯二磺酸、T169、STP-0404、VM-3500、XVIR-110、ACC-017和卡博特韦。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV integrase inhibitors. Examples of HIV integrase inhibitors that can be combined or co-administered include, but are not limited to, elvitegravir, elvitegravir (extended release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrosine kinase inhibitors, derivatives of tyrosine kinase inhibitors, quercetin, derivatives of quercetin, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bicagvir, AVX-15567 , cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, distilbenesulphonic acid, T169, STP-0404, VM-3500, XVIR-110, ACC-017 and cabotegravir.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV非催化位点或变构整合酶抑制剂(NCINI)组合或共同施用。可组合或共同施用的HIV非催化位点或变构整合酶抑制剂(NCINI)的示例包括CX-05045、CX-05168和CX-14442。HIV衣壳抑制剂的其他示例包括但不限于以下专利中所述的那些:美国专利公布号US2014221356和US2016016973中。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV non-catalytic sites or allosteric integrase inhibitors (NCINIs). Examples of HIV non-catalytic sites or allosteric integrase inhibitors (NCINIs) that can be combined or co-administered include CX-05045, CX-05168, and CX-14442. Other examples of HIV capsid inhibitors include, but are not limited to, those described in the following patents: U.S. Patent Publication Nos. US2014221356 and US2016016973.
HIV病毒感染性因子抑制剂HIV virus infectious factor inhibitor
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV病毒感染性因子抑制剂组合或共同施用。HIV病毒感染性因子抑制剂的示例包括但不限于2-氨基-N-(2-甲氧基苯基)-6-((4-硝基苯基)硫基)苯甲酰胺衍生物和Irino-L。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV viral infectivity factor inhibitors. Examples of HIV viral infectivity factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.
HIV进入抑制剂HIV entry inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV进入抑制剂组合或共同施用。可组合或共同施用的HIV进入(融合)抑制剂的示例包括但不限于AAR-501、LBT-5001、赛尼克韦罗、CCR5抑制剂、gp41抑制剂、CD4附着抑制剂、gp120抑制剂、gp160抑制剂和CXCR4抑制剂。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV entry inhibitors. Examples of HIV entry (fusion) inhibitors that can be combined or co-administered include, but are not limited to, AAR-501, LBT-5001, seneviroxetine, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与CCR5抑制剂组合或共同施用。可组合或共同施用的CCR5抑制剂的示例包括但不限于阿普韦罗、维克韦罗、马拉韦罗、马拉韦罗(长效可注射纳米乳剂)、森尼韦罗、勒罗利单抗(PRO-140)、阿达他韦(RAP-101)、尼非韦罗(TD-0232)、抗GP120/CD4或CCR5双特异性抗体、B-07、MB-66、多肽C25P、TD-0680、赛拉韦罗和vMIP(Haimipu)。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a CCR5 inhibitor. Examples of CCR5 inhibitors that may be combined or co-administered include, but are not limited to, apuvirol, vicovirol, maraviroc, maraviroc (long-acting injectable nanoemulsion), sennevirol, lerolizumab (PRO-140), adatasvir (RAP-101), nifevirol (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, selavirol, and vMIP (Haimipu).
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与gp41抑制剂组合或共同施用。可组合或共同施用的gp41抑制剂的示例包括但不限于艾博卫泰、恩夫韦肽、格瑞弗森(gp41/gp120/gp160抑制剂)、BMS-986197、恩夫韦肽生物改良药、恩夫韦肽生物类似物、HIV-1融合抑制剂(P26-Bapc)、ITV-1、ITV-2、ITV-3、ITV-4、CPT-31、Cl3hmAb、lipuvirtide、PIE-12三聚体和西夫韦肽。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a gp41 inhibitor. Examples of gp41 inhibitors that may be combined or co-administered include, but are not limited to, Abuvirtide, Enfuvirtide, Grefsen (gp41/gp120/gp160 inhibitor), BMS-986197, Enfuvirtide bioimprovers, Enfuvirtide biosimilars, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and Sifuvirtide.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与CD4附接抑制剂组合或共同施用。可组合或共同施用的CD4附接抑制剂的示例包括依巴利珠单抗(ibalizumab)和CADA类似物。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a CD4 attachment inhibitor. Examples of CD4 attachment inhibitors that can be combined or co-administered include ibalizumab and CADA analogs.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与gp120抑制剂组合或共同施用。可组合或共同施用的gp120抑制剂的示例包括但不限于抗HIV杀微生物剂、Radha-108(receptol)3B3-PE38、BMS818251、BanLec、基于膨润土的纳米医药、福斯坦沙韦(fostemsavir)氨基丁三醇、IQP-0831、VVX-004和BMS-663068。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a gp120 inhibitor. Examples of gp120 inhibitors that can be combined or co-administered include, but are not limited to, anti-HIV microbicides, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与gp160抑制剂组合或共同施用。可组合或共同施用的gp160抑制剂的示例包括但不限于防已诺林碱。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a gp160 inhibitor. Examples of gp160 inhibitors that can be combined or co-administered include, but are not limited to, fangchinoline.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与CXCR4抑制剂组合或共同施用。可组合或共同施用的CXCR4抑制剂的示例包括普乐沙福、ALT-1188、N15肽和vMIP(Haimipu)。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a CXCR4 inhibitor. Examples of CXCR4 inhibitors that can be combined or co-administered include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).
成熟抑制剂Maturation inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV成熟抑制剂组合或共同施用。可组合或共同施用的HIV成熟抑制剂的示例包括BMS-955176、GSK-3640254和GSK-2838232。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV maturation inhibitors. Examples of HIV maturation inhibitors that can be combined or co-administered include BMS-955176, GSK-3640254, and GSK-2838232.
潜伏期逆转剂Latency reversal agents
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与潜伏期逆转剂(LRA)组合或共同施用。潜伏期逆转剂的示例包括但不限于toll样受体(TLR)激动剂(包括TLR7激动剂,例如GS-9620(维沙莫特)、TLR8激动剂例如GS-9688(赛尔甘托莫德)和TLR9激动剂例如来非莫特(MGN-1703))、组蛋白脱乙酰酶(HDAC)抑制剂、蛋白酶体抑制剂(诸如万珂)、蛋白激酶C(PKC)活化剂、Smyd2抑制剂、BET-溴结构域4(BRD4)抑制剂(诸如ZL-0580、阿帕贝隆)、离子霉素、IAP拮抗剂(细胞凋亡蛋白的抑制剂,诸如APG-1387、LBW-242)、SMAC模拟物(包括TL32711、LCL161、GDC-0917、HGS1029、AT-406、Debio-1143)、PMA、SAHA(辛二酸胺异羟肟酸或辛二酰、苯胺和异羟肟酸)、NIZ-985、IL-15调节抗体(包括IL-15、IL-15融合蛋白和IL-15受体激动剂)、JQ1、双硫仑、两性霉素B和泛素抑制剂(诸如拉格唑拉类似物、APH-0812、GSK-343)。PKC活化剂的示例包括但不限于吲哚内酰胺、prostratin、巨大戟醇B和DAG-内酯。TLR7激动剂的附加示例包括但不限于描述于美国专利号US2010/143301中的那些。TLR8激动剂的附加示例包括但不限于描述于美国专利号US2017/071944中的那些。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with latency reversal agents (LRAs). Examples of latency reversal agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists, such as GS-9620 (visamod), TLR8 agonists such as GS-9688 (sergantomod), and TLR9 agonists such as lefemod (MGN-1703)), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apaberon), ionomycin, IAP antagonists (apoptotic protein In some embodiments, the present invention relates to activators of PKC, such as succinate, succinate-1, succinate-2, succinate-3, succinate-4, succinate-5, succinate-6, succinate-7, succinate-8, succinate-9, succinate-10, succinate-11, succinate-12, succinate-13, succinate-14, succinate-15, succinate-16, succinate-17, succinate-18, succinate-19, succinate-20, succinate-21, succinate-22, succinate-23, succinate-24, succinate-30, succinate-31, succinate-32, succinate-33, succinate-34, succinate-35, succinate-36, succinate-37, succinate-38, succinate-39, succinate-40, succinate-50, succinate-60, succinate-71, succinate-80, succinate-19, succinate-21, succinate-31, succinate-32, succinate-33, succinate-15, succinate-160, succinate-170, succinate-23, succinate-39, succinate-40, succinate-50, succinate-18, succinate-23, succinate-35, succinate-19, succinate-23, succinate-36, succinate-19, succinate-23, succinate-37, succinate-19, succinate-2 Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Pat. No. US2017/071944.
组蛋白脱乙酰酶(HDAC)抑制剂Histone deacetylase (HDAC) inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与组蛋白脱乙酰酶1、组蛋白脱乙酰酶9(HDAC9、HD7、HD7b、HD9、HDAC、HDAC7、HDAC7B、HDAC9B、HDAC9FL、HDRP、MITR;基因ID:9734)的抑制剂组合或共同施用。HDAC抑制剂的示例包括但不限于艾贝司他(abexinostat)、ACY-241、AR-42、BEBT-908、贝利司他(belinostat)、CKD-581、CS-055(HBI-8000)、CT-101、CUDC-907(非美诺司他(fimepinostat))、恩替司他(entinostat)、吉维司他(givinostat)、莫西司他(mocetinostat)、帕比司他(panobinostat)、普瑞司他(pracinostat)、奎西诺司他(quisinostat)(JNJ-26481585)、瑞米司他、利可林司他(ricolinostat)、罗米地辛、SHP-141、TMB-ADC、丙戊酸(VAL-001)、伏立诺他、替莫司汀(tinostamustine)、瑞美司他(remetinostat)和恩替司他(entinostat)。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with an inhibitor of histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.
衣壳抑制剂Capsid inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与衣壳抑制剂组合或共同施用。可组合或共同施用的衣壳抑制剂的示例包括但不限于衣壳聚合抑制剂或衣壳破坏化合物、HIV核衣壳p7(NCp7)抑制剂(诸如偶氮二甲酰胺)、HIV p24衣壳蛋白抑制剂、来那卡帕韦(GS-6207)、GS-CA1、AVI-621、AVI-101、AVI-201、AVI-301和AVI-CAN1-15系列、PF-3450074、HIV-1衣壳抑制剂(HIV-1感染,山东大学)和(WO 2019/087016(GSK))中描述的化合物。衣壳抑制剂的其他示例包括但不限于以下专利中所述的那些:美国专利公布号US2018051005、US2016108030。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a capsid inhibitor. Examples of capsid inhibitors that may be combined or co-administered include, but are not limited to, capsid polymerization inhibitors or capsid destruction compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, lenacapvir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), and compounds described in (WO 2019/087016 (GSK)). Other examples of capsid inhibitors include, but are not limited to, those described in the following patents: U.S. Patent Publication Nos. US2018051005, US2016108030.
HIV长效治疗Long-term HIV treatment
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV长效治疗组合或共同施用。作为可组合或共同施用的长效方案的示例包括但不限于卡博特韦、利匹韦林、任何整合酶LA、VM-1500LAI、马拉韦罗(LAI)、替诺福韦植入物、伊斯拉曲韦植入物、多拉韦林、雷特格韦和长效度鲁特韦。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with HIV long-acting treatments. Examples of long-acting regimens that can be combined or co-administered include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500LAI, maraviroc (LAI), tenofovir implant, isclatravir implant, doravirine, raltegravir, and long-acting dulutegravir.
另外涵盖的HIV长效治疗包括本文所述的抗HIV广泛中和抗体(bNAb),其在Fc区中具有血清半衰期延长的氨基酸取代。已经描述了增加抗体的半衰期的Fc区氨基酸取代。例如,“YTE突变体”(在位置252处的甲硫氨酸至酪氨酸取代、在位置254处的丝氨酸至苏氨酸取代和在位置256处的苏氨酸至谷氨酸取代(EU编号))表现出相对于相同抗体的野生型版本的四倍增加的半衰期(Dall’Acqua等人,J Biol Chem,281:23514-24(2006);Robbie等人,Antimicrob Agents Chemotherap.,57(12):6147-6153(2013))。还参见例如美国专利号7,658,921。在另一个示例中,M428L和N434S(EU编号;“LS”)取代可增加bNAb的药代动力学半衰期。在其他实施方案中,本文所述的bNAb包含T250Q和M428L(EU编号)突变。在其他实施方案中,本文所述的bNAb包含H433K和N434F(EU编号)突变。可与如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体组合或共同施用的例示性血清半衰期延长的bNAb包括3BNC117-LS、10-1074-LS、10-1074-LS-J、GS-5423和GS-2872。HIV long-acting treatments covered in addition include anti-HIV broadly neutralizing antibodies (bNAbs) described herein, which have amino acid substitutions with extended serum half-life in the Fc region. Fc region amino acid substitutions that increase the half-life of antibodies have been described. For example, "YTE mutants" (methionine to tyrosine substitutions at position 252, serine to threonine substitutions at position 254, and threonine to glutamic acid substitutions at position 256 (EU numbering)) show a half-life (Dall'Acqua et al., J Biol Chem, 281: 23514-24 (2006) relative to the wild-type version of the same antibody; Robbie et al., Antimicrob Agents Chemotherap., 57 (12): 6147-6153 (2013)). See also, for example, U.S. Patent No. 7,658,921. In another example, M428L and N434S (EU numbering; "LS") substitutions can increase the pharmacokinetic half-life of bNAbs. In other embodiments, the bNAbs described herein comprise T250Q and M428L (EU numbering) mutations. In other embodiments, the bNAbs described herein comprise H433K and N434F (EU numbering) mutations. Exemplary bNAbs with extended serum half-life that can be combined or co-administered with one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides include 3BNC117-LS, 10-1074-LS, 10-1074-LS-J, GS-5423, and GS-2872.
细胞色素P450 3抑制剂Cytochrome P450 3 inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与细胞色素P450 3抑制剂组合或共同施用。细胞色素P450 3抑制剂的示例包括但不限于美国专利号7,939,553中描述的那些。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a cytochrome P450 3 inhibitor. Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Pat. No. 7,939,553.
RNA聚合酶抑制剂RNA polymerase inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与RNA聚合酶抑制剂组合或共同施用。RNA聚合酶调节剂的示例包括但不限于美国专利号10,065,958和8,008,264中描述的那些。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with RNA polymerase inhibitors. Examples of RNA polymerase modulators include, but are not limited to, those described in U.S. Pat. Nos. 10,065,958 and 8,008,264.
免疫检查点调节剂Immune checkpoint modulators
在各种实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂和/或与一种或多种刺激性免疫检查点蛋白或受体的一种或多种刺激剂、活化剂或激动剂组合或共同施用。抑制性免疫检查点的阻断或抑制可正向调节T细胞或NK细胞活化并防止感染细胞的免疫逃逸。刺激免疫检查点的活化或刺激可以增强免疫检查点抑制剂在感染性治疗中的效果。在各种实施方案中,免疫检查点蛋白或受体调节T细胞应答(例如Xu等人,J Exp Clin Cancer Res.(2018)37:110)。在各种实施方案中,免疫检查点蛋白或受体调节NK细胞应答(例如以下文献中所综述的:Davis等人,Semin Immunol.(2017)31:64–75;以及Chiossone等人,Nat RevImmunol.(2018)18(11):671-688)。In various embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulating immune checkpoints can enhance the effect of immune checkpoint inhibitors in infectious treatments. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37: 110). In various embodiments, the immune checkpoint protein or receptor modulates NK cell responses (e.g., as reviewed in Davis et al., Semin Immunol. (2017) 31:64–75; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).
免疫检查点蛋白或受体的示例包括但不限于CD27(NCBI基因ID:939)、CD70(NCBI基因ID:970)、CD40(NCBI基因ID:958)、CD40LG(NCBI基因ID:959)、CD47(NCBI基因ID:961)、CD48(SLAMF2;NCBI基因ID:962)、含跨膜和免疫球蛋白结构域蛋白2(TMIGD2、CD28H;NCBI基因ID:126259)、CD84(LY9B、SLAMF5;NCBI基因ID:8832)、CD96(NCBI基因ID:10225)、CD160(NCBI基因ID:11126)、MS4A1(CD20;NCBI基因ID:931)、CD244(SLAMF4;NCBI基因ID:51744);CD276(B7H3;NCBI基因ID:80381);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4;NCBI基因ID:79679);V-set免疫调节受体(VSIR、B7H5、VISTA;NCBI基因ID:64115);免疫球蛋白超家族成员11(IGSF11、VSIG3;NCBI基因ID:152404);自然杀伤细胞细胞毒性受体3配体1(NCR3LG1、B7H6;NCBI基因ID:374383);HERV-H LTR-相关2(HHLA2、B7H7;NCBI基因ID:11148);诱导型T细胞共刺激物(ICOS、CD278;NCBI基因ID:29851);诱导型T细胞共刺激物配体(ICOSLG、B7H2;NCBI基因ID:23308);TNF受体超家族成员4(TNFRSF4、OX40;NCBI基因ID:7293);TNF超家族成员4(TNFSF4、OX40L;NCBI基因ID:7292);TNFRSF8(CD30;NCBI基因ID:943)、TNFSF8(CD30L;NCBI基因ID:944);TNFRSF10A(CD261、DR4、TRAILR1;NCBI基因ID:8797)、TNFRSF9(CD137;NCBI基因ID:3604)、TNFSF9(CD137L;NCBI基因ID:8744);TNFRSF10B(CD262、DR5、TRAILR2;NCBI基因ID:8795)、TNFRSF10(TRAIL;NCBI基因ID:8743);TNFRSF14(HVEM、CD270;NCBI基因ID:8764)、TNFSF14(HVEML;NCBI基因ID:8740);CD272(B和T淋巴细胞相关(BTLA);NCBI基因ID:151888);TNFRSF17(BCMA、CD269;NCBI基因ID:608)、TNFSF13B(BAFF;NCBI基因ID:10673);TNFRSF18(GITR;NCBI基因ID:8784)、TNFSF18(GITRL;NCBI基因ID:8995);MHC I类多肽相关序列A(MICA;NCBI基因ID:100507436);MHC I类多肽相关序列B(MICB;NCBI基因ID:4277);CD274(CD274、PDL1、PD-L1;NCBI基因ID:29126);程序性细胞死亡1(PDCD1、PD1、PD-1;CD279;NCBI基因ID:5133);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152;NCBI基因ID:1493);CD80(B7-1;NCBI基因ID:941)、CD28(NCBI基因ID:940);nectin细胞粘附分子2(NECTIN2、CD112;NCBI基因ID:5819);CD226(DNAM-1;NCBI基因ID:10666);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155;NCBI基因ID:5817);含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R;NCBI基因ID:79037);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT;NCBI基因ID:201633);含T细胞免疫球蛋白和粘蛋白结构域4(TIMD4;TIM4;NCBI基因ID:91937);甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3;NCBI基因ID:84868);半乳凝集素9(LGALS9;NCBI基因ID:3965);淋巴细胞活化3(LAG3、CD223;NCBI基因ID:3902);信号传导淋巴细胞活化分子家族成员1(SLAMF1、SLAM、CD150;NCBI基因ID:6504);淋巴细胞抗原9(LY9、CD229、SLAMF3;NCBI基因ID:4063);SLAM家族成员6(SLAMF6、CD352;NCBI基因ID:114836);SLAM家族成员7(SLAMF7、CD319;NCBI基因ID:57823);UL16结合蛋白1(ULBP1;NCBI基因ID:80329);UL16结合蛋白2(ULBP2;NCBI基因ID:80328);UL16结合蛋白3(ULBP3;NCBI基因ID:79465);视黄酸早期转录物1E(RAET1E;ULBP4;NCBI基因ID:135250);视黄酸早期转录物1G(RAET1G;ULBP5;NCBI基因ID:353091);视黄酸早期转录物1L(RAET1L;ULBP6;NCBI基因ID:154064);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A;NCBI基因ID:3821);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314;NCBI基因ID:22914);杀伤细胞凝集素样受体C2(KLRC2、CD159c、NKG2C;NCBI基因ID:3822);杀伤细胞凝集素样受体C3(KLRC3、NKG2E;NCBI基因ID:3823);杀伤细胞凝集素样受体C4(KLRC4、NKG2F;NCBI基因ID:8302);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1;NCBI基因ID:3802);杀伤细胞免疫球蛋白样受体,两个Ig结构域和长胞质尾2(KIR2DL2;NCBI基因ID:3803);杀伤细胞免疫球蛋白样受体,两个Ig结构域和长胞质尾3(KIR2DL3;NCBI基因ID:3804);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1、KIR、CD158E1;NCBI基因ID:3811)(例如利瑞鲁单抗(IPH2102/BMS-986015)、IPH-4102);杀伤细胞凝集素样受体D1(KLRD1;NCBI基因ID:3824)和促分裂原活化蛋白激酶激酶激酶激酶1(MAP4K1,又名造血祖细胞激酶1(HPK1);NCBI基因ID:11184)。Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27 (NCBI gene ID: 939), CD70 (NCBI gene ID: 970), CD40 (NCBI gene ID: 958), CD40LG (NCBI gene ID: 959), CD47 (NCBI gene ID: 961), CD48 (SLAMF2; NCBI gene ID: 962), transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2, CD28H; NCBI gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI gene ID: 8832), CD96 (NCBI gene ID: 10225), CD160 (NCBI gene ID: 11126), MS 4A1 (CD20; NCBI gene ID: 931), CD244 (SLAMF4; NCBI gene ID: 51744); CD276 (B7H3; NCBI gene ID: 80381); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4; NCBI gene ID: 79679); V-set immunomodulatory receptor (VSIR, B7H5, VISTA; NCBI gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI gene ID: 152404); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI gene ID: 374383); HERV-H LTR-related 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell co-stimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell co-stimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L; NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA); NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC Class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; CD279; NCBI Gene ID: 5133); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI Gene ID: 5819); CD226 (DNAM-1; NCBI Gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); PVR-related immunoglobulin domain-containing protein (PVRIG, CD112R; NCBI Gene ID: 79037); T cell with Ig and ITIM domains cellular immune receptor (TIGIT; NCBI gene ID: 201633); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4; NCBI gene ID: 91937); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI gene ID: 84868); galectin 9 (LGALS9; NCBI gene ID: 3965); lymphocyte activation 3 (LAG3, CD223; NCBI gene ID: 3902); signal transduction lymphocytes Cell activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI gene ID: 6504); Lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823); UL16 binding protein 1 (ULBP1; NCBI gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI Gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154 064); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A; NCBI gene ID: 3821); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI gene ID: 22914); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI gene ID: 3822); killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI gene ID: 3823); killer cell Lectin-like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 8302); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3; NCBI Gene ID: 3804); Cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1, KIR, CD158E1; NCBI Gene ID: 3811) (e.g., lirelumab (IPH2102/BMS-986015), IPH-4102); killer cell lectin-like receptor D1 (KLRD1; NCBI Gene ID: 3824), and mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1); NCBI Gene ID: 11184).
在各种实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与一种或多种T细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂组合或共同施用。例示性T细胞抑制性免疫检查点蛋白或受体包括但不限于CD274(CD274、PDL1、PD-L1);程序性细胞死亡1配体2(PDCD1LG2、PD-L2、CD273);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);淋巴细胞活化3(LAG3、CD223);甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);以及杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1)。利瑞鲁单抗是结合并阻断KIR2DL1/2L3受体的例示性抗体。在各种实施方案中,将如本文所述的融合多肽、多核苷酸、载体、LNP、免疫原性组合物和/或药物组合物与一种或多种T细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂组合。例示性T细胞刺激性免疫检查点蛋白或受体包括但不限于CD27、CD70;CD40、CD40LG;诱导型T细胞共刺激物(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF18(GITR)、TNFSF18(GITRL);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);CD244(2B4、SLAMF4)、脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155)。参见例如Xu等人,J Exp Clin Cancer Res.(2018)37:110。In various embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immune globin domain proteins (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). Lirelumab is an exemplary antibody that binds to and blocks the KIR2DL1/2L3 receptor. In various embodiments, the fusion polypeptides, polynucleotides, vectors, LNPs, immunogenic compositions and/or pharmaceutical compositions described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37:110.
在各种实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与一种或多种NK细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂组合或共同施用。例示性NK细胞抑制性免疫检查点蛋白或受体包括但不限于杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A)(例如莫纳利珠单抗(monalizumab)(IPH2201));和杀伤细胞凝集素样受体D1(KLRD1、CD94)。在各种实施方案中,将如本文所述的药剂与一种或多种NK细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂组合。例示性NK细胞刺激性免疫检查点蛋白或受体包括但不限于CD16、CD226(DNAM-1);CD244(2B4、SLAMF4);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);SLAM家族成员7(SLAMF7)。参见例如Davis等人,SeminImmunol.(2017)31:64–75;Fang等人,Semin Immunol.(2017)31:37-54;以及Chiossone等人,Nat Rev Immunol.(2018)18(11):671-688。In various embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A) (e.g., monalizumab (IPH2201)); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agent as described herein is combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include but are not limited to CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31: 64–75; Fang et al., Semin Immunol. (2017) 31: 37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688.
在一些实施方案中,一种或多种免疫检查点抑制剂包括PD-L1(CD274)、PD-1(PDCD1)或CTLA4的蛋白质(例如,抗体或其片段或抗体模拟物)抑制剂。在一些实施方案中,一种或多种免疫检查点抑制剂包括PD-L1(CD274)、PD-1(PDCD1)或CTLA4的有机小分子抑制剂。在一些实施方案中,CD274或PDCD1的小分子抑制剂选自GS-4224、GS-4416、INCB086550和MAX10181。在一些实施方案中,CTLA4的小分子抑制剂包括BPI-002。In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitors of CTLA4 include BPI-002.
可以共同施用的CTLA4抑制剂的示例包括但不限于:伊匹单抗、曲美木单抗、BMS-986218、AGEN1181、AGEN1884、BMS-986249、MK-1308、REGN-4659、ADU-1604、CS-1002、BCD-145、APL-509、JS-007、BA-3071、ONC-392、AGEN-2041、JHL-1155、KN-044、CG-0161、ATOR-1144、PBI-5D3H5、BPI-002,以及多特异性抑制剂FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、XmAb-20717(PD-1/CTLA4)和AK-104(CTLA4/PD-1)。Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to, ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATO R-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).
可共同施用的PD-L1(CD274)或PD-1(PDCD1)抑制剂的示例包括但不限于派姆单抗、纳武单抗、西米单抗、匹地利珠单抗、AMP-224、MEDI0680(AMP-514)、斯巴达珠单抗、阿替利珠单抗、阿维鲁单抗、度伐利尤单抗、BMS-936559、CK-301、PF-06801591、BGB-A317(替雷利珠单抗)、GLS-010(WBP-3055)、AK-103(HX-008)、AK-105、CS-1003、HLX-10、MGA-012、BI-754091、AGEN-2034、JS-001(特瑞普利单抗)、JNJ-63723283、杰诺单抗(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、SHR-1210(卡瑞利珠单抗)、Sym-021、ABBV-181(布格利单抗)、PD1-PIK、BAT-1306(MSB0010718C)、CX-072、CBT-502、TSR-042(多塔利单抗)、MSB-2311、JTX-4014、BGB-A333、SHR-1316、CS-1001(WBP-3155、KN-035、IBI-308(信迪利单抗)、HLX-20、KL-A167、STI-A1014、STI-A1015(IMC-001)、BCD-135、FAZ-053、TQB-2450、MDX1105-01、GS-4224、GS-4416、INCB086550、MAX10181,以及多特异性抑制剂FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-013(PD-1/LAG-3)、FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、RO-7121661(PD-1/TIM-3)、XmAb-20717(PD-1/CTLA4)、AK-104(CTLA4/PD-1)、M7824(PD-L1/TGFβ-EC结构域)、CA-170(PD-L1/VISTA)、CDX-527(CD27/PD-L1)、LY-3415244(TIM3/PDL1)和INBRX-105(4-1BB/PDL1)。Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that may be co-administered include, but are not limited to, pembrolizumab, nivolumab, simumab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalizumab), JNJ-63723283, genol monoclonal antibody (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (buglilimab), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (dotarizumab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP- 3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD -L1)MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-104(CTLA4/PD-1), M7824(PD-L1/TGFβ -EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1) and INBRX-105 (4-1BB/PDL1).
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与抗TIGIT抗体(诸如艾替利单抗(etigilimab)、BMS-986207、替拉格鲁单抗(tiragolumab)(又名MTIG-7192A;RG-6058;RO 7092284)、维博利单抗(MK-7684)、AGEN1307、AGEN1327、AGEN1777、COM-902、IBI-939、AB154、SGN-TGT、MG1131和EOS884448(EOS-448)。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with anti-TIGIT antibodies (such as etigilimab, BMS-986207, tiragolumab (also known as MTIG-7192A; RG-6058; RO 7092284), vibriolimab (MK-7684), AGEN1307, AGEN1327, AGEN1777, COM-902, IBI-939, AB154, SGN-TGT, MG1131, and EOS884448 (EOS-448).
TNF受体超家族(TNFRSF)成员激动剂或活化剂TNF receptor superfamily (TNFRSF) member agonists or activators
在各种实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与一种或多种TNF受体超家族(TNFRSF)成员的一种或多种激动剂组合或共同施用,例如以下TNF受体超家族中的一者或多者的激动剂:TNFRSF1A(NCBI基因ID:7132)、TNFRSF1B(NCBI基因ID:7133)、TNFRSF4(OX40、CD134;NCBI基因ID:7293)、TNFRSF5(CD40;NCBI基因ID:958)、TNFRSF6(FAS、NCBI基因ID:355)、TNFRSF7(CD27、NCBI基因ID:939)、TNFRSF8(CD30、NCBI基因ID:943)、TNFRSF9(4-1BB、CD137、NCBI基因ID:3604)、TNFRSF10A(CD261、DR4、TRAILR1、NCBI基因ID:8797)、TNFRSF10B(CD262、DR5、TRAILR2、NCBI基因ID:8795)、TNFRSF10C(CD263、TRAILR3、NCBI基因ID:8794)、TNFRSF10D(CD264、TRAILR4、NCBI基因ID:8793)、TNFRSF11A(CD265、RANK、NCBI基因ID:8792)、TNFRSF11B(NCBI基因ID:4982)、TNFRSF12A(CD266、NCBI基因ID:51330)、TNFRSF13B(CD267、NCBI基因ID:23495)、TNFRSF13C(CD268、NCBI基因ID:115650)、TNFRSF16(NGFR、CD271、NCBI基因ID:4804)、TNFRSF17(BCMA、CD269、NCBI基因ID:608)、TNFRSF18(GITR、CD357、NCBI基因ID:8784)、TNFRSF19(NCBI基因ID:55504)、TNFRSF21(CD358、DR6、NCBI基因ID:27242)和TNFRSF25(DR3、NCBI基因ID:8718)。In various embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with one or more agonists of one or more TNF receptor superfamily (TNFRSF) members, such as agonists of one or more of the following TNF receptor superfamily members: TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 72 93), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 355), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8797), I gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRS F13C (CD268, NCBI gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) and TNFRSF25 (DR3, NCBI gene ID: 8718).
可共同施用的示例抗TNFRSF4(OX40)抗体包括但不限于MEDI6469、MEDI6383、MEDI0562(他沃立珠单抗)、MOXR0916、PF-04518600、RG-7888、GSK-3174998、INCAGN1949、BMS-986178、GBR-8383、ABBV-368,以及WO2016179517、WO2017096179、WO2017096182、WO2017096281和WO2018089628中描述的那些。Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavolizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.
可以共同施用的示例抗TNFRSF5(CD40)抗体包括但不限于RG7876、SEA-CD40、APX-005M和ABBV-428。Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.
在一些实施方案中,共同施用抗TNFRSF7(CD27)抗体伐立鲁单抗(CDX-1127)。In some embodiments, the anti-TNFRSF7 (CD27) antibody varilutumab (CDX-1127) is co-administered.
可共同施用的示例抗TNFRSF9(4-1BB、CD137)抗体包括但不限于乌瑞鲁单抗、乌托鲁单抗(PF-05082566)、AGEN2373和ADG-106。Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, usurelumab, utolumab (PF-05082566), AGEN2373, and ADG-106.
可共同施用的示例抗TNFRSF18(GITR)抗体包括但不限于MEDI1873、FPA-154、INCAGN-1876、TRX-518、BMS-986156、MK-1248、GWN-323,以及WO2017096179、WO2017096276、WO2017096189和WO2018089628中描述的那些。在一些实施方案中,共同施用共同靶向TNFRSF4(OX40)和TNFRSF18(GITR)的抗体或其片段。此类抗体例如在WO2017096179和WO2018089628中描述。Exemplary anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.
双特异性和三特异性自然杀伤(NK)细胞衔接物Bispecific and trispecific natural killer (NK) cell engagers
在各种实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与双特异性NK细胞衔接物(BiKE)或三特异性NK细胞衔接物(TriKE)(例如,不具有Fc)或者抗以下项的双特异性抗体(例如,具有Fc)组合或共同施用:NK细胞活化受体(例如,CD16A)、C型凝集素受体(CD94/NKG2C、NKG2D、NKG2E/H和NKG2F)、天然细胞毒性受体(NKp30、NKp44和NKp46)、杀伤细胞C型凝集素样受体(NKp65、NKp80)、Fc受体FcγR(其介导抗体依赖性细胞毒性)、SLAM家族受体(例如,2B4、SLAM6和SLAM7)、杀伤细胞免疫球蛋白样受体(KIR)(KIR-2DS和KIR-3DS)、DNAM-1和CD137(4-1BB)。视情况而定,抗CD16结合双特异性分子可具有或可不具有Fc。可以共同施用的例示性双特异性NK细胞衔接物靶向CD16和一种或多种如本文所述的HIV相关抗原。BiKE和TriKE例如在以下文献中描述:Felices等人,Methods MolBiol.(2016)1441:333–346;Fang等人,Semin Immunol.(2017)31:37-54。三特异性NK细胞衔接物(TRiKE)的示例包括OXS-3550、HIV-TriKE和CD16-IL-15-B7H3 TriKe。In various embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a bispecific NK cell engager (BiKE) or a trispecific NK cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc) against: NK cell activating receptors (e.g., CD16A), C-type lectin receptors (CD94/NK KG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (4-1BB). Depending on the circumstances, the anti-CD16 binding bispecific molecule may or may not have Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in Felices et al., Methods Mol Biol. (2016) 1441: 333–346; Fang et al., Semin Immunol. (2017) 31: 37-54. Examples of trispecific NK cell engagers (TRiKE) include OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.
吲哚胺-吡咯-2,3-双加氧酶(IDO1)抑制剂Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors
在各种实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与吲哚胺2,3-双加氧酶1(IDO1;NCBI基因ID:3620)的抑制剂组合。IDO1抑制剂的示例包括但不限于BLV-0801、艾卡哚司他、F-001287、GBV-1012、GBV-1028、GDC-0919、吲哚莫德、NKTR-218、基于NLG-919的疫苗、PF-06840003、吡喃萘醌衍生物(SN-35837)、瑞米司他、SBLK-200802、BMS-986205和shIDO-ST、EOS-200271、KHK-2455、LY-3381916。In various embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icadolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.
Toll样受体(TLR)激动剂Toll-like receptor (TLR) agonists
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与toll样受体(TLR)的激动剂组合或共同施用,该toll样受体(TLR)的激动剂例如TLR1(NCBI基因ID:7096)、TLR2(NCBI基因ID:7097)、TLR3(NCBI基因ID:7098)、TLR4(NCBI基因ID:7099)、TLR5(NCBI基因ID:7100)、TLR6(NCBI基因ID:10333)、TLR7(NCBI基因ID:51284)、TLR8(NCBI基因ID:51311)、TLR9(NCBI基因ID:54106)和/或TLR10(NCBI基因ID:81793)的激动剂。可以共同施用的示例TLR7激动剂包括但不限于AL-034、DSP-0509、GS-9620(维沙莫特)、维沙莫特类似物、LHC-165、TMX-101(咪喹莫特)、GSK-2245035、瑞喹莫德、DSR-6434、DSP-3025、IMO-4200、MCT-465、MEDI-9197、3M-051、SB-9922、3M-052、Limtop、TMX-30X、TMX-202、RG-7863、RG-7854、RG-7795,以及US20100143301(Gilead Sciences)、US20110098248(Gilead Sciences)和US20090047249(Gilead Sciences)、US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(VentirxPharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(Ventirx Pharma)、US20140275167(NoviraTherapeutics)和US20130251673(Novira Therapeutics)中所公开的化合物。可共同施用的TLR7/TLR8激动剂是NKTR-262、特拉莫德和BDB-001。可共同施用的示例TLR8激动剂包括但不限于E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫(motolimod)、瑞喹莫德、GS-9688(赛尔甘托莫德)、VTX-1463、VTX-763、3M-051、3M-052,以及US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(ArrayBiopharma)、US20100029585(Ventirx Pharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(Ventirx Pharma)、US20140275167(Novira Therapeutics)和US20130251673(Novira Therapeutics)中所公开的化合物。可共同施用的示例TLR9激动剂包括但不限于AST-008(卡罗托莫德(cavrotolimod))、可比托莫德(cobitolimod)、CMP-001、IMO-2055、IMO-2125、S-540956、利尼莫德(litenimod)、MGN-1601、BB-001、BB-006、IMO-3100、IMO-8400、IR-103、IMO-9200、阿格托莫德(agatolimod)、DIMS-9054、DV-1079、DV-1179、AZD-1419、lefitolimod(MGN-1703)、CYT-003、CYT-003-QbG10、替索莫德(tilsotolimod)和PUL-042。TLR3激动剂的示例包括雷他莫德、聚ICLC、、Apoxxim、、IPH-33、MCT-465、MCT-475和ND-1.1。TLR4激动剂的示例包括G-100和GSK-1795091。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Exemplary TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (visamod), visamod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences)、US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(VentirxPharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). TLR7/TLR8 agonists that can be co-administered are NKTR-262, teramod and BDB-001. Exemplary TLR8 agonists that can be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688 (sergantomod), VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janss en), US20140073642(Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128189(Janssen), US20140350031(Janssen), WO2014/023813(Janssen), US2008023425 1(Array Biopharma), US20080306050 (ArrayBiopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include, but are not limited to, AST-008 (cavrotolimod), cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include retamod, polyICLC, 、Apoxxim、 , IPH-33, MCT-465, MCT-475 and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.
CDK抑制剂或拮抗剂CDK inhibitors or antagonists
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与CDK抑制剂或拮抗剂组合或共同施用。在一些实施方案中,本文所述的药剂与CDK的抑制剂或拮抗剂组合。在一些实施方案中,CDK抑制剂或拮抗剂选自VS2-370。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a CDK inhibitor or antagonist. In some embodiments, the agents described herein are combined with an inhibitor or antagonist of CDK. In some embodiments, the CDK inhibitor or antagonist is selected from VS2-370.
STING激动剂、RIG-I和NOD2调节剂STING agonists, RIG-I and NOD2 modulators
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与干扰素基因刺激物(STING)受体(又名干扰素应答刺激物cGAMP相互作用物1(STING1);跨膜蛋白173(TMEM173);NCBI基因ID:340061)激动剂组合或共同施用。在一些实施方案中,STING受体激动剂或活化剂选自ADU-S100(MIW-815)、SB-11285、MK-1454、SR-8291、STING激动剂(潜伏性HIV)、5,6-二甲基呫吨酮-4-醋酸(DMXAA)、环状GAMP(cGAMP)和环状二AMP。在一些实施方案中,将本文所述的药剂与RIG-I调节剂(诸如RGT-100)或NOD2调节剂(诸如SB-9200和IR-103)组合。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a stimulator of interferon genes (STING) receptor (also known as interferon response stimulator cGAMP interactor 1 (STING1); transmembrane protein 173 (TMEM173); NCBI gene ID: 340061) agonist. In some embodiments, the STING receptor agonist or activator is selected from ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with a RIG-I modulator (such as RGT-100) or a NOD2 modulator (such as SB-9200 and IR-103).
在一些实施方案中,附加治疗剂是DExD/H-box解旋酶58(DDX58;又名RIG-I、RIG1、RIGI、RLR-1、SGMRT2;NCBI基因ID:23586)的激动剂。例示性RIG-I激动剂包括索那吉韦(inarigivir soproxil)(SB-9200;GS-9992);SB-40、SB-44、ORI-7246、ORI-9350、ORI-7537、ORI-9020、ORI-9198、ORI-7170、RGT-100和KIN1148,如Hemann等人,J Immunol May1,2016,196(1Supplement)76.1所述。另外的RIG-I激动剂在以下文献中描述:例如Elion等人,Cancer Res.(2018)78(21):6183-6195;以及Liu等人,J Virol.(2016)90(20):9406-19。RIG-I激动剂可例如从Invivogen(invivogen.com)商购获得。在一些实施方案中,本文所述的药剂与含核苷酸结合寡聚化结构域蛋白2(NOD2;NCBI基因ID:64127)激动剂诸如索那吉韦(SB-9200;GS-9992)和IR-103组合。In some embodiments, the additional therapeutic agent is an agonist of DExD/H-box helicase 58 (DDX58; also known as RIG-I, RIG1, RIGI, RLR-1, SGMRT2; NCBI Gene ID: 23586). Exemplary RIG-I agonists include inarigivir soproxil (SB-9200; GS-9992); SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, RGT-100, and KIN1148, as described in Hemann et al., J Immunol May 1, 2016, 196 (1 Supplement) 76.1. Additional RIG-I agonists are described in, for example, Elion et al., Cancer Res. (2018) 78(21): 6183-6195; and Liu et al., J Virol. (2016) 90(20): 9406-19. RIG-I agonists are commercially available, for example, from Invivogen (invivogen.com). In some embodiments, the agents described herein are combined with nucleotide binding oligomerization domain-containing protein 2 (NOD2; NCBI gene ID: 64127) agonists such as sonagivir (SB-9200; GS-9992) and IR-103.
LAG-3和TIM-3抑制剂LAG-3 and TIM-3 inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与抗TIM-3诸如TSR-022、LY-3321367、MBG-453、INCAGN-2390组合或共同施用。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with anti-TIM-3 such as TSR-022, LY-3321367, MBG-453, INCAGN-2390.
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与抗LAG-3(淋巴细胞活化)抗体诸如瑞拉利单抗(ONO-4482)、LAG-525、MK-4280、REGN-3767、INCAGN2385组合或共同施用。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with an anti-LAG-3 (lymphocyte activation) antibody such as relalizumab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385.
白介素或细胞因子受体激动剂Interleukin or cytokine receptor agonists
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与白介素受体激动剂诸如IL-2、IL-7、IL-15、IL-10、IL-12受体激动剂组合或共同施用。可以共同施用的IL-2受体激动剂的示例包括普留净(阿白介素、IL-2);BC-IL(Cel-Sci)、聚乙二醇化IL-2(例如,NKTR-214);IL-2的修饰变体(例如,THOR-707、Fc-IL-2融合蛋白)、贝培阿地白介素、AIC-284、ALKS-4230、CUI-101、Neo-2/15。可共同施用的IL-15受体激动剂的示例包括但不限于ALT-803、NKTR-255和hetIL-15、白介素-15/Fc融合蛋白、AM-0015、NIZ-985、SO-C101、IL-15(聚乙二醇化Il-15)、P-22339和IL-15-PD-1融合蛋白N-809。可以共同施用的IL-7受体激动剂的示例包括CYT-107。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with interleukin receptor agonists such as IL-2, IL-7, IL-15, IL-10, IL-12 receptor agonists. Examples of IL-2 receptor agonists that can be co-administered include Proleukin (albeukin, IL-2); BC-IL (Cel-Sci), PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707, Fc-IL-2 fusion proteins), bepei aldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2/15. Examples of IL-15 receptor agonists that can be co-administered include, but are not limited to, ALT-803, NKTR-255 and hetIL-15, interleukin-15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 (pegylated 11-15), P-22339, and IL-15-PD-1 fusion protein N-809. Examples of IL-7 receptor agonists that can be co-administered include CYT-107.
可组合或共同施用的另外的基于免疫的疗法的示例包括干扰素α;干扰素α-2b;干扰素α-n3;聚乙二醇化干扰素α;干扰素γ;fms相关酪氨酸激酶3(FLT3)激动剂(例如,GS-3583、CDX-301);gepon;诺姆福隆、聚乙二醇干扰素α-2a、聚乙二醇干扰素α-2b、RPI-MN。在各种实施方案中,在第一时间点施用fms相关酪氨酸激酶3(FLT3)激动剂(例如,GS-3583、CDX-301),并且在第一时间点后至少6、7、8、9、10天(例如,1周)的时间点施用一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体。Examples of additional immune-based therapies that can be combined or co-administered include interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; fms-related tyrosine kinase 3 (FLT3) agonists (e.g., GS-3583, CDX-301); gepon; nomofuron, pegylated interferon alpha-2a, pegylated interferon alpha-2b, RPI-MN. In various embodiments, an fms-related tyrosine kinase 3 (FLT3) agonist (e.g., GS-3583, CDX-301) is administered at a first time point, and one or more fusion polypeptides or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are administered at a time point at least 6, 7, 8, 9, 10 days (e.g., 1 week) after the first time point.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与fms相关酪氨酸激酶3(FLT3)激动剂(例如,GS-3583、CDX-301)组合或共同施用。可共同施用的例示性FLT3激动剂描述于例如WO 2020/263830A1中。在各种实施方案中,与在不存在FLT3激动剂的情况下施用一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体相比,FLT3激动剂的共同施用增加了疫苗诱导的T细胞应答。In some embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNP) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with fms-related tyrosine kinase 3 (FLT3) agonists (e.g., GS-3583, CDX-301). Exemplary FLT3 agonists that can be co-administered are described in, for example, WO 2020/263830A1. In various embodiments, co-administration of FLT3 agonists increases vaccine-induced T cell responses compared to administration of one or more fusion polypeptides or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNP) comprising such polynucleotides, or vectors expressing such fusion polypeptides in the absence of FLT3 agonists.
磷脂酰肌醇3-激酶(PI3K)抑制剂Phosphatidylinositol 3-kinase (PI3K) inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与PI3K抑制剂组合或共同施用。可组合或共同施用的PI3K抑制剂的示例包括艾德利西布(idelalisib)、阿博利西布(alpelisib)、布帕利西布(buparlisib)、乳清酸CAI、科潘利西布(copanlisib)、杜韦利西布(duvelisib)、格达利西布(gedatolisib)、来那替尼、帕努利西布(panulisib)、哌立福辛、伊达利西布(pictilisib)、匹拉利西布(pilaralisib)、甲磺酸普口奎替尼、瑞格替尼、瑞格替尼钠、索诺利西布(sonolisib)、塔塞利西布(taselisib)、AMG-319、AZD-8186、BAY-1082439、CLR-1401、CLR-457、CUDC-907、DS-7423、EN-3342、GSK-2126458、GSK-2269577、GSK-2636771、INCB-040093、LY-3023414、MLN-1117、PQR-309、RG-7666、RP-6530、RV-1729、SAR-245409、SAR-260301、SF-1126、TGR-1202、UCB-5857、VS-5584、XL-765和ZSTK-474。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a PI3K inhibitor. Examples of PI3K inhibitors that may be combined or co-administered include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puroquitinib mesylate, regoratinib, regoratinib sodium, sonolisib, taselixib, sib), AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN -1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.
二酰甘油激酶抑制剂Diacylglycerol kinase inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与二酰甘油激酶(DGK)(例如,二酰甘油激酶α(DGKα)和二酰甘油激酶ζ(DGKζ))的抑制剂组合或共同施用。可组合或共同施用的DGK抑制剂的示例包括但不限于利坦色林和在WO2020006016和WO2020006018中描述的DGK抑制剂。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with inhibitors of diacylglycerol kinase (DGK) (e.g., diacylglycerol kinase α (DGKα) and diacylglycerol kinase ζ (DGKζ). Examples of DGK inhibitors that may be combined or co-administered include, but are not limited to, ritanserin and the DGK inhibitors described in WO2020006016 and WO2020006018.
α-4/β-7拮抗剂Alpha-4/beta-7 antagonists
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与α-4/β-7拮抗剂组合或共同施用。可组合或共同施用的整联蛋白α-4/β-7拮抗剂的示例包括PTG-100、TRK-170、阿利鲁单抗(abrilumab)、依曲利珠单抗(etrolizumab)、甲基卡罗格拉斯(carotegrast methyl)和维多珠单抗(vedolizumab)。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with an alpha-4/beta-7 antagonist. Examples of integrin alpha-4/beta-7 antagonists that can be combined or co-administered include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.
HPK1/MAP4K1抑制剂HPK1/MAP4K1 inhibitors
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与促分裂原活化蛋白激酶激酶激酶激酶激酶1(MAP4K1;又名造血祖细胞激酶1(HPK1);NCBI基因ID:11184)的抑制剂组合或共同施用。HPK1抑制剂的示例包括但不限于ZYF-0272和ZYF-0057。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase kinase kinase 1 (MAP4K1; also known as hematopoietic progenitor kinase 1 (HPK1); NCBI Gene ID: 11184). Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.
HIV靶向抗体HIV-targeted antibodies
可组合或共同施用的HIV抗体、双特异性抗体和“抗体样”治疗蛋白的示例包括Fab衍生物、bNAb(广泛中和HIV-1抗体)、TMB-360、TMB-370以及靶向HIV gp120或gp41的那些抗体、靶向HIV的抗体募集分子、抗CD63单克隆抗体、抗GB病毒C抗体、抗GP120/CD4、gp120双特异性单克隆抗体、CCR5双特异性抗体、抗Nef单结构域抗体、抗Rev抗体、骆驼科来源的抗CD18抗体、骆驼科来源的抗ICAM-1抗体、DCVax-001、gp140靶向抗体、基于gp41的HIV治疗抗体、人重组mAb、依巴利珠单抗、依巴利珠单抗(第二代)、Immuglo、MB-66、靶向KLIC的克隆3人单克隆抗体(HIV感染)。如本文所述,可使用各种bNAb。Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins that can be combined or co-administered include Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, TMB-370, and those targeting HIV gp120 or gp41, antibody recruitment molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140 targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, clone 3 human monoclonal antibodies targeting KLIC (HIV infection). As described herein, various bNAbs can be used.
在某些实施方案中,共同施用的抗体或其抗原结合片段或者抗原结合分子是或来源于靶向HIV-1的人中和抗体(例如,单克隆抗体)。“中和抗体”是可中和HIV在体外引发和/或维持宿主和/或靶细胞中的感染的能力的抗体。本公开提供了中和单克隆人抗体,其中该抗体识别来自HIV的抗原,例如gp120多肽。在某些实施方案中,“中和抗体”可抑制HIV-1病毒(例如,SF162和/或JR-CSF)的进入,中和指数>1.5或>2.0(Kostrikis LG等人,J.Virol.,70(1):445--458(1996))。In certain embodiments, the co-administered antibody or its antigen-binding fragment or antigen-binding molecule is or is derived from a human neutralizing antibody (e.g., monoclonal antibody) targeting HIV-1. "Neutralizing antibodies" are antibodies that can neutralize HIV's ability to cause and/or maintain infection in a host and/or target cell in vitro. The present disclosure provides neutralizing monoclonal human antibodies, wherein the antibody recognizes an antigen from HIV, such as a gp120 polypeptide. In certain embodiments, "neutralizing antibodies" can inhibit entry of HIV-1 viruses (e.g., SF162 and/or JR-CSF), with a neutralization index >1.5 or >2.0 (Kostrikis LG et al., J. Virol., 70 (1): 445--458 (1996)).
在一些实施方案中,共同施用的抗体或其抗原结合片段或者抗原结合分子是或来源于靶向HIV-1的人广谱中和抗体(例如,单克隆抗体)。所谓“广泛中和抗体”意指在中和测定中中和多于一种HIV-1病毒种类(来自不同的进化枝和进化枝内的不同毒株)的抗体。广泛中和抗体可中和HIV-1的至少2、3、4、5、6、7、8、9种或更多种不同的毒株,这些毒株属于相同或不同的进化枝。可在组合疗法中作为附加治疗剂共同施用的例示性广泛中和抗体(bNAb)在例如8,673,307、9,493,549、9,783,594和WO 2012/154312、WO2012/158948、WO2013/086533、WO 2013/142324、WO2014/063059、WO 2014/089152、WO 2015/048462、WO2015/103549、WO 2015/117008、WO2016/014484、WO 2016/154003、WO 2016/196975、WO2016/149710、WO2017/096221、WO 2017/133639、WO 2017/133640中进行了描述,它们的全部内容据此以引用方式并入本文用于所有目的。可共同施用的例示性bNAb包括但不限于12A12、12A21、NIH45-46、bANC131、8ANC134、IB2530、INC9、8ANC195、8ANC196、10-259、10-303、10-410、10-847、10-996、10-1074、10-1074-LS、10-1074-LS-J、10-1121、10-1130、10-1146、10-1341、10-1369、10-1074GM、PGT-121、PGT-121.414、GS-9721、GS-9722、GS-2872。另外的示例包括在以下文献中描述的那些:Sajadi等人,Cell.(2018)173(7):1783-1795;Sajadi等人,J Infect Dis.(2016)213(1):156-64;Klein等人,Nature,492(7427):118-22(2012);Horwitz等人,Proc Natl Acad Sci U S A,110(41):16538-43(2013);Scheid等人,Science,333:1633-1637(2011);Scheid等人,Nature,458:636-640(2009);Eroshkin等人,Nucleic Acids Res.,42(数据库特辑):Dl 133-9(2014);Mascola等人,Immunol Rev.,254(l):225-44(2013),诸如2F5、4E10、M66.6、CAP206-CH12、10E81(它们所有都结合gp41的MPER);PG9、PG16、CH01-04(它们所有都结合V1V2-聚糖)、2G12(其与外部结构域聚糖结合);b12、HJ16、CH130-149、VRC01-03、VRC-PG04、04b、VRC-CH30-34、3BNC62、3BNC89、3BNC91、3BNC95、3BNC104、3BNC117、3BNC176、8ANC131、GS-9723、GS-5423(它们所有都与CD4结合位点结合),这些文献据此全文以引用方式并入本文用于所有目的。In some embodiments, the co-administered antibody or antigen-binding fragment thereof or antigen-binding molecule is or is derived from a broadly neutralizing antibody (e.g., a monoclonal antibody) targeting HIV-1. The so-called "broadly neutralizing antibody" means an antibody that neutralizes more than one HIV-1 virus species (from different clades and different strains within clades) in a neutralization assay. Broadly neutralizing antibodies can neutralize at least 2, 3, 4, 5, 6, 7, 8, 9 or more different strains of HIV-1, which belong to the same or different clades. Exemplary broadly neutralizing antibodies (bNAbs) that can be co-administered as additional therapeutic agents in combination therapy are described, for example, in 8,673,307, 9,493,549, 9,783,594 and WO 2012/154312, WO 2012/158948, WO 2013/086533, WO 2013/142324, WO 2014/063059, WO 2014/089152, WO 2015/048462, WO 2015/103549, WO 2015/117008, WO 2016/014484, WO 2016/154003, WO 2016/196975, WO 2016/149710, WO 2017/096221, WO The invention is described in WO 2017/133639, WO 2017/133640, the entire contents of which are hereby incorporated by reference for all purposes. Exemplary bNAbs that can be co-administered include, but are not limited to, 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1074-LS, 10-1074-LS-J, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, 10-1074GM, PGT-121, PGT-121.414, GS-9721, GS-9722, and GS-2872. Additional examples include those described in Sajadi et al., Cell. (2018) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427):118-22 (2012); Horwitz et al., Proc Natl Acad Sci U S A, 110(41):16538-43 (2013); Scheid et al., Science, 333:1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42(Database Special):D1 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44(2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to the V1V2-glycan), 2G12 (which binds to the external domain glycan); b12, HJ16, CH130-149, V RC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC117, 3BNC176, 8ANC131, GS-9723, GS-5423 (all of which bind to the CD4 binding site), which are hereby incorporated by reference in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与选自以下的gp120的表位或区域结合:(i)第三可变环(V3)和/或包含N332寡甘露糖聚糖的高甘露糖补丁;(ii)第二可变环(V2)和/或Env三聚体顶点;(iii)CD4结合位点(CD4bs);(iv)gp120/gp41交界面;或者(v)gp120的沉默面。广泛中和抗体结合的gp120的前述表位或区域描述于例如,McCoy,,Retrovirology(2018)15:70;Sok和Burton,Nat Immunol.2018 19(11):1179-1188;Possas等人,Expert Opin Ther Pat.2018年7月;28(7):551-560;以及Stephenson和Barouch,Curr HIV/AIDS Rep(2016)13:31–37中,这些文献据此全文以引用方式并入本文以用于所有目的。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp120 selected from: (i) the third variable loop (V3) and/or the high mannose patch comprising the N332 oligomannose glycan; (ii) the second variable loop (V2) and/or the Env trimer apex; (iii) the CD4 binding site (CD4bs); (iv) the gp120/gp41 interface; or (v) the silent face of gp120. The aforementioned epitopes or regions of gp120 to which broadly neutralizing antibodies bind are described in, e.g., McCoy, , Retrovirology (2018) 15:70; Sok and Burton, Nat Immunol. 2018 19(11):1179-1188; Possas et al., Expert Opin Ther Pat. 2018 Jul;28(7):551-560; and Stephenson and Barouch, Curr HIV/AIDS Rep (2016) 13:31–37, which are hereby incorporated by reference in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与第三可变环(V3)和/或包含N332寡甘露糖聚糖的高甘露糖补丁中的gp120的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:GS-9722、PGT-121.60、PGT-121.66、PGT-121、PGT-121.414、PGT-122、PGT-123、PGT-124、PGT-125、PGT-126、PGT-128、PGT-130、PGT-133、PGT-134、PGT-135、PGT-136、PGT-137、PGT-138、PGT-139、10-1074、VRC24、2G12、BG18、354BG8、354BG18、354BG42、354BG33、354BG129、354BG188、354BG411、354BG426、DH270.1、DH270.6、PGDM12、VRC41.01、PGDM21、PCDN-33A、BF520.1和VRC29.03。与包含N332寡甘露糖聚糖的第三可变环(V3)和/或高甘露糖斑块中的gp120结合并且可用作第二抗体或其抗原结合片段的附加广泛中和抗体描述于例如WO 2012/030904、WO 2014/063059、WO 2016/149698、WO2017/106346、WO 2018/075564、WO 2018/125813和WO 2018/237148,这些专利据此全文以引用方式并入本文用于所有目的。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp120 in the third variable loop (V3) and/or the high mannose patch comprising the N332 oligomannose glycan, and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of GS-9722, PGT-121.60, PGT-121.66, PGT-121, PGT-121.414, PGT-122, PGT-123, PG-124, PGT-125, PGT-126, PGT-127, PGT-128, PGT-129, PGT-130, PGT-131, PGT-132, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, PGT-140, PGT-141, PGT-142, PGT-143, PGT-144, PGT-145, PGT-146, PGT-147, PGT-148, PGT-149, PGT-150, PGT-151, PGT-152, PGT-153, PGT-154, PGT-155, PGT-156, PGT-157, PGT-158, PGT-159, T-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG 42. 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. Additional broadly neutralizing antibodies that bind to gp120 in the third variable loop (V3) comprising N332 oligomannose glycans and/or high mannose plaques and can be used as secondary antibodies or antigen-binding fragments thereof are described in, e.g., WO 2012/030904, WO 2014/063059, WO 2016/149698, WO 2017/106346, WO 2018/075564, WO 2018/125813, and WO 2018/237148, which are hereby incorporated by reference in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广泛中和抗体(bNAb)组合或共同施用,该广谱中和抗体与CD4结合位点(CD4bs)中的gp120的表位或区域结合,并且与选自以下的抗体的CDR和/或VH和VL区域竞争或者包含这些区域:b12、F105、VRC01、VRC07、VRC07-523、VRC03、VRC06、VRC06b01、VRC08、VRC0801、NIH45-46、GS-9723、GS-5423、3BNC117、3BNC60、VRC-PG04、PGV04、CH103、44-VRC13.01、1NC9、12A12、N6、N49-P7、NC-Cow1、IOMA、CH235和CH235.12、N49P6、N49P7、N49P11、N49P9和N60P25。与gp120 CD4结合位点(CD4bs)结合并且可用作第二抗体或其抗原结合片段的其他广泛中和抗体描述于例如WO 2012/154312、WO 2012/158948、WO 2013/090644、WO 2013/192589、WO 2018/125813中,这些专利据此全文以引用方式并入本文用于所有目的。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp120 in the CD4 binding site (CD4bs) and competes with or comprises the CDRs and/or VH and VL regions of an antibody selected from the group consisting of b12, F105, VRC01, VRC07, VRC0 7-523, VRC03, VRC06, VRC06b01, VRC08, VRC0801, NIH45-46, GS-9723, GS-5423, 3BNC117, 3BNC60, VRC-PG04, PGV04, CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cow1, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9, and N60P25. Other broadly neutralizing antibodies that bind to the gp120 CD4 binding site (CD4bs) and can be used as secondary antibodies or antigen-binding fragments thereof are described in, e.g., WO 2012/154312, WO 2012/158948, WO 2013/090644, WO 2013/192589, WO 2018/125813, which are hereby incorporated by reference in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与第二可变环(V2)和/或Env三聚体顶点中的gp120的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:PG9、PG16、PGC14、PGG14、PGT-142、PGT-143、PGT-144、PGT-145、CH01、CH59、PGDM1400、CAP256、CAP256-VRC26.08、CAP256-VRC26.09、CAP256-VRC26.25、PCT64-24E和VRC38.01。与第二可变环(V2)和/或Env三聚体顶点中的gp120结合并且可用作第二抗体或其抗原结合片段的附加广泛中和抗体描述于例如WO 2010/107939、WO 2012/030904、WO2018/075564和WO 2018/125813中,这些专利据此全文以引用方式并入本文以用于所有目的。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp120 in the second variable loop (V2) and/or the apex of the Env trimer and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHO1, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01. Additional broadly neutralizing antibodies that bind to gp120 in the second variable loop (V2) and/or the Env trimer apex and can be used as a secondary antibody or antigen-binding fragment thereof are described in, for example, WO 2010/107939, WO 2012/030904, WO 2018/075564, and WO 2018/125813, which are hereby incorporated by reference in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与gp120/gp41交界面中的gp120的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:PGT-151、CAP248-2B、35O22、8ANC195、ACS202、VRC34和VRC34.01。与gp120/gp41交界面中的gp120结合并且可用作第二抗体或其抗原结合片段的附加广泛中和抗体描述于例如WO 2011/038290、WO 2012/030904和WO2017/079479中,这些专利据此全文以引用方式并入本文以用于所有目的。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp120 in the gp120/gp41 interface and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34, and VRC34.01. Additional broadly neutralizing antibodies that bind to gp120 in the gp120/gp41 interface and can be used as secondary antibodies or antigen-binding fragments thereof are described, for example, in WO 2011/038290, WO 2012/030904, and WO 2017/079479, which are hereby incorporated by reference in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与gp120沉默面的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:VRC-PG05和SF12。参见例如Schoofs等人,“Broad and Potent Neutralizing Antibodies Recognize the SilentFace of the HIV Envelope,”Immunity(2019)5月14日.pii:S1074-7613(19)30194-3(PMID 31126879)。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of the silent face of gp120 and competes with or comprises the VH and VL regions of an antibody selected from VRC-PG05 and SF12. See, e.g., Schoofs et al., "Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope," Immunity (2019) May 14. pii:S1074-7613(19)30194-3 (PMID 31126879).
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与膜近侧区域(MPER)中的gp41的表位或区域结合。与MPER中的gp41结合并且可用作第二抗体或其抗原结合片段的附加广泛中和抗体描述于例如WO 2011/034582、WO 2011/038290、WO 2011/046623和WO 2013/070776中,这些专利据此全文以引用方式并入本文以用于所有目的。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp41 in the membrane proximal region (MPER). Additional broadly neutralizing antibodies that bind to gp41 in the MPER and can be used as secondary antibodies or antigen-binding fragments thereof are described, for example, in WO 2011/034582, WO 2011/038290, WO 2011/046623, and WO 2013/070776, which are hereby incorporated by reference herein in their entirety for all purposes.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与膜近侧区域(MPER)中的gp41的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:10E8、10E8v4、10E8-5R-100cF、4E10、DH511.11P、2F5、7b2和LN01。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises the VH and VL regions of an antibody selected from the group consisting of: 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与广谱中和抗体(bNAb)组合或共同施用,该广谱中和抗体与gp41融合肽的表位或区域结合,并且与选自以下的抗体的VH和VL区域竞争或者包含这些区域:VRC34和ACS202。In some embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined or co-administered with a broadly neutralizing antibody (bNAb) that binds to an epitope or region of the gp41 fusion peptide and competes with or comprises the VH and VL regions of an antibody selected from VRC34 and ACS202.
可共同施用的另外的抗体的示例包括巴威单抗(bavituximab)、UB-421、BF520.1、BiIA-SG、CH01、CH59、C2F5、C4E10、C2F5+C2G12+C4E10、CAP256V2LS、3BNC117、3BNC117-LS、3BNC60、DH270.1、DH270.6、D1D2、10-1074-LS、Cl3hmAb、GS-9722(依帕韦单抗)、PGT-121.414、PGT-121.60、PGT-121.66、PGT122、PGT-123、PGT-124、PGT-125、PGT-126、PGT-151、PGT-130、PGT-133、PGT-134、PGT-135、PGT-128、PGT-136、PGT-137、PGT-138、PGT-139、MDX010(伊匹单抗)、DH511、DH511-2、N6、N6LS、N49P6、N49P7、N49P7.1、N49P9、N49P11、N60P1.1、N60P25.1、N60P2.1、N60P31.1、N60P22、NIH 45--46、PGC14、PGG14、PGT-142、PGT-143、PGT-144、PGDM1400、PGDM12、PGDM21、PCDN-33A、2Dm2m、4Dm2m、6Dm2m、PGDM1400、MDX010(伊匹单抗)、VRC01、VRC-01-LS、A32、7B2、10E8、VRC-07-523、VRC07-523LS、VRC24、VRC41.01、10E8VLS、3810109、10E8v4、IMC-HIV、iMabm36、eCD4-Ig、IOMA、CAP256-VRC26.25、DRVIA7,VRC-HIVMAB080-00-AB、VRC-HIVMAB060-00-AB、P2G12、VRC07、354BG8、354BG18、354BG42、354BG33、354BG129、354BG188、354BG411、354BG426、VRC29.03、CAP256、CAP256-VRC26.08、CAP256-VRC26.09、CAP256-VRC26.25、PCT64-24E和VRC38.01、PGT-151、CAP248-2B、35O22、ACS202、VRC34和VRC34.01、10E8、10E8v4、10E8-5R-100cF、4E10、DH511.11P、2F5、7b2和LN01。Examples of additional antibodies that can be co-administered include bavituximab, UB-421, BF520.1, BiIA-SG, CHO1, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (epavirumab), PGT-121.414, PGT-121.60, PGT-121.66, PGT-121.70 2. PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45--46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080-00-AB, VR C-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC2 6.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2 and LN01.
HIV双特异性和三特异性抗体的示例包括MGD014、B12BiTe、BiIA-SG、TMB-双特异性、SAR-441236、VRC-01/PGDM-1400/10E8v4、10E8.4/iMab、10E8v4/PGT121-VRC01。Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01/PGDM-1400/10E8v4, 10E8.4/iMab, 10E8v4/PGT121-VRC01.
在一些实施方案中,bNAb可以在患者体内表达。体内递送的bNAb的示例包括AAV8-VRC07、编码抗HIV抗体VRC01的mRNA和编码3BNC117的工程化B细胞(Hartweger等人,J.Exp.Med.2019,1301)。In some embodiments, bNAbs can be expressed in vivo in patients. Examples of bNAbs delivered in vivo include AAV8-VRC07, mRNA encoding the anti-HIV antibody VRC01, and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).
药代动力学增强剂Pharmacokinetic enhancers
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与药代动力学增强剂组合。可组合或共同施用的药代动力学增强剂的示例包括可比司他和利托那韦。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers that can be combined or co-administered include cobicistat and ritonavir.
附加治疗剂Additional therapeutic agents
可与如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体组合的附加治疗剂的示例包括WO 2004/096286(Gilead Sciences)、WO 2006/015261(Gilead Sciences)、WO2006/110157(Gilead Sciences)、WO 2012/003497(Gilead Sciences)、WO 2012/003498(Gilead Sciences)、WO 2012/145728(Gilead Sciences)、WO 2013/006738(GileadSciences)、WO 2013/159064(Gilead Sciences)、WO 2014/100323(Gilead Sciences)、US2013/0165489(University of Pennsylvania)、US 2014/0221378(Japan Tobacco)、US2014/0221380(Japan Tobacco)、WO 2009/062285(Boehringer Ingelheim)、WO 2010/130034(Boehringer Ingelheim)、WO 2013/006792(Pharma Resources)、US 20140221356(Gilead Sciences)、US 20100143301(Gilead Sciences)和WO 2013/091096(BoehringerIngelheim)中公开的化合物。Examples of additional therapeutic agents that can be combined with one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides include WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2013/0165489 (University of Pennsylvania), US Compounds disclosed in 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).
HIV疫苗HIV vaccine
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与HIV疫苗组合。可组合或共同施用的HIV疫苗的示例包括肽疫苗、重组亚基蛋白疫苗、活载体疫苗、DNA疫苗、HIV MAG DNA疫苗、CD4来源的肽疫苗、疫苗组合、腺病毒载体疫苗(腺病毒载体,诸如Ad5、Ad26或Ad35)、猿猴腺病毒(黑猩猩、大猩猩、恒河猴即rhAd)、腺相关病毒载体疫苗、黑猩猩腺病毒疫苗(例如,ChAdOX1、ChAd68、ChAd3、ChAd63、ChAd83、ChAd155、ChAd157、Pan5、Pan6、Pan7、Pan9)、基于柯萨奇病毒的疫苗、基于肠病毒的疫苗、大猩猩腺病毒疫苗、基于慢病毒载体的疫苗、沙粒病毒疫苗(诸如LCMV、皮钦德)、基于双分段或三分段的沙粒病毒的疫苗、基于三聚体的HIV-1疫苗、基于麻疹病毒的疫苗、基于黄病毒载体的疫苗、基于烟草花叶病毒载体的疫苗、基于水痘带状疱疹病毒的疫苗、基于人副流感病毒3(PIV3)的疫苗、基于痘病毒的疫苗(经修饰的牛痘病毒安卡拉(Ankara)(MVA))、正痘病毒来源的NYVAC和禽痘病毒来源的ALVAC(金丝雀痘病毒)毒株);基于鸡痘病毒的疫苗、基于弹状病毒的疫苗,诸如VSV和马拉巴病毒;基于重组人CMV(rhCMV)的疫苗、基于甲病毒的疫苗,诸如西门利克森林病毒、委内瑞拉马脑炎病毒和辛德毕斯病毒;(参见Lauer,Clinical andVaccine Immunology,2017,DOI:10.1128/CVI.00298-16);LNP配制的基于mRNA的治疗疫苗;LNP配制的自复制RNA/自扩增RNA疫苗。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with HIV vaccines. Examples of HIV vaccines that can be combined or co-administered include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26 or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey i.e. rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pichinde), bi- or tripartite-segmented arenavirus-based vaccines, trimer-based vaccines. HIV-1 vaccine, measles virus-based vaccine, flavivirus vector-based vaccine, tobacco mosaic virus vector-based vaccine, varicella-zoster virus-based vaccine, human parainfluenza virus 3 (PIV3)-based vaccine, poxvirus-based vaccine (modified vaccinia virus Ankara (MVA)), orthopoxvirus-derived NYVAC and fowlpox virus-derived ALVAC (canarypox virus) strain); fowlpox virus-based vaccine, rhabdovirus-based vaccine, such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccine, alphavirus-based vaccine, such as Semliki Forest virus, Venezuelan equine encephalitis virus and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128/CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccine; LNP-formulated self-replicating RNA/self-amplifying RNA vaccine.
可共同施用的HIV疫苗的示例包括但不限于AAVLP-HIV疫苗、AE-298p、抗CD40.Env-gp140疫苗、Ad4-EnvC150、BG505 SOSIP.664gp140佐剂疫苗、BG505 SOSIP.GT1.1gp140佐剂疫苗、ChAdOx1.tHIVconsv1疫苗、CMV-MVA三联疫苗、ChAdOx1.HTI、Chimigen HIV疫苗、ConM SOSIP.v7gp140、ALVAC HIV(vCP1521)、AIDSVAX B/E(gp120)、单体gp120HIV-1C亚型疫苗、MPER-656脂质体亚基疫苗、Remune、ITV-1、Contre Vir、Ad5-ENVA-48、DCVax-001(CDX-2401)、Vacc-4x、Vacc-C5、VAC-3S、多级DNA重组腺病毒-5(rAd5)、rAd5 gag-pol envA/B/C疫苗、Pennvax-G、Pennvax-GP、Pennvax-G/MVA-CMDR、HIV-TriMix-mRNA疫苗、HIV-LAMP-vax、Ad35、Ad35-GRIN、NAcGM3/VSSP ISA-51、poly-ICLC佐剂疫苗、TatImmune、GTU-multiHIV(FIT-06)、ChAdV63.HIVconsv、gp140[delta]V2.TV1+MF-59、rVSVIN HIV-1gag疫苗、SeV-EnvF、SeV-Gag疫苗、AT-20、DNK-4、ad35-Grin/ENV、TBC-M4、HIVAX、HIVAX-2、基于N123-VRC-34.01诱导抗原的HIV疫苗、NYVAC-HIV-PT1、NYVAC-HIV-PT4、DNA-HIV-PT123、rAAV1-PG9DP、GOVX-B11、GOVX-B21、GOVX-C55、TVI-HIV-1、Ad-4(Ad4-env Clade C+Ad4-mGag)、Paxvax、EN41-UGR7C、EN41-FPA2、ENOB-HV-11、ENOB-HV-12、PreVaxTat、AE-H、MYM-V101、CombiHIVvac、ADVAX、MYM-V201、MVA-CMDR、MagaVax、DNA-Ad5 gag/pol/nef/nev(HVTN505)、MVATG-17401、ETV-01、CDX-1401、表达SCaVII的DNA和Sev载体疫苗、rcAD26.MOS1.HIV-Env、Ad26.Mod.HIV疫苗、Ad26.Mod.HIV+MVA镶嵌疫苗+gp140、AGS-004、AVX-101、AVX-201、PEP-6409、SAV-001、ThV-01、TL-01、TUTI-16、VGX-3300、VIR-1111、IHV-001和病毒样颗粒疫苗(诸如假病毒颗粒疫苗)、CombiVICHvac、LFn-p24 B/C融合疫苗、基于GTU的DNA疫苗、HIV gag/pol/nef/env DNA疫苗、抗TAT HIV疫苗、缀合多肽疫苗、树突细胞疫苗(诸如DermaVir)、基于gag的DNA疫苗、GI-2010、gp41 HIV-1疫苗、HIV疫苗(PIKA佐剂)、i-key/MHC II类抗原杂合肽疫苗、ITV-2、ITV-3、ITV-4、LIPO-5、多级Env疫苗、MVA疫苗、Pennvax-GP、pp71缺陷型HCMV载体HIV gag疫苗、rgp160 HIV疫苗、RNActive HIV疫苗、SCB-703、Tat Oyi疫苗、TBC-M4、UBI HIV gp120、Vacc-4x+罗米地辛、变体gp120多肽疫苗、rAd5gag-pol env A/B/C疫苗、DNA.HTI和MVA.HTI、VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP、INO-6145、JNJ-9220、gp145 C.6980;基于eOD-GT8 60mer的疫苗、PD-201401、env(A,B,C,A/E)/gag(C)DNA疫苗、gp120(A,B,C,A/E)蛋白疫苗、PDPHV-201401、Ad4-EnvCN54、EnvSeq-1 Envs HIV-1疫苗(GLA-SE佐剂)、HIV p24gag初免-加强质粒DNA疫苗、HIV-1iglb12中和VRC-01抗体-刺激抗CD4疫苗、基于沙粒病毒载体的疫苗()、MVA-BN HIV-1疫苗方案、UBI HIV gp120、基于mRNA的预防性疫苗、VPI-211、多聚体HIV gp120疫苗(福瑞德哈金森癌症研究中心)、TBL-1203HI、CH505 TFchTrimer、CD40.HIVRI.Env疫苗、Drep-HIV-PT-1、mRNA-1644和mRNA-1574。Examples of HIV vaccines that can be co-administered include, but are not limited to, AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvant vaccine, BG505 SOSIP.GT1.1gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7gp140, ALVAC HIV (vCP1521), AIDSVAX B/E (gp120), monomeric gp120 HIV-1C subtype vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-stage DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol envA/B/C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G/MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, HIV vaccine based on N123-VRC-34.01 induced antigen, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA expressing SCaVII and Sev vector vaccine, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001 and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine (such as DermaVir), gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key/MHC class II antigen hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 peptide vaccine, rAd5gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccine, PD-201401, env(A,B,C,A/E)/gag(C) DNA vaccine, gp120(A,B,C,A/E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, HIV-1iglb12 neutralizing VRC-01 antibody-stimulated anti-CD4 vaccine, arenavirus vector-based vaccine ( ), MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA-based preventive vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Research Center), TBL-1203HI, CH505 TFchTrimer, CD40.HIVRI.Env vaccine, Drep-HIV-PT-1, mRNA-1644 and mRNA-1574.
节育药(避孕药)组合疗法Birth control pill combination therapy
在某些实施方案中,将本文所述的药剂与节育或避孕方案组合。可组合或共同施用的用于节育(避孕)的治疗剂包括醋酸环丙孕酮、去氧孕烯、地诺孕素、屈螺酮、戊酸雌二醇、乙炔雌二醇、炔诺醇、依托孕烯、左旋甲基四氢叶酸、左炔诺孕酮、利奈孕酮、醋酸甲羟孕酮、炔雌醇甲醚、米非司酮、米索前列醇、醋酸诺美孕酮、去甲孕酮、异炔诺酮、诺孕酯、奥美昔芬、醋酸西格索尼、醋酸乌利司他以及它们的任何组合。In certain embodiments, the agents described herein are combined with birth control or contraceptive regimens. Therapeutic agents for birth control (contraception) that may be combined or co-administered include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinyl estradiol methyl ether, mifepristone, misoprostol, nomegestrol acetate, norprogesterone acetate, norethisterone, norgestimate, ormeloxifene, sigsone acetate, ulipristal acetate, and any combination thereof.
在一个实施方案中,将本文所公开的药剂或其药学上可接受的盐与选自以下项的一种、两种、三种、四种或更多种附加治疗剂组合:(依法韦仑、富马酸替诺福韦二吡呋酯和恩曲他滨);(;利匹韦林、富马酸替诺福韦二吡呋酯和恩曲他滨);(埃替拉韦、可比司他、富马酸替诺福韦二吡呋酯和恩曲他滨);(富马酸替诺福韦二吡呋酯和恩曲他滨;TDF+FTC);(替诺福韦艾拉酚胺和恩曲他滨);(替诺福韦艾拉酚胺、恩曲他滨和利匹韦林);(替诺福韦艾拉酚胺、恩曲他滨、可比司他和埃替拉韦);BIKTARVY(比卡格韦+恩曲他滨+替诺福韦艾拉酚胺),阿德福韦;阿德福韦双特戊酯;可比司他;恩曲他滨;替诺福韦;替诺福韦艾拉酚胺和埃替拉韦;替诺福韦艾拉酚胺+埃替拉韦(直肠制剂,HIV感染);替诺福韦二吡呋酯;富马酸替诺福韦二吡呋酯;替诺福韦艾拉酚胺;半富马酸替诺福韦艾拉酚胺;(度鲁特韦、阿巴卡韦和拉米夫定);度鲁特韦、硫酸阿巴卡韦和拉米夫定;雷特格韦;聚乙二醇化的雷特格韦;雷特格韦和拉米夫定;拉米夫定+洛匹那韦+利托那韦+阿巴卡韦;马拉韦罗;替诺福韦+恩曲他滨+马拉韦罗、恩夫韦肽;(;洛匹那韦和利托那韦);(齐多夫定和拉米夫定;AZT+3TC);(;硫酸阿巴卡韦和拉米夫定;ABC+3TC);(硫酸阿巴卡韦、齐多夫定和拉米夫定;ABC+AZT+3TC);利匹韦林;盐酸利匹韦林;硫酸阿扎那韦和可比司他;阿扎那韦和可比司他;地瑞拉韦和可比司他;阿扎那韦;硫酸阿扎那韦;度鲁特韦;埃替拉韦;利托那韦;硫酸阿扎那韦和利托那韦;地瑞拉韦;拉米夫定;普拉汀;福沙那韦;福沙那韦钙依法韦仑;依曲韦林;奈非那韦;甲磺酸奈非那韦;干扰素;地达诺新;司他夫定;茚地那韦;硫酸茚地那韦;替诺福韦和拉米夫定;齐多夫定;奈韦拉平;沙喹那韦;甲磺酸沙喹那韦;阿地白介素;扎西他滨;替拉那韦;安普那韦;地拉夫定;甲磺酸地拉夫定;Radha-108(受体醇);拉米夫定和富马酸替诺福韦二吡呋酯;依法韦仑、拉米夫定和富马酸替诺福韦二吡呋酯;叠氮膦;拉米夫定、奈韦拉平和齐多夫定;阿巴卡韦;和硫酸阿巴卡韦。In one embodiment, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY (bicagvir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir alafenamide and elvitegravir; tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection); tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (dulutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; raltegravir; pegylated raltegravir; raltegravir and lamivudine; lamivudine + lopinavir + ritonavir + abacavir; maraviroc; tenofovir + emtricitabine + maraviroc, enfuvirtide; ( ; lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( ; abacavir sulfate and lamivudine; ABC+3TC); (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; platinum; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphinothricin; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.
在一些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与逆转录酶的HIV核苷或核苷酸抑制剂和逆转录酶的HIV非核苷抑制剂组合。在另一个具体实施方案中,将本文所公开的药剂或其药物组合物与HIV逆转录酶的核苷或核苷酸抑制剂和HIV蛋白酶抑制化合物组合。在另外的实施方案中,将本文所公开的药剂或其药物组合物与HIV逆转录酶的核苷或核苷酸抑制剂、HIV逆转录酶的非核苷抑制剂和药代动力学增强剂组合。在某些实施方案中,将本文所公开的药剂或其药物组合物与逆转录酶的至少一种HIV核苷抑制剂、整合酶抑制剂和药代动力学增强剂组合。在另一个实施方案中,将本文所公开的药剂或其药物组合物与逆转录酶的两种HIV核苷或核苷酸抑制剂组合。In some embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the agents disclosed herein or their pharmaceutical compositions are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase and HIV protease inhibitory compounds. In additional embodiments, the agents disclosed herein or their pharmaceutical compositions are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase, non-nucleoside inhibitors of HIV reverse transcriptase, and pharmacokinetic enhancers. In certain embodiments, the agents disclosed herein or their pharmaceutical compositions are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the agents disclosed herein or their pharmaceutical compositions are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.
在一个实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与硫酸阿巴卡韦、替诺福韦、替诺福韦二吡呋酯、富马酸替诺福韦二吡呋酯、半富马酸替诺福韦二吡呋酯、替诺福韦艾拉酚胺或半富马酸替诺福韦艾拉酚胺组合。In one embodiment, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
在另一个实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与替诺福韦、替诺福韦二吡呋酯、富马酸替诺福韦二吡呋酯、替诺福韦艾拉酚胺或半富马酸替诺福韦艾拉酚胺组合。In another embodiment, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.
在又一个实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与第一附加治疗剂和第二附加治疗剂组合,该第一附加治疗剂选自硫酸阿巴卡韦、替诺福韦、替诺福韦二吡呋酯、富马酸替诺福韦二吡呋酯、替诺福韦艾拉酚胺和半富马酸替诺福韦艾拉酚胺,该第二附加治疗剂选自恩曲他滨和拉米夫定。In another embodiment, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.
在又一个实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与第一附加治疗剂和第二附加治疗剂组合,该第一附加治疗剂选自度鲁特韦、卡博特韦、伊斯拉曲韦、地瑞拉韦、比卡格韦、依斯沙韦林、利匹韦林和来那卡帕韦,该第二附加治疗剂选自恩曲他滨和拉米夫定。In yet another embodiment, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a first additional therapeutic agent selected from dolutegravir, cabotegravir, islatravir, darunavir, bicagavir, essavirine, rilpivirine, and lenacapasvir, and a second additional therapeutic agent selected from emtricitabine and lamivudine.
在另一个实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与第一附加治疗剂和第二附加治疗剂组合,该第一附加治疗剂选自替诺福韦、替诺福韦二吡呋酯、富马酸替诺福韦二吡呋酯、替诺福韦艾拉酚胺和半富马酸替诺福韦艾拉酚胺,其中该第二附加治疗剂是恩曲他滨。In another embodiment, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a first additional therapeutic agent and a second additional therapeutic agent selected from tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, wherein the second additional therapeutic agent is emtricitabine.
将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与第一附加治疗剂(避孕剂)组合,该第一附加治疗剂选自:醋酸环丙孕酮、去氧孕烯、地诺孕素、屈螺酮、戊酸雌二醇、乙炔雌二醇、炔诺醇、依托孕烯、左旋甲基四氢叶酸、左炔诺孕酮、利奈孕酮、醋酸甲羟孕酮、炔雌醇甲醚、米非司酮、米索前列醇、醋酸诺美孕酮、去甲孕酮、异炔诺酮、诺孕酯、奥美昔芬、醋酸西格索尼、醋酸乌利司他以及它们的任何组合。One or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a first additional therapeutic agent (contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinyl estradiol methyl ether, mifepristone, misoprostol, nomegestrol acetate, norprogesterone acetate, norethisterone, norgestimate, ormeloxifene, sigsone acetate, ulipristal acetate, and any combination thereof.
基因疗法和细胞疗法Gene therapy and cell therapy
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与基因或细胞疗法方案组合。基因疗法和细胞疗法包括但不限于使基因沉默的基因修饰;直接杀伤感染细胞的基因方法;免疫细胞的输注,所述免疫细胞被设计成替换大部分患者自身的免疫系统以增强对被感染细胞的免疫应答,或激活患者自身的免疫系统以杀死被感染细胞,或找到并杀死被感染细胞;修饰细胞活性的基因方法,以进一步改变针对感染的内源性免疫应答。细胞疗法的示例包括但不限于LB-1903、ENOB-HV-01、ENOB-HV-21、ENOB-HV-31、GOVX-B01、过表达ALDH1的HSPC(LV-800,HIV感染)、AGT103-T和基于SupT1细胞的疗法。树突状细胞疗法的示例包括但不限于AGS-004。CCR5基因编辑剂包括但不限于SB-728T、SB-728-HSPC。CCR5基因抑制剂包括但不限于Cal-1和慢病毒载体CCR5 shRNA/TRIM5α/TAR诱饵转导的自体CD34阳性造血祖细胞(HIV感染/HIV相关淋巴瘤)。在一些实施方案中,将表达C34-CCR5/C34-CXCR4的CD4阳性T细胞与一种或多种融合多肽共同施用。在一些实施方案中,将本文所述的药剂与AGT-103转导的自体T细胞疗法或AAV-eCD4-Ig基因疗法共同施用。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNP) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with gene or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells, which are designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill infected cells; gene methods that modify cell activity to further change the endogenous immune response to infection. Examples of cell therapy include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPC (LV-800, HIV infection) overexpressing ALDH1, AGT103-T, and SupT1 cell-based therapy. Examples of dendritic cell therapy include, but are not limited to, AGS-004. CCR5 gene editors include but are not limited to SB-728T, SB-728-HSPC. CCR5 gene inhibitors include but are not limited to Cal-1 and autologous CD34-positive hematopoietic progenitor cells (HIV infection/HIV-related lymphoma) transduced with lentiviral vector CCR5 shRNA/TRIM5α/TAR decoy. In some embodiments, CD4-positive T cells expressing C34-CCR5/C34-CXCR4 are co-administered with one or more fusion polypeptides. In some embodiments, the agents described herein are co-administered with autologous T cell therapy transduced with AGT-103 or AAV-eCD4-Ig gene therapy.
基因编辑物Gene editing
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与基因编辑物(例如,HIV靶向基因编辑物)组合。在各种实施方案中,基因组编辑系统可选自:CRISPR/Cas9复合物、锌指核酸酶复合物、TALEN复合物、归巢内切核酸酶复合物和大范围核酸酶复合物。例示性HIV靶向CRISPR/Cas9系统包括但不限于EBT-101。In certain embodiments, one or more fusion polypeptides as disclosed herein or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with gene editors (e.g., HIV targeted gene editors). In various embodiments, the genome editing system can be selected from: CRISPR/Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and meganuclease complexes. Exemplary HIV targeted CRISPR/Cas9 systems include, but are not limited to, EBT-101.
CAR-T细胞疗法CAR-T cell therapy
在一些实施方案中,可以将本文所述的药剂与经工程化以表达嵌合抗原受体(CAR)的免疫效应细胞群体共同施用,其中CAR包含HIV抗原结合结构域。HIV抗原包括HIV包膜蛋白或其部分、gp120或其部分、gp120上的CD4结合位点、gp120上的CD4-诱导的结合位点、gp120上的N聚糖、gp120的V2、gp41上的膜近侧区域。免疫效应细胞是T细胞或NK细胞。在一些实施方案中,T细胞是CD4+ T细胞、CD8+ T细胞或它们的组合。细胞可以是自体的或同种异体的。HIV CAR-T的示例包括A-1801、A-1902、可转换CAR-T、VC-CAR-T、CMV-N6-CART、抗HIV duoCAR-T、抗CD4CART细胞疗法、CD4 CAR+C34-CXCR4+CCR5 ZFN T细胞、双重抗CD4CART-T细胞疗法(CD4 CAR+C34-CXCR4 T细胞)、抗CD4 MicAbody抗体+抗MicAbody CAR T细胞疗法(iNKG2D CAR,HIV感染)、GP-120CAR-T疗法、经基因工程化以表达CD4 CAR和C46肽的自体造血干细胞。In some embodiments, the agents described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. HIV antigens include HIV envelope proteins or portions thereof, gp120 or portions thereof, CD4 binding sites on gp120, CD4-induced binding sites on gp120, N polysaccharides on gp120, V2 of gp120, and membrane proximal regions on gp41. Immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+ T cells, CD8+ T cells, or combinations thereof. Cells can be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4CART cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4CART-T cell therapy (CD4 CAR+C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.
TCR-T细胞疗法TCR-T cell therapy
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与TCR-T细胞群体组合。TCR-T细胞被工程化以靶向病毒感染细胞表面上存在的HIV来源的肽,例如ImmTAV。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a TCR-T cell population. TCR-T cells are engineered to target HIV-derived peptides present on the surface of virally infected cells, such as ImmTAV.
B细胞疗法B-cell therapy
在某些实施方案中,将如本文所公开的一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体与经基因修饰以表达广泛中和抗体诸如3BNC117的B细胞群体组合(Hartweger等人,J.Exp.Med.2019,1301;Moffett等人,Sci.Immunol.4,eaax0644(2019),2019年5月17日)。In certain embodiments, one or more fusion polypeptides as disclosed herein, or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides are combined with a population of B cells genetically modified to express a broadly neutralizing antibody such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019), May 17, 2019).
8.试剂盒8. Test kit
还提供了试剂盒,该试剂盒包括一个或多个单位剂量的如本文所述的融合多肽或复合融合多肽中的一者或多者或如本文所述的编码此类融合多肽或复合融合多肽的一种或多种多核苷酸或如本文所述的表达此类融合多肽或复合融合多肽的一种或多种载体。在一些实施方案中,试剂盒包括两个或更多个单位剂量的如本文所述的融合多肽或复合融合多肽中的一者或多者或编码如本文所述的此类融合多肽或复合融合多肽的两种或更多种多核苷酸或表达如本文所述的此类融合多肽或复合融合多肽的两种或更多种载体。在一些实施方案中,一个或多个单位剂量在单个容器中。在一些实施方案中,一个或多个单位剂量在两个或更多个单独的容器中。在某些实施方案中,单位剂量可以相同或不同,例如可以包含相同或不同的单位剂量,例如可以包含多肽、多核苷酸、载体或它们的组合。Also provided is a kit, the kit includes one or more unit doses of fusion polypeptides as described herein or one or more of the composite fusion polypeptides or one or more polynucleotides encoding such fusion polypeptides or composite fusion polypeptides as described herein or one or more carriers expressing such fusion polypeptides or composite fusion polypeptides as described herein. In some embodiments, the kit includes two or more unit doses of fusion polypeptides as described herein or one or more of the composite fusion polypeptides or two or more polynucleotides encoding such fusion polypeptides or composite fusion polypeptides as described herein or two or more carriers expressing such fusion polypeptides or composite fusion polypeptides as described herein. In some embodiments, one or more unit doses are in a single container. In some embodiments, one or more unit doses are in two or more separate containers. In certain embodiments, the unit doses may be identical or different, for example, identical or different unit doses may be included, for example, polypeptides, polynucleotides, carriers, or combinations thereof may be included.
在各种实施方案中,试剂盒包括一个或多个药物包或一个或多个容器(例如,小瓶、安瓿、预装注射器),所述药物包或容器含有本文所述的药物组合物的一种或多种成分,诸如如本文所述的一种或多种融合多肽或如本文所述的编码此类融合多肽的一种或多种多核苷酸或如本文所述的表达此类融合多肽的一种或多种载体。在各种实施方案中,试剂盒包括一个或多个容器,所述容器包含水性溶液形式的如本文所述的一种或多种融合多肽或如本文所述的编码此类融合多肽的一种或多种多核苷酸或如本文所述的表达此类融合多肽的一种或多种载体。在各种实施方案中,试剂盒包括一个或多个容器,所述容器包含冻干形式的如本文所述的一种或多种融合多肽或如本文所述的编码此类融合多肽的一种或多种多核苷酸或如本文所述的表达此类融合多肽的一种或多种载体。In various embodiments, the kit includes one or more pharmaceutical packages or one or more containers (e.g., vials, ampoules, prefilled syringes) containing one or more ingredients of the pharmaceutical compositions described herein, such as one or more fusion polypeptides as described herein or one or more polynucleotides encoding such fusion polypeptides as described herein or one or more vectors expressing such fusion polypeptides as described herein. In various embodiments, the kit includes one or more containers comprising one or more fusion polypeptides as described herein in the form of aqueous solutions or one or more polynucleotides encoding such fusion polypeptides as described herein or one or more vectors expressing such fusion polypeptides as described herein. In various embodiments, the kit includes one or more containers comprising one or more fusion polypeptides as described herein in a lyophilized form or one or more polynucleotides encoding such fusion polypeptides as described herein or one or more vectors expressing such fusion polypeptides as described herein.
在一些实施方案中,试剂盒包括一个或多个单位剂量的能够表达融合多肽的一种或多种病毒载体。在一些实施方案中,单位剂量的一种或多种病毒载体在每次施用约103至约1012个病毒病灶形成单位(FFU)或噬菌斑形成单位(PFU)或感染单位(IU)或病毒颗粒(vp)的范围内,例如为约104至约107个病毒FFU或PFU或IU或vp,例如约103至约104、105、106、107、108、109、1010、1011、1012、1013、1014或1015个病毒FFU或PFU或IU或vp。In some embodiments, the kit includes one or more unit doses of one or more viral vectors capable of expressing the fusion polypeptide. In some embodiments, the unit dose of one or more viral vectors is within the range of about 10 3 to about 10 12 viral focus forming units (FFU) or plaque forming units (PFU) or infectious units (IU) or viral particles (vp) per administration, for example, about 10 4 to about 10 7 viral FFU or PFU or IU or vp, for example, about 10 3 to about 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , 10 12 , 10 13 , 10 14 or 10 15 viral FFU or PFU or IU or vp.
在一些实施方案中,试剂盒包括第一融合多肽和第二融合多肽或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码该第一和第二融合多肽,该第一和第二多肽从N末端到C末端按顺序包含任选地通过一个或多个接头结合或连接的以下多肽片段:In some embodiments, the kit includes a first fusion polypeptide and a second fusion polypeptide or one or more vectors comprising one or more polynucleotides encoding the first and second fusion polypeptides, the first and second polypeptides comprising, in order from N-terminus to C-terminus, the following polypeptide fragments optionally bound or linked by one or more linkers:
·SEQ ID NO:6、4、16和26,以及SEQ ID NO:7、5、27和17;SEQ ID NOs: 6, 4, 16 and 26, and SEQ ID NOs: 7, 5, 27 and 17;
·SEQ ID NO:12、24、8和10,以及SEQ ID NO:9、25、13和11;SEQ ID NOs: 12, 24, 8 and 10, and SEQ ID NOs: 9, 25, 13 and 11;
·SEQ ID NO:14、22、18、24和20,以及SEQ ID NO:15、25、19、23和21;SEQ ID NOs: 14, 22, 18, 24 and 20, and SEQ ID NOs: 15, 25, 19, 23 and 21;
·SEQ ID NO:26、16、4和6,以及SEQ ID NO:7、27、5和17;SEQ ID NOs: 26, 16, 4 and 6, and SEQ ID NOs: 7, 27, 5 and 17;
·SEQ ID NO:8、24、12和10,以及SEQ ID NO:13、25、9和11;SEQ ID NOs: 8, 24, 12 and 10, and SEQ ID NOs: 13, 25, 9 and 11;
·SEQ ID NO:22、24、14、18和20,以及SEQ ID NO:25、23、15、21和19;SEQ ID NOs: 22, 24, 14, 18 and 20, and SEQ ID NOs: 25, 23, 15, 21 and 19;
·SEQ ID NO:20、6、4、18、16和26,以及SEQ ID NO:7、19、5、21、27和17;SEQ ID NOs: 20, 6, 4, 18, 16 and 26, and SEQ ID NOs: 7, 19, 5, 21, 27 and 17;
·SEQ ID NO:8、24、14、12、22和10,以及SEQ ID NO:9、13、25、23、15和11;SEQ ID NOs: 8, 24, 14, 12, 22 and 10, and SEQ ID NOs: 9, 13, 25, 23, 15 and 11;
·SEQ ID NO:18、26、20、4、6和16,以及SEQ ID NO:7、21、17、5、27和19;SEQ ID NOs: 18, 26, 20, 4, 6 and 16, and SEQ ID NOs: 7, 21, 17, 5, 27 and 19;
·SEQ ID NO:22、24、12、14、8和10,以及SEQ ID NO:15、25、9、23、13和11;SEQ ID NOs: 22, 24, 12, 14, 8 and 10, and SEQ ID NOs: 15, 25, 9, 23, 13 and 11;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 8, 30, 14, 12, 26 and 10;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:7、21、5、25、33和19;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 7, 21, 5, 25, 33 and 19;
·SEQ ID NO:24、6、4、20、18和32,以及SEQ ID NO:8、30、14、12、26和10;SEQ ID NOs: 24, 6, 4, 20, 18 and 32, and SEQ ID NOs: 8, 30, 14, 12, 26 and 10;
·SEQ ID NO:8、30、14、12、26和10,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NOs: 8, 30, 14, 12, 26 and 10, and SEQ ID NOs: 9, 13, 31, 27, 15 and 11;
·SEQ ID NO:7、21、5、25、33和19,以及SEQ ID NO:9、13、31、27、15和11;SEQ ID NOs: 7, 21, 5, 25, 33 and 19, and SEQ ID NOs: 9, 13, 31, 27, 15 and 11;
·SEQ ID NO:20、32、24、4、6和18,以及SEQ ID NO:26、30、12、14、8和10;SEQ ID NOs: 20, 32, 24, 4, 6 and 18, and SEQ ID NOs: 26, 30, 12, 14, 8 and 10;
·SEQ ID NO:6、20、4、24、32和18,以及SEQ ID NO:8、12、30、26、14和10;SEQ ID NOs: 6, 20, 4, 24, 32 and 18, and SEQ ID NOs: 8, 12, 30, 26, 14 and 10;
·SEQ ID NO:7、25、19、5、33和21,以及SEQ ID NO:15、31、9、27、13和11;SEQ ID NOs: 7, 25, 19, 5, 33 and 21, and SEQ ID NOs: 15, 31, 9, 27, 13 and 11;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、20、10和28;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 26, 20, 10 and 28;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:26、10、20和28;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 26, 10, 20 and 28;
·SEQ ID NO:24、6、16和18,以及SEQ ID NO:7、25、17和19;SEQ ID NOs: 24, 6, 16 and 18, and SEQ ID NOs: 7, 25, 17 and 19;
·SEQ ID NO:7、19、17和25,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 7, 19, 17 and 25, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:24、16、6和18,以及SEQ ID NO:27、11、21和29;SEQ ID NOs: 24, 16, 6 and 18, and SEQ ID NOs: 27, 11, 21 and 29;
·SEQ ID NO:7、25、17和19,以及SEQ ID NO:11、27、21和29;SEQ ID NOs: 7, 25, 17 and 19, and SEQ ID NOs: 11, 27, 21 and 29;
·SEQ ID NO:7、25、17和19,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 7, 25, 17 and 19, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:22、6、20和28,以及SEQ ID NO:23、7、21和29;SEQ ID NOs: 22, 6, 20 and 28, and SEQ ID NOs: 23, 7, 21 and 29;
·SEQ ID NO:22、20、6和28,以及SEQ ID NO:7、21、23和29;SEQ ID NOs: 22, 20, 6 and 28, and SEQ ID NOs: 7, 21, 23 and 29;
·SEQ ID NO:26、10、20和28,以及SEQ ID NO:21、27、11和29;SEQ ID NOs: 26, 10, 20 and 28, and SEQ ID NOs: 21, 27, 11 and 29;
·SEQ ID NO:22、6、16、20、18、28、26和10;或SEQ ID NO: 22, 6, 16, 20, 18, 28, 26 and 10; or
·SEQ ID NO:7、21、19、17、27、25、29和11。· SEQ ID NO: 7, 21, 19, 17, 27, 25, 29 and 11.
在一些实施方案中,试剂盒包括一种或多种融合多肽、或包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:70-101、105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQID NO:70-101、105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,试剂盒包括一种或多种融合多肽、或包含编码一种或多种融合多肽的一种或多种多核苷酸的一种或多种载体,这些融合多肽包含以下或由以下组成:SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项的氨基酸序列,或与SEQ ID NO:82-83、85-87、98-101、209和222-223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In some embodiments, the kit includes one or more fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, which fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223 and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70-101, 105-112, 200-209, 222-223 and 227. In some embodiments, the kit includes one or more fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding one or more fusion polypeptides, which fusion polypeptides comprise or consist of the amino acid sequence of any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209 and 222-223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82-83, 85-87, 98-101, 209 and 222-223.
在一些实施方案中,试剂盒包括以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 88, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively; or
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes first, second, third, and fourth viral vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 83, respectively;
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码第一融合多肽和第二融合多肽:包含SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide of SEQ ID NOs: 84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 85, respectively;
c)第三病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和c) a third viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 86 and 87, respectively; and
d)第四病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。d) a fourth viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 88 and 89, respectively.
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes first, second, third, and fourth viral vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively;
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide of SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively;
c)第三病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:84和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和c) a third viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 84 and 88, respectively; and
d)第四病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。d) a fourth viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 89, respectively.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes first, second, third, and fourth viral vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively;
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide of SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively;
c)第三病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及c) a third viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
d)第四病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。d) a fourth viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes first, second, third, and fourth viral vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 82 and 86, respectively;
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码第一融合多肽和第二融合多肽:包含SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide of SEQ ID NOs: 83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 83 and 87, respectively;
c)第三病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;以及c) a third viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
d)第四病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。d) a fourth viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 85 and 101, respectively.
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 90 and 91, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 92 and 93, respectively.
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 96, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively;
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:220和221的融合多肽,或分别与SEQ IDNO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 95 and 97, respectively;
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 94 and 95, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 96 and 97, respectively;
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 100, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 99 and 101, respectively.
在一些实施方案中,试剂盒包括第一和第二病毒载体,这些病毒载体包含一种或多种多核苷酸,该一种或多种多核苷酸编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes a first and a second viral vector comprising one or more polynucleotides encoding the following first and second fusion polypeptides, optionally bound or linked by one or more linkers:
a)第一病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;和a) a first viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 98 and 99, respectively; and
b)第二病毒载体,其包含一种或多种多核苷酸,该一种或多种多核苷酸编码以下第一融合多肽和第二融合多肽:包含SEQ ID NO:100和101的融合多肽,或分别与SEQ IDNO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。b) a second viral vector comprising one or more polynucleotides encoding a first fusion polypeptide and a second fusion polypeptide comprising a fusion polypeptide comprising SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively.
在一些实施方案中,试剂盒包括第一和第二病毒载体,该第一和第二病毒载体包含编码以下第一复合融合多肽和第二复合融合多肽的多核苷酸:In some embodiments, the kit includes first and second viral vectors comprising polynucleotides encoding the following first composite fusion polypeptide and second composite fusion polypeptide:
a)第一病毒载体,其包含多核苷酸,该多核苷酸编码以下第一复合融合多肽:包含SEQ ID NO:105的复合融合多肽,或与SEQ ID NO:105至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;和a) a first viral vector comprising a polynucleotide encoding a first composite fusion polypeptide comprising a composite fusion polypeptide comprising SEQ ID NO: 105, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 105; and
b)第二病毒载体,其包含多核苷酸,该多核苷酸编码以下第一复合融合多肽:包含SEQ ID NO:109的复合融合多肽,或与SEQ ID NO:109至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。b) a second viral vector comprising a polynucleotide encoding a first composite fusion polypeptide comprising a composite fusion polypeptide comprising SEQ ID NO: 109, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 109.
在一些实施方案中,试剂盒包括第一和第二病毒载体,该第一和第二病毒载体包含编码以下第一复合融合多肽和第二复合融合多肽的多核苷酸:In some embodiments, the kit includes first and second viral vectors comprising polynucleotides encoding the following first composite fusion polypeptide and second composite fusion polypeptide:
a)第一病毒载体,其包含多核苷酸,该多核苷酸编码以下第一复合融合多肽:包含SEQ ID NO:107的复合融合多肽,或与SEQ ID NO:107至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽;和a) a first viral vector comprising a polynucleotide encoding a first composite fusion polypeptide comprising a composite fusion polypeptide comprising SEQ ID NO: 107, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 107; and
b)第二病毒载体,其包含多核苷酸,该多核苷酸编码以下第一复合融合多肽:包含SEQ ID NO:111的复合融合多肽,或与SEQ ID NO:111至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的复合融合多肽。b) a second viral vector comprising a polynucleotide encoding a first composite fusion polypeptide comprising a composite fusion polypeptide comprising SEQ ID NO: 111, or a composite fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 111.
在一些实施方案中,试剂盒包括以下第一融合多肽和第二融合多肽、或包含一种或多种多核苷酸的一种或多种载体,该一种或多种多核苷酸从N末端到C末端按顺序编码任选地通过一个或多个接头结合或连接的以下第一融合多肽和第二融合多肽:In some embodiments, the kit includes the following first and second fusion polypeptides, or one or more vectors comprising one or more polynucleotides encoding the following first and second fusion polypeptides in order from N-terminus to C-terminus, optionally bound or linked by one or more linkers:
·SEQ ID NO:70和71的融合多肽,或分别与SEQ ID NO:70和71中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:70 and 71, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:70 and 71, respectively;
·SEQ ID NO:71和70的融合多肽,或分别与SEQ ID NO:71和70中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:71 and 70, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:71 and 70, respectively;
·SEQ ID NO:72和73的融合多肽,或分别与SEQ ID NO:72和73中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:72 and 73, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:72 and 73, respectively;
·SEQ ID NO:73和72的融合多肽,或分别与SEQ ID NO:73和72中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:73 and 72, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:73 and 72, respectively;
·SEQ ID NO:74和75的融合多肽,或分别与SEQ ID NO:74和75中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:74 and 75, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:74 and 75, respectively;
·SEQ ID NO:75和74的融合多肽,或分别与SEQ ID NO:75和74中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:75 and 74, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:75 and 74, respectively;
·SEQ ID NO:76和77的融合多肽,或分别与SEQ ID NO:76和77中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:76 and 77, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:76 and 77, respectively;
·SEQ ID NO:77和76的融合多肽,或分别与SEQ ID NO:77和76中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:77 and 76, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:77 and 76, respectively;
·SEQ ID NO:78和79的融合多肽,或分别与SEQ ID NO:78和79中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:78 and 79, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:78 and 79, respectively;
·SEQ ID NO:79和78的融合多肽,或分别与SEQ ID NO:79和78中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:79 and 78, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:79 and 78, respectively;
·SEQ ID NO:80和81的融合多肽,或分别与SEQ ID NO:80和81中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:80 and 81, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:80 and 81, respectively;
·SEQ ID NO:81和80的融合多肽,或分别与SEQ ID NO:81和80中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:81 and 80, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:81 and 80, respectively;
·SEQ ID NO:82和83的融合多肽,或分别与SEQ ID NO:82和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 83, respectively;
·SEQ ID NO:83和82的融合多肽,或分别与SEQ ID NO:83和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 82, respectively;
·SEQ ID NO:84和85的融合多肽,或分别与SEQ ID NO:84和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:84 and 85, respectively;
·SEQ ID NO:85和84的融合多肽,或分别与SEQ ID NO:85和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 84, respectively;
·SEQ ID NO:86和87的融合多肽,或分别与SEQ ID NO:86和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 87, respectively;
·SEQ ID NO:87和86的融合多肽,或分别与SEQ ID NO:87和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 86, respectively;
·SEQ ID NO:88和89的融合多肽,或分别与SEQ ID NO:88和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 89, respectively;
·SEQ ID NO:89和88的融合多肽,或分别与SEQ ID NO:89和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 88, respectively;
·SEQ ID NO:82和85的融合多肽,或分别与SEQ ID NO:82和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 85, respectively;
·SEQ ID NO:85和82的融合多肽,或分别与SEQ ID NO:85和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 82, respectively;
·SEQ ID NO:82和86的融合多肽,或分别与SEQ ID NO:82和86中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 86, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 86, respectively;
·SEQ ID NO:86和82的融合多肽,或分别与SEQ ID NO:86和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:86 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:86 and 82, respectively;
·SEQ ID NO:82和88的融合多肽,或分别与SEQ ID NO:82和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:82 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:82 and 88, respectively;
·SEQ ID NO:88和82的融合多肽,或分别与SEQ ID NO:88和82中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 82, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 82, respectively;
·SEQ ID NO:83和87的融合多肽,或分别与SEQ ID NO:83和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:83 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:83 and 87, respectively;
·SEQ ID NO:87和83的融合多肽,或分别与SEQ ID NO:87和83中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 83, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 83, respectively;
·SEQ ID NO:85和87的融合多肽,或分别与SEQ ID NO:85和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 87, respectively;
·SEQ ID NO:87和85的融合多肽,或分别与SEQ ID NO:87和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 85, respectively;
·SEQ ID NO:88和87的融合多肽,或分别与SEQ ID NO:88和87中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 87, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 87, respectively;
·SEQ ID NO:87和88的融合多肽,或分别与SEQ ID NO:87和88中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:87 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:87 and 88, respectively;
·SEQ ID NO:84和88的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:84 and 88, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:88和84的融合多肽,或分别与SEQ ID NO:88和84中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:88 and 84, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:88 and 84, respectively;
·SEQ ID NO:85和89的融合多肽,或分别与SEQ ID NO:85和89中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 89, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 89, respectively;
·SEQ ID NO:89和85的融合多肽,或分别与SEQ ID NO:89和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:89 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:89 and 85, respectively;
·SEQ ID NO:85和101的融合多肽,或分别与SEQ ID NO:85和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:85 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:85 and 101, respectively;
·SEQ ID NO:101和85的融合多肽,或分别与SEQ ID NO:101和85中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 85, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 85, respectively;
·SEQ ID NO:90和91的融合多肽,或分别与SEQ ID NO:90和91中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:90 and 91, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:90 and 91, respectively;
·SEQ ID NO:91和90的融合多肽,或分别与SEQ ID NO:91和90中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:91 and 90, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:91 and 90, respectively;
·SEQ ID NO:92和93的融合多肽,或分别与SEQ ID NO:92和93中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:92 and 93, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:92 and 93, respectively;
·SEQ ID NO:93和92的融合多肽,或分别与SEQ ID NO:93和92中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:93 and 92, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:93 and 92, respectively;
·SEQ ID NO:94和95的融合多肽,或分别与SEQ ID NO:94和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 95, respectively;
·SEQ ID NO:95和94的融合多肽,或分别与SEQ ID NO:95和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 94, respectively;
·SEQ ID NO:96和97的融合多肽,或分别与SEQ ID NO:96和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 97, respectively;
·SEQ ID NO:97和96的融合多肽,或分别与SEQ ID NO:97和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 96, respectively;
·SEQ ID NO:94和96的融合多肽,或分别与SEQ ID NO:94和96中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:94 and 96, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:94 and 96, respectively;
·SEQ ID NO:96和94的融合多肽,或分别与SEQ ID NO:96和94中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:96 and 94, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:96 and 94, respectively;
·SEQ ID NO:95和97的融合多肽,或分别与SEQ ID NO:95和97中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:95 and 97, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:95 and 97, respectively;
·SEQ ID NO:97和95的融合多肽,或分别与SEQ ID NO:97和95中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:97 and 95, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:97 and 95, respectively;
·SEQ ID NO:220和221的融合多肽,或分别与SEQ ID NO:220和221中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 220 and 221, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 220 and 221, respectively;
·SEQ ID NO:221和220的融合多肽,或分别与SEQ ID NO:221和220中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 221 and 220, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 221 and 220, respectively;
·SEQ ID NO:98和100的融合多肽,或分别与SEQ ID NO:98和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 100, respectively;
·SEQ ID NO:100和98的融合多肽,或分别与SEQ ID NO:100和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 100 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 98, respectively;
·SEQ ID NO:99和101的融合多肽,或分别与SEQ ID NO:99和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;· a fusion polypeptide of SEQ ID NOs:99 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 101, respectively;
·SEQ ID NO:101和99的融合多肽,或分别与SEQ ID NO:101和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs: 101 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 99, respectively;
·SEQ ID NO:98和99的融合多肽,或分别与SEQ ID NO:98和99中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:98 and 99, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:98 and 99, respectively;
·SEQ ID NO:99和98的融合多肽,或分别与SEQ ID NO:99和98中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;a fusion polypeptide of SEQ ID NOs:99 and 98, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs:99 and 98, respectively;
·SEQ ID NO:100和101的融合多肽,或分别与SEQ ID NO:100和101中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽;或者a fusion polypeptide of SEQ ID NOs: 100 and 101, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 100 and 101, respectively; or
·SEQ ID NO:101和100的融合多肽,或分别与SEQ ID NO:101和100中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的融合多肽。· A fusion polypeptide of SEQ ID NOs: 101 and 100, or a fusion polypeptide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 101 and 100, respectively.
在一些实施方案中,试剂盒包括多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:130-167、210-219和225-226中的任一项的核酸序列,或与SEQ ID NO:130-167、210-219和225-226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。在一些实施方案中,试剂盒包括多核苷酸,该多核苷酸包含以下或由以下组成:SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项的核酸序列,或与SEQ ID NO:139、140、142、143、145、146、148、149、150、152、155、158、225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的核酸序列。In some embodiments, the kit includes a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NOs: 130-167, 210-219, and 225-226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 130-167, 210-219, and 225-226. In some embodiments, the kit includes a polynucleotide comprising or consisting of a nucleic acid sequence of any one of SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226, or a nucleic acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 139, 140, 142, 143, 145, 146, 148, 149, 150, 152, 155, 158, 225, and 226.
在一些实施方案中,试剂盒包括以下第一多核苷酸和第二多核苷酸,或包含以下第一多核苷酸和第二多核苷酸的一种或多种载体:In some embodiments, the kit includes the following first and second polynucleotides, or one or more vectors comprising the following first and second polynucleotides:
·SEQ ID NO:130和132的多核苷酸,或分别与SEQ ID NO:130和132中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 132, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 132, respectively;
·SEQ ID NO:130和134的多核苷酸,或分别与SEQ ID NO:130和134中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 130 and 134, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 130 and 134, respectively;
·SEQ ID NO:131和133的多核苷酸,或分别与SEQ ID NO:131和133中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 133, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 133, respectively;
·SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 131 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively;
·SEQ ID NO:132和136的多核苷酸,或分别与SEQ ID NO:132和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 132 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 132 and 136, respectively;
·SEQ ID NO:133和135的多核苷酸,或分别与SEQ ID NO:133和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 135, respectively;
·SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 133 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively;
·SEQ ID NO:134和136的多核苷酸,或分别与SEQ ID NO:134和136中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 134 and 136, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 134 and 136, respectively;
·SEQ ID NO:135和137的多核苷酸,或分别与SEQ ID NO:135和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 135 and 137, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 135 and 137, respectively;
·SEQ ID NO:138和141的多核苷酸,或分别与SEQ ID NO:138和141中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 141, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 141, respectively;
·SEQ ID NO:138和144的多核苷酸,或分别与SEQ ID NO:138和144中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 138 and 144, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 138 and 144, respectively;
·SEQ ID NO:139和142的多核苷酸,或分别与SEQ ID NO:139和142中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 142, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 142, respectively;
·SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 139 and 145, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively;
·SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 140 and 146, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively;
·SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 142 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively;
·SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 143 and 149, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively;
·SEQ ID NO:145和148的多核苷酸,或分别与SEQ ID NO:145和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 145 and 148, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 145 and 148, respectively;
·SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 152, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively;
·SEQ ID NO:150和155的多核苷酸,或分别与SEQ ID NO:150和155中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 150 and 155, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 155, respectively;
·SEQ ID NO:151和153的多核苷酸,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 153, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively;
·SEQ ID NO:151和156的多核苷酸,或分别与SEQ ID NO:151和156中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 151 and 156, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 156, respectively;
·SEQ ID NO:152和158的多核苷酸,或分别与SEQ ID NO:152和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 152 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 152 and 158, respectively;
·SEQ ID NO:153和159的多核苷酸,或分别与SEQ ID NO:153和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 153 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 153 and 159, respectively;
·SEQ ID NO:154和157的多核苷酸,或分别与SEQ ID NO:154和157中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 154 and 157, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157, respectively;
·SEQ ID NO:155和158的多核苷酸,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 155 and 158, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively;
·SEQ ID NO:156和159的多核苷酸,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 156 and 159, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively;
·SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 160 and 161, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively;
·SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 162 and 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively;
·SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 164 and 165, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively;
·SEQ ID NO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 166 and 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively;
·SEQ ID NO:210和211的多核苷酸,或分别与SEQ ID NO:210和211中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 210 and 211, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 210 and 211, respectively;
·SEQ ID NO:212和213的多核苷酸,或分别与SEQ ID NO:212和213中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 212 and 213, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 212 and 213, respectively;
·SEQ ID NO:214和215的多核苷酸,或分别与SEQ ID NO:214和215中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 214 and 215, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 214 and 215, respectively;
·SEQ ID NO:216和217的多核苷酸,或分别与SEQ ID NO:216和217中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 216 and 217, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 216 and 217, respectively;
·SEQ ID NO:218和219的多核苷酸,或分别与SEQ ID NO:218和219中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;· a polynucleotide of SEQ ID NOs: 218 and 219, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 219, respectively;
·SEQ ID NO:218和226的多核苷酸,或分别与SEQ ID NO:218和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;或者a polynucleotide of SEQ ID NOs: 218 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 218 and 226, respectively; or
·SEQ ID NO:225和226的多核苷酸,或分别与SEQ ID NO:225和226中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。· A polynucleotide of SEQ ID NOs: 225 and 226, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 225 and 226, respectively.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:131和135的多核苷酸,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 131 and 135, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively; and
b)第二载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:133和137的多核苷酸,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,第一和第二病毒载体是腺病毒载体。b) a second vector comprising the following first and second polynucleotides: polynucleotides comprising SEQ ID NOs: 133 and 137, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively. In some embodiments, the first and second viral vectors are adenoviral vectors.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:139和145的多核苷酸,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 139 and 145, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; and
b)第二载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:142和148的多核苷酸,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,第一和第二病毒载体是腺病毒载体。b) a second vector comprising the following first and second polynucleotides: polynucleotides comprising SEQ ID NOs: 142 and 148, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively. In some embodiments, the first and second viral vectors are adenoviral vectors.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146的多核苷酸,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 140 and 146, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively; and
b)第二载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149的多核苷酸,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,第一和第二病毒载体是淋巴细胞性脉络丛脑膜炎哺乳动物沙粒病毒(LCMV)病毒载体。b) a second vector comprising the following first and second polynucleotides: polynucleotides comprising SEQ ID NOs: 143 and 149, or polynucleotides at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively. In some embodiments, the first and second viral vectors are lymphocytic choriomeningitis mammalian arenavirus (LCMV) viral vectors.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152的多核苷酸,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 150 and 152, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
b)第二载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQID NO:155和158的多核苷酸,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。在一些实施方案中,第一和第二病毒载体是卡利哺乳动物沙粒病毒(又名皮钦德哺乳动物沙粒病毒或皮钦德沙粒病毒)病毒载体。b) a second vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, respectively. In some embodiments, the first and second viral vectors are Cali mammalian arenavirus (also known as Pichinde mammalian arenavirus or Pichinde arenavirus) viral vectors.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,每个载体包含第一和第二多核苷酸:In some embodiments, the kit includes first, second, third, and fourth viral vectors, each vector comprising a first and a second polynucleotide:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:140和146,或分别与SEQ ID NO:140和146中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 140 and 146, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 140 and 146, respectively;
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:143和149,或分别与SEQ ID NO:143和149中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 143 and 149, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 143 and 149, respectively.
c)第三病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和c) a third viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 150 and 152, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively; and
d)第四病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:154和157或SEQ ID NO:155和158,或分别与SEQ ID NO:154和157或SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。d) a fourth viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 154 and 157 or SEQ ID NOs: 155 and 158, respectively.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,每个载体包含第一和第二多核苷酸:In some embodiments, the kit includes first, second, third, and fourth viral vectors, each vector comprising a first and a second polynucleotide:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:150和152,或分别与SEQ ID NO:150和152中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 150 and 152, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 150 and 152, respectively;
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:155和158,或分别与SEQ ID NO:155和158中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 155 and 158, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 155 and 158, respectively.
c)第三病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:151和153,或分别与SEQ ID NO:151和153中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;和c) a third viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 151 and 153, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 151 and 153, respectively; and
d)第四病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:156和159,或分别与SEQ ID NO:156和159中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。在一些实施方案中,第一、第二、第三和第四病毒载体中的一者或多者是腺病毒载体。d) a fourth viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 156 and 159, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 156 and 159, respectively. In some embodiments, one or more of the first, second, third, and fourth viral vectors are adenoviral vectors.
在一些实施方案中,试剂盒包括第一、第二、第三和第四病毒载体,每个载体包含第一和第二多核苷酸:In some embodiments, the kit includes first, second, third, and fourth viral vectors, each vector comprising a first and a second polynucleotide:
a)第一病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:131和135,或分别与SEQ ID NO:131和135中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;a) a first viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 131 and 135, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 131 and 135, respectively;
b)第二病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:133和137,或分别与SEQ ID NO:133和137中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。b) a second viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 133 and 137, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 133 and 137, respectively.
c)第三病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:139和145,或分别与SEQ ID NO:139和145中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同;以及c) a third viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 139 and 145, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 139 and 145, respectively; and
d)第四病毒载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:142和148,或分别与SEQ ID NO:142和148中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同。d) a fourth viral vector comprising the following first and second polynucleotides: comprising SEQ ID NOs: 142 and 148, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 142 and 148, respectively.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:160和161的多核苷酸,或分别与SEQ ID NO:160和161中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 160 and 161, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 160 and 161, respectively; and
b)第二载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:162和163的多核苷酸,或分别与SEQ ID NO:162和163中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 162 and 163, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 162 and 163, respectively.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:164和165的多核苷酸,或分别与SEQ ID NO:164和165中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 164 and 165, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 164 and 165, respectively; and
b)第二载体,其包含以下第一和第二多核苷酸:包含SEQ ID NO:166和167的多核苷酸,或分别与SEQ ID NO:166和167中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second vector comprising the following first and second polynucleotides: a polynucleotide comprising SEQ ID NOs: 166 and 167, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 166 and 167, respectively.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:210的多核苷酸,或与SEQ ID NO:210至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 210, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 210; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:211的多核苷酸,或与SEQ ID NO:211至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:211, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:211.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:212的多核苷酸,或与SEQ ID NO:212至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 212, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 212; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:213的多核苷酸,或与SEQ ID NO:213至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:213, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:213.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:214的多核苷酸,或与SEQ ID NO:214至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 214, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 214; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:215的多核苷酸,或与SEQ ID NO:215至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:215, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:215.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:216的多核苷酸,或与SEQ ID NO:216至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 216, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 216; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:217的多核苷酸,或与SEQ ID NO:217至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:217, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:217.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 218; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:219的多核苷酸,或与SEQ ID NO:219至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:219, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:219.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:218的多核苷酸,或与SEQ ID NO:218至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 218, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 218; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在一些实施方案中,试剂盒包括含有以下第一多核苷酸和第二多核苷酸的第一和第二病毒载体:In some embodiments, the kit includes first and second viral vectors comprising the following first polynucleotides and second polynucleotides:
a)第一病毒载体,该第一病毒载体包含以下第一多核苷酸:包含SEQ ID NO:225的多核苷酸,或与SEQ ID NO:225至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸;和a) a first viral vector comprising a first polynucleotide comprising SEQ ID NO: 225, or a polynucleotide that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 225; and
b)第二病毒载体,该第二病毒载体包含以下第二多核苷酸:包含SEQ ID NO:226的多核苷酸,或与SEQ ID NO:226至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的多核苷酸。b) a second viral vector comprising the following second polynucleotide: a polynucleotide comprising SEQ ID NO:226, or a polynucleotide at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:226.
在一些实施方案中,试剂盒包括复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:105-112、200-209、222-223和227中的任一项的氨基酸序列,或与SEQ ID NO:105-112、200-209、222-223和227中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。在一些实施方案中,试剂盒包括复合融合多肽或包含编码复合融合多肽的多核苷酸的载体,该复合融合多肽包含以下或由以下组成:SEQ ID NO:209、222和223中的任一项的氨基酸序列,或与SEQ ID NO:209、222和223中的任一项至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In some embodiments, the kit includes a composite fusion polypeptide or a vector comprising a polynucleotide encoding the composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 105-112, 200-209, 222-223 and 227. In some embodiments, the kit includes a composite fusion polypeptide or a vector comprising a polynucleotide encoding the composite fusion polypeptide, which composite fusion polypeptide comprises or consists of: an amino acid sequence of any one of SEQ ID NOs: 209, 222 and 223, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 209, 222 and 223.
在该试剂盒的各种实施方案中,该一种或多种融合多肽不包含对应于Gag 54-146、Gag 370-500、Pol 1-55、Pol 118-128、Pol 321-366、Pol 432-541、Pol 607-682、Pol709-746、Pol 828-839、Pol 921-931、Nef 1-63、Nef 100-116和Nef 149-206或其片段或亚序列的任何多肽片段,其中Gag、Pol和Nef氨基酸位置编号分别对应于SEQ ID NO:1、2和3。在该试剂盒的各种实施方案中,该一种或多种融合多肽不包含具有以下氨基酸序列的任何多肽片段:SEQ ID NO:35-47或其片段或亚序列的氨基酸序列,或与SEQ ID NO:35-47中的任一项或其片段或亚序列至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相同的氨基酸序列。In various embodiments of the kit, the one or more fusion polypeptides do not comprise any polypeptide fragments corresponding to Gag 54-146, Gag 370-500, Pol 1-55, Pol 118-128, Pol 321-366, Pol 432-541, Pol 607-682, Pol709-746, Pol 828-839, Pol 921-931, Nef 1-63, Nef 100-116 and Nef 149-206, or fragments or subsequences thereof, wherein the Gag, Pol and Nef amino acid position numbers correspond to SEQ ID NOs: 1, 2 and 3, respectively. In various embodiments of the kit, the one or more fusion polypeptides do not comprise any polypeptide fragment having an amino acid sequence of SEQ ID NOs: 35-47, or a fragment or subsequence thereof, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 35-47, or a fragment or subsequence thereof.
在一些实施方案中,试剂盒还包括一个或多个单位剂量的一种或多种附加治疗剂。例如,在一些实施方案中,试剂盒包括一种或多种Toll样受体(TLR)的一种或多种激动剂或活化剂。在一些实施方案中,TLR激动剂或活化剂选自TLR2激动剂、TLR3激动剂、TLR4激动剂、TLR5激动剂、TLR7激动剂、TLR8激动剂和TLR9激动剂。在一些实施方案中,TLR7激动剂选自GS 9620(维沙莫特)、R848(瑞喹莫德)、DS-0509、LHC-165和TMX-101(咪喹莫特),并且/或者其中TLR8激动剂选自GS-9688(赛尔甘托莫德)、R848(瑞喹莫德)和NKTR-262(双TLR7/TLR8激动剂)。In some embodiments, the kit also includes one or more additional therapeutic agents of one or more unit doses. For example, in some embodiments, the kit includes one or more agonists or activators of one or more Toll-like receptors (TLR). In some embodiments, TLR agonists or activators are selected from TLR2 agonists, TLR3 agonists, TLR4 agonists, TLR5 agonists, TLR7 agonists, TLR8 agonists and TLR9 agonists. In some embodiments, TLR7 agonists are selected from GS 9620 (Weisamod), R848 (Resiquimod), DS-0509, LHC-165 and TMX-101 (Imiquimod), and/or wherein TLR8 agonists are selected from GS-9688 (Sergantomod), R848 (Resiquimod) and NKTR-262 (double TLR7/TLR8 agonists).
在一些实施方案中,试剂盒包括抑制性免疫检查点蛋白或受体的一种或多种拮抗剂或抑制剂和/或刺激性免疫检查点蛋白或受体的一种或多种活化剂或激动剂。在一些实施方案中,一种或多种免疫检查点蛋白或受体选自:CD27、CD70;CD40、CD40LG;CD47、CD48(SLAMF2)、含跨膜和免疫球蛋白结构域蛋白2(TMIGD2、CD28H)、CD84(LY9B、SLAMF5)、CD96、CD160、MS4A1(CD20)、CD244(SLAMF4);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);自然杀伤细胞细胞毒性受体3配体1(NCR3LG1、B7H6);HERV-H LTR相关2(HHLA2、B7H7);诱导型T细胞共刺激因子(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF8(CD30)、TNFSF8(CD30L);TNFRSF10A(CD261、DR4、TRAILR1)、TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF10B(CD262、DR5、TRAILR2)、TNFRSF10(TRAIL);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));TNFRSF17(BCMA、CD269)、TNFSF13B(BAFF);TNFRSF18(GITR)、TNFSF18(GITRL);MHC I类多肽相关序列A(MICA);MHC I类多肽相关序列B(MICB);CD274(CD274、PDL1、PD-L1);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155);含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);含T细胞免疫球蛋白和粘蛋白结构域蛋白4(TIMD4;TIM4;甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);淋巴细胞活化3(LAG3、CD223);信号转导淋巴细胞活化分子家族成员1(SLAMF1、SLAM、CD150);淋巴细胞抗原9(LY9、CD229、SLAMF3);SLAM家族成员6(SLAMF6、CD352);SLAM家族成员7(SLAMF7、CD319);UL16结合蛋白1(ULBP1);UL16结合蛋白2(ULBP2);UL16结合蛋白3(ULBP3);视黄酸早期转录物1E(RAET1E;ULBP4);视黄酸早期转录物1G(RAET1G;ULBP5);视黄酸早期转录物1L(RAET1L;ULBP6);淋巴细胞活化3(CD223);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);杀伤细胞凝集素样受体C2(KLRC2、CD159c、NKG2C);杀伤细胞凝集素样受体C3(KLRC3、NKG2E);杀伤细胞凝集素样受体C4(KLRC4、NKG2F);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体D1(KLRD1);以及SLAM家族成员7(SLAMF7)。在一些实施方案中,试剂盒包括一种或多种T细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂。在一些实施方案中,T细胞抑制性免疫检查点蛋白或受体选自:CD274(CD274、PDL1、PD-L1);程序性细胞死亡1配体2(PDCD1LG2、PD-L2、CD273);程序性细胞死亡1(PDCD1、PD1、PD-1);细胞毒性T淋巴细胞相关蛋白4(CTLA4、CD152);CD276(B7H3);含V-set结构域的T细胞活化抑制剂1(VTCN1、B7H4);V-set免疫调节受体(VSIR、B7H5、VISTA);免疫球蛋白超家族成员11(IGSF11、VSIG3);TNFRSF14(HVEM、CD270)、TNFSF14(HVEML);CD272(B和T淋巴细胞相关(BTLA));含PVR相关免疫球蛋白结构域蛋白(PVRIG、CD112R);具有Ig和ITIM结构域的T细胞免疫受体(TIGIT);淋巴细胞活化3(LAG3、CD223);甲型肝炎病毒细胞受体2(HAVCR2、TIMD3、TIM3);半乳凝集素9(LGALS9);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);以及杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1)。利瑞鲁单抗是结合并阻断KIR2DL1/2L3受体的例示性抗体。在一些实施方案中,试剂盒包括一种或多种T细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂。在一些实施方案中,T细胞刺激性免疫检查点蛋白或受体选自:CD27、CD70、CD40、CD40LG;诱导型T细胞共刺激物(ICOS、CD278);诱导型T细胞共刺激物配体(ICOSLG、B7H2);TNF受体超家族成员4(TNFRSF4、OX40);TNF超家族成员4(TNFSF4、OX40L);TNFRSF9(CD137)、TNFSF9(CD137L);TNFRSF18(GITR)、TNFSF18(GITRL);CD80(B7-1)、CD28;nectin细胞粘附分子2(NECTIN2、CD112);CD226(DNAM-1);脊髓灰质炎病毒受体(PVR)细胞粘附分子(PVR、CD155)。在一些实施方案中,试剂盒包括一种或多种NK细胞抑制性免疫检查点蛋白或受体的一种或多种阻断剂或抑制剂。在一些实施方案中,NK细胞抑制性免疫检查点蛋白或受体选自:杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR、CD158E1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾1(KIR2DL1);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾2(KIR2DL2);杀伤细胞免疫球蛋白样受体、两个Ig结构域和长胞质尾3(KIR2DL3);杀伤细胞免疫球蛋白样受体、三个Ig结构域和长胞质尾1(KIR3DL1);杀伤细胞凝集素样受体C1(KLRC1、NKG2A、CD159A)(例如莫纳利珠单抗(monalizumab)(IPH2201));和杀伤细胞凝集素样受体D1(KLRD1、CD94)。在一些实施方案中,试剂盒包括一种或多种NK细胞刺激性免疫检查点蛋白或受体的一种或多种激动剂或活化剂。在一些实施方案中,NK细胞刺激性免疫检查点蛋白或受体选自CD16、CD226(DNAM-1);杀伤细胞凝集素样受体K1(KLRK1、NKG2D、CD314);以及SLAM家族成员7(SLAMF7)。在一些实施方案中,一种或多种免疫检查点抑制剂包括PD-L1(CD274)、PD-1(PDCD1)或CTLA4的蛋白质抑制剂。在一些实施方案中,CTLA4的蛋白质或抗体抑制剂选自:伊匹单抗、曲美木单抗、BMS-986218、AGEN1181、AGEN1884、BMS-986249、MK-1308、REGN-4659、ADU-1604、CS-1002、BCD-145、APL-509、JS-007、BA-3071、ONC-392、AGEN-2041、JHL-1155、KN-044、CG-0161、ATOR-1144、PBI-5D3H5、FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、XmAb-20717(PD-1/CTLA4)和AK-104(CTLA4/PD-1)。在各种实施方案中,与在不存在CTLA4的蛋白质或抗体抑制剂的情况下施用一种或多种融合多肽或编码此类融合多肽的多核苷酸、包含此类多核苷酸的脂质体复合物(例如,LNP)或表达此类融合多肽的载体相比,CTLA4的蛋白质或抗体抑制剂的共同施用增加了疫苗诱导的T细胞应答。在一些实施方案中,PD-L1(CD274)或PD-1(PDCD1)的蛋白质抑制剂选自:派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、西米单抗(cemiplimab)、匹地利珠单抗(pidilizumab)、AMP-224、MEDI0680(AMP-514)、斯巴达珠单抗(spartalizumab)、阿替利珠单抗(atezolizumab)、阿维鲁单抗(avelumab)、度伐利尤单抗(durvalumab)、BMS-936559、CK-301、PF-06801591、BGB-A317(替雷利珠单抗(tislelizumab))、GLS-010(WBP-3055)、AK-103(HX-008)、AK-105、CS-1003、HLX-10、MGA-012、BI-754091、AGEN-2034、JS-001(特瑞普利单抗(toripalimab))、JNJ-63723283、杰诺单抗(genolimzumab)(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、SHR-1210(卡瑞利珠单抗(camrelizumab))、Sym-021、ABBV-181、PD1-PIK、BAT-1306(MSB0010718C)、CX-072、CBT-502、TSR-042(多塔利单抗(dostarlimab))、MSB-2311、JTX-4014、BGB-A333、SHR-1316、CS-1001(WBP-3155、KN-035、IBI-308(信迪利单抗(sintilimab))、HLX-20、KL-A167、STI-A1014、STI-A1015(IMC-001)、BCD-135、FAZ-053、TQB-2450、MDX1105-01、FPT-155(CTLA4/PD-L1/CD28)、PF-06936308(PD-1/CTLA4)、MGD-013(PD-1/LAG-3)、FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4)、KN-046(PD-1/CTLA4)、MEDI-5752(CTLA4/PD-1)、RO-7121661(PD-1/TIM-3)、XmAb-20717(PD-1/CTLA4)、AK-104(CTLA4/PD-1)、M7824(PD-L1/TGFβ-EC结构域)、CA-170(PD-L1/VISTA)、CDX-527(CD27/PD-L1)、LY-3415244(TIM3/PDL1)和INBRX-105(4-1BB/PDL1)。在一些实施方案中,一种或多种免疫检查点抑制剂包含CD274(PDL1、PD-L1)、程序性细胞死亡1(PDCD1、PD1、PD-1)或CTLA4的小分子抑制剂。在一些实施方案中,CD274或PDCD1的小分子抑制剂选自GS-4224、GS-4416、INCB086550和MAX10181。在一些实施方案中,CTLA4的小分子抑制剂包括BPI-002。In some embodiments, the kit includes one or more antagonists or inhibitors of inhibitory immune checkpoint proteins or receptors and/or one or more activators or agonists of stimulatory immune checkpoint proteins or receptors. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137 ), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC Class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain protein (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT ); T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4; TIM4; hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signal transducer lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2 ); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, N KG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7). In some embodiments, the kit includes one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the T cell inhibitory immune checkpoint protein or receptor is selected from: CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated Immunoglobulin domain proteins (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). Lirelumab is an exemplary antibody that binds to and blocks the KIR2DL1/2L3 receptor.In some embodiments, the kit includes one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the T cell stimulatory immune checkpoint protein or receptor is selected from: CD27, CD70, CD40, CD40LG; inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the kit includes one or more NK cell inhibitory immune checkpoint protein or receptor one or more blockers or inhibitors. In some embodiments, the NK cell inhibitory immune checkpoint protein or receptor is selected from: killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A) (e.g., monalizumab (IPH2201)); and killer cell lectin-like receptor D1 (KLRD1, CD94). In some embodiments, the kit includes one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. In some embodiments, NK cell stimulatory immune checkpoint proteins or receptors are selected from CD16, CD226 (DNAM-1); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, one or more immune checkpoint inhibitors include protein inhibitors of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the protein or antibody inhibitor of CTLA4 is selected from: ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, C G-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4) and AK-104 (CTLA4/PD-1). In various embodiments, the co-administration of a protein or antibody inhibitor of CTLA4 increases the vaccine-induced T cell response compared to administration of one or more fusion polypeptides or polynucleotides encoding such fusion polypeptides, liposome complexes (e.g., LNPs) comprising such polynucleotides, or vectors expressing such fusion polypeptides in the absence of a protein or antibody inhibitor of CTLA4. In some embodiments, the protein inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from: pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), elizumab), GLS-010(WBP-3055), AK-103(HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001(toripalimab), JNJ-63723283, genolimzumab(CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210(camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306(MSB001 0718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD -013(PD-1/LAG-3), FS-118(LAG-3/PD-L1)MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-1 04 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1) and INBRX-105 (4-1BB/PDL1). In some embodiments, one or more immune checkpoint inhibitors include small molecule inhibitors of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.
在一些实施方案中,试剂盒包括一种或多种抗病毒剂。在一些实施方案中,一种或多种抗病毒剂选自:HIV蛋白酶抑制剂、HIV逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或变构)整合酶抑制剂、HIV进入(融合)抑制剂、HIV成熟抑制剂、潜伏期逆转剂和衣壳抑制剂。In some embodiments, the kit includes one or more antiviral agents. In some embodiments, the one or more antiviral agents are selected from: HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents and capsid inhibitors.
任选地与此类容器相关联的可以是管理药物或生物产品的制造、使用或销售的政府机构所规定形式的通知,该通知反映了该机构批准用于人施用的制造、使用或销售。Optionally associated with such container(s) may be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
9.设计可用于促进抗病毒免疫应答的融合多肽的方法9. Methods for designing fusion polypeptides that can be used to promote antiviral immune responses
提供了用于设计能够在人体内引发对一种或多种病毒抗原的免疫应答的疫苗构建体或免疫原的方法。免疫原性融合多肽采用计算、经验和手动步骤的组合来设计,可以用于引发对高度可变病毒的免疫应答。这些设计方法可以用于产生能够在人体中诱导对所需靶病毒(包括但不限于人类免疫缺陷病毒(HIV)、乙型肝炎病毒(HBV)、人乳头瘤病毒(HPV)、单纯疱疹病毒(HSV)、埃博拉病毒、寨卡病毒和基孔肯雅病病毒)的一种或多种病毒抗原的免疫应答的免疫原。一般来讲,免疫原设计方法提供了针对以下项设计的疫苗构建体:基于广泛的群体的最大表位覆盖率,在本文中称为“群体”构建体或抗原。通常,包含每个构建体的片段代表一个或多个MHC I类和/或MHC II类T细胞表位。基于群体的多肽片段可组合并组装成免疫原性融合多肽。Provided is a method for designing a vaccine construct or immunogen that can induce an immune response to one or more viral antigens in the human body. Immunogenic fusion polypeptides are designed using a combination of calculations, experience, and manual steps, and can be used to induce an immune response to highly variable viruses. These design methods can be used to produce immunogens that can induce an immune response to one or more viral antigens of a desired target virus (including but not limited to human immunodeficiency virus (HIV), hepatitis B virus (HBV), human papillomavirus (HPV), herpes simplex virus (HSV), Ebola virus, Zika virus, and chikungunya virus) in the human body. Generally speaking, the immunogen design method provides a vaccine construct designed for the following items: based on the maximum epitope coverage of a wide population, referred to herein as a "population" construct or antigen. Typically, the fragment comprising each construct represents one or more MHC I class and/or MHC II class T cell epitopes. The polypeptide fragments based on the population can be combined and assembled into immunogenic fusion polypeptides.
大部分步骤可以在计算机中执行,但一些步骤可以手动执行(例如,包含和/或排除对某些多肽序列的选择;对一个或多个接头的选择),并且可基于实验数据(例如,实验确定的MHC II类表位)并入信息。输入信息是病毒序列数据集(例如,对于HIV而言,是内部和公开获得的HIV群体数据集)。如图1的流程图所汇总,疫苗设计方法涉及以下步骤中的至少2个,例如至少3个:Most of the steps can be performed in a computer, but some steps can be performed manually (e.g., inclusion and/or exclusion of certain polypeptide sequences; selection of one or more linkers), and information can be incorporated based on experimental data (e.g., experimentally determined MHC class II epitopes). The input information is a viral sequence dataset (e.g., for HIV, an internal and publicly available HIV population dataset). As summarized in the flowchart of Figure 1, the vaccine design method involves at least 2 of the following steps, for example at least 3:
1.鉴定保守区。在天然存在的病毒序列中,所有9个氨基酸片段(9聚体)都被认为是潜在的T细胞表位。患者间病毒群体中具有至少80%保守性的9聚体位置被鉴定为保守区并包括在内以供进一步分析。1. Identification of conserved regions. In naturally occurring viral sequences, all 9 amino acid fragments (9-mers) were considered potential T cell epitopes. 9-mer positions with at least 80% conservation in viral populations between patients were identified as conserved regions and included for further analysis.
2.从保守区构建二价序列。这可以通过采用基于图形的算法来完成。由保守区组装9聚体,以包括最大数量的天然存在的9聚体。2. Construct bivalent sequences from conserved regions. This can be done by using a graph-based algorithm. 9-mers are assembled from conserved regions to include the maximum number of naturally occurring 9-mers.
3.排列多肽片段以减少或避免在连接部处产生人类可识别的新表位以及与人类蛋白质的交叉反应性。这可通过评估连接部周围的9聚体的MHC I类结合、与宿主(例如,人、狗、猫、马)蛋白的交叉识别、以及如果同时开发多个插入序列则检查多个抗原序列之间是否存在相同或基本上相同的9聚体来完成。如本文所用,“基本上相同的”9聚体具有9个相同氨基酸残基中的至少5个,例如具有至少55%(9个中的5个)、例如至少65%(9个中的6个)、例如至少75%(9个中的7个)、例如至少85%(9个中的8个)的相同氨基酸残基。3. Arrange the polypeptide fragments to reduce or avoid the generation of human-recognizable new epitopes and cross-reactivity with human proteins at the junction. This can be accomplished by evaluating the MHC class I binding of the 9-mer around the junction, cross-recognition with host (e.g., human, dog, cat, horse) proteins, and if multiple insertion sequences are developed simultaneously, checking whether there are identical or substantially identical 9-mers between multiple antigen sequences. As used herein, "substantially identical" 9-mers have at least 5 of the 9 identical amino acid residues, such as at least 55% (5 of 9), such as at least 65% (6 of 9), such as at least 75% (7 of 9), such as at least 85% (8 of 9) identical amino acid residues.
在一个方面,这些方法包括筛选基于群体/保守性的构建体的一组候选多肽片段的MHC肽结合亲和力。可以使用一种或多种算法来预测MHC结合亲和力。示例性预测算法包括NetMHC(Vita等人,Nucleic Acids Res 2015 43:D405-D412)、NetMHCpan(Andreattaand Nielsen Bioinformatics 2016 32:511-517)和MHCflurry(O’Donnell等人,CellSyst 2018 7:12-132)。其他T细胞表位预测工具是可公开获得的并且例如在Sanchez-Trincado等人,J.Immunology Res.2017,文章编号2680160中描述。用于鉴定MHC结合肽的另外的方法包括例如如US 10,055,540、WO 2019/104203中所述的采用机器学习工具的那些方法,以及Bulik-Sullivan等人,Nature Biotechnology 2019 37:55中所述的“EDGE”工具。In one aspect, these methods include screening the MHC peptide binding affinity of a group of candidate polypeptide fragments of a construct based on population/conservatism. One or more algorithms can be used to predict MHC binding affinity. Exemplary prediction algorithms include NetMHC (Vita et al., Nucleic Acids Res 2015 43: D405-D412), NetMHCpan (Andreatta and Nielsen Bioinformatics 2016 32: 511-517) and MHCflurry (O'Donnell et al., CellSyst 2018 7: 12-132). Other T cell epitope prediction tools are publicly available and are described, for example, in Sanchez-Trincado et al., J.Immunology Res. 2017, article number 2680160. Additional methods for identifying MHC-binding peptides include, for example, those employing machine learning tools as described in US 10,055,540, WO 2019/104203, and the "EDGE" tool described in Bulik-Sullivan et al., Nature Biotechnology 2019 37:55.
在一些实施方案中,本公开提供了用于产生二价基于群体/保守性的构建体的方法,这些构建体被设计成通过提供数学确定和提高的所有潜在T细胞表位的覆盖率来捕获病毒蛋白质组(例如,HIV蛋白质组)的独特多样性,并例如通过保留与天然存在的病毒蛋白质组中发现的相同顺序的多肽片段来确保该对构建的多肽中的每个多肽中的表位保留原始输入病毒序列的位置信息。因此,所得的该对多肽的表位将更类似于天然存在的病毒序列的表位,从而增加了它们引发相关T细胞反应的可能性。In some embodiments, the present disclosure provides methods for generating bivalent population/conservative-based constructs designed to capture the unique diversity of viral proteomes (e.g., HIV proteomes) by providing mathematically determined and improved coverage of all potential T cell epitopes, and ensuring that the epitopes in each polypeptide of the pair of constructed polypeptides retain the positional information of the original input viral sequence, for example, by retaining polypeptide fragments of the same order as those found in the naturally occurring viral proteome. Therefore, the resulting epitopes of the pair of polypeptides will be more similar to the epitopes of the naturally occurring viral sequences, thereby increasing the likelihood that they will elicit relevant T cell responses.
通常,此处描述的方法包括使用基于图形的方法就所有潜在T细胞表位(“PTE”)在病毒蛋白质组序列群体中的覆盖率最初提供了一组数学确定和提高的PTE。与类似的基于图形的疫苗设计方法不同,此处描述的方法仅使用在自然序列中也相邻的相邻PTE来构建连接的PTE片段。这提供了保留PTE在序列源集中的位置信息的构建体。同样与其他基于图形的方法不同,此处描述的方法同时构建了二价构建体,以提供对群体中最高度保守的PTE的最大覆盖。结果得到初始二价疫苗构建体,其有利地最大化高度保守的PTE,这些PTE最有可能与天然序列中的保守表位高度相似。更有利地,仅使用最高度保守的PTE降低了逃逸突变体的可能性,因为高度保守的序列更有可能对病毒功能至关重要。In general, the methods described herein include using a graph-based approach to initially provide a set of mathematically determined and improved PTEs for the coverage of all potential T cell epitopes ("PTEs") in a population of viral proteome sequences. Unlike similar graph-based vaccine design methods, the methods described herein only use adjacent PTEs that are also adjacent in the natural sequence to construct connected PTE fragments. This provides a construct that retains the positional information of the PTE in the sequence source set. Also unlike other graph-based methods, the methods described herein simultaneously construct a bivalent construct to provide maximum coverage of the most highly conserved PTEs in the population. The result is an initial bivalent vaccine construct that advantageously maximizes highly conserved PTEs that are most likely to be highly similar to conserved epitopes in the natural sequence. More advantageously, using only the most highly conserved PTEs reduces the possibility of escape mutants because highly conserved sequences are more likely to be essential for viral function.
本文所述的方法通常从使用本文称为“保守分析”或“保守算法”的过程鉴定保守区二价序列开始。这些方法通常还包括使用本文称为“保守步行算法”或“CWA”的过程构建具有最大表位覆盖率同时保留来自天然序列的PTE的位置信息的二价疫苗构建体的步骤。因此,在一些具体实施中,该方法中的初始步骤是针对选定的一组病毒基因鉴定病毒蛋白质组中的一组所有保守区。在用于设计融合多肽以引发对HIV-1的免疫应答的具体实施中,该组HIV-1病毒基因选自Gag、Pol和Nef中的两个或更多个。在一些具体实施中,该组病毒基因由Gag、Pol和Nef组成。在一些具体实施中,该组病毒基因由Pol和Nef组成。The methods described herein usually start with the process identification of the conserved region bivalent sequence using the process referred to herein as "conservative analysis" or "conservative algorithm". These methods usually also include the step of using the process referred to herein as "conservative walking algorithm" or "CWA" to construct a bivalent vaccine construct with maximum epitope coverage while retaining the positional information of the PTE from the native sequence. Therefore, in some specific implementations, the initial step in the method is to identify a group of all conserved regions in the viral protein group for a selected group of viral genes. In the specific implementation for designing fusion polypeptide to cause an immune response to HIV-1, the group of HIV-1 viral genes is selected from two or more of Gag, Pol and Nef. In some specific implementations, the group of viral genes is composed of Gag, Pol and Nef. In some specific implementations, the group of viral genes is composed of Pol and Nef.
根据此处描述的方法,首先将病毒蛋白质组序列群体与参考序列(例如,由GenBank登录号K03455鉴定的HIV参考序列HXB2)进行比对。由Gag、Nef和Pol基因编码的多肽的参考序列在本文中以SEQ ID NO:1-3提供于表A中。病毒蛋白质组序列的初始输入或“源”群体由从天然存在的病毒获得的序列组成。此类序列可例如从洛斯阿拉莫斯国家实验室、美国卫生与公众服务部和美国国立卫生研究院维护的HIV数据库中公开获得。在本文所述方法的一些具体实施中,源病毒序列可由对应于特定病毒组和/或进化枝的序列组成。在一些具体实施中,为了改进保守区和序列的鉴定,输入病毒序列可限于单个病毒进化枝和/或组。在一些具体实施中,输入病毒序列限于组M进化枝B序列。According to the method described herein, first the viral proteome sequence population is compared with a reference sequence (e.g., HIV reference sequence HXB2 identified by GenBank accession number K03455). The reference sequence of the polypeptide encoded by Gag, Nef and Pol genes is provided in Table A herein with SEQ ID NO:1-3. The initial input or "source" population of the viral proteome sequence is composed of sequences obtained from naturally occurring viruses. Such sequences can be publicly available, for example, from the HIV database maintained by Los Alamos National Laboratory, the U.S. Department of Health and Human Services and the National Institutes of Health. In some specific implementations of the methods described herein, the source viral sequence can be composed of sequences corresponding to specific viral groups and/or clades. In some specific implementations, in order to improve the identification of conserved regions and sequences, the input viral sequence can be limited to a single viral clade and/or group. In some specific implementations, the input viral sequence is limited to group M clade B sequences.
源病毒序列与参考序列的比对可使用多种比对算法来实现,例如快速傅里叶变换算法MAFFT。Katoh等人,2002Nucleic Acids Res.30(14):3059-66。基础MAFFT软件是可公开获得和例如在伯克利软件套件(BSD)许可下分发的。Alignment of source viral sequences with reference sequences can be achieved using a variety of alignment algorithms, such as the Fast Fourier Transform algorithm MAFFT. Katoh et al., 2002 Nucleic Acids Res. 30(14):3059-66. The underlying MAFFT software is publicly available and distributed, for example, under the Berkeley Software Distribution (BSD) license.
接下来,将保守算法应用于比对后的序列。对于比对中的每个序列,从第一个氨基酸位置开始,该方法一次移动一个氨基酸位置并产生长度为9个氨基酸的所有可能的氨基酸片段,在本文中称为“9聚体”。因此,对于比对中的每个序列,该算法产生一组从N末端氨基酸开始的9个氨基酸子序列(“9聚体”),每个子序列与前面的子序列重叠八个氨基酸,使得比对中每个长度为l的序列含有(l-8)个9聚体。Next, the conservative algorithm is applied to the aligned sequences. For each sequence in the alignment, starting from the first amino acid position, the method moves one amino acid position at a time and generates all possible amino acid fragments of 9 amino acids in length, referred to herein as "9-mers". Therefore, for each sequence in the alignment, the algorithm generates a set of 9 amino acid subsequences ("9-mers") starting from the N-terminal amino acid, each of which overlaps the previous subsequence by eight amino acids, so that each sequence of length 1 in the alignment contains (1-8) 9-mers.
接下来,对于每个9聚体位置,该方法鉴定两个最常见的独特9聚体以及它们在比对的源病毒蛋白质组序列集中的流行率。换句话说,从位置i开始,每个位置的两个最常见的独特9聚体是基于它们的频率来鉴定的,计算为独特9聚体在比对中在位置i出现的次数除以比对中的序列总数。Next, for each 9-mer position, the method identifies the two most common unique 9-mers and their prevalence in the aligned set of source viral proteome sequences. In other words, starting at position i, the two most common unique 9-mers at each position are identified based on their frequency, calculated as the number of times a unique 9-mer occurs at position i in the alignment divided by the total number of sequences in the alignment.
计算上,每个长度为l的序列含有l-8个9聚体。我们将从位置i开始的所有9聚体定义为sij,频率定义为fij,j=1,2,3,…m。在位置i总共有m个独特的9聚体。每两个独特的9聚体(siu,siv)可构成一个9聚体对,其频率为fiu+fiv。并且每个9聚体本身可以构成一个9聚体对,如(siu,siu),其频率为fiu。因此,在每个位置总共有m+(m–1)+(m–2)+…+2+1=m*(m+1)/2个9聚体对。Computationally, each sequence of length l contains l-8 9-mers. We define all 9-mers starting from position i as s ij and the frequency as fij , j = 1, 2, 3, ... m. There are a total of m unique 9-mers at position i. Every two unique 9-mers (s iu , s iv ) can form a 9-mer pair with frequency fiu +f iv . And each 9-mer itself can form a 9-mer pair, such as (s iu , s iu ), with frequency fiu . Therefore, there are a total of m+(m–1)+(m–2)+…+2+1=m*(m+1)/2 9-mer pairs at each position.
然后,该方法通过将含有两个最常见的9聚体中任一个的比对的源病毒蛋白质组序列集的比例相加来计算每个9聚体位置的二价保守性。为此,通过将比对中含有两个最常见的独特9聚体中任一个的序列的比例相加来计算每个位置的“二价保守性”。如本文所用,“二价保守性”是指在9聚体位置含有与两个最普遍的氨基酸片段中的任一个完全相同的9个氨基酸片段(9聚体)的序列的百分比。The method then calculates the bivalent conservation of each 9-mer position by adding the proportion of the aligned source viral proteome sequence set containing either of the two most common 9-mers. To this end, the "bivalent conservation" of each position is calculated by adding the proportion of sequences in the alignment containing either of the two most common unique 9-mers. As used herein, "bivalent conservation" refers to the percentage of sequences containing a 9-amino acid fragment (9-mer) that is exactly the same as either of the two most common amino acid fragments at a 9-mer position.
接下来,通过提取比对中具有所需二价保守性(例如,大于80%或大于90%的二价保守性,这意味着位置i处两个最常见的9聚体在保守区的新比对中占该位置处9聚体的80%以上或90%以上)的序列来产生保守区的新比对。换句话说,该方法将新比对中的保守区鉴定为其中每个位置处两个最常见的9聚体的频率之和大于某个截止值(例如,大于80%或大于90%)的那些保守区。因此,该方法还计算了保守区的新比对中每个位置处每对独特9聚体的频率。Next, a new alignment of the conserved region is generated by extracting sequences in the alignment that have a desired bivalent conservation (e.g., greater than 80% or greater than 90% bivalent conservation, meaning that the two most common 9-mers at position i account for more than 80% or more than 90% of the 9-mers at that position in the new alignment of the conserved region). In other words, the method identifies conserved regions in the new alignment as those conserved regions in which the sum of the frequencies of the two most common 9-mers at each position is greater than a certain cutoff value (e.g., greater than 80% or greater than 90%). Therefore, the method also calculates the frequency of each pair of unique 9-mers at each position in the new alignment of the conserved region.
在一些具体实施中,可将进一步的选择标准应用于保守区,诸如限于具有大于90%的保守性的区域并去除少于35个氨基酸的短片段。In some implementations, further selection criteria can be applied to conserved regions, such as limiting to regions with greater than 90% conservation and removing short stretches of less than 35 amino acids.
使用这组修改的保守区,该方法的某些具体实施应用CWA来构建二价序列构建体。CWA将9聚体对连接在保守区的比对的相邻位置,这些位置共享八个氨基酸的重叠。Using this modified set of conserved regions, certain implementations of the method apply CWA to construct bivalent sequence constructs. CWA connects 9-mer pairs at aligned adjacent positions of the conserved regions that share an overlap of eight amino acids.
计算上,每个9聚体s含有9个氨基酸,我们写为s[x:y]表示从位置x到y的氨基酸子序列,总共y-x+1个氨基酸:Computationally, each 9-mer s contains 9 amino acids, which we write as s[x:y] to represent the amino acid subsequence from position x to y, with a total of y-x+1 amino acids:
siu[2:9]==si+1p[1:8]且siv[2:9]==si+1q[1:8] siu [2:9] == si+ 1p [1:8] and siv [2:9] == si +1q [1:8]
或者or
siu[2:9]==si+1q[1:8]且siv[2:9]==si+1p[1:8]。 siu [2:9] == si +1q [1:8] and siv [2:9] == si +1p [1:8].
接下来,该算法构建了有向无环图,其中每个9聚体对是一个节点,相邻节点之间的边由相邻位置中连接的9聚体对形成,每条边的权重等于下游9聚体对的频率。这种有向无环图是位置De Brujin图。此类图已结合下一代测序数据的组装进行了描述,例如如Ronen等人,Bioinformatics 2012 28:188-196所述。该方法还添加了源节点,将其与第一个位置的所有节点连接;以及宿节点,将其与最后一个位置的所有节点连接。然后将权重取反,找到从源节点到宿节点的最佳路径,其中最佳路径被定义为从源节点到宿节点的所有路径中所有9聚体对的频率之和最大的路径。例如,使用Bellman–Ford算法执行找到最佳路径的任务。通常,Bellman-Ford算法计算加权有向图中从单个源顶点到所有其他顶点的最短路径,该加权有向图由一组由边连接的顶点组成,其中边具有与它们相关的方向。计算步骤可以汇总如下:Next, the algorithm constructs a directed acyclic graph in which each 9-mer pair is a node, and the edges between adjacent nodes are formed by the 9-mer pairs connected in adjacent positions, and the weight of each edge is equal to the frequency of the downstream 9-mer pair. This directed acyclic graph is a positional De Brujin graph. Such graphs have been described in conjunction with the assembly of next-generation sequencing data, such as Ronen et al., Bioinformatics 2012 28: 188-196. The method also adds a source node, connecting it to all nodes in the first position; and a sink node, connecting it to all nodes in the last position. The weights are then reversed to find the best path from the source node to the sink node, where the best path is defined as the path with the largest sum of the frequencies of all 9-mer pairs in all paths from the source node to the sink node. For example, the task of finding the best path is performed using the Bellman–Ford algorithm. Typically, the Bellman-Ford algorithm calculates the shortest path from a single source vertex to all other vertices in a weighted directed graph, which consists of a set of vertices connected by edges, where the edges have directions associated with them. The calculation steps can be summarized as follows:
·(4-1)将每个9聚体对作为节点处理,并在步骤3中的相邻节点之间构建边缘;(4-1) Treat each 9-mer pair as a node and build edges between adjacent nodes in step 3;
·(4-2)添加源节点并将其与第1个位置的所有节点连接;(4-2) Add the source node and connect it to all nodes at the first position;
·(4-3)添加宿节点并将其与最后一个位置的所有节点连接;(4-3) Add the sink node and connect it to all nodes in the last position;
·(4-4)每个边缘的权重等于下游9聚体对的频率;(4-4) The weight of each edge is equal to the frequency of the downstream 9-mer pair;
·(4-5)使用Bellman–Ford算法将所有权重取反并找到最佳路径。(4-5) Use the Bellman–Ford algorithm to invert all weights and find the best path.
该方法的另外的步骤是基于最佳二价9聚体对路径构建二价疫苗序列,并且如果最佳二价9聚体对路径内相邻位置的两个9聚体共享8个氨基酸的重叠,则连接它们。如果最佳二价9聚体路径内相邻位置的两个9聚体共享八个氨基酸的重叠,则通过连接它们来构建二价构建体,从而产生连接的9聚体的两个序列,它们一起形成二价构建体。连接的相邻9聚体对均具有8个氨基酸重叠,因此它们将被组装成两个序列。例如,可将一个9聚体对(AIIIIIIIS(SEQ ID NO:190)、MIIIIIIII(SEQ ID NO:191))与另一个9聚体对(IIIIIIISK(SEQ ID NO:192)、IIIIIIIIR(SEQ ID NO:184))连接,并且形成两个序列(二价序列):AIIIIIIISK(SEQ ID NO:193)和MIIIIIIIIR(SEQ ID NO:194)。The other step of the method is to build a bivalent vaccine sequence based on the best bivalent 9 aggressiveness to the path, and if the best bivalent 9 aggressiveness to the two 9 aggressiveness of adjacent positions in the path share 8 amino acid overlaps, then connect them. If the two 9 aggressiveness of adjacent positions in the best bivalent 9 aggressiveness path share eight amino acid overlaps, then build a bivalent construct by connecting them, thereby producing two sequences of the 9 aggressiveness connected, and they form a bivalent construct together. The adjacent 9 aggressiveness connected is to all having 8 amino acid overlaps, so they will be assembled into two sequences. For example, a 9 aggressiveness can be connected to (AIIIIIIIS (SEQ ID NO:190), MIIIIIIIII (SEQ ID NO:191)) and another 9 aggressiveness to (IIIIIIISK (SEQ ID NO:192), IIIIIIIIR (SEQ ID NO:184)), and form two sequences (bivalent sequences): AIIIIIIISK (SEQ ID NO:193) and MIIIIIIIR (SEQ ID NO:194).
计算上,可以将该方法描述为基于位置De Brujin图形的二价疫苗序列设计算法,其包括以下5个基本步骤:Computationally, this method can be described as a bivalent vaccine sequence design algorithm based on positional De Brujin graphs, which includes the following 5 basic steps:
步骤1:对所有群体序列进行比对Step 1: Align all population sequences
步骤2:对于每个9聚体位置,找出所有独特9聚体及其频率,并构建具有频率的9聚体对集。每个长度为l的序列含有l-8个9聚体。我们将从位置i开始的所有9聚体定义为sij,频率定义为fij,j=1,2,3,…m。在位置i总共有m个独特的9聚体。每两个独特的9聚体(siu,siv)可构成一个9聚体对,其频率为fiu+fiv。并且每个9聚体本身可以构成一个9聚体对,如(siu,siu),其频率为fiu。因此,在每个位置总共有m+(m–1)+(m–2)+…+2+1=m*(m+1)/2个9聚体对。Step 2: For each 9-mer position, find all unique 9-mers and their frequencies, and construct a set of 9-mer pairs with frequencies. Each sequence of length l contains l-8 9-mers. We define all 9-mers starting from position i as s ij and the frequencies as fij , j = 1, 2, 3, ... m. There are a total of m unique 9-mers at position i. Every two unique 9-mers (s iu , s iv ) can form a 9-mer pair with a frequency of fiu +f iv . And each 9-mer itself can form a 9-mer pair, such as (s iu , s iu ), with a frequency of fiu . Therefore, there are a total of m+(m–1)+(m–2)+…+2+1=m*(m+1)/2 9-mer pairs at each position.
步骤3:如果相邻位置中的9聚体对不具有任何冲突的氨基酸,则连接它们。如本文所用,“冲突的氨基酸残基”是指两个9聚体之间的重叠位置处的不同氨基酸残基。每个9聚体s含有9个氨基酸,我们写为s[x:y]表示从位置x到y的氨基酸子序列,总共y-x+1个氨基酸:Step 3: If the 9-mer pairs in adjacent positions do not have any conflicting amino acids, connect them. As used herein, "conflicting amino acid residues" refer to different amino acid residues at overlapping positions between two 9-mers. Each 9-mer s contains 9 amino acids, which we write as s[x:y] to represent the amino acid subsequence from position x to y, a total of y-x+1 amino acids:
siu[2:9]==si+1p[1:8]且siv[2:9]==si+1q[1:8] siu [2:9] == si+ 1p [1:8] and siv [2:9] == si +1q [1:8]
或者or
siu[2:9]==si+1q[1:8]且siv[2:9]==si+1p[1:8] siu [2:9] == si +1q [1:8] and siv [2:9] == si +1p [1:8]
步骤4:根据路径内所有9聚体的频率之和找到从第1个9聚体位置到最后一个位置的最佳路径。基本思路是将最大覆盖率二价疫苗构建问题建模为经典图论问题,其中解决方案是在有向无环图中找到最小路径。Step 4: Find the best path from the first 9-mer position to the last position based on the sum of the frequencies of all 9-mers in the path. The basic idea is to model the maximum coverage bivalent vaccine construction problem as a classic graph theory problem, where the solution is to find the minimum path in a directed acyclic graph.
步骤5:基于最佳二价9聚体对路径构建二价疫苗序列,并且如果最佳二价9聚体对路径内相邻位置的两个9聚体共享8个氨基酸的重叠,则连接它们。以例如以下情况为例:Step 5: construct a bivalent vaccine sequence based on the best bivalent 9-mer pair path, and connect two 9-mers at adjacent positions within the best bivalent 9-mer pair path if they share an overlap of 8 amino acids. Take the following case as an example:
情况1:如果siu[2:9]=si+1p[1:8]且siv[2:9]=si+1q[1:8],则连接siu与si+1p以及siv与si+1q;Case 1: If siu [2:9] = si +1p [1:8] and siv [2:9] = si +1q [1:8], then connect siu to si +1p and siv to si +1q ;
情况2:如果siu[2:9]=si+1q[1:8]且siv[2:9]=si+1p[1:8],则连接siu与si+1q以及siv与si+1p;Case 2: If siu [2:9] = si +1q [1:8] and siv [2:9] = si +1p [1:8], then connect siu to si +1q and siv to si +1p ;
情况3:如果siu[2:9]=si+1p[1:8]且siv[2:9]=si+1q[1:8]且siu[2:9]=si+1q[1:8]且siv[2:9]=si+1p[1:8],则连接的选择基于自然序列中的两个连接的流行率:Case 3: If siu [2:9] = si +1p [1:8] and siv [2:9] = si +1q [1:8] and siu [2:9] = si +1q [1:8] and siv [2:9] = si +1p [1:8], then the choice of connection is based on the prevalence of the two connections in the natural sequence:
将输入序列中six和si+1y共存的流行率表示为Cixy Denote the prevalence of co-occurrence of s ix and s i+1y in the input sequence as C ixy
如果Ciup+Civq>Ciuq+Civp,则连接siu与si+1p以及siv与si+1q;If Ciup + Civq > Ciuq + Civp , connect siu with si +1p and si +1q with si +1q ;
如果Ciuq+Civp>Ciup+Civq,则连接siu与si+1q以及siv与si+1p;If Ciuq + Civp > Ciup + Civq , then connect siu with si +1q and si +1p with si +1p ;
如果Ciup+Civq=Ciuq+Civp,则回溯并组合位置i-1和i中9聚体对共存的流行率,直到第1个位置。如果两个不同的连接之间没有区别,则随机选择一个。If Ciup + Civq = Ciuq + Civp , then backtrack and combine the prevalence of coexistence of 9-mer pairs in positions i-1 and i, until position 1. If there is no distinction between two different connections, then one is chosen at random.
在一些具体实施中,通过进行人类蛋白质组交叉识别分析进一步改进构建体,例如通过包括在人类蛋白质组数据库诸如UniProt中搜索构建体中的所有9聚体以鉴定与人类肽具有一定氨基酸序列同一性(例如,至少5个残基)或与人类蛋白质共享面向T细胞受体(TCR)的残基的任何9聚体的方法。然后可以从构建体中排除任何此类9聚体。在一些具体实施中,可例如通过对连接片段进行HLA结合分析、人类蛋白质组交叉识别分析或这两种分析任选地重新排列多肽片段,以减少或避免有害连接反应。在设计抗癌疫苗的背景下用于减少新抗原的连接表位呈递的例示性方法在WO 2019/104203中描述。另选地,如果开发了多个抗原序列,多肽片段可被重新排列以避免在抗原序列之间的连接部处出现几乎相同或相同的9聚体。In some implementations, the construct is further improved by performing a human proteome cross-recognition analysis, for example, by including a method of searching all 9-mers in the construct in a human proteome database such as UniProt to identify any 9-mers that have a certain amino acid sequence identity (e.g., at least 5 residues) with human peptides or share residues facing the T cell receptor (TCR) with human proteins. Any such 9-mers can then be excluded from the construct. In some implementations, the polypeptide fragments can be optionally rearranged, for example, by performing HLA binding analysis, human proteome cross-recognition analysis, or both analyses on the connected fragments to reduce or avoid harmful connection reactions. An exemplary method for reducing the presentation of the connection epitope of a new antigen in the context of designing an anti-cancer vaccine is described in WO 2019/104203. Alternatively, if multiple antigen sequences are developed, the polypeptide fragments can be rearranged to avoid the appearance of almost identical or identical 9-mers at the junction between the antigen sequences.
在一些具体实施中,通过计算机执行以下步骤中的一个或多个步骤来进一步限定保守区:(i)去除短多肽片段,例如长度为35个或更少氨基酸(例如长度为9-35个氨基酸)的多肽片段;(ii)去除在人类中为弱免疫原性或非免疫原性的片段;(iii)去除在预定序列群体中保守性小于90%(在某些情况下,保守性小于80%)的片段;(iv)包括来自HIV-1蛋白的已知在人类中为免疫原性的另外的片段(例如Env、Gag、Nef和Pol)(参见例如hiv.lanl.gov/content/immunology/maps/maps.html中的表位图;Fischer等人,Nat Med.(2007)13(1):100-6;以及Addo等人,J Virol,(2003)77(3):2081-92)。In some embodiments, the conserved regions are further defined by computer-performed one or more of the following steps: (i) removing short polypeptide fragments, such as polypeptide fragments of 35 or fewer amino acids in length (e.g., 9-35 amino acids in length); (ii) removing fragments that are weakly immunogenic or non-immunogenic in humans; (iii) removing fragments that are less than 90% conserved (in some cases, less than 80% conserved) in a predetermined sequence population; (iv) including additional fragments from HIV-1 proteins that are known to be immunogenic in humans (e.g., Env, Gag, Nef, and Pol) (see, e.g., epitope maps at hiv.lanl.gov/content/immunology/maps/maps.html; Fischer et al., Nat Med. (2007) 13(1): 100-6; and Addo et al., J Virol, (2003) 77(3): 2081-92).
在一些具体实施中,相邻的多肽片段可任选地被接头序列分开,如上文所述。在一些实施方案中,一个或多个接头序列包括可切割接头,任选地还包括位于可切割接头附近的附加接头序列。另外的接头可以是另一种可切割接头、聚丙氨酸接头、聚甘氨酸接头、柔性接头或刚性接头,如上文和本文所述。在一些实施方案中,弗林蛋白酶识别位点在2A可切割接头的N末端前或位于该处。在特定具体实施中,在接头序列包含口蹄疫病毒(FMDV)可切割肽、FMDV 2A或其衍生物的情况下,另外的接头序列可以是REKR(SEQ ID NO:61)序列或其衍生物。在一些具体实施中,接头选自短聚丙氨酸肽,例如由2至4个丙氨酸残基组成或者具有序列AAY(SEQ ID NO:49)或AAX的肽,其中X是任何氨基酸残基(SEQ ID NO:50)。In some implementations, adjacent polypeptide fragments can be optionally separated by a linker sequence, as described above. In some embodiments, one or more linker sequences include a cleavable linker, optionally also including an additional linker sequence located near the cleavable linker. Additional linkers can be another cleavable linker, a polyalanine linker, a polyglycine linker, a flexible linker or a rigid linker, as described above and herein. In some embodiments, the furin recognition site is before or located at the N-terminal of the 2A cleavable linker. In a specific implementation, in the case where the linker sequence comprises a foot-and-mouth disease virus (FMDV) cleavable peptide, FMDV 2A or its derivatives, additional linker sequences can be REKR (SEQ ID NO: 61) sequence or its derivatives. In some implementations, the linker is selected from a short polyalanine peptide, for example, composed of 2 to 4 alanine residues or having a peptide of sequence AAY (SEQ ID NO: 49) or AAX, wherein X is any amino acid residue (SEQ ID NO: 50).
在一些具体实施中,在二价多肽的每个相邻保守区之间插入接头。在一些具体实施中,例如,当没有产生有害连接表位时,在多肽中相同蛋白质的相邻片段之间没有接头插入。可以在不同蛋白质的相邻片段之间插入接头。In some embodiments, a linker is inserted between each adjacent conserved region of a bivalent polypeptide. In some embodiments, no linker is inserted between adjacent fragments of the same protein in a polypeptide, for example, when no deleterious junction epitopes are generated. A linker may be inserted between adjacent fragments of different proteins.
实施例Example
提供以下实施例以说明而非限制受权利要求书保护的本发明。The following examples are provided to illustrate but not to limit the claimed invention.
实施例1Example 1
产生二价疫苗构建体的保守分析和保守步行分析(CWA)的图解具体实施Schematic illustration of the implementation of conservation analysis and conservative walking analysis (CWA) to generate bivalent vaccine constructs
该实施例通过保守分析和CWA的具体实施以产生基于由HIV-1 Gag、Nef和/或Pol基因编码的保守蛋白质区域的二价疫苗构建体描述了基于群体的二价多肽构建体的设计。This example describes the design of population-based bivalent polypeptide constructs through the implementation of conservation analysis and CWA to generate bivalent vaccine constructs based on conserved protein regions encoded by HIV-1 Gag, Nef and/or Pol genes.
首先,我们针对选定的一组病毒基因鉴定病毒蛋白质组中的一组所有保守区。在该实施例中,该组病毒基因由HIV-1 Gag、Pol和Nef组成。First, we identified a set of all conserved regions in the viral proteome for a selected set of viral genes. In this example, the set of viral genes consisted of HIV-1 Gag, Pol, and Nef.
计算上,保守算法和CWA的组合为基于位置De Brujin图的二价疫苗序列设计算法,其包括以下5个基本步骤,如图3所示:Computationally, the combination of the conservative algorithm and CWA is a bivalent vaccine sequence design algorithm based on the positional De Brujin graph, which includes the following five basic steps, as shown in Figure 3:
步骤1:将一组源病毒蛋白质组序列与参考序列进行比对。Step 1: Align a set of source viral proteome sequences with reference sequences.
在步骤1中,将病毒蛋白质组序列的源群体与参考序列进行比对。在该实施例中,所使用的参考序列是由GenBank登录号K03455鉴定的HIV-1HXB2。HXB2参考多肽Gag、Nef和Pol的氨基酸序列在本文中分别以SEQ ID NO:1、2和3提供于表A中。病毒蛋白质组序列的源群体由从天然存在的病毒获得的序列组成。此类序列可例如从洛斯阿拉莫斯国家实验室、美国卫生与公众服务部和美国国立卫生研究院(hiv.lanl.gov)维护的HIV数据库中公开获得,该数据库是用于该实施例中的序列源群体的数据库。出于说明的目的,我们将分析集中在病毒序列的一个子集,此处为组M进化枝B的序列。使用多重比对算法、特别是快速傅里叶变换算法MAFFT进行比对。Katoh等人,(2002)Nucleic Acids Res.30(14):3059-66。基础MAFFT软件是可公开获得和例如在伯克利软件套件(BSD)许可下分发的。In step 1, the source population of viral proteome sequences is compared with a reference sequence. In this embodiment, the reference sequence used is HIV-1 HXB2 identified by GenBank accession number K03455. The amino acid sequences of the HXB2 reference polypeptides Gag, Nef and Pol are provided in Table A herein as SEQ ID NOs: 1, 2 and 3, respectively. The source population of viral proteome sequences consists of sequences obtained from naturally occurring viruses. Such sequences can be publicly obtained, for example, from the HIV database maintained by Los Alamos National Laboratory, the U.S. Department of Health and Human Services and the National Institutes of Health (hiv.lanl.gov), which is a database of the sequence source population used in this embodiment. For the purpose of illustration, we will focus our analysis on a subset of viral sequences, here the sequences of group M clade B. Use a multiple alignment algorithm, particularly the fast Fourier transform algorithm MAFFT, for comparison. Katoh et al., (2002) Nucleic Acids Res.30(14):3059-66. The underlying MAFFT software is publicly available and distributed, for example, under the Berkeley Software Distribution (BSD) license.
步骤2:对于每个9聚体位置,找出所有独特9聚体及其频率,并构建具有频率的9聚Step 2: For each 9-mer position, find all unique 9-mers and their frequencies and construct a 9-mer with frequencies 体对集Body pair set
在步骤2中,我们将保守算法应用于该组比对的序列。对于比对中的每个序列,从N末端的第一个氨基酸开始,该算法一次移动一个氨基酸位置以产生长度为9个氨基酸的一组所有可能的氨基酸片段,称为“9聚体”。因此,对于比对中的每个序列,该算法产生一组从N末端氨基酸开始的9个氨基酸子序列(“9聚体”),每个子序列与前面的子序列重叠八个氨基酸,使得比对中每个长度为l的序列含有(l-8)个9聚体。In step 2, we apply the conservative algorithm to the set of aligned sequences. For each sequence in the alignment, starting from the first amino acid at the N-terminus, the algorithm moves one amino acid position at a time to generate a set of all possible amino acid fragments of length 9 amino acids, called "9-mers". Therefore, for each sequence in the alignment, the algorithm generates a set of 9 amino acid subsequences ("9-mers") starting from the N-terminal amino acid, each of which overlaps the previous subsequence by eight amino acids, such that each sequence of length 1 in the alignment contains (1-8) 9-mers.
接下来,对于每个9聚体位置,该方法鉴定两个最常见的独特9聚体以及它们在比对的源病毒蛋白质组序列集中的流行率。换句话说,从位置i开始,每个位置的两个最常见的独特9聚体是基于它们的频率来鉴定的,计算为独特9聚体在比对中在位置i出现的次数除以比对中的序列总数。Next, for each 9-mer position, the method identifies the two most common unique 9-mers and their prevalence in the aligned set of source viral proteome sequences. In other words, starting at position i, the two most common unique 9-mers at each position are identified based on their frequency, calculated as the number of times a unique 9-mer occurs at position i in the alignment divided by the total number of sequences in the alignment.
计算上,每个长度为l的序列含有l-8个9聚体。我们将从位置i开始的所有9聚体定义为sij,频率定义为fij,j=1,2,3,…m。在位置i总共有m个独特的9聚体。每两个独特的9聚体(siu,siv)可构成一个9聚体对,其频率为fiu+fiv。并且每个9聚体本身可以构成一个9聚体对,如(siu,siu),其频率为fiu。因此,在每个位置总共有m*(m+1)/2个9聚体对。Computationally, each sequence of length l contains l-8 9-mers. We define all 9-mers starting from position i as s ij and the frequency as fij , j = 1, 2, 3, ... m. There are a total of m unique 9-mers at position i. Every two unique 9-mers (s iu , s iv ) can form a 9-mer pair with frequency fiu +f iv . And each 9-mer itself can form a 9-mer pair, such as (s iu , s iu ), with frequency fiu . Therefore, there are a total of m*(m+1)/2 9-mer pairs at each position.
然后,该方法通过将含有两个最常见的9聚体中任一个的比对的源病毒蛋白质组序列集的比例相加来计算每个9聚体位置的二价保守性。为此,通过将比对中含有两个最常见的独特9聚体中任一个的序列的比例相加来计算每个位置的“二价保守性”。The method then calculates the bivalent conservation of each 9-mer position by summing the proportion of the aligned source viral proteome sequence sets that contain either of the two most common 9-mers. To do this, the "bivalent conservation" of each position is calculated by summing the proportion of sequences in the alignment that contain either of the two most common unique 9-mers.
接下来,通过提取比对中具有所需二价保守性的序列来产生保守区的新比对。在该实施例中,我们使用大于80%或大于90%的二价保守性,这意味着位置i处两个最常见的9聚体在保守区的新比对中占该位置处9聚体的80%以上或90%以上。换句话说,该方法将新比对中的保守区鉴定为其中每个位置处两个最常见的9聚体的频率之和大于某个截止值(例如,大于80%或大于90%)的那些。因此,该方法还计算了保守区的新比对中每个位置处每对独特9聚体的频率。Next, a new alignment of the conserved region is generated by extracting sequences with the desired bivalent conservation in the alignment. In this embodiment, we use a bivalent conservation greater than 80% or greater than 90%, which means that the two most common 9-mers at position i account for more than 80% or more than 90% of the 9-mers at that position in the new alignment of the conserved region. In other words, the method identifies the conserved region in the new alignment as those in which the sum of the frequencies of the two most common 9-mers at each position is greater than a certain cutoff value (e.g., greater than 80% or greater than 90%). Therefore, the method also calculates the frequency of each pair of unique 9-mers at each position in the new alignment of the conserved region.
这在图4A中以图形方式说明。图4A示出了一组假设的10个输入自然序列,每个序列在第一个9聚体内具有单个氨基酸变异。在该组10个序列中,在第三个氨基酸位置处具有“L”的9聚体出现6次,在该位置处具有“I”的9聚体出现3次,并且在该位置处具有“I”但在第一个位置具有不同氨基酸的9聚体出现一次。因此,保守算法选择两个最普遍的9聚体,它们一起占比对序列群体中该位置处可能的9聚体的90%。This is illustrated graphically in Figure 4A. Figure 4A shows a hypothetical set of 10 input natural sequences, each with a single amino acid variation within the first 9-mer. In this set of 10 sequences, the 9-mer with an "L" at the third amino acid position occurs 6 times, the 9-mer with an "I" at this position occurs 3 times, and the 9-mer with an "I" at this position but with a different amino acid in the first position occurs once. Therefore, the conservative algorithm selects the two most prevalent 9-mers, which together account for 90% of the possible 9-mers at this position in the sequence population.
使用该分析,确定群体中所有蛋白质序列中每个位置的高度保守的9聚体的分布。这在图4B中以图形方式说明。该图示出了从洛斯阿拉莫斯HIV序列数据库获得的9,846个组M进化枝B输入序列中由Gag基因p24蛋白编码的蛋白质的保守分布。y轴显示二价保守性,x轴显示9聚体相对于参考序列(来自HXB2的Gag p24)的位置。在图的顶部,水平条将保守区描绘为每个位置处使用两个最普遍的9聚体的具有至少80%二价保守性的区域。带正方形的深灰色线绘制了每个位置处使用两个最普遍的9聚体的二价保守性,而带菱形的浅灰色线示出了每个位置处仅使用最普遍的9聚体的保守性。该分析表明,使用两个最普遍的9聚体改进了对输入群体的结构保守序列的鉴定。Using this analysis, determine the distribution of highly conservative 9-mers in each position in all protein sequences in the colony. This is illustrated graphically in Fig. 4B. The figure shows the conservative distribution of proteins encoded by Gag gene p24 protein in 9,846 group M clade B input sequences obtained from Los Alamos HIV sequence database. The y-axis shows bivalent conservation, and the x-axis shows the position of 9-mer relative to the reference sequence (Gag p24 from HXB2). At the top of the figure, horizontal bars depict the conservative region as a region with at least 80% bivalent conservation using two of the most common 9-mers at each position. The dark grey line with squares has drawn the bivalent conservation using two of the most common 9-mers at each position, and the light grey line with diamonds shows the conservation of only the most common 9-mers at each position. This analysis shows that the identification of the structural conservative sequences of the input colony has been improved using two of the most common 9-mers.
我们接下来应用进一步的选择标准来定义保守区,包括限于具有大于90%二价保守性的区域并去除少于35个氨基酸的短片段,例如长度为9-35个氨基酸的片段。We next applied further selection criteria to define conserved regions, including limiting to regions with greater than 90% bivalent conservation and removing short fragments of less than 35 amino acids, such as fragments 9–35 amino acids in length.
我们还包括来自某些区域的一些附加片段,这些区域具有至少80%的二价保守性并且已知具有高度免疫原性,特别是与参考序列HXB2_K03455的氨基酸64-99对应的Nef区域(参见例如hiv.lanl.gov/content/immunology/maps/maps.html的表位图;Fischer等人,Nat Med.(2007)13(1):100-6;以及Addo等人,J Virol,(2003)77(3):2081-92)。We also included some additional fragments from certain regions that have at least 80% bivalent conservation and are known to be highly immunogenic, particularly the Nef region corresponding to amino acids 64-99 of the reference sequence HXB2_K03455 (see, e.g., epitope maps at hiv.lanl.gov/content/immunology/maps/maps.html; Fischer et al., Nat Med. (2007) 13(1):100-6; and Addo et al., J Virol, (2003) 77(3):2081-92).
步骤3:如果相邻位置中的9聚体对不具有任何冲突的氨基酸,则连接它们。Step 3: If the 9-mer pairs in adjacent positions do not have any conflicting amino acids, they are connected.
使用这组修改的保守区,我们应用CWA来构建二价序列构建体。CWA将9聚体对连接在保守区的比对的相邻位置,这些位置共享八个氨基酸的重叠。Using this modified set of conserved regions, we applied CWA to construct bivalent sequence constructs. CWA connects 9-mer pairs at aligned adjacent positions of the conserved regions that share an overlap of eight amino acids.
计算上,每个9聚体s含有9个氨基酸,s[x:y]表示从位置x到y的氨基酸子序列,总共y-x+1个氨基酸:Computationally, each 9-mer s contains 9 amino acids, and s[x:y] represents the amino acid subsequence from position x to y, with a total of y-x+1 amino acids:
siu[2:9]==si+1p[1:8]且siv[2:9]==si+1q[1:8] siu [2:9] == si+ 1p [1:8] and siv [2:9] == si +1q [1:8]
或者or
siu[2:9]==si+1q[1:8]且siv[2:9]==si+1p[1:8]。 siu [2:9] == si +1q [1:8] and siv [2:9] == si +1p [1:8].
步骤4:根据路径内所有9聚体的频率之和找到从第一个9聚体位置到最后一个位Step 4: Find the sum of the frequencies of all 9-mers in the path from the first 9-mer position to the last position. 置的最佳路径。The best path for the configuration.
在步骤4中,该算法构建了有向无环图,其中每个9聚体对是一个节点,相邻节点之间的边由相邻位置中连接的9聚体对形成,每条边的权重等于下游9聚体对的频率。这种有向无环图是位置De Brujin图。此类图已结合下一代测序数据的组装进行了描述,例如如Ronen等人,Bioinformatics(2012)28:188-196所述。In step 4, the algorithm constructs a directed acyclic graph in which each 9-mer pair is a node, and the edges between adjacent nodes are formed by the 9-mer pairs connected in adjacent positions, and the weight of each edge is equal to the frequency of the downstream 9-mer pair. This directed acyclic graph is a positional De Brujin graph. Such a graph has been described in conjunction with the assembly of next-generation sequencing data, such as Ronen et al., Bioinformatics (2012) 28: 188-196.
在本实施例中,我们添加源节点并将其与第一个位置的所有节点连接;并且我们添加宿节点并将其与最后一个位置的所有节点连接。在有向图中,源节点是仅具有流出的节点,并且宿节点是仅具有流入的节点。此处,源节点是与第一个位置的所有9聚体对节点连接的虚设节点,并且宿节点是与最后一个位置的所有9聚体对节点连接的虚设节点。In this embodiment, we add a source node and connect it to all nodes in the first position; and we add a sink node and connect it to all nodes in the last position. In a directed graph, a source node is a node with only outflows, and a sink node is a node with only inflows. Here, the source node is a dummy node connected to all 9-mer pairs of nodes in the first position, and the sink node is a dummy node connected to all 9-mer pairs of nodes in the last position.
然后我们将所有权重取反并找到从源节点到宿节点的最佳路径,其中最佳路径是根据所有9聚体对的频率之和来定义的。例如,使用Bellman–Ford算法执行找到最佳路径的任务。通常,Bellman-Ford算法计算加权有向图中从单个源顶点到所有其他顶点的最短路径。有向图由一组由边连接的顶点组成,其中边具有与它们相关的方向。We then invert all weights and find the best path from the source node to the sink node, where the best path is defined as the sum of the frequencies of all 9-mer pairs. The task of finding the best path is performed, for example, using the Bellman–Ford algorithm. In general, the Bellman–Ford algorithm computes the shortest path from a single source vertex to all other vertices in a weighted directed graph. A directed graph consists of a set of vertices connected by edges, where the edges have directions associated with them.
计算上,基本思路是将最大覆盖率二价疫苗构建问题建模为经典图论问题,其中解决方案是在有向无环图中找到最小路径。计算步骤汇总如下:Computationally, the basic idea is to model the maximum coverage bivalent vaccine construction problem as a classic graph theory problem, where the solution is to find the minimum path in a directed acyclic graph. The computational steps are summarized as follows:
·(4-1)将每个9聚体对作为节点处理,并在步骤3中的相邻节点之间构建边缘;(4-1) Treat each 9-mer pair as a node and build edges between adjacent nodes in step 3;
·(4-2)添加源节点并将其与第1个位置的所有节点连接;(4-2) Add the source node and connect it to all nodes at the first position;
·(4-3)添加宿节点并将其与最后一个位置的所有节点连接;(4-3) Add the sink node and connect it to all nodes in the last position;
·(4-4)每个边缘的权重等于下游9聚体对的频率;以及(4-4) The weight of each edge is equal to the frequency of the downstream 9-mer pair; and
·(4-5)使用Bellman–Ford算法将所有权重取反并找到最佳路径。(4-5) Use the Bellman–Ford algorithm to invert all weights and find the best path.
步骤5:基于最佳二价9聚体对路径构建二价疫苗序列,并且如果最佳二价9聚体对Step 5: Construct a bivalent vaccine sequence based on the best bivalent 9-mer pair path, and if the best bivalent 9-mer pair 路径内相邻位置的两个9聚体共享8个氨基酸的重叠,则连接它们。Two 9-mers at adjacent positions within the path were connected if they shared an overlap of 8 amino acids.
在步骤5中,如果最佳二价9聚体路径内相邻位置的两个9聚体共享八个氨基酸的重叠,则通过连接它们来构建二价构建体,从而产生连接的9聚体的两个序列,它们一起形成二价构建体。连接的相邻9聚体对均具有8个氨基酸重叠,因此它们被组装成两个序列。例如,将一个9聚体对(AIIIIIIIS(SEQ ID NO:190)、MIIIIIIII(SEQ ID NO:191))与另一个9聚体对(IIIIIIISK(SEQ ID NO:192)、IIIIIIIIR(SEQ ID NO:184))连接,并且形成两个序列(二价序列):AIIIIIIISK(SEQ ID NO:193)和MIIIIIIIIR(SEQ ID NO:194)。In step 5, if two 9 aggressiveness of adjacent positions in the best bivalent 9 aggressiveness path share eight amino acid overlaps, then bivalent constructs are built by connecting them, thereby producing two sequences of the 9 aggressiveness connected, and they form a bivalent construct together. The adjacent 9 aggressiveness of connection all has 8 amino acid overlaps, so they are assembled into two sequences. For example, a 9 aggressiveness pair (AIIIIIIIS (SEQ ID NO:190), MIIIIIIIII (SEQ ID NO:191)) is connected to another 9 aggressiveness pair (IIIIIIISK (SEQ ID NO:192), IIIIIIIIR (SEQ ID NO:184)), and two sequences (bivalent sequences) are formed: AIIIIIIISK (SEQ ID NO:193) and MIIIIIIIR (SEQ ID NO:194).
该方法在图5A至图5C中以图形方式说明。图5A示出了一组假设的9个源病毒序列,这些序列在第一个位置具有2个独特9聚体,并且在第二个相邻位置具有3个独特9聚体。每个序列的频率在序列的右侧表示为“次”,例如“x5”表示序列在源集中出现5次。图5B描绘了位置De Brujin图的构建,其中每个节点是一个二价9聚体对。当相邻位置的两个二价9聚体对共享八个氨基酸的重叠时,将它们连接起来形成一条边。以这种方式产生有向无环图。图5C示出了最佳路径的发现。如上所述,最佳路径是根据所有9聚体对的频率之和来定义的。这是通过找到相邻9聚体之间提供关于输入序列的最高保守性的连接来实现的。因此,在图5C中,如四对中的顶部组所示连接两个9聚体对提供了以下二价序列:The method is illustrated graphically in Figures 5A to 5C. Figure 5A shows a set of 9 hypothetical source virus sequences that have 2 unique 9-mers in the first position and 3 unique 9-mers in the second adjacent position. The frequency of each sequence is indicated as "times" on the right side of the sequence, for example "x5" means that the sequence appears 5 times in the source set. Figure 5B depicts the construction of a positional De Brujin graph, where each node is a bivalent 9-mer pair. When two bivalent 9-mer pairs at adjacent positions share an overlap of eight amino acids, they are connected to form an edge. A directed acyclic graph is generated in this way. Figure 5C shows the discovery of the optimal path. As described above, the optimal path is defined based on the sum of the frequencies of all 9-mer pairs. This is achieved by finding the connection between adjacent 9-mers that provides the highest conservation with respect to the input sequence. Therefore, in Figure 5C, connecting two 9-mer pairs as shown in the top group of four pairs provides the following bivalent sequence:
GIIIIIIIIK(SEQ ID NO:195)×0GIIIIIIIIIK (SEQ ID NO: 195) × 0
AIIIIIIIIH(SEQ ID NO:196)×0。AIIIIIIIIIH(SEQ ID NO:196)×0.
这些序列都不存在于图5A所示的源序列中。None of these sequences exist in the source sequence shown in FIG5A .
相比之下,在图5C中如四对中的底部组所示连接两个9聚体对提供了以下二价序列:In contrast, joining two 9-mer pairs as shown in the bottom group of four pairs in Figure 5C provides the following bivalent sequence:
GIIIIIIIIH(SEQ ID NO:178)×3GIIIIIIIIIH (SEQ ID NO: 178) × 3
AIIIIIIIIK(SEQ ID NO:177)×4。AIIIIIIIIIK (SEQ ID NO: 177) × 4.
这些中的每一者在图5A所示的源序列中分别存在3次或4次。因此,算法选择的是这些第二对二价序列,因为它相对于源序列最大化保守性。Each of these is present 3 or 4 times respectively in the source sequence shown in Figure 5 A. Therefore, it is these second pairs of bivalent sequences that the algorithm selects because it maximizes conservation relative to the source sequence.
计算上,这可以通过以下示例性情况来说明:Computationally, this can be illustrated by the following example case:
情况1:如果siu[2:9]=si+1p[1:8]且siv[2:9]=si+1q[1:8],则连接siu与si+1p以及siv与si+1q;Case 1: If siu [2:9] = si +1p [1:8] and siv [2:9] = si +1q [1:8], then connect siu to si +1p and siv to si +1q ;
情况2:如果siu[2:9]=si+1q[1:8]且siv[2:9]=si+1p[1:8],则连接siu与si+1q以及siv与si+1p;Case 2: If siu [2:9] = si +1q [1:8] and siv [2:9] = si +1p [1:8], then connect siu to si +1q and siv to si +1p ;
情况3:如果siu[2:9]=si+1p[1:8]且siv[2:9]=si+1q[1:8]且siu[2:9]=si+1q[1:8]且siv[2:9]=si+1p[1:8],则连接的选择基于自然序列中的两个连接的流行率:Case 3: If siu [2:9] = si +1p [1:8] and siv [2:9] = si +1q [1:8] and siu [2:9] = si +1q [1:8] and siv [2:9] = si +1p [1:8], then the choice of connection is based on the prevalence of the two connections in the natural sequence:
将输入序列中six和si+1y共存的流行率表示为Cixy Denote the prevalence of co-occurrence of s ix and s i+1y in the input sequence as C ixy
如果Ciup+Civq>Ciuq+Civp,则连接siu与si+1p以及siv与si+1q;If Ciup + Civq > Ciuq + Civp , connect siu with si +1p and si +1q with si +1q ;
如果Ciuq+Civp>Ciup+Civq,则连接siu与si+1q以及siv与si+1p;If Ciuq + Civp > Ciup + Civq , then connect siu with si +1q and si +1p with si +1p ;
如果Ciup+Civq=Ciuq+Civp,则回溯并组合位置i-1和i中9聚体对共存的流行率,直到第一个位置。如果两个不同的连接之间没有区别,则随机选择一个。If Ciup + Civq = Ciuq + Civp , then backtrack and combine the prevalence of coexistence of 9-mer pairs in positions i-1 and i, until the first position. If there is no distinction between two different connections, then choose one at random.
这种回溯和共存流行率方法考虑了长于9个氨基酸的肽的流行率,并进一步将本算法与其他基于图形的方法区分开来。This backtracking and co-occurrence prevalence approach takes into account the prevalence of peptides longer than 9 amino acids and further distinguishes the present algorithm from other graph-based methods.
接下来,使用以下三种不同接头策略中的一种来组合来自天然序列中彼此不相邻的区域(即,由于它们缺乏8个氨基酸重叠而不能根据上述CWA结合的区域)的构建序列:1.无需任何接头直接融合;2.在每两个保守区之间插入‘AAA’(SEQ ID NO:48)接头;3.同一蛋白质内的片段无需任何接头直接融合,并在不同蛋白质的片段之间插入F2A接头。Next, constructed sequences from regions that are not adjacent to each other in the native sequence (i.e., regions that cannot be combined according to the above CWA because they lack 8 amino acid overlap) were combined using one of the following three different linker strategies: 1. Direct fusion without any linker; 2. Insertion of an ‘AAA’ (SEQ ID NO: 48) linker between every two conserved regions; 3. Direct fusion of fragments within the same protein without any linker, and insertion of an F2A linker between fragments of different proteins.
保守步行分析(CWA)方法的概述在图1和图2中示出。An overview of the Conservative Walking Analysis (CWA) method is shown in FIGS. 1 and 2 .
实施例2Example 2
应用于由HIV-1基因编码的蛋白质的保守分析和保守步行分析(CWA)的图解具体Schematic illustration of conservation analysis and conservation walking analysis (CWA) applied to proteins encoded by HIV-1 genes 实施Implementation
该实施例描述了基于(1)Gag、Pol和Nef或(2)Pol和Nef的保守HIV-1区域的类似具体实施。This example describes similar implementations based on conserved HIV-1 regions of (1) Gag, Pol, and Nef or (2) Pol and Nef.
在以上实施例1中,应用保守算法来鉴定靶基因Gag、Nef和Pol的蛋白质编码区中的一组所有候选保守区。在该实施例中,我们利用(1)Gag、Pol和Nef、(2)Pol和Nef的蛋白质编码区产生不同的二价构建体。如在以上实施例1的步骤1-2中,我们首先比对源序列,然后应用保守算法来鉴定靶基因(其来自(1)Gag和Nef、Pol或(2)Pol和Env)的蛋白质编码区中的一组所有候选保守区。如上所述,然后我们基于保守性和已知的免疫原性应用进一步的选择标准(参见例如hiv.lanl.gov/content/immunology/maps/maps.html的表位图,以及Fischer等人,Nat Med.(2007)13(1):100-6)。在包括由Pol基因编码的多肽片段的某些序列中,我们排除了包括逆转录酶中的“YMDD”基序(SEQ ID NO:197)和蛋白酶中的“DTG”基序中的一者或两者的序列片段,因为它们可能影响酶活性表达和维持中的一者或两者。In Example 1 above, a conservative algorithm was applied to identify a group of all candidate conserved regions in the protein coding regions of the target genes Gag, Nef and Pol. In this example, we used (1) Gag, Pol and Nef, (2) Pol and Nef protein coding regions to produce different bivalent constructs. As in steps 1-2 of Example 1 above, we first aligned the source sequences and then applied a conservative algorithm to identify a group of all candidate conserved regions in the protein coding regions of the target genes (which are from (1) Gag and Nef, Pol or (2) Pol and Env). As described above, we then applied further selection criteria based on conservatism and known immunogenicity (see, for example, epitope maps at hiv.lanl.gov/content/immunology/maps/maps.html, and Fischer et al., Nat Med. (2007) 13(1): 100-6). Among certain sequences including polypeptide fragments encoded by the Pol gene, we excluded sequence fragments including one or both of the "YMDD" motif in reverse transcriptase (SEQ ID NO: 197) and the "DTG" motif in protease because they may affect one or both of the expression and maintenance of enzyme activity.
使用这组修改的保守区,我们应用CWA来构建二价序列构建体,如在实施例1的步骤3-5中。Using this modified set of conserved regions, we applied CWA to construct bivalent sequence constructs as in steps 3-5 of Example 1.
一些多肽片段通过聚丙氨酸接头(例如,AA、AAA(SEQ ID NO:48)或AAY(SEQ IDNO:49))连接,该接头被选择用于证实目的,因为它是较小的柔性接头,不太可能对蛋白质结构有重要影响。一些多肽片段通过天然短接头(例如,K、I、LI、EE、PPV、LIK、KIL、QEE或SEG)连接,这些天然短接头选自侧接待融合的保守多肽片段的天然HIV蛋白序列。如果我们确定可以融合多肽片段而不产生有害或不希望的连接表位(例如,可能刺激可与自身抗原交叉反应的T细胞的连接表位),则使用融合方法。如果我们确定可能会产生有害或不希望的连接表位,则在多肽片段之间插入柔性接头或天然短接头。Some polypeptide fragments are connected by a polyalanine linker (e.g., AA, AAA (SEQ ID NO: 48) or AAY (SEQ ID NO: 49)), which is selected for confirmation purposes because it is a smaller flexible linker that is unlikely to have a significant effect on the protein structure. Some polypeptide fragments are connected by natural short linkers (e.g., K, I, LI, EE, PPV, LIK, KIL, QEE or SEG), which are selected from natural HIV protein sequences flanking the conserved polypeptide fragments to be fused. If we determine that the polypeptide fragments can be fused without generating harmful or undesirable connecting epitopes (e.g., connecting epitopes that may stimulate T cells that cross-react with self-antigens), the fusion method is used. If we determine that harmful or undesirable connecting epitopes may be generated, flexible linkers or natural short linkers are inserted between the polypeptide fragments.
对于该实施例,我们对可能存在有害表位的连接区域进行了进一步分析,并排列了片段以减少或避免此类连接表位的产生。For this example, we further analyzed the junctional regions where deleterious epitopes might be present and arranged the fragments to reduce or avoid the generation of such junctional epitopes.
肽片段的不同排列产生不同的连接9聚体,可以诱导不同的连接反应。我们开发了一种多肽片段排列工具来检查MHC结合亲和力和与人类肽的交叉识别,用于每种排列中的所有连接9聚体。我们内部开发的多肽片段排列工具搜索肽的不同排列,并基于在9聚体的连接部上应用以下描述的两种分析的计算机预测结果来确定连接反应最小的最佳排列:(1)计算机HLA结合分析以及(2)人类蛋白质组分析以鉴定可能引发可识别自身抗原的T细胞的表位)。每两个相邻片段之间的连接反应分数由预测与靶HLA等位基因具有高结合亲和力的连接9聚体的数量与预测具有带任何连接9聚体的肽或T细胞识别基序的人类蛋白质的数目之和确定。每种片段排列的分数由每种片段排列中所有连接区域的连接反应分数之和确定。Different arrangements of peptide fragments produce different linked 9-mers that can induce different ligation reactions. We developed a peptide fragment alignment tool to examine MHC binding affinity and cross-recognition with human peptides for all linked 9-mers in each arrangement. Our in-house developed peptide fragment alignment tool searches different arrangements of peptides and determines the best arrangement with the least ligation reaction based on the in silico prediction results of two analyses applied to the linked parts of the 9-mers described below: (1) in silico HLA binding analysis and (2) human proteome analysis to identify epitopes that may elicit T cells that can recognize self-antigens). The ligation reaction score between each two adjacent fragments is determined by the sum of the number of linked 9-mers predicted to have high binding affinity to the target HLA allele and the number of human proteins predicted to have peptides or T cell recognition motifs with any of the linked 9-mers. The score for each fragment arrangement is determined by the sum of the ligation reaction scores for all linked regions in each fragment arrangement.
1)当有少于15个肽片段时,我们内部开发的多肽片段排列工具搜索所有可能的排列,并确定连接反应最小(片段排列分数最低)的最佳排列。1) When there are fewer than 15 peptide fragments, our in-house developed peptide fragment alignment tool searches all possible alignments and determines the best alignment with the minimum ligation reaction (lowest fragment alignment score).
2)当有至少15个肽片段时,我们内部开发的多肽片段排列工具使用“贪婪”策略。它首先创建所有连接部,然后根据预测的连接反应从最佳连接部开始。接下来,它迭代地搜索下一个兼容的最佳连接部并组装所有肽片段。2) When there are at least 15 peptide fragments, our in-house developed peptide fragment alignment tool uses a "greedy" strategy. It first creates all the linkers and then starts with the best linker based on the predicted ligation reaction. Next, it iteratively searches for the next compatible best linker and assembles all the peptide fragments.
计算机MHC I类(人HLA)结合分析:抗原加工、呈递和T细胞受体识别是很复杂的过程,尚未完全了解。细胞内和细胞外抗原在内体区室内被加工,并且细胞质被蛋白酶体加工并被运输到内体区室,诸如ER,在那里它们的肽片段与MHC分子相互作用。稳定的肽-MHC复合物被运输到细胞表面,在那里它们可以被表达TCR的T细胞以适当的特异性识别。抗原加工和呈递中最具选择性的步骤之一是HLA结合。HLA结合亲和力可以使用各种工具(诸如NetMHC或MHCflurry)或源自免疫肽组分析的大型内部数据集来预测,并通过实验结合数据以及从患者样品中定义的表位来确认。这些工具是可公开获得的并且例如在Lundegarrd等人,Nucleic Acids Res.2008年7月1日;36(Web Server issue):W509-12以及O’Donnell等人,Cell Systems 2018 7:129–132中所述。在该实施例中,我们使用了4.0版本的NetMHC。默认设置用于NetMHC中的所有参数,以及肽序列和HLA等位基因的输入信息。IC50值小于1,000nM的预测结合亲和力被认为是低结合亲和力。Computer MHC class I (human HLA) binding analysis: Antigen processing, presentation and T cell receptor recognition are very complex processes that are not yet fully understood. Intracellular and extracellular antigens are processed in endosomal compartments, and the cytoplasm is processed by proteasomes and transported to endosomal compartments, such as ER, where their peptide fragments interact with MHC molecules. Stable peptide-MHC complexes are transported to the cell surface, where they can be recognized by T cells expressing TCR with appropriate specificity. One of the most selective steps in antigen processing and presentation is HLA binding. HLA binding affinity can be predicted using various tools (such as NetMHC or MHCflurry) or large internal data sets derived from immunopeptidome analysis, and confirmed by experimental binding data and epitopes defined from patient samples. These tools are publicly available and are described, for example, in Lundegarrd et al., Nucleic Acids Res. 2008 July 1; 36 (Web Server issue): W509-12 and O'Donnell et al., Cell Systems 2018 7: 129–132. In this example, we used NetMHC version 4.0. Default settings were used for all parameters in NetMHC, as well as input information for peptide sequences and HLA alleles. Predicted binding affinities with IC50 values less than 1,000 nM were considered low binding affinities.
人类蛋白质组交叉识别分析:类似于人类肽的表位可诱导可能与自身抗原交叉反应的一种或多种耐受原反应。我们在公共人类蛋白质数据库(例如Uniprot、NCBI)中搜索了我们的疫苗中的所有9聚体。如果HIV肽9聚体与人类肽9聚体具有至少5个残基的氨基酸序列同一性,并且预计两者对相同等位基因都具有高结合亲和力,则它们被认为是交叉保守的9聚体。我们从UniProt数据库下载了所有人类蛋白质序列,并构建了一种工具来支持在具有多达4个错配(至少5个匹配)的所有人类蛋白质9聚体中高效搜索给定的9聚体。Human proteome cross-recognition analysis: Epitopes similar to human peptides may induce one or more tolerogenic responses that may cross-react with self-antigens. We searched all 9-mers in our vaccine in public human protein databases (e.g., UniProt, NCBI). HIV peptide 9-mers were considered cross-conserved 9-mers if they had at least 5 residues of amino acid sequence identity with human peptide 9-mers and both were predicted to have high binding affinity for the same allele. We downloaded all human protein sequences from the UniProt database and built a tool to support efficient searching for a given 9-mer among all human protein 9-mers with up to 4 mismatches (at least 5 matches).
图6示出了人类蛋白质组交叉识别分析的结果。在该实施例中,我们在人类蛋白质数据库中搜索了HIV-1肽9聚体,并鉴定了共享一定数目的氨基酸(暂定至少5个)并基于本文所述的计算机MHC I类分析预测对相同等位基因具有高结合亲和力(例如,IC50小于约1000nM或百分位等级在多肽片段群体中的前5%内)的所有人类蛋白质9聚体。排除了这种既与人类蛋白质的肽片段具有显著或高序列同一性(例如,具有至少55%(9个氨基酸残基中的5个)、例如至少65%(9个氨基酸残基中的6个)、例如至少75%(9个氨基酸残基中的7个)、例如至少85%(9个氨基酸残基中的8个))又具有高预测MHC I类结合亲和力的HIV 9聚体,因为它们可能诱导可能与人类自身抗原(本文定义为“有害表位”)交叉反应的一种或多种耐受原应答。Figure 6 shows the results of the human proteome cross-recognition analysis. In this example, we searched for HIV-1 peptide 9-mers in the human protein database and identified all human protein 9-mers that shared a certain number of amino acids (tentatively at least 5) and were predicted to have high binding affinity to the same allele based on the computer MHC class I analysis described herein (e.g., IC50 less than about 1000nM or percentile rank within the top 5% of the polypeptide fragment population). Such HIV 9-mers that have both significant or high sequence identity with peptide fragments of human proteins (e.g., having at least 55% (5 of 9 amino acid residues), such as at least 65% (6 of 9 amino acid residues), such as at least 75% (7 of 9 amino acid residues), such as at least 85% (8 of 9 amino acid residues)) and high predicted MHC class I binding affinity were excluded because they may induce one or more tolerogenic responses that may cross-react with human self-antigens (defined herein as "harmful epitopes").
图7示出了多肽片段排列分析能够如何减少或消除连接区中有害或不希望的表位的可能呈现。在例示的默认排列中,预测Seg 2与Seg 3之间以及Seg 3与Seg 4之间的连接9聚体会产生可能在人体中诱导耐受原或自身反应性应答的连接序列(例如,基于计算机HLA结合分析具有高MHC结合亲和力或基于人类蛋白质组交叉识别分析与人类蛋白质发生交叉识别)。我们应用了一种算法,该算法搜索不同的排列并确定产生减少或消除的可能在人体中诱导耐受原或自身反应性应答的预测连接序列的排列。另外,如果开发了多个抗原序列,多肽片段也被重新排列以避免在抗原序列之间的连接处出现相同或几乎相同的9聚体。FIG7 illustrates how polypeptide fragment alignment analysis can reduce or eliminate the possible presentation of harmful or undesirable epitopes in junction regions. In the illustrated default alignment, the junction 9-mers between Seg 2 and Seg 3 and between Seg 3 and Seg 4 are predicted to produce junction sequences that are likely to induce tolerogenic or autoreactive responses in humans (e.g., have high MHC binding affinity based on computer HLA binding analysis or cross-recognition with human proteins based on human proteome cross-recognition analysis). We applied an algorithm that searches different alignments and identifies alignments that produce predicted junction sequences that are reduced or eliminated in terms of the potential to induce tolerogenic or autoreactive responses in humans. In addition, if multiple antigen sequences are developed, the polypeptide fragments are also rearranged to avoid the presence of identical or nearly identical 9-mers at the junctions between antigen sequences.
本文所述的融合多肽和复合融合多肽是根据本文所述的免疫原设计方法设计的示例性免疫原性融合多肽序列。具有由HIV-1 Gag、Nef和Pol基因编码的多肽片段的SEQ IDNO:70-101(提供于表E中),特别是SEQ ID NO:94-101(免疫原版本1)的融合多肽,以及SEQID NO:105-112、200-209、222-223和227(提供于表F中)的复合融合多肽是根据该方法设计的示例性免疫原性融合多肽序列。图8提供了含有免疫原版本1的融合蛋白的病毒载体的示意图。The fusion polypeptides and composite fusion polypeptides described herein are exemplary immunogenic fusion polypeptide sequences designed according to the immunogen design method described herein. Fusion polypeptides of SEQ ID NO: 70-101 (provided in Table E), particularly SEQ ID NO: 94-101 (immunogen version 1), which are polypeptide fragments encoded by HIV-1 Gag, Nef and Pol genes, and composite fusion polypeptides of SEQ ID NO: 105-112, 200-209, 222-223 and 227 (provided in Table F) are exemplary immunogenic fusion polypeptide sequences designed according to the method. Figure 8 provides a schematic diagram of a viral vector containing a fusion protein of immunogen version 1.
实施例3Example 3
用深度测序分析和免疫原性数据改进的免疫原设计:免疫原版本2Improved immunogen design using deep sequencing analysis and immunogenicity data: Immunogen version 2
在以上实施例1中,应用保守算法来鉴定靶基因Gag、Nef和Pol的蛋白质编码区中的一组所有候选保守区。在实施例2中,我们利用(1)Gag、Pol和Nef、(2)Pol和Nef的蛋白质编码区产生不同的二价构建体。在该实施例中,我们通过结合深度测序数据和免疫原性数据来描述免疫原版本2的设计,以鉴定来自免疫原版本1的哪些保守区将被包括在缩短的二价多肽构建体中。对于这种改进的免疫原的设计,如在以上实施例1的步骤1-2中,我们首先比对源序列,然后应用本文所述的保守步行算法(CWA)来鉴定靶基因的蛋白质编码区中的一组所有候选保守区。靶基因是Gag、Nef和Pol,并且我们应用CWA在这些区中构建二价序列,如实施例1的步骤3-5中所示。In Example 1 above, a conservative algorithm was applied to identify a set of all candidate conserved regions in the protein coding regions of the target genes Gag, Nef, and Pol. In Example 2, we used the protein coding regions of (1) Gag, Pol, and Nef, and (2) Pol and Nef to generate different bivalent constructs. In this example, we describe the design of immunogen version 2 by combining deep sequencing data and immunogenicity data to identify which conserved regions from immunogen version 1 will be included in the shortened bivalent polypeptide construct. For the design of this improved immunogen, as in steps 1-2 of Example 1 above, we first aligned the source sequences and then applied the conservative walking algorithm (CWA) described herein to identify a set of all candidate conserved regions in the protein coding regions of the target genes. The target genes are Gag, Nef, and Pol, and we apply CWA to construct bivalent sequences in these regions, as shown in steps 3-5 of Example 1.
使用深度测序的患者内保守性分析。除了从下载的群体序列中获得的9聚体之外,HIV-1B亚型慢性感染个体的病毒深度测序数据,以鉴定这些保守区内的患者内多样性。为了使用深度测序数据鉴定患者内的9聚体变体,分析N=238个HIV慢性感染的未治疗受试者的深度测序数据以评估由CWA限定的保守区内的患者内多样性。为了使用深度测序数据来评估患者内的9聚体变体,组装深度测序读段以产生特定于受试者的共有序列。将读段与受试者特定的共有序列进行比对,然后基于受试者特定的共有序列与HXB2参考序列的比对,将比对映射到HXB2位置坐标。在每个9聚体位置,提取完全覆盖该9聚体的27bp的对应测序读段,并将其转化为9聚体氨基酸序列。只有测序读段深度≥1000的9聚体位置被纳入分析,并且变体以1%的截止频率进行分析。使用9聚体变体来评估二价疫苗序列的准种变体覆盖率。此处,我们将9聚体位置的患者内保守性定义为被二价疫苗序列覆盖而没有逃逸变体的患者(总N=238个样品)的百分比。患者内高度保守的9聚体是在>70%的患者中被基于群体的二价疫苗序列覆盖而没有任何逃逸变体的9聚体。如实施例1所述,评估基于群体保守性选择的Pol、Gag和Nef区域的患者内保守性。Intra-patient conservation analysis using deep sequencing. In addition to the 9-mers obtained from the downloaded population sequences, deep sequencing data of viruses from individuals chronically infected with HIV-1B subtype were used to identify intra-patient diversity within these conserved regions. In order to identify intra-patient 9-mer variants using deep sequencing data, deep sequencing data from N = 238 untreated subjects with chronic HIV infection were analyzed to assess intra-patient diversity within the conserved regions defined by CWA. In order to use deep sequencing data to assess intra-patient 9-mer variants, deep sequencing reads were assembled to generate subject-specific consensus sequences. The reads were aligned to the subject-specific consensus sequence and then mapped to HXB2 position coordinates based on the alignment of the subject-specific consensus sequence with the HXB2 reference sequence. At each 9-mer position, the corresponding sequencing read of 27 bp that completely covered the 9-mer was extracted and converted into a 9-mer amino acid sequence. Only 9-mer positions with a sequencing read depth ≥ 1000 were included in the analysis, and variants were analyzed at a cutoff frequency of 1%. The 9-mer variants were used to assess the quasispecies variant coverage of the bivalent vaccine sequence. Here, we define the intra-patient conservation of 9-mer positions as the percentage of patients (total N=238 samples) covered by the bivalent vaccine sequence without escape variants. A highly intra-patient conserved 9-mer is a 9-mer that is covered by the population-based bivalent vaccine sequence in >70% of patients without any escape variants. As described in Example 1, the intra-patient conservation of Pol, Gag, and Nef regions selected based on population conservation was evaluated.
图10提供了示出用于设计免疫原版本2的方法的基本方法的流程图。SEQ ID NO:82-89的融合多肽是根据该方法设计的例示性氨基酸序列。Figure 10 provides a flow chart showing the basic method for designing immunogen version 2. The fusion polypeptides of SEQ ID NOs: 82-89 are exemplary amino acid sequences designed according to this method.
来自洛斯阿拉莫斯国家实验室(LANL)数据库的已知表位和Gilead ELISPOT测定鉴定的表位。为了评估先前鉴定的保守区的免疫原性,分析了描述的CD8+ T细胞表位(例如,来自LANL数据库)和内部进行的ELISpot测定。Pol、Gag和Nef的保守区中具有>1个由ELISPOT测定定义或来自LANL数据库的映射表位的任何9聚体位置被认为是免疫原性区域。免疫原性结果不限于特定的HLA等位基因。Known epitopes from the Los Alamos National Laboratory (LANL) database and epitopes identified by the Gilead ELISPOT assay. To assess the immunogenicity of previously identified conserved regions, described CD8+ T cell epitopes (e.g., from the LANL database) and ELISpot assays performed in-house were analyzed. Any 9-mer position in the conserved regions of Pol, Gag, and Nef with >1 mapped epitope defined by the ELISPOT assay or from the LANL database was considered an immunogenic region. Immunogenicity results were not limited to specific HLA alleles.
图10A至图10C示出了通过组合深度测序数据和免疫原性数据为免疫原版本2选择的区域。对于图中的每个9聚体位置,患者内保守性表示为黑色水平线。在每个9聚体区域重叠的表位数目在图中显示为堆叠条。我们选择了这样的氨基酸9聚体,其具有>70%的患者内保守性并且与通过LANL数据库报告的或通过ELISpot测定定义的表位重叠。在鉴定了用于改进的免疫原的氨基酸9聚体后,将来自相同病毒蛋白且连续的那些9聚体连接(例如,经由接头或直接融合)以形成图中突出显示的融合氨基酸片段。Figures 10A to 10C show the regions selected for immunogen version 2 by combining deep sequencing data and immunogenicity data. For each 9-mer position in the figure, intra-patient conservation is represented as a black horizontal line. The number of epitopes overlapping in each 9-mer region is shown as a stacked bar in the figure. We selected such amino acid 9-mers that have> 70% intra-patient conservation and overlap with epitopes reported by the LANL database or defined by ELISpot assays. After identifying the amino acid 9-mers for improved immunogens, those 9-mers from the same viral protein and continuous are connected (e.g., via a linker or direct fusion) to form the fusion amino acid fragments highlighted in the figure.
我们利用(1)Gag和Pol、(2)Pol和Nef的蛋白质编码区产生不同的二价构建体。在最后的步骤中,我们将实施例2中描述的我们内部开发的多肽片段排列工具应用于片段,以减少或消除连接区中有害或不期望的表位的可能呈递。我们在免疫原2的片段重排期间将Nef保守序列锚定到疫苗序列的C末端,因为我们先前的实验显示将Nef片段定位到疫苗序列的C末端更可能诱导免疫应答。图11提供了含有免疫原版本2的融合蛋白(例如,SEQ IDNO:82-89)的病毒载体的示意图。We used the protein coding regions of (1) Gag and Pol, and (2) Pol and Nef to generate different bivalent constructs. In the final step, we applied our internally developed polypeptide fragment alignment tool described in Example 2 to the fragments to reduce or eliminate the possible presentation of harmful or undesirable epitopes in the junction region. We anchored the Nef conserved sequence to the C-terminus of the vaccine sequence during the fragment rearrangement of immunogen 2 because our previous experiments showed that positioning the Nef fragment to the C-terminus of the vaccine sequence was more likely to induce an immune response. Figure 11 provides a schematic diagram of a viral vector containing a fusion protein (e.g., SEQ ID NO: 82-89) of immunogen version 2.
改进的免疫原设计的中值应答和表位密度。为了评估缩短的免疫原是否富含免疫原性区域,我们在根据实施例1-2的方法设计的融合蛋白(例如,免疫原版本1;SEQ ID NO:94-101)和根据实施例1-3的方法设计的融合蛋白(例如,免疫原版本2;SEQ ID NO:82-89)之间比较了每个样品的内部定义的表位数目。图12A至图12B示出了中值应答在大小改变的情况下保持稳定。总共分析了93个样品。我们测量了在每个样品中鉴定的表位的中值数目。免疫原版本2的表位的中值数目是4,而免疫原1的表位的中值数目是5。使用较短的免疫原版本2观察到两个无应答者。通过评估表位率来检查表位密度。表位率定义为体外临床试验定义的表位数目除以免疫原中潜在的表位总数。如表1所示,表位率分析结果表明,在免疫原版本1(长度为516-527个氨基酸)的融合蛋白的大小减小至免疫原版本2(长度为351-365个氨基酸)的融合蛋白之后,我们使表位密度最大化。免疫原版本1的表位率在免疫原版本2中保持不变。我们将表位率定义为通过ELISpot测定识别为表位的所有9聚体的百分比(表位总数/9聚体位置的数目)。Improved median response and epitope density of immunogen design. In order to evaluate whether the shortened immunogen is rich in immunogenic regions, we compared the number of internally defined epitopes for each sample between fusion proteins designed according to the methods of Examples 1-2 (e.g., immunogen version 1; SEQ ID NO: 94-101) and fusion proteins designed according to the methods of Examples 1-3 (e.g., immunogen version 2; SEQ ID NO: 82-89). Figures 12A to 12B show that the median response remains stable under size changes. A total of 93 samples were analyzed. We measured the median number of epitopes identified in each sample. The median number of epitopes for immunogen version 2 was 4, while the median number of epitopes for immunogen 1 was 5. Two non-responders were observed using the shorter immunogen version 2. The epitope density was examined by evaluating the epitope rate. The epitope rate is defined as the number of epitopes defined in the in vitro clinical trial divided by the total number of potential epitopes in the immunogen. As shown in Table 1, the results of epitope rate analysis indicate that we maximized epitope density after the size of the fusion protein of immunogen version 1 (516-527 amino acids in length) was reduced to the fusion protein of immunogen version 2 (351-365 amino acids in length). The epitope rate of immunogen version 1 remained unchanged in immunogen version 2. We defined the epitope rate as the percentage of all 9-mers recognized as epitopes by the ELISpot assay (total number of epitopes/number of 9-mer positions).
表1Table 1
免疫原版本1和2之间的表位率分析Epitope ratio analysis between immunogen versions 1 and 2
实施例4Example 4
适于从单个初免载体和单个加强载体表达的缩短的构建体:免疫原版本3Shortened construct suitable for expression from a single priming vector and a single boosting vector: Immunogen version 3
在该实施例中,如在以上实施例1的步骤1-2中,我们首先比对源序列,然后应用CWA来鉴定靶基因的蛋白质编码区中的一组所有候选保守区。在该实施例中,靶基因是Gag、Nef和Pol。我们应用CWA在这些区中构建二价序列,如实施例1的步骤3-5中所示。In this example, as in steps 1-2 of Example 1 above, we first aligned the source sequences and then applied CWA to identify a set of all candidate conserved regions in the protein coding regions of the target genes. In this example, the target genes are Gag, Nef, and Pol. We applied CWA to construct bivalent sequences in these regions, as shown in steps 3-5 of Example 1.
如上面的实施例3,我们应用深度测序和免疫原性数据来鉴定免疫原版本1内保留在缩短的免疫原中的高度保守和免疫原性区域的子集。图13提供了示出免疫原版本3的融合多肽的基本方法的流程图。SEQ ID NO:90-93是根据该方法设计的例示性融合多肽。我们利用与实施例3中所述相同的方法来设计免疫原版本3的缩短的二价融合多肽(长度为391-394个氨基酸),其长度使得四个融合多肽可从两个病毒载体(例如,两个沙粒病毒载体)表达。免疫原性数据显示Gag p24和Nef片段(64-76)引发强免疫应答,因此Nef 64-76保留在免疫原版本3中。对于Pol,如上所述,我们鉴定了Pol中的连续区域,其具有>75%的患者内保守性并且含有通过体外测定定义的多个表位。图14A至图14D示出了为免疫原3选择的区域。我们利用(1)Gag和Pol、(2)Pol和Nef的蛋白质编码区产生不同的二价构建体。在最后的步骤中,我们将实施例2中描述的我们内部开发的多肽片段排列工具应用于片段,以减少或消除连接区中有害或不期望的表位的可能呈递。Nef的保守子序列位于免疫原版本3融合多肽的C末端。图15提供了含有免疫原版本3的融合蛋白(例如,SEQ ID NO:90-93)的病毒载体的示意图。As in Example 3 above, we applied deep sequencing and immunogenicity data to identify a subset of highly conserved and immunogenic regions within immunogen version 1 that were retained in the shortened immunogen. Figure 13 provides a flow chart showing the basic method for fusion polypeptides of immunogen version 3. SEQ ID NO: 90-93 are exemplary fusion polypeptides designed according to this method. We used the same method as described in Example 3 to design a shortened bivalent fusion polypeptide (391-394 amino acids in length) of immunogen version 3, the length of which allowed four fusion polypeptides to be expressed from two viral vectors (e.g., two arenavirus vectors). Immunogenicity data showed that Gag p24 and Nef fragments (64-76) elicited a strong immune response, so Nef 64-76 was retained in immunogen version 3. For Pol, as described above, we identified a continuous region in Pol that had >75% intra-patient conservation and contained multiple epitopes defined by in vitro assays. Figures 14A to 14D show the regions selected for immunogen 3. We generated different bivalent constructs using the protein coding regions of (1) Gag and Pol, and (2) Pol and Nef. In the final step, we applied our in-house developed polypeptide fragment alignment tool described in Example 2 to the fragments to reduce or eliminate the possible presentation of harmful or undesirable epitopes in the junction region. The conserved subsequence of Nef is located at the C-terminus of the immunogen version 3 fusion polypeptide. Figure 15 provides a schematic diagram of a viral vector containing a fusion protein of immunogen version 3 (e.g., SEQ ID NO: 90-93).
实施例5Example 5
免疫原1中含有免疫原性融合多肽的病毒表达载体Viral expression vector containing immunogenic fusion polypeptide in immunogen 1
在该实施例中,我们产生了编码计算定义的多肽片段(所述多肽片段含有由Gag、Nef和Pol基因编码的HIV-1的保守区作为转基因)的病毒表达载体,并证实了转基因在哺乳动物细胞中的表达。含有保守区的多肽片段通过多种方法串联或连接,包括直接融合、通过添加蛋白水解切割位点序列或在各区之间添加柔性接头来连接各区。In this example, we generated viral expression vectors encoding computationally defined polypeptide fragments containing conserved regions of HIV-1 encoded by Gag, Nef and Pol genes as transgenes and demonstrated expression of the transgenes in mammalian cells. The polypeptide fragments containing the conserved regions were tandemly or linked by a variety of methods, including direct fusion, linking the regions by adding proteolytic cleavage site sequences or adding flexible linkers between the regions.
方法method
体外靶基因表达的评估。为了改进编码疫苗表达盒的病毒载体的组装,将基因克隆到含有用于克隆靶基因的限制性位点和GFP标记的载体质粒(ThermoFisherScientific)中。按照制造商的方案将DNA转化到One Shot TOP10感受态细胞(Invitrogen,Carlsbad,CA)中,并接种到补充有100μg/ml氨苄青霉素的LB琼脂板上。将板在37℃下孵育过夜。从板中挑出单个菌落并接种到10ml液体LB+氨苄青霉素培养物中,并在Eppendorf台式摇床中以250rpm在37℃下摇动过夜。按照制造商的方案使用QIAprep Spin miniprep试剂盒(Qiagen,Germantown,MD)处理细菌沉淀,以获得质粒DNA。通过使用NanoDropTM2000(Thermo Scientific)读取280nm处的吸光度来确定核酸浓度。为了评估体外表达,将表达SEQ ID NO:105、107、109或111的复合融合蛋白的腺病毒血清型5(Ad5)表达载体用于转导单核细胞衍生的树突细胞(moDC),如下文实施例9中所概述。在转导后第2天,当细胞存活率仍>80%时,通过流式细胞术评估它们的GFP表达或沉淀。通过ELISA评估细胞裂解物的HIV-1 Gag p24表达。Evaluation of target gene expression in vitro. In order to improve the assembly of the viral vector encoding the vaccine expression cassette, the gene was cloned into a vector plasmid (ThermoFisherScientific) containing a restriction site for cloning the target gene and a GFP marker. DNA was transformed into One Shot TOP10 competent cells (Invitrogen, Carlsbad, CA) according to the manufacturer's protocol and inoculated onto an LB agar plate supplemented with 100 μg/ml ampicillin. The plate was incubated overnight at 37 ° C. Single colonies were picked out from the plate and inoculated into 10 ml liquid LB+ ampicillin culture, and shaken overnight at 37 ° C with 250 rpm in an Eppendorf table shaker. Bacterial precipitation was processed using QIAprep Spin miniprep kit (Qiagen, Germantown, MD) according to the manufacturer's protocol to obtain plasmid DNA. The nucleic acid concentration was determined by reading the absorbance at 280 nm using NanoDrop TM 2000 (Thermo Scientific). To evaluate in vitro expression, adenovirus serotype 5 (Ad5) expression vectors expressing composite fusion proteins of SEQ ID NO: 105, 107, 109 or 111 were used to transduce monocyte-derived dendritic cells (moDCs) as outlined in Example 9 below. On day 2 after transduction, when cell viability was still >80%, they were evaluated by flow cytometry for GFP expression or precipitation. Cell lysates were evaluated for HIV-1 Gag p24 expression by ELISA.
含有编码融合多肽变体的转基因的病毒表达载体的构建。使用标准方法(VectorBiolabs)通过体外重组产生了表达HIV-1计算定义的疫苗免疫原的Ad5载体,该载体采用各种方法连接保守的HIV-1序列。使用经密码子偏好以改进人类表达(IDT)的合成寡核苷酸通过PCR产生表达盒,并且使用标准基因克隆技术将其置于CMV启动子的控制下。针对该评估开发的免疫原版本1复合融合多肽构建体在表F中列出,并在图19中示意性描绘。The construction of the transgenic viral expression vector containing the encoding fusion polypeptide variant. The Ad5 vector expressing the vaccine immunogen defined by HIV-1 calculation was produced by in vitro recombination using standard methods (VectorBiolabs), and the vector was connected to the conservative HIV-1 sequence using various methods. The synthetic oligonucleotides using codon preference to improve human expression (IDT) were used to produce expression cassettes by PCR, and standard gene cloning techniques were used to place it under the control of the CMV promoter. The immunogen version 1 composite fusion polypeptide construct developed for this evaluation is listed in Table F, and schematically depicted in Figure 19.
结果result
图20中描绘的数据表明,所有保守区融合多肽序列都被有效表达(图20A)和转导(图20B),如GFP表达和Gag p24 ELISA所证明的。The data depicted in Figure 20 demonstrate that all conserved region fusion polypeptide sequences were efficiently expressed (Figure 20A) and transduced (Figure 20B) as demonstrated by GFP expression and Gag p24 ELISA.
实施例6Example 6
免疫原2中含有免疫原性融合多肽的病毒表达载体Viral expression vector containing immunogenic fusion polypeptide in immunogen 2
本实施例评估Ad5病毒表达载体的体外靶基因表达和构建。采用类似的策略来评估保守区HIV免疫原2(SEQ ID NO:82-89)的表达,如上文实施例5中针对免疫原版本1融合多肽所述。免疫原版本2融合多肽构建体在表E中列出,并在图21中示意性描绘。This example evaluates in vitro target gene expression and construction of Ad5 viral expression vectors. A similar strategy was used to evaluate the expression of conserved region HIV immunogen 2 (SEQ ID NO: 82-89) as described above for immunogen version 1 fusion polypeptides in Example 5. Immunogen version 2 fusion polypeptide constructs are listed in Table E and schematically depicted in Figure 21.
结果result
图22A至图22B中描绘的数据证明所有保守区多肽序列导致编码SEQ ID NO:82-89的融合多肽的多核苷酸的有效表达(图22A)和转导(图22B)。The data depicted in Figures 22A-22B demonstrate that all of the conserved region polypeptide sequences resulted in efficient expression (Figure 22A) and transduction (Figure 22B) of polynucleotides encoding the fusion polypeptides of SEQ ID NOs: 82-89.
实施例7Example 7
免疫原3中含有免疫原性融合多肽的病毒表达载体Viral expression vector containing immunogenic fusion polypeptide in immunogen 3
本实施例评估Ad5病毒表达载体的体外靶基因表达和构建。采用类似的策略来评估保守区HIV免疫原3(SEQ ID NO:90-93)的表达,如上文实施例5中针对免疫原版本1的融合多肽所述。免疫原版本3融合多肽构建体在表E中列出,并在图23中示意性描绘。This example evaluates in vitro target gene expression and construction of Ad5 viral expression vectors. A similar strategy was used to evaluate the expression of conserved region HIV immunogen 3 (SEQ ID NO: 90-93), as described above for immunogen version 1 fusion polypeptides in Example 5. Immunogen version 3 fusion polypeptide constructs are listed in Table E and schematically depicted in Figure 23.
结果result
图24A至图24B中描绘的数据证明所有保守区多肽序列导致编码SEQ ID NO:90-93的融合多肽的多核苷酸的有效表达(图24A)和转导(图24B)。The data depicted in Figures 24A-24B demonstrate that all of the conserved region polypeptide sequences resulted in efficient expression (Figure 24A) and transduction (Figure 24B) of polynucleotides encoding the fusion polypeptides of SEQ ID NOs: 90-93.
然后,我们在各种病毒载体系统中测试了这些构建体在体外和体内引发T细胞反应的效率。We then tested the efficiency of these constructs in eliciting T cell responses in vitro and in vivo in various viral vector systems.
实施例8Example 8
体内T细胞活化测定In vivo T cell activation assay
在该实施例中,我们评估了在小鼠模型中通过疫苗构建体体内引发T细胞的功效。为此,我们用表达计算定义的保守区疫苗免疫原序列的Ad5载体来免疫小鼠组。我们研究了这些应答的大小和功能表型,以确定疫苗序列的免疫原性。In this example, we evaluated the efficacy of in vivo T cell priming by vaccine constructs in a mouse model. To do this, we immunized groups of mice with Ad5 vectors expressing computationally defined conserved region vaccine immunogen sequences. We studied the magnitude and functional phenotype of these responses to determine the immunogenicity of the vaccine sequences.
疫苗以同源(相对于病毒表达载体)的初免-加强方法施用。初免-加强对中的每个病毒Ad5载体具有在融合多肽构建体中编码的HIV基因片段的不同重排。这种基因重排减少或消除了连接反应的形成。载体在其可稳定表达的转基因大小上有所不同。在疫苗免疫原的设计中,两个长度小于600个氨基酸的互补融合多肽各自从单一病毒载体表达。可容纳较大转基因的载体可例如使用F2A接头结合两个片段(本文中描述为“复合融合多肽;”参见表F)。我们使用表达复合融合多肽的载体,在有和没有F2A接头的情况下,在初免序列中和再次在初免-加强序列中测试了每个单独融合多肽序列的免疫原性。含有F2A接头的载体也具有N末端组织纤溶酶原(t-PA)信号肽序列(MDAMKRGLCCVLLLCGAVFVSAR(SEQ ID NO:121))。免疫原版本1融合多肽构建体在表E中列出,并在图25中示意性描绘。免疫原版本1复合融合多肽构建体在表F中列出,并在图19中示意性描绘。The vaccine is administered in a homologous (relative to viral expression vector) primary immunity-boosting method. Each viral Ad5 vector in the primary immunity-boosting pair has a different rearrangement of the HIV gene fragment encoded in the fusion polypeptide construct. This gene rearrangement reduces or eliminates the formation of a ligation reaction. The vector is different in the size of the transgene that can be stably expressed. In the design of the vaccine immunogen, two complementary fusion polypeptides less than 600 amino acids in length are expressed from a single viral vector. A vector that can accommodate a larger transgene can, for example, use an F2A joint to combine two fragments (described herein as "composite fusion polypeptides; " see Table F). We use a vector expressing a composite fusion polypeptide, and in the presence and absence of an F2A joint, the immunogenicity of each individual fusion polypeptide sequence is tested in the primary immunity sequence and again in the primary immunity-boosting sequence. The vector containing the F2A joint also has an N-terminal tissue plasminogen (t-PA) signal peptide sequence (MDAMKRGLCCVLLLCGAVFVSAR (SEQ ID NO: 121)). Immunogen Version 1 fusion polypeptide constructs are listed in Table E and schematically depicted in Figure 25. Immunogen Version 1 composite fusion polypeptide constructs are listed in Table F and schematically depicted in Figure 19.
方法method
免疫原性的体内评估In vivo assessment of immunogenicity
免疫.通过在两条后腿肌肉中进行肌内(I.M.)注射用1×109PFU表达HIV免疫原的Ad5载体免疫五周或六周龄的Balb/c小鼠。以100μl磷酸盐缓冲盐水(PBS)注射液(50μl/四头肌)施用疫苗载体。在疫苗免疫之前用异氟烷麻醉小鼠。将动物圈养在动物设施(Bioqual,Maryland)中,并根据批准的IACUC方案进行实验。该方案的示意图提供于图26中。Immunization. Balb/c mice, five or six weeks old, were immunized with 1×10 9 PFU of Ad5 vector expressing HIV immunogen by intramuscular (IM) injection in both hind leg muscles. Vaccine vector was administered as 100 μl phosphate buffered saline (PBS) injection (50 μl/quadriceps). Mice were anesthetized with isoflurane prior to vaccine immunization. Animals were housed in an animal facility (Bioqual, Maryland) and experiments were performed according to approved IACUC protocols. A schematic diagram of the protocol is provided in FIG26 .
单一载体免疫原性。将小鼠随机分成8组,用1×109PFU的表达HIV免疫原的Ad5载体(SEQ ID NO:94-101,在图25中示意性描绘)通过在两个后腿肌肉中肌内(I.M.)注射进行初免,并在收获脾细胞之前休息16天。通过如前所述的IFN-γELISpot测定分析脾细胞来评估免疫原性(Miyahira等人,J Immunol Methods,(1995)181(1):45-54)。Single vector immunogenicity. Mice were randomly divided into 8 groups and primed with 1×10 9 PFU of Ad5 vector expressing HIV immunogen (SEQ ID NO: 94-101, schematically depicted in FIG25 ) by intramuscular (IM) injection in both hind leg muscles and rested for 16 days before harvesting splenocytes. Immunogenicity was assessed by analyzing splenocytes by IFN-γ ELISpot assay as previously described (Miyahira et al., J Immunol Methods, (1995) 181(1):45-54).
ELISpot测定。将预包被的条带ELISpot板(Cellular Technologies Limited)用于所有ELISpot分析。简而言之,将来自免疫动物的2×105个脾细胞接种到每个孔中。具有由跨越HIV Gag、Pol和Nef保守区序列的11个氨基酸残基重叠的15聚体肽的肽池用于IFN-γELISpot测定以评估疫苗免疫原性。2.5ng/ml PMA和250ng/mL离子霉素以及1μg/mL ConA用作阳性对照。将板在37℃下在5% CO2中孵育过夜,直至18小时。刺激过夜后,将细胞从板中取出,并将孔在PBS中洗涤两次,然后用含有0.05%吐温的PBS洗涤两次。然后在室温下将生物素化的抗IFN-γ检测抗体添加到板中保持2小时。然后将板用含有0.05%吐温的PBS洗涤三次,然后添加链霉亲和素缀合的碱性磷酸酶(AP)。然后将孔用0.05%吐温-PBS洗涤两次,然后用蒸馏水洗涤两次,然后添加蓝色显色剂溶液。然后将板在室温下孵育15分钟,然后使用自来水停止反应。然后将孔干燥过夜,并在Immunospot ELISpot读数器上对斑点形成单位(SFU)进行计数。所有板的设置相同,并且计数以每106个脾细胞的SFU表示。载体变体的示意图提供于图25中,免疫方案提供于图26中,结果示于图27至图28中。ELISpot assay. Pre-coated strip ELISpot plates (Cellular Technologies Limited) were used for all ELISpot analyses. Briefly, 2×10 5 splenocytes from immunized animals were inoculated into each well. A peptide pool with 15-mer peptides overlapping by 11 amino acid residues spanning HIV Gag, Pol and Nef conserved region sequences was used for IFN-γ ELISpot assay to evaluate vaccine immunogenicity. 2.5ng/ml PMA and 250ng/mL ionomycin and 1μg/mL ConA were used as positive controls. The plates were incubated overnight at 37°C in 5% CO 2 for up to 18 hours. After stimulation overnight, the cells were removed from the plates and the wells were washed twice in PBS and then twice with PBS containing 0.05% Tween. Biotinylated anti-IFN-γ detection antibodies were then added to the plates for 2 hours at room temperature. The plates were then washed three times with PBS containing 0.05% Tween, and streptavidin-conjugated alkaline phosphatase (AP) was then added. The wells were then washed twice with 0.05% Tween-PBS, then washed twice with distilled water, and then a blue developer solution was added. The plates were then incubated at room temperature for 15 minutes, and then tap water was used to stop the reaction. The wells were then dried overnight, and spot forming units (SFU) were counted on an Immunospot ELISpot reader. The settings for all plates were the same, and the counts were expressed as SFU per 10 6 splenocytes. A schematic diagram of the vector variant is provided in Figure 25, the immunization scheme is provided in Figure 26, and the results are shown in Figures 27 to 28.
同源初免-加强。将小鼠随机分成6组。第1组和第2组小鼠分别用表达具有N末端t-PA前导序列的二价融合多肽SEQ ID NO:105(Seq 94-F2A-95)和SEQ ID NO:109(Seq 98-F2A-99)的1×109PFU的Ad5载体通过在两个后腿肌肉中肌内(i.m.)注射进行免疫,并在收获脾细胞之前休息16天。第3组和第4组小鼠分别用表达具有N末端t-PA前导序列的二价融合多肽SEQ ID NO:107(Seq 96-F2A-97)和SEQ ID NO:111(Seq 100-F2A-101)的1×109PFU的Ad5载体通过在两个后腿肌肉中i.m.注射进行免疫,并在收获脾细胞之前休息16天。Homologous prime-boost. Mice were randomly divided into 6 groups. Group 1 and group 2 mice were immunized with 1×10 9 PFU of Ad5 vector expressing bivalent fusion polypeptides SEQ ID NO: 105 (Seq 94-F2A-95) and SEQ ID NO: 109 (Seq 98-F2A-99) with N-terminal t-PA leader sequence by intramuscular (im) injection in both hind leg muscles and rested for 16 days before harvesting spleen cells. Group 3 and group 4 mice were immunized with 1×10 9 PFU of Ad5 vector expressing bivalent fusion polypeptides SEQ ID NO: 107 (Seq 96-F2A-97) and SEQ ID NO: 111 (Seq 100-F2A-101) with N- terminal t-PA leader sequence by im injection in both hind leg muscles and rested for 16 days before harvesting spleen cells.
第5组和第6组小鼠分别用表达第1组或第3组所用HIV免疫原的1×109PFU的Ad5载体Seq-94-F2A-95(tPA-SEQ ID NO:105)和Seq 96-F2A-97(tPA-SEQ ID NO:107)通过在两个后腿肌肉中i.m.注射进行免疫,并在用表达相同抗原但重新排列以最小化连接反应的载体(分别在组2和组4中使用的Seq 98-F2A-99(tPA-SEQ ID NO:109)和Seq 100-F2A-101(tPA-SEQ ID NO:111)免疫原)同源加强前休息29天。通过如先前所述的ELISpot测定(Miyahira等人,J Immunol Methods,(1995)181(1):45-54)在第36天分析脾细胞来评估免疫原性和细胞表型,在初免后第16天和初免/加强后第36天用流式细胞术进行ICS。载体变体的示意图提供于图19中,免疫方案提供于图29中,结果示于图30至图31中。Groups 5 and 6 mice were immunized with 1×10 9 PFU of Ad5 vectors Seq-94-F2A-95 (tPA-SEQ ID NO: 105) and Seq 96-F2A-97 (tPA-SEQ ID NO: 107) expressing the HIV immunogen used in Group 1 or Group 3, respectively, by im injection in both hind leg muscles and rested for 29 days before homologous boosting with vectors expressing the same antigen but rearranged to minimize ligation reactions (Seq 98-F2A-99 (tPA-SEQ ID NO: 109) and Seq 100-F2A-101 (tPA-SEQ ID NO: 111) immunogens used in Groups 2 and 4, respectively). Immunogenicity and cell phenotype were assessed by analyzing splenocytes at day 36 by ELISpot assay as previously described (Miyahira et al., J Immunol Methods, (1995) 181(1):45-54), and ICS was performed by flow cytometry at day 16 post-prime and day 36 post-prime/boost. A schematic diagram of the vector variants is provided in FIG19 , the immunization schedule is provided in FIG29 , and the results are shown in FIG30 to FIG31 .
流式细胞术。使用血细胞计数器确定制备的单细胞悬液的细胞计数。在存在高尔基体抑制剂(Golgi plug)的情况下,用相关HIV肽刺激1×106个细胞/条件共6小时(不超过18小时)。洗涤的细胞首先用live dead Aqua(Thermo fisher L34957)染料进行表面染色,然后与荧光缀合的抗小鼠抗体的混合物在4℃孵育20分钟。CD3 APC-Cy7克隆17A2、CD4 PE-Cy7克隆GK 1.5、CD8 percp-Cy5.5克隆53-6.7用于表面染色。在表面染色之后,将细胞固定并透化,为细胞内细胞因子染色做准备。简而言之,将已用表面抗体染色的1×106个细胞与200μl BD cytofix/cytoperm缓冲液在冰上孵育25分钟。随后,将细胞每次用200μl 1XPerm缓冲液洗涤两次,然后与每1×106个细胞用100μl Perm缓冲液稀释的抗体混合物一起孵育。将荧光团缀合的抗小鼠抗IFN-γAPC克隆XMG1.2、抗IL-2PE克隆JES6-5H4和抗TNF-αFITC克隆MP6-XT22的混合物用于细胞内细胞因子染色。透化的细胞然后用100μl Perm缓冲液洗涤两次,并立即在MACSQUANT 10分析仪上使用MACS Quantify版本2.13(MiltenyiBiotech)进行分析,并使用FlowJo软件版本10.7(TreeStar)进行分析。Flow cytometry. Cell counts of prepared single cell suspensions were determined using a hemocytometer. 1×10 6 cells/condition were stimulated with relevant HIV peptides for 6 hours (no more than 18 hours) in the presence of Golgi plugs. Washed cells were first surface stained with live dead Aqua (Thermo fisher L34957) dye and then incubated with a mixture of fluorescently conjugated anti-mouse antibodies at 4°C for 20 minutes. CD3 APC-Cy7 clone 17A2, CD4 PE-Cy7 clone GK 1.5, CD8 percp-Cy5.5 clone 53-6.7 were used for surface staining. After surface staining, the cells were fixed and permeabilized in preparation for intracellular cytokine staining. Briefly, 1×10 6 cells stained with surface antibodies were incubated on ice for 25 minutes with 200 μl BD cytofix/cytoperm buffer. Subsequently, the cells were washed twice with 200 μl 1X Perm buffer each time and then incubated with an antibody mixture diluted with 100 μl Perm buffer per 1×10 6 cells. A mixture of fluorophore-conjugated anti-mouse anti-IFN-γ APC clone XMG1.2, anti-IL-2PE clone JES6-5H4, and anti-TNF-α FITC clone MP6-XT22 was used for intracellular cytokine staining. The permeabilized cells were then washed twice with 100 μl Perm buffer and immediately analyzed using MACS Quantify version 2.13 (Miltenyi Biotech) on a MACSQUANT 10 analyzer and analyzed using FlowJo software version 10.7 (TreeStar).
结果result
表达免疫原版本1融合多肽(SEQ ID NO:94-101;在图25中描绘)的各种病毒Ad5载体构建体在引发T细胞应答中是有效的。如图26所示,通过IM免疫在Balb/C小鼠模型中研究了这些序列的免疫原性。Various viral Ad5 vector constructs expressing immunogenic version 1 fusion polypeptides (SEQ ID NOs: 94-101; depicted in Figure 25) were effective in eliciting T cell responses. As shown in Figure 26, the immunogenicity of these sequences was investigated in the Balb/C mouse model by IM immunization.
具有HIV-1 Gag、Pol和Nef序列片段的初免二价融合多肽SEQ ID NO:94-95和加强二价融合多肽SEQ ID NO:98-99诱导对HIV-1 Gag的稳健应答(图27A(i和ii))、对Pol蛋白(蛋白酶、RT和整合酶)的弱但可检测的应答(图27A(iii至vi))。在该模型中没有检测到对HIV-Nef的应答(图27A(vii和viii)),这可能是由于先前描述的Balb/c小鼠中HIV-1Gag表位的免疫优势模式,并且反映了可在Balb/c小鼠中呈递的Nef表位的缺乏。The primary bivalent fusion polypeptides SEQ ID NOs: 94-95 and the booster bivalent fusion polypeptides SEQ ID NOs: 98-99 with HIV-1 Gag, Pol and Nef sequence fragments induced a robust response to HIV-1 Gag (Figure 27A (i and ii)), a weak but detectable response to Pol proteins (protease, RT and integrase) (Figure 27A (iii to vi)). No response to HIV-Nef was detected in this model (Figure 27A (vii and viii)), which may be due to the previously described immunodominant pattern of the HIV-1 Gag epitope in Balb/c mice and reflects the lack of Nef epitopes that can be presented in Balb/c mice.
具有HIV-1Pol和Nef的初免二价融合多肽SEQ ID NO:96-97和加强二价融合多肽SEQ ID NO:100-101诱导对HIV-1Pol尤其是蛋白酶和RT的稳健应答(图28(i和ii))、对Pol整合酶的较弱应答(图28(iii和iv))。用这组序列也没有观察到对HIV-Nef的应答(图28(v和vi)),这证实了来自前一组序列的观察结果(图27A(vii和viii))。The primary bivalent fusion polypeptides SEQ ID NOs: 96-97 and the booster bivalent fusion polypeptides SEQ ID NOs: 100-101 with HIV-1Pol and Nef induced a robust response to HIV-1Pol, especially protease and RT (FIG. 28 (i and ii)), and a weaker response to Pol integrase (FIG. 28 (iii and iv)). No response to HIV-Nef was observed with this group of sequences (FIG. 28 (v and vi)), which confirms the observations from the previous group of sequences (FIG. 27A (vii and viii)).
为了测试将被设计成确保>80%的循环HIV-1病毒序列覆盖率的这些二价构建体序列组合成单一构建体是否影响免疫原性,使用如图19所示的F2A接头(SEQ ID NO:105、107、109和111)组合各个序列。复合融合多肽各自具有N末端tPA前导序列。将二价融合多肽对SEQ ID NO:94和95组合成Seq 94-F2A-95(tPA-SEQ ID NO:105),将SEQ ID NO:96和97组合成Seq 96-F2A-Seq 97(tPA-SEQ ID NO:107),将SEQ ID NO:98和99组合成Seq 98-F2A-Seq 99(tPA-SEQ ID NO:109),将SEQ ID NO:100和101组合成Seq 100-F2A-Seq 101(tPA-SEQ ID NO:111)。To test whether combining these bivalent construct sequences designed to ensure >80% coverage of circulating HIV-1 viral sequences into a single construct affects immunogenicity, the individual sequences were combined using the F2A linker (SEQ ID NOs: 105, 107, 109, and 111) as shown in Figure 19. The composite fusion polypeptides each had an N-terminal tPA leader sequence. The bivalent fusion polypeptide pairs SEQ ID NOs:94 and 95 were combined into Seq 94-F2A-95 (tPA-SEQ ID NO: 105), SEQ ID NOs:96 and 97 were combined into Seq 96-F2A-Seq 97 (tPA-SEQ ID NO: 107), SEQ ID NOs:98 and 99 were combined into Seq 98-F2A-Seq 99 (tPA-SEQ ID NO: 109), and SEQ ID NOs: 100 and 101 were combined into Seq 100-F2A-Seq 101 (tPA-SEQ ID NO: 111).
为了测试免疫原性,这些组合序列在Balb/C小鼠中通过IM免疫测试(图29),作为单一载体以仅初免模式(图30A)和以同源初免加强组合模式(图30B)。序列Seq 94-F2A-95(tPA-SEQ ID NO:105)和Seq 98-F2A-99(tPA-SEQ ID NO:107)用作具有HIV-1 Gag、Pol和Nef序列片段的二价融合多肽,并在同源载体初免加强组合模式中作为初免和加强序列进行测试。Seq 96-F2A-97(tPA-SEQ ID NO:109)和Seq 100-F2A-Seq 101(tPA-SEQ ID NO:111)用作具有HIV-1Pol和Nef的二价融合多肽,并在同源载体初免-加强组合模式中作为初免和加强序列进行测试。初免和加强融合多肽编码相似的区域,但是被重新排列以减少或消除类似于来自人蛋白质组的表位的从头表位的产生,并且减少或消除了初免加强序列中的连接反应的加强。To test immunogenicity, these combination sequences were tested by IM immunization in Balb/C mice (Figure 29), as single vectors in prime-only mode (Figure 30A) and in homologous prime-boost combination mode (Figure 30B). Sequences Seq 94-F2A-95 (tPA-SEQ ID NO: 105) and Seq 98-F2A-99 (tPA-SEQ ID NO: 107) were used as bivalent fusion polypeptides with HIV-1 Gag, Pol and Nef sequence fragments and tested as prime and boost sequences in homologous vector prime-boost combination mode. Seq 96-F2A-97 (tPA-SEQ ID NO: 109) and Seq 100-F2A-Seq 101 (tPA-SEQ ID NO: 111) were used as bivalent fusion polypeptides with HIV-1 Pol and Nef and tested as prime and boost sequences in homologous vector prime-boost combination mode. The prime and boost fusion polypeptides encode similar regions but are rearranged to reduce or eliminate the generation of de novo epitopes that resemble epitopes from the human proteome and to reduce or eliminate boosting of ligation reactions within the prime-boost sequence.
组合序列Seq 94-F2A-95(tPA-SEQ ID NO:105)和Seq 98-F2A-99(tPA-SEQ IDNO:109)在作为单一初免或在初免/加强组合中测试免疫原性时是免疫原性的(图31A,分别对HIV-Gag(i)、Pol(蛋白酶和RT(iii)、Pol(整合酶(v))和Nef(vii)的应答,以及图27,对HIV-1 Gag(i和ii)、Pol(蛋白酶、RT和整合酶(iii至vi))和Nef(vii和viii)的应答)。与F2A串联的二价序列不抑制它们的免疫原性。总之,对HIV-1 Gag的应答是稳健的,对Pol蛋白(蛋白酶、RT和整合酶)的应答较弱但可检测,对HIV-Nef有最小的应答。由初免序列Seq 94-F2A-95(tPA-SEQ ID NO:105)诱导的应答被加强序列Seq 98-F2A-99(tPA-SEQ ID NO:109)增强,特别是对于Pol(整合酶)(图30B(vi))和Nef(图30B(viii))。对F2A和tPA序列没有产生应答。Combination sequences Seq 94-F2A-95 (tPA - SEQ ID NO: 105) and Seq 98-F2A-99 (tPA - SEQ ID NO: 109) were immunogenic when tested for immunogenicity as single primes or in prime/boost combinations ( FIG. 31A , responses to HIV-Gag (i), Pol (protease and RT (iii), Pol (integrase (v)), and Nef (vii), respectively, and FIG. 27 , responses to HIV-1 Gag (i and ii), Pol (protease, RT, and integrase (iii to vi)), and Nef (vii and viiii)). The bivalent sequences in tandem with F2A did not inhibit their immunogenicity. Overall, responses to HIV-1 Gag were robust, responses to Pol proteins (protease, RT, and integrase) were weak but detectable, and there was minimal response to HIV-Nef. The immunogenicity of the priming sequences Seq 94-F2A-95 (tPA - SEQ ID NO: 105) and Seq 98-F2A-99 (tPA - SEQ ID NO: 109) were immunogenic when tested for immunogenicity as single primes or in prime/boost combinations ( FIG. 31A , responses to HIV-Gag (i), Pol (protease and RT (iii), Pol (integrase (v)), and Nef (vii), respectively, and FIG. 27 , responses to HIV-1 Gag (i and ii), Pol (protease, RT, and integrase (iii to vi)), and Nef (vii and viiii)). The bivalent sequences in tandem with F2A did not inhibit their immunogenicity. Overall, responses to HIV-1 Gag were robust, responses to Pol proteins (protease, RT, and integrase) were weak but detectable, and there was minimal response to HIV-Nef. The responses induced by the booster sequence Seq 98-F2A-99 (tPA-SEQ ID NO: 109) were enhanced, particularly for Pol (integrase) ( FIG. 30B (vi)) and Nef ( FIG. 30B (viii)). No responses were generated to the F2A and tPA sequences.
组合的序列Seq 96-F2A-97(tPA-SEQ ID NO:107)和Seq 100-F2A-101(tPA-SEQID NO:111)在作为单一初免或在初免/加强组合中测试免疫原性时是免疫原性的,诱导了对HIV-1Pol特别是蛋白酶和RT的稳健应答,而对整合酶则检测到较弱应答(图31A(i至iv))。由组合载体Seq 96-F2A-97(tPA-SEQ ID NO:107)诱导的对Pol(蛋白酶和RT,图31B(i))的IFN-γELISpot应答的大小比先前观察到的表达SEQ ID NO:96或97的融合多肽的单独载体(图28(i))的应答弱。按顺序用Seq 96-F2A-97(tPA-SEQ ID NO:107)和Seq 100-F2A-101(tPA-SEQ ID NO:111)给药来加强应答(图31B(ii))。由初免序列Seq 96-F2A-97(tPA-SEQ ID NO:107)诱导的应答被加强序列Seq 100-F2A-101(tPA-SEQ ID NO:111)增强,特别是针对Pol(整合酶)(图31B(iv))和Nef(图31B(vi))两者。The combined sequences Seq 96-F2A-97 (tPA-SEQ ID NO: 107) and Seq 100-F2A-101 (tPA-SEQ ID NO: 111) were immunogenic when tested for immunogenicity as a single prime or in a prime/boost combination, inducing robust responses to HIV-1 Pol, particularly protease and RT, while weaker responses were detected to integrase (Figure 31A (i to iv)). The magnitude of the IFN-γ ELISpot response to Pol (protease and RT, Figure 31B (i)) induced by the combined vector Seq 96-F2A-97 (tPA-SEQ ID NO: 107) was weaker than the response previously observed for the single vector expressing the fusion polypeptide of SEQ ID NO: 96 or 97 (Figure 28 (i)). Seq 96-F2A-97 (tPA-SEQ ID NO: 107) and Seq 100-F2A-101 (tPA-SEQ ID NO: 111) were sequentially administered to boost the response ( FIG. 31B (ii)). The response induced by the priming sequence Seq 96-F2A-97 (tPA-SEQ ID NO: 107) was enhanced by the boosting sequence Seq 100-F2A-101 (tPA-SEQ ID NO: 111), particularly against both Pol (integrase) ( FIG. 31B (iv)) and Nef ( FIG. 31B (vi)).
产生细胞因子的能力是效应和记忆CD4+和CD8+ T细胞的功能量度。我们使用单一载体初免免疫和同源初免/加强免疫两者评估用表达SEQ ID NO:105、107、109或111的复合融合蛋白的Ad5载体免疫后产生的CD4+和CD8+ T细胞应答的表型和功能特征。使用ICS和流式细胞术测量应答。The ability to produce cytokines is a functional measure of effector and memory CD4+ and CD8+ T cells. We used both single vector prime immunization and homologous prime/boost immunization to evaluate the phenotypic and functional characteristics of CD4+ and CD8+ T cell responses generated following immunization with Ad5 vectors expressing composite fusion proteins of SEQ ID NO: 105, 107, 109 or 111. Responses were measured using ICS and flow cytometry.
图32至图35显示了用Seq 94-F2A-95(tPA-SEQ ID NO:105)或Seq98-F2A-99(tPA-SEQ ID NO:109)进行单一载体免疫后通过细胞内细胞因子染色(ICS),以及通过同源载体初免-加强免疫,抗HIV-1 Gag、Pol和Nef抗原的免疫原性。Y轴表示CD8+(i、ii和iii)或CD4+(iv、v和vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独细胞因子或细胞因子组合)表现出HIV-1 Gag(图32)、Pol(蛋白酶和RT)(图33)、Pol(整合酶)(图34)和Nef(图35)特异性应答,如X轴上所示。通过减去无抗原刺激的对照以排除非特异性应答来获得抗原特异性值。在对疫苗接种的应答中观察到强HIV-1 Gag特异性CD8+和CD4+ T细胞应答,证实了在CD8+ T细胞中最稳健的多功能性。同源初免-加强增强了CD8+ T细胞应答的多功能性。即使产生,疫苗接种后产生的Pol(蛋白酶、RT和整合酶)特异性和Nef特异性CD8+和CD4+ T细胞应答也弱于Gag应答,并且往往是单功能的,具有有限的加强作用。Figures 32 to 35 show the immunogenicity of anti-HIV-1 Gag, Pol and Nef antigens by intracellular cytokine staining (ICS) after single vector immunization with Seq 94-F2A-95 (tPA-SEQ ID NO: 105) or Seq98-F2A-99 (tPA-SEQ ID NO: 109), as well as by homologous vector prime-boost immunization. The Y axis represents the proportion of CD8+ (i, ii and iii) or CD4+ (iv, v and vi) T cells that exhibit HIV-1 Gag (Figure 32), Pol (protease and RT) (Figure 33), Pol (integrase) (Figure 34) and Nef (Figure 35) specific responses by expressing the cytokines IFN-γ, IL-2 and TNF-α (as individual cytokines or cytokine combinations), as shown on the X axis. Antigen specificity values were obtained by subtracting controls without antigen stimulation to exclude nonspecific responses. Strong HIV-1 Gag-specific CD8+ and CD4+ T cell responses were observed in response to vaccination, demonstrating the most robust polyfunctionality in CD8+ T cells. Homologous prime-boost enhanced the polyfunctionality of CD8+ T cell responses. Even when generated, Pol (protease, RT, and integrase)-specific and Nef-specific CD8+ and CD4+ T cell responses generated after vaccination were weaker than Gag responses and tended to be monofunctional with limited boosting effects.
图36至图38显示了用Seq 96-F2A-97(tPA-SEQ ID NO:107)或Seq100-F2A-101(tPA-SEQ ID NO:111)进行单一载体免疫后通过细胞内细胞因子染色(ICS),以及通过同源载体初免-加强免疫,抗HIV-1Pol和Nef抗原的免疫原性。Y轴表示CD8+(i、ii和iii)或CD4+(iv、v和vi)T细胞的比例,这些T细胞通过表达细胞因子IFN-γ、IL-2和TNF-α(作为单独细胞因子或细胞因子组合)表现出HIV-1Pol(蛋白酶和RT)(图36)、Pol(整合酶)(图37)和Nef(图38)特异性应答,如X轴上所示。通过减去无抗原刺激的对照以排除非特异性应答来获得抗原特异性值。在对疫苗接种的应答中观察HIV-1Pol(蛋白酶和RT)特异性CD4+和CD8+ T细胞应答,其中CD8+ T细胞的应答稳健。Seq 100-F2A-101(tPA-SEQ ID NO:111)显示具有多功能性的强免疫原性(产生≥2个细胞因子)。在对疫苗接种的应答中产生了低水平的Pol(整合酶)和Nef特异性CD4+和CD8+ T细胞应答,并且在CD4+ T细胞中观察到更高的应答。Seq 100-F2A-101(tPA-SEQ ID NO:111)证实并诱导了主要的单核因子产生。用编码融合多肽的载体进行同源载体初免-加强免疫增强了CD4+和CD8+ T细胞应答。Figures 36 to 38 show the immunogenicity of anti-HIV-1 Pol and Nef antigens by intracellular cytokine staining (ICS) after single vector immunization with Seq 96-F2A-97 (tPA-SEQ ID NO: 107) or Seq100-F2A-101 (tPA-SEQ ID NO: 111), as well as by primary-boost immunization with homologous vectors. The Y axis represents the proportion of CD8+ (i, ii and iii) or CD4+ (iv, v and vi) T cells that express HIV-1 Pol (protease and RT) (Figure 36), Pol (integrase) (Figure 37) and Nef (Figure 38) specific responses by expressing cytokines IFN-γ, IL-2 and TNF-α (as individual cytokines or cytokine combinations), as shown on the X axis. Antigen-specific values were obtained by subtracting controls without antigen stimulation to exclude nonspecific responses. HIV-1Pol (protease and RT) specific CD4+ and CD8+ T cell responses were observed in response to vaccination, with CD8+ T cell responses being robust. Seq 100-F2A-101 (tPA-SEQ ID NO: 111) showed strong immunogenicity with multifunctionality (producing ≥ 2 cytokines). Low levels of Pol (integrase) and Nef specific CD4+ and CD8+ T cell responses were produced in response to vaccination, and higher responses were observed in CD4+ T cells. Seq 100-F2A-101 (tPA-SEQ ID NO: 111) confirmed and induced major monokine production. Homologous vector prime-boost immunization with a vector encoding a fusion polypeptide enhanced CD4+ and CD8+ T cell responses.
数据与以下结论一致:上述测试的HIV-1二价序列作为单独的初免序列或者当与F2A接头组合时(Seq 96-F2A-Seq97(tPA-SEQ ID NO:107)除外)是免疫原性的,并且在同源初免加强免疫中也是免疫原性的。产生的应答大小是抗原特异性、CD4+和CD8+的,并表达多功能性。The data are consistent with the conclusion that the HIV-1 bivalent sequences tested above are immunogenic as single prime sequences or when combined with the F2A linker (except Seq 96-F2A-Seq97 (tPA-SEQ ID NO: 107) and are also immunogenic in homologous prime boost immunizations. The magnitude of the responses generated are antigen specific, CD4+ and CD8+, and express multifunctionality.
实施例9Example 9
表明免疫原1-3诱导的人T细胞活化的体外测定In vitro assay demonstrating human T cell activation induced by immunogens 1-3
在该实施例中,我们建立了一种用于测试表达载体中的疫苗构建体在人体中引发T细胞的功效的体外方法。该方法在疫苗学中的应用允许评估转基因盒在人体中的抗原加工、呈递和T细胞初免,以及研究免疫参数,包括可能改变引发功效的佐剂和免疫调节剂。In this example, we established an in vitro method for testing the efficacy of vaccine constructs in expression vectors to prime T cells in humans. The application of this method in vaccinology allows the evaluation of antigen processing, presentation and T cell priming of transgenic cassettes in humans, as well as the study of immune parameters, including adjuvants and immunomodulators that may alter priming efficacy.
方法method
单核细胞纯化和单核细胞来源的树突细胞(moDC)的成熟。将新鲜分离或冷冻保存的PBMC用于基于moDC的T细胞刺激测定中。使用EasySep人抗CD14阳性选择抗体试剂盒(StemCell Technologies)从感染或未感染HIV、ART初治型或接受ART的个体的PBMCS中纯化CD14+单核细胞。在建立培养之前使用流式细胞术来确认分离的CD14+单核细胞的纯度>90%。为了产生未成熟的moDC,将2×106个纯化的CD14+单核细胞在6孔培养板中的3mLmoDC分化培养基(含有10%热灭活胎牛血清、1%青霉素链霉素/mL、0.5mM HEPES、800U/mLGM-CSF(Miltenyi Biotec)和1000U IL-4(Miltenyi Biotec)的完整RPMI 1640)中培养。将板在37℃和5% CO2下孵育6天,每天监测以确保单核细胞的粘附。为了产生成熟的moDC,向粘附的未成熟moDC培养物中补充重组可溶性CD40L(0.5μg/ml)、IFN-γ(1,000U/ml)、PGE2(5μM)、TNF-α(10ng/ml)、IL-6(100ng/ml)和IL-1β(10ng/ml),在第6天再添加3ml moDC分化培养基,并在37℃和5%CO2下再孵育48小时。Purification of monocytes and maturation of monocyte-derived dendritic cells (moDCs). Freshly isolated or cryopreserved PBMCs were used in moDC-based T cell stimulation assays. CD14+ monocytes were purified from PBMCs of individuals infected or not infected with HIV, ART-naive or receiving ART using the EasySep Human Anti-CD14 Positive Selection Antibody Kit (StemCell Technologies). Flow cytometry was used to confirm that the purity of the isolated CD14+ monocytes was >90% before establishing the culture. To generate immature moDCs, 2×10 6 purified CD14+ monocytes were cultured in 3 mL of moDC differentiation medium (complete RPMI 1640 containing 10% heat-inactivated fetal bovine serum, 1% penicillin-streptomycin/mL, 0.5 mM HEPES, 800 U/mL GM-CSF (Miltenyi Biotec) and 1000 U IL-4 (Miltenyi Biotec)) in 6-well culture plates. The plates were incubated at 37°C and 5% CO2 for 6 days and monitored daily to ensure adherence of monocytes. To generate mature moDCs, adherent immature moDC cultures were supplemented with recombinant soluble CD40L (0.5 μg/ml), IFN-γ (1,000 U/ml), PGE2 (5 μM), TNF-α (10 ng/ml), IL-6 (100 ng/ml), and IL-1β (10 ng/ml), and 3 ml of moDC differentiation medium were added on day 6 and incubated for another 48 hours at 37°C and 5% CO2 .
在第8天,使用冰冷的PBS和细胞刮刀分离粘附的成熟moDC,以手动分离moDC。在该程序之后,使用moDC分化培养基洗涤未附着的细胞并将其转移到50ml离心管中。将所得细胞混合物在室温下以1500rpm离心5分钟。接下来,弃去上清液,并将细胞沉淀重悬于5mlmoDC分化培养基中。分离成熟的moDC级分并对其进行染色,以用抗CD11c+、抗HLA-DR+、抗CD14-、抗CD40+、抗DCSIGN+、抗CD83、抗CD86和抗OX40L抗体表征moDC的分化表型。On day 8, adherent mature moDCs were separated using ice-cold PBS and a cell scraper to manually isolate moDCs. After the procedure, unattached cells were washed with moDC differentiation medium and transferred to a 50 ml centrifuge tube. The resulting cell mixture was centrifuged at 1500 rpm for 5 minutes at room temperature. Next, the supernatant was discarded and the cell pellet was resuspended in 5 ml moDC differentiation medium. Mature moDC fractions were separated and stained to characterize the differentiation phenotype of moDCs with anti-CD11c+, anti-HLA-DR+, anti-CD14-, anti-CD40+, anti-DCSIGN+, anti-CD83, anti-CD86, and anti-OX40L antibodies.
用腺病毒5(Ad5)病毒载体转导moDC。收获纯化的moDC,在无血清培养基中洗涤两次,然后以107/ml重悬于X-Vivo 15(BioWhittaker,Walkersville,MD)中。在转导之前,将细胞在37℃水浴中平衡20-30分钟。将表达疫苗免疫原的Ad5原液或空载体对照在冰上解冻,并以500的感染复数(MOI)加入到moDC悬浮液中。轻轻混合细胞并立即置于37℃培养箱中。2小时后,添加含有GM-CSF和IL-4的温moDC分化培养基,将moDC稀释至终浓度为106/ml。将转导的moDC(4×106)转移至T75细胞培养瓶中并在加入自体PBMC之前于37℃在5% CO2中再维持48小时。moDCs were transduced with adenovirus 5 (Ad5) viral vectors. Purified moDCs were harvested, washed twice in serum-free medium, and then resuspended in X-Vivo 15 (BioWhittaker, Walkersville, MD) at 10 7 /ml. Prior to transduction, cells were equilibrated in a 37°C water bath for 20-30 minutes. Ad5 stocks expressing vaccine immunogens or empty vector controls were thawed on ice and added to the moDC suspension at a multiplicity of infection (MOI) of 500. The cells were gently mixed and immediately placed in a 37°C incubator. After 2 hours, warm moDC differentiation medium containing GM-CSF and IL-4 was added to dilute the moDCs to a final concentration of 10 6 /ml. Transduced moDCs (4×10 6 ) were transferred to a T75 cell culture flask and maintained at 37°C in 5% CO 2 for an additional 48 hours before the addition of autologous PBMCs.
自体PBMC与moDC的共培养。在评估我们的保守区疫苗的免疫原性的实验中,对自体PBMC计数并将80×106个PBMC与4×106个moDC共培养,这些moDC已用表达疫苗免疫原的Ad5载体或Ad5空载体对照转导。在存在IL-2(50U/ml)、IL-7(10ng/ml)、依法韦仑(0.1μM)和埃替拉韦(0.1μM)的情况下,PBMC-moDC共培养持续10天。以1:20的moDC:PBMC比率建立moDC和PBMC的共培养。Co-culture of autologous PBMCs with moDCs. In experiments evaluating the immunogenicity of our conserved region vaccines, autologous PBMCs were counted and 80×10 6 PBMCs were co-cultured with 4×10 6 moDCs that had been transduced with Ad5 vectors expressing the vaccine immunogen or Ad5 empty vector controls. PBMC-moDC co-cultures were continued for 10 days in the presence of IL-2 (50 U/ml), IL-7 (10 ng/ml), efavirenz (0.1 μM), and elvitegravir (0.1 μM). Co-cultures of moDCs and PBMCs were established at a moDC:PBMC ratio of 1:20.
IFN-γELISpot测定。将预包被的条带ELISpot板(Cellular TechnologiesLimited)用于所有ELISpot分析。简而言之,将来自第10天的moDC-PBMC培养物的3×104个细胞接种到每个孔中。将由跨越整个HIV保守区免疫原的11个氨基酸重叠的15聚体组成的疫苗匹配的肽组装到384ELISpot板中,每个单独孔对应于单个15聚体肽,并用于IFN-γELISpot测定中以评估疫苗免疫原性。对于阳性对照,添加50ng/ml PMA(Sigma)。将板在37℃、5% CO2下孵育24小时。刺激24小时后,将细胞从板中取出,并将孔在PBS中洗涤三次,然后用含有0.05%吐温的PBS洗涤三次。然后在室温下将生物素化的抗IFN-γ检测抗体添加到板中保持2小时。然后将板用含有0.05%吐温的PBS洗涤三次,然后添加链霉亲和素缀合的碱性磷酸酶(AP)。然后将孔用0.05%吐温-PBS洗涤两次,然后用蒸馏水洗涤两次,然后添加蓝色显色剂溶液。然后将板在室温下孵育15分钟,然后使用自来水停止反应。然后将孔干燥过夜,并在Immunospot ELISpot读数器上对斑点形成单位(SFU)进行计数。所有板的设置相同,并且计数以每3×104个PBMC的SFU表示。SFU计算为测试孔中的斑点数减去培养基对照孔中的平均斑点数。阳性应答定义为与培养基对照孔相比>3倍的SFU且每孔>5个斑点(3×104个细胞)。培养基对照孔含有用与肽刺激的测试孔相似的DMSO组成重构的培养基。图39描绘了概述moDC-PBMC培养和ELISpot测定的示意图。IFN-γ ELISpot assay. Pre-coated strip ELISpot plates (Cellular Technologies Limited) were used for all ELISpot analyses. In brief, 3×10 4 cells from the 10th day moDC-PBMC culture were inoculated into each well. Vaccine-matched peptides consisting of 15-mers overlapping by 11 amino acids spanning the entire HIV conserved region immunogen were assembled into 384 ELISpot plates, with each individual well corresponding to a single 15-mer peptide and used in IFN-γ ELISpot assays to assess vaccine immunogenicity. For the positive control, 50 ng/ml PMA (Sigma) was added. The plates were incubated at 37°C, 5% CO 2 for 24 hours. After 24 hours of stimulation, the cells were removed from the plates, and the wells were washed three times in PBS and then washed three times with PBS containing 0.05% Tween. The biotinylated anti-IFN-γ detection antibody was then added to the plate for 2 hours at room temperature. The plate was then washed three times with PBS containing 0.05% Tween, followed by the addition of streptavidin-conjugated alkaline phosphatase (AP). The wells were then washed twice with 0.05% Tween-PBS, then twice with distilled water, and then a blue color developer solution was added. The plate was then incubated at room temperature for 15 minutes, and then the reaction was stopped using tap water. The wells were then dried overnight, and the spot forming units (SFU) were counted on the Immunospot ELISpot reader. The settings for all plates were the same, and the counts were expressed as SFU per 3×10 4 PBMCs. SFU was calculated as the number of spots in the test well minus the average number of spots in the culture medium control well. A positive response was defined as >3 times the SFU compared to the culture medium control well and >5 spots per well (3×10 4 cells). The culture medium control well contained a culture medium reconstructed with a DMSO composition similar to that of the peptide-stimulated test well. Figure 39 depicts a schematic diagram outlining moDC-PBMC culture and ELISpot assays.
体外病毒抑制测定。评估疫苗诱导的CD8+ T细胞抑制自体CD4+ T细胞的HIV-1感染的能力以确定细胞毒性。使用负磁珠选择(StemCell Technologies)从冷冻保存的PBMC中分离出CD4+ T细胞,静置24小时并在RPMI和10% FBS中培养。24小时后,将培养的CD4+ T细胞洗涤、计数并加入到50ml锥形管中,用HIV-1BaL以0.01的感染复数(MOI)旋转接种。通过以1200g离心2小时进行旋转接种。感染后,将CD4+ T细胞洗涤两次并在RPMI和10% FBS和IL-2(30U/ml)中培养72小时。72小时后,在PBMC-moDC共培养物结束时使用负磁珠选择(StemCell Technologies)分离CD8+ T细胞,用CFSE标记并计数。同时,将培养的CD4+ T细胞洗涤、计数并接种在U型底96孔板中,其中疫苗诱导的CD8+ T细胞在RPMI和10% FBS中的比率为1:1。在CD4+ T细胞和CD8+ T细胞共培养后三天,将细胞用活力染料和表面标记染色,随后根据制造商的方案使用IC固定/透化试剂盒(BD Biosciences)进行HIV-1 Gag(Beckman Coulter)的细胞内检测。将细胞与荧光缀合的抗人抗体的混合物在4℃孵育30分钟。使用FACS缓冲液(PBS、2% FCS、0.1% NaN3)将染色的细胞洗涤两次,使用FACSDiva软件(BD)通过LSR II流式细胞仪进行采集,并使用FlowJo软件版本10.2(TreeStar)进行分析。对于表面染色,细胞用抗CD4 BV605克隆OKT4、抗CD8 BV650克隆RPA-T8、抗CD3 AF700克隆SK7、抗CD20 BV421克隆2H7、Live-dead Aqua染料(ThermoFischer)染色。对于p24的细胞内检测,使用Cytofix/cytoperm缓冲液(BD Biosciences)固定和透化细胞,并用抗HIV Gagp24 PE(KC57)染色。根据细胞可用性,所有实验一式两份或一式三份进行。将未感染的CD4+T细胞作为阴性对照包括在内,并且将在没有CD8+ T细胞的情况下培养的感染的CD4+ T细胞作为100%感染性对照。只有当通过流式细胞术对每个独立样品检测到>0.1%的p24 Gag+CD4-细胞时,才认为是生产性感染。In vitro viral inhibition assay. The ability of vaccine-induced CD8+ T cells to inhibit HIV-1 infection of autologous CD4+ T cells was evaluated to determine cytotoxicity. CD4+ T cells were isolated from cryopreserved PBMCs using negative magnetic bead selection (StemCell Technologies), left to stand for 24 hours and cultured in RPMI and 10% FBS. After 24 hours, the cultured CD4+ T cells were washed, counted and added to 50 ml conical tubes and spin-inoculated with HIV-1BaL at a multiplicity of infection (MOI) of 0.01. Spin-inoculation was performed by centrifugation at 1200g for 2 hours. After infection, CD4+ T cells were washed twice and cultured in RPMI and 10% FBS and IL-2 (30U/ml) for 72 hours. After 72 hours, CD8+ T cells were isolated using negative magnetic bead selection (StemCell Technologies) at the end of the PBMC-moDC co-culture, labeled with CFSE and counted. At the same time, the cultured CD4+ T cells were washed, counted and inoculated in a U-bottom 96-well plate, where the ratio of vaccine-induced CD8+ T cells in RPMI and 10% FBS was 1:1. Three days after the co-culture of CD4+ T cells and CD8+ T cells, the cells were stained with viability dyes and surface markers, and then the intracellular detection of HIV-1 Gag (Beckman Coulter) was performed using an IC fixation/permeabilization kit (BD Biosciences) according to the manufacturer's protocol. The cells were incubated at 4°C for 30 minutes with a mixture of fluorescently conjugated anti-human antibodies. The stained cells were washed twice using FACS buffer (PBS, 2% FCS, 0.1% NaN 3 ), collected by LSR II flow cytometer using FACSDiva software (BD), and analyzed using FlowJo software version 10.2 (TreeStar). For surface staining, cells were stained with anti-CD4 BV605 clone OKT4, anti-CD8 BV650 clone RPA-T8, anti-CD3 AF700 clone SK7, anti-CD20 BV421 clone 2H7, Live-dead Aqua dye (ThermoFischer). For intracellular detection of p24, cells were fixed and permeabilized using Cytofix/cytoperm buffer (BD Biosciences) and stained with anti-HIV Gagp24 PE (KC57). All experiments were performed in duplicate or triplicate depending on cell availability. Uninfected CD4+T cells were included as negative controls, and infected CD4+T cells cultured in the absence of CD8+T cells were used as 100% infectious controls. Productive infection was considered only when >0.1% p24 Gag+CD4- cells were detected for each independent sample by flow cytometry.
结果result
在该实施例中,我们使用本文所述的体外T细胞引发测定来评估免疫原性并解码CD8+ T细胞对疫苗免疫原的应答(图39提供的示意图)。我们集中在确定保守区疫苗内诱导抗原特异性T细胞应答的表位,并评估了预先存在的应答对诱导从头应答的影响。用含有疫苗转基因的病毒载体转导单核细胞衍生的DC,能够在体外引发自体疫苗抗原特异性T细胞。该测定可促进疫苗构建体的临床前评估,并在开始大规模疫苗试验之前,为在广泛的参与者范围中鉴定保守区疫苗内的免疫原性区域提供有用的工具。In this example, we used the in vitro T cell elicitation assay described herein to evaluate immunogenicity and decode the response of CD8+ T cells to vaccine immunogens (schematic diagram provided in Figure 39). We focused on determining the epitopes that induce antigen-specific T cell responses within the conserved region vaccine and evaluated the effects of pre-existing responses on inducing de novo responses. DCs derived from monocytes were transduced with viral vectors containing vaccine transgenes, which can induce autologous vaccine antigen-specific T cells in vitro. This assay can facilitate the preclinical evaluation of vaccine constructs and provide a useful tool for identifying immunogenic regions within conserved region vaccines in a wide range of participants before starting large-scale vaccine trials.
我们在N=93个HIV-1+参与者样品中完成了免疫原1(SEQ ID NO:105、107、109和111)的免疫原性的评估。在moDC的转导效率方面观察到患者与患者之间的差异,这种差异可反映受体表达促进病毒载体的摄取的差异,如在异类人类群体中所预期的那样(图40至图41)。We completed an assessment of the immunogenicity of Immunogen 1 (SEQ ID NOs: 105, 107, 109, and 111) in N = 93 HIV-1+ participant samples. Patient-to-patient variability was observed in the transduction efficiency of moDCs, which may reflect differences in receptor expression facilitating uptake of viral vectors, as expected in a heterogeneous human population (Figures 40-41).
图40中描绘的热图总结了在用SEQ ID NO:105、107、109和111体外初免后,在所有93名参与者中对每种HIV蛋白的免疫应答的广度的分布图。我们的数据显示体外疫苗接种导致在80%(74/93)的测试样品中诱导对保守区(≥1个表位)的应答,表明疫苗接种使免疫应答重新集中于保守区。另外,尽管用保守区疫苗进行疫苗接种加强了25%的预先存在的可检测应答,但疫苗接种后鉴定的所有应答中的69%是从头T细胞应答,主要针对在疫苗前条件下未检测到的保守Gag和Pol表位(Ad5空载体对照)(图42)。疫苗接种还显著增强了对Gag、Pol和Nef抗原的免疫应答的广度(应答的中值总广度=5,中值Gag广度=2,中值Pol广度=2和中值Nef广度=0;图40)。详细的分析进一步表明,疫苗接种显著提高了对Gag、Pol和Nef的每一者内的≥3个表位有应答的参与者的比例(图41)。考虑到来自STEP试验的数据,我们选择评估大于3个表位的应答。参见Janes等人,J Infect Dis(2013)208(8):1231-1239;ClinicalTrials.gov identifier:NCT00095576。The heat map depicted in Figure 40 summarizes the distribution diagram of the breadth of the immune response to each HIV protein in all 93 participants after in vitro priming with SEQ ID NO: 105, 107, 109 and 111. Our data show that in vitro vaccination leads to induction of responses to conserved regions (≥1 epitope) in 80% (74/93) of the test samples, indicating that vaccination refocuses the immune response on the conserved region. In addition, although vaccination with conserved region vaccines enhances 25% of pre-existing detectable responses, 69% of all responses identified after vaccination are de novo T cell responses, mainly for conserved Gag and Pol epitopes that are not detected under pre-vaccine conditions (Ad5 empty vector control) (Figure 42). Vaccination also significantly enhances the breadth of the immune response to Gag, Pol and Nef antigens (median total breadth of response = 5, median Gag breadth = 2, median Pol breadth = 2 and median Nef breadth = 0; Figure 40). Detailed analysis further showed that vaccination significantly increased the proportion of participants who responded to ≥3 epitopes within each of Gag, Pol, and Nef (Figure 41). Given the data from the STEP trial, we chose to evaluate responses to greater than 3 epitopes. See Janes et al., J Infect Dis (2013) 208(8): 1231-1239; ClinicalTrials.gov identifier: NCT00095576.
为了确定疫苗诱导的CD8+ T细胞是否能够体外消除HIV-1感染的细胞,我们进行了HIV-1病毒抑制测定。来自参与者的CD4+ T细胞用HIV-1BaL感染,并单独或在纯化疫苗或空载体引发的CD8+ T细胞存在下共培养。在我们的分析中使用了来自51/68名参与者的数据,这些参与者都表现出使用HIV-1BaL的生产性感染率(≥0.1%p24 Gag+细胞)(图43)。图44B中的数据显示,与空载体引发的CD8+ T细胞相比,在疫苗(SEQ ID NO:105、107、109和111)引发的CD8+ T细胞的存在下,来自69%(N=35/51)参与者的CD8+ T细胞显示增加的HIV-1BaL体外抑制。为了评估应答的广度与CD8+ T细胞介导的HIV-1BaL抑制之间是否存在关联,我们评估了每个参与者的广度和细胞毒性,这些参与者都表现出HIV-1BaL的生产性感染率(≥0.1%p24 Gag+细胞)。图44B中的数据显示残留Gag+细胞%与Gag/Pol广度之间缺乏相关性,这可表明应答的质量更重要。To determine whether vaccine-induced CD8+ T cells can eliminate HIV-1 infected cells in vitro, we performed an HIV-1 viral suppression assay. CD4+ T cells from participants were infected with HIV-1BaL and co-cultured alone or in the presence of purified vaccine or empty vector-induced CD8+ T cells. Data from 51/68 participants, all of whom showed productive infection rates (≥0.1% p24 Gag+ cells) using HIV-1BaL (Figure 43), were used in our analysis. The data in Figure 44B show that CD8+ T cells from 69% (N=35/51) of participants showed increased HIV-1BaL in vitro suppression in the presence of CD8+ T cells triggered by the vaccine (SEQ ID NO: 105, 107, 109 and 111) compared to CD8+ T cells triggered by the empty vector. To assess whether there is an association between the breadth of the response and CD8+ T cell-mediated suppression of HIV-1BaL, we assessed breadth and cytotoxicity in each participant who demonstrated productive infection rates of HIV-1BaL (≥0.1% p24 Gag+ cells). The data in Figure 44B show a lack of correlation between the % residual Gag+ cells and the breadth of Gag/Pol, which may indicate that the quality of the response is more important.
我们还使用上述moDC-T细胞初免测定在N=3个参与者中评估了免疫原版本2(SEQID NO:82-89)和免疫原版本3(SEQ ID NO:90-93)的免疫原性。在图45A和图45B中总结的数据显示了对每种免疫原的总、Gag、Pol和Nef免疫应答的广度和大小。对于免疫原版本2,在单个供体中,用疫苗序列体外初免导致应答从2个独立表位扩展到14个独立表位;对于免疫原版本3,应答的中值广度为3。We also evaluated the immunogenicity of immunogen version 2 (SEQ ID NO: 82-89) and immunogen version 3 (SEQ ID NO: 90-93) in N = 3 participants using the moDC-T cell priming assay described above. The data summarized in Figures 45A and 45B show the breadth and magnitude of the total, Gag, Pol, and Nef immune responses to each immunogen. For immunogen version 2, in vitro priming with the vaccine sequence resulted in responses extending from 2 to 14 independent epitopes in a single donor; for immunogen version 3, the median breadth of the response was 3.
实施例10Example 10
非人灵长类动物(NHP)沙粒病毒载体数据Non-human primate (NHP) arenavirus vector data
非人灵长类动物中的异源初免-加强。NHP中的猿猴免疫缺陷病毒感染用作评估HIV疫苗载体免疫原性的良好模型。为了评估NHP中的有复制能力的LCMV(TT1)和有复制能力的PICV(TT2)载体(例如,如WO2016075250和WO2017198726中所述的载体)的免疫原性,我们开发了表达来源于SIVsme543毒株的全长SIV蛋白Gag、Env或Pol的载体。氨基酸序列在表2中提供。用沙粒病毒载体通过IM途径免疫来自印度的健康恒河猴。将表达Gag和Env的载体(复制减毒型皮钦德沙粒病毒(TT2)和复制减毒型LCMV沙粒病毒(TT1))施用于左四头肌,而将表达Pol的载体(TT2和TT1)施用于右四头肌。施用的剂量如下:1×106RCV的TT2 Gag、1×106RCV的TT2 Env、1×106RCV的TT2 Pol1/Pol2、4×106RCV的TT1Gag、4×106RCV的TT1 Env和2×106RCV的TT1 Pol1/Pol2。在安慰剂组中,对NHP施用由10mM HEPES、150mM NaCl、20mM甘氨酸和0.1%恒河猴血清白蛋白组成的安慰剂缓冲溶液。Heterologous prime-boost in non-human primates. Simian immunodeficiency virus infection in NHPs is used as a good model to evaluate the immunogenicity of HIV vaccine vectors. To evaluate the immunogenicity of replication-competent LCMV (TT1) and replication-competent PICV (TT2) vectors (e.g., vectors as described in WO2016075250 and WO2017198726) in NHPs, we developed vectors expressing full-length SIV proteins Gag, Env or Pol derived from the SIV sme543 strain. The amino acid sequences are provided in Table 2. Healthy rhesus macaques from India were immunized by the IM route with arenavirus vectors. Vectors expressing Gag and Env (replication-attenuated Pichinde arenavirus (TT2) and replication-attenuated LCMV arenavirus (TT1)) were administered to the left quadriceps, while vectors expressing Pol (TT2 and TT1) were administered to the right quadriceps. The doses administered were as follows: 1×10 6 RCV of TT2 Gag, 1×10 6 RCV of TT2 Env, 1×10 6 RCV of TT2 Pol1/Pol2, 4×10 6 RCV of TT1 Gag, 4×10 6 RCV of TT1 Env, and 2×10 6 RCV of TT1 Pol1/Pol2. In the placebo group, NHPs were administered a placebo buffer solution consisting of 10 mM HEPES, 150 mM NaCl, 20 mM glycine, and 0.1% rhesus serum albumin.
IFN-γELISpot测定。将预包被的条带ELISpot板(MabTech)用于所有ELISpot分析。简而言之,将在分析的每个时间点从全血分离的2×105个PBMC接种到每个孔中。将跨越SIV免疫原Gag、Env和Pol的11个氨基酸重叠的15聚体组成的SIV smE543肽以1μg/ml的最终浓度组装到96孔ELISpot板中。为了确定对Gag、Env和Pol应答的广度,分别以1μg/ml的最终浓度分别测试了12、16或23个肽的子池。每个子池具有由11个氨基酸重叠的15聚体组成的10个肽。每个样品一式两份地测试。对于阳性对照,添加5μg/ml PHA(Sigma)。培养基对照孔含有用与肽刺激的测试孔相似的DMSO组成重构的细胞培养基。将板在37℃、5% CO2下孵育20-24小时。过夜刺激后,将细胞从板中取出,并将孔在PBS中洗涤三次,然后用含有0.05%吐温的PBS洗涤三次。然后在室温下将生物素化的抗IFN-γ检测抗体添加到板中保持2小时。然后将板用含有0.05%吐温的PBS洗涤三次,然后添加链霉亲和素缀合的碱性磷酸酶(AP)。然后将孔用0.05%吐温-PBS洗涤两次,然后用蒸馏水洗涤两次,然后添加蓝色显色剂溶液。然后将板在室温下孵育15分钟,然后使用自来水停止反应。然后将孔干燥过夜,并在Immunospot ELISpot读数器上对斑点形成单位(SFU)进行计数。所有板的设置相同,并且计数以每2×105个PBMC的SFU表示。为了使用CTL单色免疫斑点计数软件确定合适的斑点计数,相对于样品归一化多个参数。在非特异性斑点开始出现之前,将信号灵敏度设定为最高值。斑点尺寸被减小到所有真实斑点都被计数但伪影没有被计数的程度。设置背景信号减少以避免计数伪影。SFU计算为测试孔中的斑点数减去培养基对照孔中的平均斑点数。阳性应答定义为与培养基对照孔相比>3倍的SFU且每1×106个PBMC>50个斑点。IFN-γ ELISpot assay. Pre-coated strip ELISpot plates (MabTech) were used for all ELISpot analyses. In brief, 2×10 5 PBMCs isolated from whole blood were inoculated into each well at each time point analyzed. SIV smE543 peptides consisting of 15-mers overlapping by 11 amino acids spanning the SIV immunogens Gag, Env and Pol were assembled into 96-well ELISpot plates at a final concentration of 1 μg/ml. To determine the breadth of responses to Gag, Env and Pol, sub-pools of 12, 16 or 23 peptides were tested at a final concentration of 1 μg/ml, respectively. Each sub-pool had 10 peptides consisting of 15-mers overlapping by 11 amino acids. Each sample was tested in duplicate. For the positive control, 5 μg/ml PHA (Sigma) was added. The culture medium control wells contained cell culture medium reconstituted with a DMSO composition similar to that of the peptide-stimulated test wells. The plates were incubated at 37°C, 5% CO 2 for 20-24 hours. After overnight stimulation, the cells were removed from the plate and the wells were washed three times in PBS and then three times with PBS containing 0.05% Tween. Biotinylated anti-IFN-γ detection antibodies were then added to the plate for 2 hours at room temperature. The plate was then washed three times with PBS containing 0.05% Tween, followed by the addition of streptavidin-conjugated alkaline phosphatase (AP). The wells were then washed twice with 0.05% Tween-PBS, then twice with distilled water, and then a blue developer solution was added. The plate was then incubated at room temperature for 15 minutes, and then tap water was used to stop the reaction. The wells were then dried overnight, and the spot forming units (SFU) were counted on the Immunospot ELISpot reader. All plates were set the same, and the counts were expressed as SFU per 2×10 5 PBMCs. In order to determine the appropriate spot counts using the CTL monochrome immunospot counting software, multiple parameters were normalized relative to the sample. Before nonspecific spots began to appear, the signal sensitivity was set to the highest value. The spot size was reduced to the extent that all true spots were counted but artifacts were not counted. Background signal reduction was set to avoid counting artifacts. SFU was calculated as the number of spots in the test wells minus the average number of spots in the medium control wells. A positive response was defined as >3-fold SFU compared to the medium control wells and >50 spots per 1×10 6 PBMCs.
SIV攻击和病毒载量。在最后一次疫苗剂量后4周(即,研究的第32周),用异源SIV病毒群(SIVmac251、8.19TCID50)的单次静脉内(IV)接种攻击研究中的所有动物。攻击病毒的病毒序列不同于疫苗序列(SIVsme543)。通过IV途径估计的SIVmac251攻击原液的AID50为0.29TCID50。攻击后,监测所有动物的临床和实验室进展以及病毒载量以确定峰值病毒载量(在攻击后2周计算)和设定点病毒载量(在攻击后10-40周内计算)。通过一式两份进行的两步RT-PCR测定定量以拷贝/ml表示的血浆SIV病毒载量。SIV attack and viral load.4 weeks after the last vaccine dose (i.e., the 32nd week of the study), all animals in the single intravenous (IV) inoculation attack study were administered to allologous SIV virus groups (SIVmac251, 8.19TCID 50 ). The viral sequence of the attack virus was different from the vaccine sequence (SIVsme543). The AID50 of the SIVmac251 attack stock solution estimated by the IV approach was 0.29TCID 50. After the attack, the clinical and laboratory progress and viral load of all animals were monitored to determine the peak viral load (calculated in 2 weeks after the attack) and the set point viral load (calculated in 10-40 weeks after the attack). The plasma SIV viral load represented by copies/ml was quantitatively measured by two-step RT-PCR performed in duplicate.
结果result
图47A显示了通过IFN-γELISpot评估的SIV特异性IFN-γ应答的大小。在第14周,通过TT1加强导致应答的稳健增加。在每次疫苗剂量后2周观察到的应答峰值大小随着每次随后的加强中均得到维持。Figure 47A shows the magnitude of the SIV-specific IFN-γ response assessed by IFN-γ ELISpot. Boosting by TT1 resulted in a robust increase in the response at week 14. The peak magnitude of the response observed 2 weeks after each vaccine dose was maintained with each subsequent boost.
图47B显示了将接受异源TT2/TT1疫苗的动物分类为中度或高度应答者。这是基于每次疫苗剂量后峰值应答的大小分别小于或大于1000SFU/百万个PBMC。大多数动物(24只中的17只)是高应答者,所有动物都对至少一种SIV免疫原显示阳性应答。Figure 47B shows the classification of animals receiving heterologous TT2/TT1 vaccines as moderate or high responders. This was based on the size of the peak response after each vaccine dose being less than or greater than 1000 SFU/million PBMCs, respectively. The majority of animals (17 of 24) were high responders, with all animals showing a positive response to at least one SIV immunogen.
图48A至图48D证实了在每次疫苗剂量后2周时峰值SIV特异性IFN-γ应答的大小。在剂量2、3和4后,维持峰值Gag-和Pol-特异性应答。Env特异性应答随着每个随后剂量的增加而增加。在四次剂量的异源疫苗后,在24个NHP中的至少21个NHP中观察到对Gag、Env和Pol的阳性应答(应答率=87.5%)。Figures 48A to 48D demonstrate the magnitude of the peak SIV-specific IFN-γ response at 2 weeks after each vaccine dose. Peak Gag- and Pol-specific responses were maintained after doses 2, 3, and 4. Env-specific responses increased with each subsequent dose. After four doses of heterologous vaccine, positive responses to Gag, Env, and Pol were observed in at least 21 of 24 NHPs (response rate = 87.5%).
就广度而言,与剂量2和4后相比,剂量3后观察到最高的总SIV特异性广度。类似地,与剂量2和4后相比,剂量3后观察到显著更高的Env和Pol特异性广度。与剂量2后相比,剂量3和4后的Gag特异性广度显著高。这些结果表明,在每次疫苗加强剂量后2周,诱导了TT2/TT1疫苗诱导的对Gag、Env和Pol特异性免疫原的应答广度。参见,例如图49A至图49D。In terms of breadth, the highest overall SIV-specific breadth was observed after dose 3 compared to after doses 2 and 4. Similarly, significantly higher Env and Pol-specific breadth was observed after dose 3 compared to after doses 2 and 4. Gag-specific breadth was significantly higher after doses 3 and 4 compared to after dose 2. These results suggest that the breadth of responses induced by the TT2/TT1 vaccine to Gag, Env, and Pol-specific immunogens was induced 2 weeks after each vaccine booster dose. See, e.g., Figures 49A to 49D.
关于SIV攻击和病毒载量,攻击后,与安慰剂组相比,在TT2/TT1组中观察到降低的病毒载量(图50A)。在用SIVmac251攻击后2周测量的中值峰值病毒载量在TT2/TT1组中为6.54log10 SIV拷贝/ml,在安慰剂组中为7.2log10 SIV拷贝/ml。与安慰剂组相比,在TT2/TT1疫苗接种的NHP中观察到峰值病毒载量的显著降低(**p=0.0046,Mann-Whitney t检验)(图50B)。将设定点病毒载量计算为攻击后10-40周内的平均SIV病毒载量。中值设定点VL在TT2/TT1组中为5.5log10 SIV拷贝/ml,在安慰剂组中为6.7log10 SIV拷贝/ml。与安慰剂组相比,在TT2/TT1疫苗接种的NHP中观察到设定点病毒载量的1.2log10 SIV拷贝/ml的显著降低(*p=0.0291,Mann-Whitney t检验)(图50C)。这些数据证明了编码SIV免疫原的PICV/LMCV复制减毒型沙粒病毒载体的异源TT2/TT1初免-加强方案在NHP的SIV攻击模型中的预防功效。About SIV attack and viral load, after attack, compared with placebo group, reduced viral load was observed in TT2/TT1 group (Figure 50A). The median peak viral load measured 2 weeks after attack with SIVmac251 was 6.54log10 SIV copies/ml in TT2/TT1 group and 7.2log10 SIV copies/ml in placebo group. Compared with placebo group, a significant reduction in peak viral load was observed in NHP vaccinated with TT2/TT1 vaccine (**p=0.0046, Mann-Whitney t test) (Figure 50B). The set point viral load was calculated as the average SIV viral load within 10-40 weeks after attack. The median set point VL was 5.5log10 SIV copies/ml in TT2/TT1 group and 6.7log10 SIV copies/ml in placebo group. A significant reduction of 1.2 log10 SIV copies/ml in set point viral load was observed in TT2/TT1 vaccinated NHPs compared to the placebo group (*p=0.0291, Mann-Whitney t test) (Figure 50C). These data demonstrate the prophylactic efficacy of the heterologous TT2/TT1 prime-boost regimen of PICV/LMCV replication-attenuated arenavirus vectors encoding SIV immunogens in the SIV challenge model of NHPs.
实施例11Embodiment 11
含有编码HIV-1免疫原版本1融合多肽的转基因的复制减毒型沙粒病毒载体Replication-attenuated arenavirus vector containing a transgene encoding a HIV-1 immunogen version 1 fusion polypeptide
在该实施例中,我们生成了基于复制减毒型沙粒病毒的病毒载体,该病毒载体编码计算定义的多肽抗原,该多肽抗原含有由作为转基因的Gag、Nef和Pol基因编码的HIV-1保守区。生成了基于皮钦德病毒(PICV)和淋巴细胞性脉络丛脑膜炎病毒(LCMV)的复制减毒型沙粒病毒载体。含有保守区的多肽片段通过不同方法串联或连接,这些方法包括直接融合或在各区之间添加各种柔性接头。转基因在两个病毒S片段(NP片段和GP片段)上被分离和编码。在第一复制减毒型LCMV载体中,用编码SEQ ID NO:98的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:100的融合多肽的多核苷酸替换GP片段。在第二复制减毒型LCMV载体中,用编码SEQ ID NO:99的融合多肽的多核苷酸替换NP片段,并用编码SEQ IDNO:101的融合多肽的多核苷酸替换GP片段。在第一复制减毒型PICV载体中,用编码SEQ IDNO:94的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:96的融合多肽的多核苷酸替换GP片段。在第二复制减毒型PICV载体中,用编码SEQ ID NO:95的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:97的融合多肽的多核苷酸替换GP片段。图25提供了融合多肽的示意图。In this example, we generated a replication-attenuated arenavirus-based viral vector encoding a computationally defined polypeptide antigen containing HIV-1 conserved regions encoded by the Gag, Nef and Pol genes as transgenes. Replication-attenuated arenavirus vectors based on Pichinde virus (PICV) and lymphocytic choriomeningitis virus (LCMV) were generated. The polypeptide fragments containing the conserved regions were tandemly or connected by different methods, including direct fusion or the addition of various flexible linkers between the regions. The transgene was isolated and encoded on two viral S fragments (NP fragment and GP fragment). In the first replication-attenuated LCMV vector, the NP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:98, and the GP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:100. In the second replication-attenuated LCMV vector, the NP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:99, and the GP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:101. In the first replicating attenuated PICV vector, the NP segment was replaced with a polynucleotide encoding a fusion polypeptide of SEQ ID NO: 94, and the GP segment was replaced with a polynucleotide encoding a fusion polypeptide of SEQ ID NO: 96. In the second replicating attenuated PICV vector, the NP segment was replaced with a polynucleotide encoding a fusion polypeptide of SEQ ID NO: 95, and the GP segment was replaced with a polynucleotide encoding a fusion polypeptide of SEQ ID NO: 97. Figure 25 provides a schematic diagram of a fusion polypeptide.
方法method
含有HIV-1融合多肽转基因多肽变体的复制减毒型沙粒病毒载体的构建和生成。表达HIV-1计算定义的疫苗免疫原的复制减毒型沙粒病毒载体如先前所述产生(Kallert人,Nat Commun.(2017)8:15327;也参见,WO2016075250和WO2017198726)。简而言之,合成cDNA序列并亚克隆到相应的主链质粒中。将每个病毒基因组片段的质粒和表达病毒反式作用因子NP和L的质粒转染到LCMV-GP互补细胞中。收获细胞培养物上清液并在HEK293悬浮细胞上进一步增殖,以生成载体原材料(第1代(P1))。针对该评估开发的载体在表3中列出,并在图25中示意性描绘。Construction and generation of replication attenuated arenavirus vectors containing HIV-1 fusion polypeptide transgenic polypeptide variants. Replication attenuated arenavirus vectors expressing HIV-1 computationally defined vaccine immunogens were produced as previously described (Kallert et al., Nat Commun. (2017) 8: 15327; See also, WO2016075250 and WO2017198726). In short, cDNA sequences were synthesized and subcloned into corresponding backbone plasmids. Plasmids of each viral genome fragment and plasmids expressing viral trans-acting factors NP and L were transfected into LCMV-GP complementing cells. Cell culture supernatants were harvested and further propagated on HEK293 suspension cells to generate vector raw materials (1st generation (P1)). The vectors developed for this evaluation are listed in Table 3 and schematically depicted in Figure 25.
表3Table 3
编码HIV-1免疫原1融合多肽的沙粒病毒载体Arenavirus vector encoding HIV-1 immunogen 1 fusion polypeptide
通过检测Gag(p24)的保守区来评估靶基因表达。我们通过免疫印迹或双免疫染色(DI)检测Gag(p24)的保守区来评估转基因表达。对于免疫印迹分析,在将全细胞裂解物应用于丙烯酰胺凝胶电泳之前,收获感染的HEK293细胞并裂解。印迹后,使用小鼠mAb[39/5.4A]孵育膜以检测HIV1 p24(Abcam(ab9071))、兔pAB ERK-2(sc-154;Santa Cruz)或用于检测成功感染的抗体(兔pAb抗LCMV-NP(University of Genf;Doron Merkler教授);小鼠mAb抗PICV-NP(University of Basel;Daniel Pinschewer教授)。Target gene expression was assessed by detecting the conserved region of Gag (p24). We assessed transgene expression by detecting the conserved region of Gag (p24) by immunoblotting or double immunostaining (DI). For immunoblot analysis, infected HEK293 cells were harvested and lysed before applying whole-cell lysates to acrylamide gel electrophoresis. After blotting, the membrane was incubated with mouse mAb [39/5.4A] to detect HIV1 p24 (Abcam (ab9071)), rabbit pAB ERK-2 (sc-154; Santa Cruz), or antibodies for detecting successful infection (rabbit pAb anti-LCMV-NP (University of Genf; Prof. Doron Merkler); mouse mAb anti-PICV-NP (University of Basel; Prof. Daniel Pinschewer).
通过病毒载体的连续传代评估稳定的转基因整合。通过在HEK293悬浮细胞中连续传代载体原材料,我们评估了复制减毒型沙粒病毒载体的转基因稳定性。为此,通过病灶形成试验确定P1原材料的感染滴度,并使用0.001的感染复数(MOI)感染HEK293细胞。在感染后72小时收获子代病毒,并再次滴定。应用相同的原理感染更多的传代。在最多八次传代后,通过转基因PCR和/或DI染色分析含病毒的上清液样品。对于转基因PCR分析,从含有病毒的上清液中提取RNA,随后使用特异性HIV转基因侧翼引物通过PCR进行逆转录和扩增。将PCR产物应用于凝胶电泳分析,以评估转基因PCR片段长度作为转基因稳定性的指标。Stable transgene integration was evaluated by continuous passage of viral vectors. We evaluated the transgene stability of replication attenuated arenavirus vectors by continuous passage of vector raw materials in HEK293 suspension cells. To this end, the infection titer of P1 raw materials was determined by focus formation assay, and HEK293 cells were infected with a multiplicity of infection (MOI) of 0.001. Progeny viruses were harvested 72 hours after infection and titrated again. The same principle was applied to infect more passages. After up to eight passages, virus-containing supernatant samples were analyzed by transgene PCR and/or DI staining. For transgene PCR analysis, RNA was extracted from the supernatant containing the virus, and then reverse transcribed and amplified by PCR using specific HIV transgene flanking primers. The PCR product was applied to gel electrophoresis analysis to evaluate the transgene PCR fragment length as an indicator of transgene stability.
结果result
通过免疫印迹分析评估HIV-1融合多肽转基因表达。我们可通过每个载体三个平行测定的细胞裂解物的免疫印迹分析来验证Gag/Nef/Pol抗原的表达。结果在图52中示出。HIV-1 fusion polypeptide transgene expression was assessed by immunoblotting analysis. We can verify the expression of Gag/Nef/Pol antigens by immunoblotting analysis of cell lysates measured in triplicate for each vector. The results are shown in Figure 52.
通过连续传代评估HIV-1融合多肽转基因的稳定整合。为了评估HIV-1免疫原1转基因是否在数次传代后在复制减毒型沙粒病毒载体中稳定编码,我们分析了细胞培养物上清液并进行了转基因PCR分析。大多数(≥50%)转基因特异性条带仍显示预期全长大小的传代水平被认为是具有稳定转基因插入的最后一个传代水平。结果示出于表4和图53至图56中。此外,在适用的情况下,将从每个传代步骤收获的上清液样品应用于双免疫染色(DI染色),以确定HIV-1 Gag和沙粒病毒-NP表达的比率。两个结果的组合允许更准确地评估HIV-1免疫原1转基因的转基因稳定性。Stable integration of HIV-1 fusion polypeptide transgenes was assessed by serial passage. In order to assess whether the HIV-1 immunogen 1 transgene is stably encoded in a replicating attenuated arenavirus vector after several passages, we analyzed the cell culture supernatant and performed transgene PCR analysis. The passage level at which the majority (≥50%) of transgene-specific bands still show the expected full-length size is considered to be the last passage level with stable transgene insertion. The results are shown in Table 4 and Figures 53 to 56. In addition, where applicable, supernatant samples harvested from each passage step were applied to double immunostaining (DI staining) to determine the ratio of HIV-1 Gag and arenavirus-NP expression. The combination of the two results allows a more accurate assessment of the transgenic stability of the HIV-1 immunogen 1 transgene.
我们发现复制减毒型LCMV HIV抗原编码载体稳定地编码转基因直至传代水平7,而复制减毒型PICV HIV抗原编码载体稳定地编码转基因直至传代水平4和6。We found that replicating attenuated LCMV HIV antigen encoding vectors stably encoded the transgene up to passage level 7, whereas replicating attenuated PICV HIV antigen encoding vectors stably encoded the transgene up to passage levels 4 and 6.
表4Table 4
用于评估转基因遗传稳定性的概述表Summary table for assessing genetic stability of transgenic
P#表示传代数P# represents the number of generations
复制减毒型LCMV HIV抗原编码载体稳定地保留了编码融合多肽SEQ ID NO 98和100(TT1-HIV-GNP1/PN1)和SEQ ID NO:99和101(TT1-HIV-GNP2/PN2)的转基因,直至传代水平7。然而,复制减毒型PICV载体TT2-HIV-GNP1/PN1稳定地保留了编码融合多肽SEQ ID NO:94和96直至传代水平6的转基因,而复制减毒型PICV载体TT2-HIV-GNP2/PN2稳定地保留了编码融合多肽SEQ ID NO:95和97直至传代水平4的转基因。The replicating attenuated LCMV HIV antigen encoding vectors stably retained the transgenes encoding the fusion polypeptides SEQ ID NOs: 98 and 100 (TT1-HIV-GNP1/PN1) and SEQ ID NOs: 99 and 101 (TT1-HIV-GNP2/PN2) until passage level 7. However, the replicating attenuated PICV vector TT2-HIV-GNP1/PN1 stably retained the transgenes encoding the fusion polypeptides SEQ ID NOs: 94 and 96 until passage level 6, and the replicating attenuated PICV vector TT2-HIV-GNP2/PN2 stably retained the transgenes encoding the fusion polypeptides SEQ ID NOs: 95 and 97 until passage level 4.
实施例12Example 12
含有编码HIV-1免疫原版本2融合多肽的转基因的复制减毒型沙粒病毒载体Replication-attenuated arenavirus vector containing a transgene encoding a HIV-1 immunogen version 2 fusion polypeptide
在该实施例中,我们生成了基于复制减毒型沙粒病毒的病毒载体,该病毒载体编码较短的计算定义的多肽抗原HIV-1免疫原2,该多肽抗原含有包括作为转基因的Gag、Nef和Pol基因的HIV-1保守区。生成了基于皮钦德病毒(PICV)和淋巴细胞性脉络丛脑膜炎病毒(LCMV)的复制减毒型沙粒病毒载体。含有保守区的多肽片段通过不同方法串联或连接,这些方法包括直接融合或在各区之间添加各种柔性接头。转基因在两个病毒S片段(NP片段和GP片段)上被分离和编码。在第一复制减毒型LCMV载体中,用编码SEQ ID NO:84的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:88的融合多肽的多核苷酸替换GP片段。在第二复制减毒型LCMV载体中,用编码SEQ ID NO:85的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:89的融合多肽的多核苷酸替换GP片段。在第一复制减毒型PICV载体中,用编码SEQ ID NO:82的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:86的融合多肽的多核苷酸替换GP片段。在第二复制减毒型PICV载体中,用编码SEQ ID NO:83的融合多肽的多核苷酸替换NP片段,并用编码SEQ ID NO:87的融合多肽的多核苷酸替换GP片段。图21提供了融合多肽的示意图。In this example, we generated a replication-attenuated arenavirus-based viral vector encoding a shorter computationally defined polypeptide antigen HIV-1 immunogen 2 containing HIV-1 conserved regions including Gag, Nef and Pol genes as transgenes. Replication-attenuated arenavirus vectors based on Pichinde virus (PICV) and lymphocytic choriomeningitis virus (LCMV) were generated. The polypeptide fragments containing the conserved regions were tandemly or linked by different methods, including direct fusion or the addition of various flexible linkers between the regions. The transgene was isolated and encoded on two viral S fragments (NP fragment and GP fragment). In the first replication-attenuated LCMV vector, the NP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:84, and the GP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:88. In the second replication-attenuated LCMV vector, the NP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:85, and the GP fragment was replaced by a polynucleotide encoding a fusion polypeptide of SEQ ID NO:89. In the first replicating attenuated PICV vector, the NP segment was replaced with a polynucleotide encoding the fusion polypeptide of SEQ ID NO: 82, and the GP segment was replaced with a polynucleotide encoding the fusion polypeptide of SEQ ID NO: 86. In the second replicating attenuated PICV vector, the NP segment was replaced with a polynucleotide encoding the fusion polypeptide of SEQ ID NO: 83, and the GP segment was replaced with a polynucleotide encoding the fusion polypeptide of SEQ ID NO: 87. Figure 21 provides a schematic diagram of the fusion polypeptide.
方法method
含有HIV-1免疫原2转基因多肽变体的复制减毒型沙粒病毒载体的构建和生成。表达HIV-1计算定义的疫苗免疫原的复制减毒型PICV和复制减毒型LCMV病毒载体如先前所述产生(Kallert人,(2017)Nat.Comm.,出处同上)。简而言之,合成cDNA序列并亚克隆到相应的主链质粒中。将每个病毒基因组片段的质粒和表达病毒反式作用因子NP和L的质粒转染到LCMV-GP互补细胞中。收获细胞培养物上清液并在HEK293悬浮细胞上进一步增殖,以生成载体原材料(第1代)。针对该评估开发的载体在表5中列出,并在图21中示意性描绘。The construction and generation of replication attenuated arenavirus vectors containing HIV-1 immunogen 2 transgenic polypeptide variants. The replication attenuated PICV and replication attenuated LCMV virus vectors expressing HIV-1 computationally defined vaccine immunogens were produced as previously described (Kallert et al., (2017) Nat. Comm., supra). In short, the cDNA sequence was synthesized and subcloned into the corresponding backbone plasmid. The plasmids of each viral genome fragment and the plasmids expressing viral trans-acting factors NP and L were transfected into LCMV-GP complementing cells. The cell culture supernatant was harvested and further propagated on HEK293 suspension cells to generate carrier raw materials (1st generation). The carriers developed for this evaluation are listed in Table 5 and schematically depicted in Figure 21.
表5Table 5
编码HIV-1免疫原2融合多肽的沙粒病毒载体Arenavirus vector encoding HIV-1 immunogen 2 fusion polypeptide
通过检测Gag(p24)的保守区来评估靶基因表达。我们通过免疫印迹或双免疫染色(DI)检测Gag(p24)的保守区来评估转基因表达。对于免疫印迹分析,在将全细胞裂解物应用于丙烯酰胺凝胶电泳之前,收获感染的HEK293细胞并裂解。印迹后,使用小鼠mAb[39/5.4A]孵育膜以检测HIV1 p24(Abcam(ab9071))、兔pAB ERK-2(sc-154;Santa Cruz)或用于检测成功感染的抗体(兔pAb抗LCMV-NP(University of Genf;Doron Merkler教授);小鼠mAb抗PICV-NP(University of Basel;Daniel Pinschewer教授)。Target gene expression was assessed by detecting the conserved region of Gag (p24). We assessed transgene expression by detecting the conserved region of Gag (p24) by immunoblotting or double immunostaining (DI). For immunoblot analysis, infected HEK293 cells were harvested and lysed before applying whole-cell lysates to acrylamide gel electrophoresis. After blotting, the membrane was incubated with mouse mAb [39/5.4A] to detect HIV1 p24 (Abcam (ab9071)), rabbit pAB ERK-2 (sc-154; Santa Cruz), or antibodies for detecting successful infection (rabbit pAb anti-LCMV-NP (University of Genf; Prof. Doron Merkler); mouse mAb anti-PICV-NP (University of Basel; Prof. Daniel Pinschewer).
通过病毒载体的连续传代评估稳定的转基因整合。通过在HEK293悬浮细胞中连续传代载体原材料,我们评估了复制减毒型沙粒病毒载体的转基因稳定性。为此,通过病灶形成试验确定P1原材料的感染滴度,并使用0.001的MOI感染HEK293细胞。在感染后72小时收获子代病毒,并再次滴定。应用相同的原理感染更多的传代。在最多八次传代后,通过转基因PCR和/或DI染色分析含病毒的上清液样品。对于转基因PCR分析,从含有病毒的上清液中提取RNA,随后使用特异性HIV转基因侧翼引物通过PCR进行逆转录和扩增。将PCR产物应用于凝胶电泳分析,以评估转基因PCR片段长度作为转基因稳定性的指标。Stable transgene integration was assessed by serial passaging of viral vectors. We assessed the transgene stability of replication-attenuated arenavirus vectors by serial passaging of vector starting materials in HEK293 suspension cells. To this end, the infectious titer of P1 starting materials was determined by focus formation assay and HEK293 cells were infected with an MOI of 0.001. Progeny viruses were harvested 72 h after infection and titrated again. The same principle was applied to infect more passages. After a maximum of eight passages, virus-containing supernatant samples were analyzed by transgene PCR and/or DI staining. For transgene PCR analysis, RNA was extracted from the virus-containing supernatant and subsequently reverse transcribed and amplified by PCR using specific HIV transgene flanking primers. PCR products were applied to gel electrophoresis analysis to assess transgene PCR fragment length as an indicator of transgene stability.
结果result
通过免疫印迹分析评估HIV免疫原2转基因表达。我们通过每个复制减毒型LCMV载体的四个(TT1-HIV(C2)-GP1/PN1)或两个(TT1-HIV(C2)-GP2/PN2)平行测定(左图)和每个复制减毒型PICV载体的一个代表性载体原液(右图)的细胞裂解物的免疫印迹分析验证了Gag/Nef/Pol抗原的表达。我们通过对传代水平1(P1)和4(P4)的HIV-1 Gag-Pol染色确定了抗原表达。当用Gag抗体染色时,用TT2-HIV(C2)-GP2/PN2感染的细胞显示约30kDa大小的另外的条带。结果在图57中示出。HIV immunogen 2 transgene expression was assessed by immunoblotting analysis. We verified the expression of Gag/Nef/Pol antigen by immunoblotting analysis of cell lysates of four (TT1-HIV (C2)-GP1/PN1) or two (TT1-HIV (C2)-GP2/PN2) parallel determinations (left figure) of each replication attenuated LCMV vector and a representative vector stock solution (right figure) of each replication attenuated PICV vector. We determined antigen expression by staining HIV-1 Gag-Pol to level 1 (P1) and 4 (P4) of passage. When dyed with Gag antibody, cells infected with TT2-HIV (C2)-GP2/PN2 showed additional bands of about 30kDa size. The result is shown in Figure 57.
通过连续传代评估HIV-1免疫原2转基因的稳定整合。为了评估HIV-1免疫原2转基因是否在数次传代后在复制减毒型沙粒病毒载体中稳定编码,我们分析了细胞培养物上清液并进行了转基因PCR分析。大多数(≥50%)转基因特异性条带仍显示预期全长大小的传代水平被认为是具有稳定转基因插入的最后一个传代水平。结果示出于表6和图58至图61中。此外,在适用的情况下,将从每个传代步骤收获的上清液样品应用于双免疫染色(DI染色),以确定HIV-1 Gag和复制减毒型沙粒病毒-NP表达的比率。两个结果的组合允许更准确地评估HIV-1免疫原2转基因的转基因稳定性。Stable integration of HIV-1 immunogen 2 transgene was evaluated by serial passage. In order to evaluate whether the HIV-1 immunogen 2 transgene is stably encoded in the replicating attenuated arenavirus vector after several passages, we analyzed the cell culture supernatant and performed transgene PCR analysis. The passage level at which the majority (≥50%) of transgene-specific bands still show the expected full-length size is considered to be the last passage level with stable transgene insertion. The results are shown in Table 6 and Figures 58 to 61. In addition, where applicable, the supernatant samples harvested from each passage step were applied to double immunostaining (DI staining) to determine the ratio of HIV-1 Gag and replicating attenuated arenavirus-NP expression. The combination of the two results allows a more accurate assessment of the transgenic stability of the HIV-1 immunogen 2 transgene.
我们发现复制减毒型LCMV HIV抗原编码载体稳定地编码转基因大于传代水平8,而复制减毒型PICV HIV抗原编码载体稳定地编码转基因直至传代水平6和8。We found that replicating attenuated LCMV HIV antigen encoding vectors stably encoded the transgene greater than passage level 8, whereas replicating attenuated PICV HIV antigen encoding vectors stably encoded the transgene up to passage levels 6 and 8.
表6Table 6
用于评估转基因遗传稳定性的概述表Summary table for assessing genetic stability of transgenic plants
P#表示传代数P# represents the number of generations
复制减毒型LCMV HIV抗原编码载体稳定地保留了编码融合多肽SEQ ID NO 84和88(TT1-HIV(C2)-GP1/PN1)和SEQ ID NO:85和89(TT1-HIV(C2)-GP2/PN2)的转基因,大于传代水平8。然而,复制减毒型PICV载体TT2-HIV(C2)-GP1/PN1稳定地保留了编码融合多肽SEQID NO:82和86直至传代水平8的转基因,而复制减毒型PICV载体TT2-HIV(C2)-GP2/PN2稳定地保留了编码融合多肽SEQ ID NO:83和87大于传代水平6的转基因。The replicating attenuated LCMV HIV antigen encoding vector stably retained the transgene encoding the fusion polypeptides SEQ ID NOs: 84 and 88 (TT1-HIV(C2)-GP1/PN1) and SEQ ID NOs: 85 and 89 (TT1-HIV(C2)-GP2/PN2) for greater than passage level 8. However, the replicating attenuated PICV vector TT2-HIV(C2)-GP1/PN1 stably retained the transgene encoding the fusion polypeptides SEQ ID NOs: 82 and 86 until passage level 8, while the replicating attenuated PICV vector TT2-HIV(C2)-GP2/PN2 stably retained the transgene encoding the fusion polypeptides SEQ ID NOs: 83 and 87 for greater than passage level 6.
实施例13Example 13
疫苗和免疫调节剂组合Vaccine and immunomodulator combinations
在非人灵长类动物中,施用编码SIV免疫原的基于腺病毒载体的疫苗与检查点抑制剂诸如αPD1抗体的组合,显示出疫苗诱导的T细胞应答的持久性增加,而与αCTLA4抗体的组合显示出T细胞应答的大小增加。参见,Pan等人,Front Immunol.(2018)9:2415;和Loffredo等人,Poster P55,“Society for Immunotherapy of Cancer(SITC)32nd AnnualMeeting and Pre-Conference Programs”;2017年11月8日至12日;National Harbor,MD)。FLT3L-FLT3相互作用导致树突状细胞的扩增和成熟。基于沙粒病毒的载体显示出树突状细胞嗜性(Flatz等人,Nat Med(2010)16(3):339-45)。因此,我们假设将DC扩增与沙粒病毒载体组合将增强用TT2/TT1复制减毒型PICV/LCMV沙粒病毒载体初免-加强方案观察到的免疫原性。In non-human primates, administration of adenoviral vector-based vaccines encoding SIV immunogens in combination with checkpoint inhibitors such as αPD1 antibodies showed an increase in the persistence of vaccine-induced T cell responses, while the combination with αCTLA4 antibodies showed an increase in the size of T cell responses. See, Pan et al., Front Immunol. (2018) 9: 2415; and Loffredo et al., Poster P55, "Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting and Pre-Conference Programs"; November 8-12, 2017; National Harbor, MD). FLT3L-FLT3 interactions lead to the expansion and maturation of dendritic cells. Arenavirus-based vectors show dendritic cell tropism (Flatz et al., Nat Med (2010) 16 (3): 339-45). Therefore, we hypothesized that combining DC expansion with arenavirus vectors would enhance the immunogenicity observed with the TT2/TT1 replication-attenuated PICV/LCMV arenavirus vector prime-boost regimen.
方法method
图62提供了在非人灵长类动物(NHP)中用沙粒病毒载体(TT2/TT1)与免疫调节剂组合进行初免-加强的免疫方案示意图。印度来源的健康恒河猴用沙粒病毒载体通过肌内(I.M.)途径免疫,用免疫调节剂通过静脉内(I.V.)途径免疫,每组十三(13)个NHP。将表达Gag和Env的载体TT2(复制减毒型皮钦德病毒(PICV))和TT1(复制减毒型LCMV))施用于左四头肌,而将表达Pol的载体(TT2和TT1)施用于右四头肌。施用剂量如下:1×106TT2 Gag、Env和Pol1/Pol2载体的有复制能力的病毒颗粒(RCV),4×106TT1 Gag、Env的RCV,和2×106TT1Pol1/Pol2的RCV。Figure 62 provides a schematic diagram of the prime-boost immunization scheme in non-human primates (NHPs) using arenavirus vectors (TT2/TT1) in combination with immunomodulators. Healthy rhesus macaques of Indian origin were immunized with arenavirus vectors by intramuscular (IM) route and immunomodulators by intravenous (IV) route, thirteen (13) NHPs per group. Vectors TT2 (replication-attenuated picinder virus (PICV)) and TT1 (replication-attenuated LCMV)) expressing Gag and Env were administered to the left quadriceps, while vectors expressing Pol (TT2 and TT1) were administered to the right quadriceps. The doses administered were as follows: 1×10 6 replication-competent viral particles (RCV) of TT2 Gag, Env, and Pol1/Pol2 vectors, 4×10 6 RCV of TT1 Gag, Env, and 2×10 6 RCV of TT1 Pol1/Pol2.
每4周施用一次异源TT2/TT1疫苗,共施用4个剂量,单独施用(组1,疫苗)或与在疫苗后立即施用的检查点抑制剂(组2中的αPD1抗体,或组3中的αCTLA4抗体,各10mg/kg)组合施用。在疫苗剂量前1周施用FLT3L-Fc FLT3激动剂(第4组,0.3mg/kg)。The heterologous TT2/TT1 vaccine was administered every 4 weeks for a total of 4 doses, either alone (Group 1, vaccine) or in combination with a checkpoint inhibitor (αPD1 antibody in Group 2, or αCTLA4 antibody in Group 3, each at 10 mg/kg) immediately after the vaccine. The FLT3L-Fc FLT3 agonist was administered 1 week before the vaccine dose (Group 4, 0.3 mg/kg).
如实施例10所述进行IFN-γELISpot测定。IFN-γ ELISpot assay was performed as described in Example 10.
结果result
图63显示了外周血中通过IFN-γELISpot评估的SIV特异性IFN-γ应答的大小。与单独的TT2/TT1疫苗相比,将αCTLA4抗体与TT2/TT1疫苗一起添加导致SIV特异性应答的大小稳健且持续的增加(在第4、6、8、10、12、14和16周时p<0.05;具有Dunnett多重比较检验的双向ANOVA)。与FLT3L-Fc FLT3激动剂的组合也导致加强后SIV特异性应答的大小显著增加(在第8、10和14周p<0.05;具有Dunnett多重比较检验的双向ANOVA)。施用αPD1抗体对疫苗诱导的T细胞应答的大小没有任何影响。检查点抑制剂αCTLA4抗体和DC激动剂FLT3L-Fc均诱导T细胞应答的峰值大小的显著增加,这与疫苗诱导的应答被这些免疫调节剂增强的结论一致。Figure 63 shows the size of SIV-specific IFN-γ responses assessed by IFN-γ ELISpot in peripheral blood. Compared with the TT2/TT1 vaccine alone, the addition of αCTLA4 antibodies together with TT2/TT1 vaccines resulted in a robust and sustained increase in the size of SIV-specific responses (p<0.05 at weeks 4, 6, 8, 10, 12, 14, and 16; two-way ANOVA with Dunnett's multiple comparison test). The combination with FLT3L-Fc FLT3 agonists also resulted in a significant increase in the size of SIV-specific responses after boosting (p<0.05 at weeks 8, 10, and 14; two-way ANOVA with Dunnett's multiple comparison test). The administration of αPD1 antibodies had no effect on the size of vaccine-induced T cell responses. Both the checkpoint inhibitor αCTLA4 antibody and the DC agonist FLT3L-Fc induced a significant increase in the peak size of T cell responses, which is consistent with the conclusion that vaccine-induced responses are enhanced by these immunomodulators.
关于广度,图64显示了在接受与αCTLA4抗体或FLT3L-Fc FLT3激动剂组合的疫苗的组中观察到在最后疫苗剂量后2周的最高总SIV特异性广度。TT2/TT1疫苗与FLT3L-FcFLT3激动剂组合施用导致Gag、Env和Pol特异性应答广度的显著增加。TT2/TT1疫苗与αCTLA4抗体组合施用导致Env和Pol特异性应答广度的显著增加。总之,这些结果与异源TT2/TT1疫苗与αCTLA4抗体或FLT3L-Fc FLT3激动剂的组合导致SIV特异性T细胞应答的广度显著增加的结论一致。About breadth, Figure 64 shows the highest total SIV-specific breadth observed 2 weeks after the last vaccine dose in the group receiving the vaccine in combination with αCTLA4 antibody or FLT3L-Fc FLT3 agonist. The administration of TT2/TT1 vaccine in combination with FLT3L-FcFLT3 agonist resulted in a significant increase in the breadth of Gag, Env and Pol specific responses. The administration of TT2/TT1 vaccine in combination with αCTLA4 antibody resulted in a significant increase in the breadth of Env and Pol specific responses. In summary, these results are consistent with the conclusion that the combination of heterologous TT2/TT1 vaccine with αCTLA4 antibody or FLT3L-Fc FLT3 agonist results in a significant increase in the breadth of SIV-specific T cell responses.
应当理解,本文所述的实施例和实施方案仅用于例示性目的,并且本领域技术人员将根据这些实施例和实施方案提出各种修改或改变,并将这些修改或改变包括在本申请的精神和权限以及所附权利要求书的范围内。本文引用的所有出版物、专利和专利申请据此全文以引用方式并入以用于所有目的。It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art will propose various modifications or changes based on these embodiments and implementations, and include these modifications or changes within the spirit and authority of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
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