CN103724406A - A MERS-CoV synthetic peptide vaccine with neutralizing activity and its application - Google Patents
A MERS-CoV synthetic peptide vaccine with neutralizing activity and its application Download PDFInfo
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Abstract
MERS-CoV synthetic peptide vaccine with neutralizing activity and application thereof. The invention relates to a MERS-CoV synthetic peptide vaccine and application thereof, wherein the peptide segment is selected from the following amino acid sequences: SEQ ID NO: 1, the amino acid sequence of the peptide fragment is as follows: CALPDTPSTLTPRSVR are provided. The vaccine or pharmaceutical composition containing the peptide segment, the physiologically acceptable carrier composition containing the peptide segment, a non-specific immune response enhancer or the variant of the peptide segment, wherein the peptide segment variant is the peptide segment which is only distinguished by conservative substitution and/or modification and still retains the antigenicity and/or immunogenicity characteristics of the peptide segment, and the peptide segment variant and the identified peptide segment preferably have more than 70 percent of identity. The peptide fragment can be used as a vaccine or a pharmaceutical composition to induce a specific neutralizing antibody to neutralize middle east respiratory distress syndrome coronavirus , so that an organism is protected against infection of MERS-CoV, and the MERS-CoV polypeptide can possibly become a key component of an ideal MERS-CoV preventive/therapeutic candidate vaccine.
Description
Technical field the present invention relates to a kind of have neutralization active MERS-CoV synthetic peptide vaccine and application thereof, and this vaccine can carry out immunity and vaccine inoculation, belongs to biological technical field.
The background technology at present known coronavirus that can infect people has six kinds, be respectively the human corona virus HCoV-229E and the HCoV-OC43 that find the sixties in 20th century, emerging SARS (Severe acute respiratory syndrome) coronavirus SARS-CoV in 2003, the human corona virus HCoV-NL63 finding for 2004, the novel human corona virus that newfound human corona virus HCoV-HKU1 in 2005 and in July, 2012 occur in Middle East: Middle East respiratory system syndromes coronavirus (MERS-CoV once claimed HCoV-EMC)
[1].
MERS-CoV be 2012 in Middle East from the new SARS sample of the one of finding suffering from the patient of an acute respiratory disease coronavirus, patient's clinical manifestation is acute respiratory infection and renal failure.British scientist, by this viral genome order-checking and system are analyzed, finds that this virus is a kind of new human corona virus (GenBank:JX869059)
[1].This viral genome total length 30118bp, genome structure holds 3 ' end to be followed successively by from 5': 5'-UTR-ORFlab-S-ORF3-ORF4a-ORF4b-ORF5-E-M-N-3 ' UTR, from phylogenetics, think that this virus belongs to the 2c subgroup of β class coronavirus, and with SARS genome similarity be 54.9%
[2].The monitoring data of U.S. CDC shows, MERS-CoV virus has higher lethality rate, dead 54 examples from April, 2012 the 114 routine patients that made a definite diagnosis in the whole world so far, and mortality ratio reaches 54%
[3].Visible this virus has high danger, probably as SARS-CoV, causes serious respiratory infection epidemic situation to break out.Research and development deposit for this viral vaccine and medicine can not be ignored.
In the adaptive immunity defence that enters and propagate at body limiting virus, neutralizing antibody is being brought into play very crucial provide protection.Studies show that, the S albumen of coronavirus is not only the main determining factor of its close preferendum, is also the major antigen target that induction body produces neutralizing antibody simultaneously, and therefore the research and development of coronavirus vaccine are conventionally using S albumen as main immunogens.But up to the present, still lack for the immunogenicity of new MERS-CoV virus S protein and in and the detail file of epitope.
We have analyzed MERS-CoV virus S protein possibility B cell epitope by bioinformatic analysis, therefrom having screened the higher synthetic peptide of part score carries out finding after animal immune, adopt in the antigen binding domain (RBD, aa367-606) of MERS-CoV virus S protein and the laboratory animal serum of 736-761 amino acids polypeptide (aa736-761) immunity and effective MERS-CoV neutralizing antibody all can be detected.Wherein RBD is traditional receptors bind region, and existing several research groups studies have shown that and point out it can induce generation neutralizing antibody
[4-8].And the neutralizing antibody inducibility of aa736-761 has no report before this, be the MERS-CoV specificity neutralizing antibody inducing antigen of the latest find of this research group and proof, also illustrate that it is the potential receptors bind related locus that MERS-CoV invades cell simultaneously.
This discovery has great importance, and not only can help to understand process and the mechanism of this new virus infection, also can provide new vaccine design thinking for blocking-up MERS-CoV infects.Be expected to become the key ingredient of the desirable MERS-CoV preventing/treating candidate vaccine of research and development.
Summary of the invention:
The problem that the present invention solves is to provide a kind of MERS-CoV synthetic peptide vaccine and application thereof, and MERS-CoV synthetic peptide immune animal can be induced to specific neutralizing antibody.
The present invention is achieved through the following technical solutions:
A synthetic peptide for Middle East respiratory system syndromes coronavirus, its amino acid residue sequence is as shown in SEQ.ID.NO.1.
The synthetic peptide of described Middle East respiratory system syndromes coronavirus preparation for Middle East respiratory system syndromes coronavirus preventative/application of therapeutic vaccine.
The synthetic peptide of described Middle East respiratory system syndromes coronavirus is in the application of the medicine of the anti-Middle East of preparation respiratory system syndromes coronavirus.
Described medicine is the medicine bringing out for the humoral immunoresponse(HI) of Middle East respiratory system syndromes coronavirus neutralizing antibody.
Compared with prior art, the present invention has following useful technique effect:
The synthetic peptide of the Middle East provided by the invention respiratory system syndromes coronavirus, is brand-new epitope section, and immunity can be induced and be produced the special neutralizing antibody of virus separately, shows good immunogenicity and immune effect.Therefore, this MERS-CoV synthetic peptide vaccine may become the key ingredient of MERS-CoV preventing/treating candidate vaccine.
Accompanying drawing explanation
Fig. 1: MERS-CoVS protein structure and antigen used position schematic diagram.
Fig. 2: the titer determination of antigen-specific IgG in immune serum.
Fig. 3: the specific recognition of the antibody serum of inducing to exo-antigen.
Fig. 4: the antibody neutralising capacity comparison of generation that different synthetic peptide is induced.
Fig. 5: RBD and SP3 (aa736-761) all can induce and produce MERS-CoV specificity neutralizing antibody.
Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.The experimental technique of unreceipted actual conditions in following examples, conventionally according to normal condition as the < < molecular cloning experiment guide > > (third edition, Science Press, 2005) condition described in the common tool book of this area such as, or the condition of advising by reagent manufacturer is carried out.
In the epi-position of MERS-CoV, screen partial synthesis peptide and carry out immunity as vaccine, to reach the immune effect for MERS-CoV, thereby reach the object of preventing/treating Middle East respiratory system syndromes, this immune effect is mainly induction and produces for the special neutralizing antibody of MERS-CoV.
Embodiment 1: in view of above-mentioned purpose, first carry out the screening of epitope peptide with synthetic:
Concrete MERS-CoV S albumen epitope peptide is selected to carry out preferably according to bioinformatics software analysis, as shown in the table
According to upper table result, synthetic SP2 (aa509-549) and SP3 (aa736-761) antigenic synthetic peptide (Fig. 1), and coupling hemocyanin (KLH), the concrete Ze Xiyuan bio tech ltd, Beijing that entrusts utilizes Peptide synthesizer to synthesize 2 polypeptide, and purity is all more than 95%.And with high performance liquid chromatography (high performance liquid chromatography, HPLC), analyze purity and the amino acid whose exactness of synthesized polypeptide.Result shows synthetic polypeptide purity >=95%; In synthetic peptide, each amino acid whose ratio and expection is consistent, illustrates that polypeptide is synthetic correct.
Adopt Bac-to-Bac baculovirus expression system eukaryotic expression MERS-CoV S albumen RBD section (aa367-606) simultaneously, and express and purifying (purifying sample is so kind as to give by doctor He Yuxian of cause of disease institute of the Chinese Academy of Sciences), as the positive control of test.
Embodiment 2: animal immune and serum are collected:
2.1 using New Zealand white rabbit as immune object, and the synthetic peptide filtering out is carried out to the humoral immunization situation that immunity is induced to detect it, and concrete immunization protocol is:
Select the New Zealand white rabbit of 2～2.5kg, by 0.5ml SP2 or SP3 (2mg/ml, be dissolved in 0.9% physiological saline) add equivalent complete Freund's adjuvant to mix and completely after emulsification at two leg outer sides and back, get at 5 and carry out subcutaneous injection, every some injection volume is about 0.2ml.
In fundamental immunity, after 15 days, carry out immunity for the second time, injected dose and position and fundamental immunity are similar, and difference is that this antigen emulsion adopts incomplete Freund's adjuvant to substitute immune complete Freund's adjuvant used for the first time.
Before each immunity, from ear vein, take 1ml venous blood to prepare serum, the second pin immunity is anaesthetized (vetanarcol 65mg/kg to rabbit in latter 10 days, ip, rabbit is lain on the back to fix and expose neck, shave hair alcohol disinfecting, in neck, right-hand cutout separation carotid artery enforcement carotid artery intubation is taken a blood sample in a large number.Blood 4 degree place and spend the night after the centrifugal 10min results supernatant liquors of 4000rpm (being serum) ,-80 ℃ of preservations after packing.
2.2 get 6 of 6-8 BALB/c male mices in age in week, add equivalent freund's adjuvant fully to mix after with 0.9% normal saline dilution in the restructuring RBD albumen of purifying and emulsification completely, subcutaneous injection mouse, complete Freund's adjuvant during for the first time with administration, full freund's adjuvant afterwards toos many or too much for use.During administration, subcutaneous injection 100ul (1ug/ul) respectively.At interval of two weeks booster immunizations once, be total to immunity 3 times.The HIV p24 albumen of purifying is as negative control.
Last after immune two weeks, to pluck eyeball of mouse and get blood, blood 4 degree are gathered in the crops supernatant liquor (being serum) ,-80 ℃ of preservations after packing after the centrifugal 10min of 4000rpm after placing and spending the night.
Embodiment 3: the detection of antigen-specific antibodies in immune serum:
In 3.1 immune serums, the ELISA of antigen-specific IgG measures: adopt SP2, SP3 and RBD are coated with elisa plate.Immune serum is made to doubling dilution with PBS from 1:100, using 2.1 times of the mean value of the A450/650 value that detects after the dilution of immune serum 1:50 not as (Cut off) dividing value, respectively organize the variation relation of laboratory animal serum detection OD value and serum dilution and see Fig. 2.A in figure, b, c represents respectively with RBD, the detected result of the antigen coated ELSA plate of SP2 and SP3 as can be seen from Figure, is respectively organized the laboratory animal immunity that all succeeds, and has produced the antibody of the antigen-specific of high titre.
In 3.2 immune serums, the western bolt of antigen-specific IgG detects: lysing cell after the eukaryon expression plasmid transfection 293T cell of employing expression MERS-S albumen, and by lysate page electrophoresis transferring film.Immune serum is diluted rear as in conjunction with primary antibodie with 5% skimmed milk 1:500, anti-mouse or anti-rabbit igg antibody detect as the specific recognition capability of two anti-antagonists, the results are shown in Figure 3.As can be seen from Figure, respectively organize all linearizing MERS-S albumen of energy specific recognition of the contained antibody of serum, identification epi-position is linear epitope.
In embodiment 4. immune serums, in the cause of disease specificity of antibody, detect with active:
The preparation of 4.1MERS-CoV and SARS-CoV pseudovirus (LV-CoVpps): surface is MERS-CoV or SARS-CoV envelope protein, the Packaging Method that core carries the false type slow virus particle of luciferase gene is:
By pNL4-3R-E-Luc carrier, respectively at pVRC-SY (nCOV) plasmid of expressing MERS-CoV S albumen, after the pVRC8304 plasmid of expression SARS S albumen mixes with 2:1, adopt transfection reagent (FugeneTM HD reagent, Roche) to carry out transfection to 293FT cell.Cell after transfection is in 37 ℃, 5%CO
2after cultivating 48h in cell culture incubator, collect, and use the ultracentrifugal method of 20% sucrose to concentrate and purifying.Its ultimate density amount adopts p24 quantification kit (Vironostika HIV-1Antigen Microelisa System, BioM é rieux) to carry out measure and calculation.
In 4.2 serum and experiment:
Serum obtains total antibody through Protein G purification column purifying.Gained antibody carries out doubling dilution with PBS, respectively gets 50ul and isopyknic LV-CoVpps suspension (viral level is 200 TCID50) and mixes, and 37 degree are hatched after 1h and are incorporated in the Huh7 Tissue Culture Plate of cultivating in 96 holes and infect.
37 ℃ of 5%CO
2hatch after 48 hours, by infected lysis and carry out uciferase activity analysis.Each sample standard deviation does 3 holes and carries out repetition, avoids error.
The following method of calculation of the active employing of neutralization of 4.3 serum obtain:
Negative control sera and LV-CoVpps are hatched to obtained relative fluorescence element enzyme value of reading altogether as RLU1,
Using immune serum and LV-CoVpps, hatch altogether the relative fluorescence element enzyme value of reading being obtained as RLU2,
The neutralization ratio of each serum (Neutralisation Rate) NR=(RLU1-RLU2)/RLU1
By SP2, in SP3 and the NP1 control peptide immunity serum that obtains, compare (Fig. 4) with data, the neutralization activity of known SP3 immune serum is obviously better than SP2 immune serum.
By SP3 immune serum and the neutralising capacity comparison (Fig. 5) to MERS-CoV and SARS-CoV respectively of RBD protein immunization serum, known SP3 serum is the same with RBD serum has a neutralization activity special to MERS-CoV, just neutralising capacity compared with RBD serum a little less than.
Reference
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[2]CORMAN?V?M，ECKERLE?I，BLEICKER?T，?et?al.Detection?of?a?novel?human?coronavirus?by?real-time?reverse-transcription?polymerase?chain?reaction[J].Euro?Surveill，2012，17(39)：
[3]MERS?Frequently?Asked?Questions?and?Answers[M].Centers?for?Disease?Control?and?Prevention(CDC).2013.
[4]LU?G，HU?Y，WANG?Q，et?al.?Molecular?basis?of?binding?between?novel?human?coronavirus?MERS-CoV?and?its?receptor?CD26[J].Nature，2013，500(7461)：227-31.
[5]MOU?H，RAJ?V?S，VAN?KUPPEVELD?F?J，et?al.The?receptor?binding?domain?of?the?new?Middle?East?respiratory?syndrome?coronavirus?maps?to?a231-residue?region?in?the?spike?protein?that?efficiently?elicits?neutralizing?antibodies[J].J?Virol,2013，87(16)：9379-83.
[6]WANG?N，SHI?X，JIANG?L，et?al.Structure?of?MERS-CoV?spike?receptor-binding?domain?complexed?with?human?receptor?DPP4[J].Cell?Res，2013，23(8)：986-93.
[7]DU?L，ZHAO?G，KOU?Z，et?al.Identification?of?a?receptor-binding?domain?in?the?s?protein?of?the?novel?human?coronavirus?middle?East?respiratory?syndrome?coronavirus?as?an?essential?target?for?vaccine?development[J].J?Virol，2013，87(17)：9939-42.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105169384A (en) * | 2015-07-22 | 2015-12-23 | 中国疾病预防控制中心病毒病预防控制所 | Recombinant NTD protein subunit vaccine for resisting MERS-CoV infection |
| KR101593641B1 (en) * | 2014-11-17 | 2016-02-12 | 주식회사 바이오노트 | Antibody recognizing nucleocapsid of Middle East respiratory syndrome coronavirus and use thereof |
| CN105543248A (en) * | 2015-03-13 | 2016-05-04 | 中国疾病预防控制中心病毒病预防控制所 | MERS-CoV spike protein coding gene optimization-based recombinant 5-type adenovirus vector vaccine |
| CN105859882A (en) * | 2016-04-13 | 2016-08-17 | 中国医学科学院病原生物学研究所 | Human-derived anti-MERS virus neutralizing antibody A1, and preparation method and application thereof |
| CN106397549A (en) * | 2016-10-11 | 2017-02-15 | 中国疾病预防控制中心病毒病预防控制所 | MERS-CoV specific polypeptides and application thereof |
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| CN111848751A (en) * | 2020-06-18 | 2020-10-30 | 河南省生物工程技术研究中心 | Dominant epitope antigen of new coronavirus S protein and application thereof |
| WO2021203397A1 (en) * | 2020-04-10 | 2021-10-14 | Tsb Therapeutics (Beijing) Co. Ltd. | Anti-sars-cov-2 antibodies and uses thereof |
| CN114057853A (en) * | 2020-08-07 | 2022-02-18 | 清华大学 | A kind of polypeptide, immunogenic conjugate and use for preventing novel coronavirus pneumonia COVID-19 |
| CN114057842A (en) * | 2020-08-07 | 2022-02-18 | 清华大学 | Polypeptide for preventing novel coronavirus pneumonia COVID-19, immunogenic conjugate and application thereof |
| CN114057847A (en) * | 2020-08-07 | 2022-02-18 | 清华大学 | A kind of polypeptide, immunogenic conjugate and use for preventing novel coronavirus pneumonia COVID-19 |
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Application publication date: 20140416 |