WO2009111849A1 - Procédé pour la production de vaccin stabilisé - Google Patents
Procédé pour la production de vaccin stabilisé Download PDFInfo
- Publication number
- WO2009111849A1 WO2009111849A1 PCT/BR2009/000058 BR2009000058W WO2009111849A1 WO 2009111849 A1 WO2009111849 A1 WO 2009111849A1 BR 2009000058 W BR2009000058 W BR 2009000058W WO 2009111849 A1 WO2009111849 A1 WO 2009111849A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- poliovirus
- hydrostatic pressure
- virus
- vaccine
- mpa
- Prior art date
Links
- 229960005486 vaccine Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims description 15
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000009931 pascalization Methods 0.000 claims abstract description 19
- 241000991587 Enterovirus C Species 0.000 claims description 43
- 230000002706 hydrostatic effect Effects 0.000 claims description 10
- 241000709664 Picornaviridae Species 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 229940124867 Poliovirus vaccine Drugs 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 208000000474 Poliomyelitis Diseases 0.000 abstract description 10
- 230000009471 action Effects 0.000 abstract description 5
- 230000006641 stabilisation Effects 0.000 abstract description 5
- 238000011105 stabilization Methods 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 2
- 229940126578 oral vaccine Drugs 0.000 abstract description 2
- 241000700605 Viruses Species 0.000 description 42
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 24
- 229910001629 magnesium chloride Inorganic materials 0.000 description 12
- 230000002238 attenuated effect Effects 0.000 description 11
- 239000003381 stabilizer Substances 0.000 description 10
- 208000015181 infectious disease Diseases 0.000 description 9
- 230000002779 inactivation Effects 0.000 description 8
- 210000003501 vero cell Anatomy 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 7
- 229930064664 L-arginine Natural products 0.000 description 7
- 235000014852 L-arginine Nutrition 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000009467 reduction Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 241000709661 Enterovirus Species 0.000 description 4
- 241000274177 Juniperus sabina Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 235000014676 Phragmites communis Nutrition 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 210000000234 capsid Anatomy 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000002277 temperature effect Effects 0.000 description 2
- KCHIOGFOPPOUJC-UHFFFAOYSA-N (methylpyridazine piperidine ethyloxyphenyl)ethylacetate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCC1CCN(C=2N=NC(C)=CC=2)CC1 KCHIOGFOPPOUJC-UHFFFAOYSA-N 0.000 description 1
- 208000006740 Aseptic Meningitis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010027201 Meningitis aseptic Diseases 0.000 description 1
- 208000033952 Paralysis flaccid Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000713311 Simian immunodeficiency virus Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000028331 flaccid paralysis Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940031551 inactivated vaccine Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940127241 oral polio vaccine Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229950011136 pirodavir Drugs 0.000 description 1
- 229960001539 poliomyelitis vaccine Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32051—Methods of production or purification of viral material
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32611—Poliovirus
- C12N2770/32651—Methods of production or purification of viral material
Definitions
- the present invention relates to vaccines field, more particularly, to stabilization of three Polio vaccine strains, present in oral vaccine against Poliomyelitis (OPV).
- Poliomyelitis is an acute infection that may manifest as a non- apparent infection, aseptic meningitis or a classic case of flaccid paralysis.
- the transmission can occur from person to person through fecal-oral and oral-oral interaction. It is caused by a virus that belongs to genus Enterovirus, family Picornaviridae, which has three serotypes: serotype 1 , serotype 2 and serotype 3.
- the OPV is considered the single vaccine which is able to make the global eradication of Polio, being recommended for countries with low indexes of coverage and heterogeneous vaccination.
- WHO World Health Organization
- the OPV containing the Sabin strains is a vaccine unstable to heat, therefore, must be stored frozen (-20 ° C) and used immediately after thawing, to ensure effective immunization against polio.
- the patent US 5.618.539 describes stabilized viral vaccines, particularly against polio, comprising an aqueous solution of live virus and a stabilizing compound, which has at least two amino or imino groups, such as basic amino acids (eg lysine, arginine etc.).
- a stabilizing compound which has at least two amino or imino groups, such as basic amino acids (eg lysine, arginine etc.).
- MgCI 2 magnesium chloride
- Viruses are a structurally diverse group of microorganisms, which differ widely in their sensitivities to action of high hydrostatic pressure. Studies on picornavirus showed great resistance of this virus to treatment with high hydrostatic pressure. Poliovirus seems to be one of the toughest viruses among all picornaviruses already characterized. High hydrostatic pressure studies on poliovirus are targeted, mostly, for viral inactivation and production of inactivated vaccine (JL Silva, P. Luan, M. Glaser, EW Voss and G. Weber.
- Treatments to maintain the virus thermal stability, especially poliovirus, are still being made through the use of chemical compounds and biological agents such as magnesium chloride and arginine.
- the objectives of this invention are: to provide an acquisition of thermal stability for OPV, containing Sabin strains for effective immunization against this infection, and provide the use of a methodology that is extremely safe, clean and economic (characterized by hydrostatic pressure use to obtain thermal stability of three vaccine strains in Sabin vaccine).
- Figures 1A, 1B and 1C show respectively, a comparison of serotypes 1 ,
- Figures 2A, 2B and 2C show respectively, high temperature effects, about ability of serotypes 1, 2 and 3 infection, of attenuated poliovirus. Circles represent stabilized virus with MgC ⁇ (91 mg/mL) and L-arginine (10 mg/mL), triangles represent virus without stabilizers. All symbols represent average of three independent experiments. Titres from infectivity test were determined by TCID50 in Vero cells.
- Hep2C and Vero cells (African green monkey cells) (CCL 81) were obtained from "American Type Collection” (ATTC). Both were maintained in medium 199 supplemented with Earle salts (Gibco) with fetal bovine serum
- the attenuated viruses poliovirus serotype 1
- LSC, 2ab poliovirus serotype 2 (P712 CH ab) and poliovirus serotype 3 (Leon 12 a 1b), used in this invention, are from vaccine Glaxo Smithkline (GSK), containing the following identification: poliovirus serotype 1-SB 1003A; poliovirus serotype 2 SB-238B, and poliovirus serotype 3-SB 359A.
- GSK vaccine Glaxo Smithkline
- Virus titre (TCID 50 /mL) was calculated using the method described by Reed and Muench (LJ. Reed and HA Muench. A simple Method of Estimating Fifty Percent End Points. American Journal Hygiene. 1938; 493-497), which allows an analysis of virus biological characteristics from cell culture and under different temperature and pressurization time conditions.
- poliovirus serotypes were cultivated in Vero cells. Confluent cell monolayers were inoculated at different Multiplicities of Infection (MOI) in growing medium 199. Then the virus was adsorbed for 1 hour at 37 0 C and monolayers were fed with 100 ml_ of maintenance medium. To obtain the virus that were used in the study with hydrostatic pressure, i.e. poliovirus serotypes (1 , 2 and 3), they were cultivated in Vero cells in a MOI of 0,01 for the poliovirus serotype 1 and serotype 2, 0,001 to poliovirus serotype 3. Each experiment was performed three times to ensure results reproducibility and standard deviation was calculated for each condition tested, as described in the state of the art for other viruses (T.
- MOI Multiplicities of Infection
- virus showed mild reduction of viral titre and total loss only to 52 0 C. This behavior was expected in light of current knowledge about thermostability of these three viruses: it is known that the
- MgCI 2 increases poliovirus capsid conformation rigidity and decreases extent of water penetration in the capsid.
- virus serotypes 1 , 2 and 3 samples were subjected to 310 MPa hydrostatic pressure for different time intervals (8, 17 and 65 hours) and in different temperatures (-10, 4, 25, 37 0 C). Hydrostatic pressure was unable to induce a detectable reduction in infectivity of three polioviruses, even after 65 hours at 37 0 C or -10 0 C. Table 1 shows these results.
- Results show that stability in relation to pressurization of each of the three poliovirus strains is similar in all conditions tested, including pressurization at 310 MPa for 8 to 65 hours and incubation at 37 0 C or -10 0 C (Table 1).
- virus stability investigation at 310 MPa for 65 hours at 37 0 C showed that pressurized particles resisted at temperature of 37 0 C for 65 hours in absence and presence of stabilizers (MgCb and L-arginine) (Table 2). This stability occurred with three polioviruses strains as observed by virus titre in cell culture evaluated by TCIDs 0 .
- High hydrostatic pressure is a technology that is extremely safe, clean and economical. Furthermore, a commercial vaccine stabilized by high hydrostatic pressure action would avoid the need of electrical energy for material storage.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention concerne le domaine des vaccins, plus particulièrement, la stabilisation des trois souches de vaccin de la poliomyélite, présentes dans un vaccin oral contre la poliomyélite (OPV). Une pression hydrostatique élevée est une technologie qui est extrêmement sûre, propre et économique. De plus, un vaccin commercial stabilisé par une haute pression hydrostatique évite la nécessité d’énergie électrique pour le stockage des matières.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BRPI0800357-2A BRPI0800357A2 (pt) | 2008-03-10 | 2008-03-10 | método para produção de uma vacina estabilizada |
| BRPI0800357-2 | 2008-03-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009111849A1 true WO2009111849A1 (fr) | 2009-09-17 |
Family
ID=41064685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BR2009/000058 WO2009111849A1 (fr) | 2008-03-10 | 2009-03-10 | Procédé pour la production de vaccin stabilisé |
Country Status (2)
| Country | Link |
|---|---|
| BR (1) | BRPI0800357A2 (fr) |
| WO (1) | WO2009111849A1 (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9169302B2 (en) | 2012-08-30 | 2015-10-27 | Merial, Inc. | Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins |
| US9283270B2 (en) | 2012-01-20 | 2016-03-15 | Serum Institute Of India Ltd. | Method for stabilization of biological molecules |
| US10080791B2 (en) | 2012-08-30 | 2018-09-25 | Merial Inc. | Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5618539A (en) * | 1989-08-15 | 1997-04-08 | Massachusetts Institute Of Technology | Stabilized vaccine compositions |
| WO1997033612A1 (fr) * | 1996-03-15 | 1997-09-18 | Immunotherapy, Inc. | Dialdehydes servant d'adjuvants immunostimulants et de reticulants pour la production de preparations immunogenes, pour la generation de cellules soumises a pression et reticulation afin de renforcer et d'augmenter la reponse immunitaire contre le cancer, les tumeurs et les affections pathogenes |
| CN1247090A (zh) * | 1998-09-04 | 2000-03-15 | 中国科学院上海生物化学研究所 | 鸡传染性法氏囊病病毒疫苗、制备方法及其应用 |
| WO2000048641A1 (fr) * | 1998-06-15 | 2000-08-24 | Bbi Bioseq, Inc. | Sterilisation cryogenique rapide et preparation de vaccin |
| WO2004042001A2 (fr) * | 2002-05-17 | 2004-05-21 | Emory University | Particules pseudovirales, procede de fabrication et compositions immunogeniques |
-
2008
- 2008-03-10 BR BRPI0800357-2A patent/BRPI0800357A2/pt not_active Application Discontinuation
-
2009
- 2009-03-10 WO PCT/BR2009/000058 patent/WO2009111849A1/fr active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5618539A (en) * | 1989-08-15 | 1997-04-08 | Massachusetts Institute Of Technology | Stabilized vaccine compositions |
| WO1997033612A1 (fr) * | 1996-03-15 | 1997-09-18 | Immunotherapy, Inc. | Dialdehydes servant d'adjuvants immunostimulants et de reticulants pour la production de preparations immunogenes, pour la generation de cellules soumises a pression et reticulation afin de renforcer et d'augmenter la reponse immunitaire contre le cancer, les tumeurs et les affections pathogenes |
| WO2000048641A1 (fr) * | 1998-06-15 | 2000-08-24 | Bbi Bioseq, Inc. | Sterilisation cryogenique rapide et preparation de vaccin |
| CN1247090A (zh) * | 1998-09-04 | 2000-03-15 | 中国科学院上海生物化学研究所 | 鸡传染性法氏囊病病毒疫苗、制备方法及其应用 |
| WO2004042001A2 (fr) * | 2002-05-17 | 2004-05-21 | Emory University | Particules pseudovirales, procede de fabrication et compositions immunogeniques |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE WPI Derwent World Patents Index; AN 2000-476846 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9283270B2 (en) | 2012-01-20 | 2016-03-15 | Serum Institute Of India Ltd. | Method for stabilization of biological molecules |
| US9169302B2 (en) | 2012-08-30 | 2015-10-27 | Merial, Inc. | Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins |
| US10080791B2 (en) | 2012-08-30 | 2018-09-25 | Merial Inc. | Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0800357A2 (pt) | 2009-10-27 |
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