WO2002032453A1 - Vaccin de synthese pour la lutte contre le virus de la peste porcine classique et son procede de preparation - Google Patents
Vaccin de synthese pour la lutte contre le virus de la peste porcine classique et son procede de preparation Download PDFInfo
- Publication number
- WO2002032453A1 WO2002032453A1 PCT/CN2001/001188 CN0101188W WO0232453A1 WO 2002032453 A1 WO2002032453 A1 WO 2002032453A1 CN 0101188 W CN0101188 W CN 0101188W WO 0232453 A1 WO0232453 A1 WO 0232453A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- swine fever
- synthetic peptide
- epitope
- vaccine
- polypeptide
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 6
- 229960005004 cholera vaccine Drugs 0.000 title abstract 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 43
- 229920001184 polypeptide Polymers 0.000 claims abstract description 35
- 241000282898 Sus scrofa Species 0.000 claims abstract description 29
- 206010037660 Pyrexia Diseases 0.000 claims abstract description 28
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 18
- 102000014914 Carrier Proteins Human genes 0.000 claims abstract description 11
- 108010078791 Carrier Proteins Proteins 0.000 claims abstract description 11
- 101710091045 Envelope protein Proteins 0.000 claims abstract description 11
- 101710188315 Protein X Proteins 0.000 claims abstract description 11
- 239000002671 adjuvant Substances 0.000 claims abstract description 10
- 230000000890 antigenic effect Effects 0.000 claims abstract description 8
- 230000008878 coupling Effects 0.000 claims abstract description 5
- 238000010168 coupling process Methods 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 4
- 102100021696 Syncytin-1 Human genes 0.000 claims abstract 7
- 229960005486 vaccine Drugs 0.000 claims description 49
- 241000710777 Classical swine fever virus Species 0.000 claims description 39
- 102000036639 antigens Human genes 0.000 claims description 4
- 108091007433 antigens Proteins 0.000 claims description 4
- 208000001726 Classical Swine Fever Diseases 0.000 claims description 3
- 206010035148 Plague Diseases 0.000 claims description 3
- 241000607479 Yersinia pestis Species 0.000 claims description 3
- 239000000427 antigen Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 230000002238 attenuated effect Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000035772 mutation Effects 0.000 description 6
- 241000282887 Suidae Species 0.000 description 5
- 102100034349 Integrase Human genes 0.000 description 4
- 101710125507 Integrase/recombinase Proteins 0.000 description 4
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 229940031567 attenuated vaccine Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 101900173079 Classical swine fever virus Envelope glycoprotein E2 Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 229940031626 subunit vaccine Drugs 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 1
- 101000609762 Gallus gallus Ovalbumin Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 101710132593 Protein E2 Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002019 anti-mutation Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000010485 coping Effects 0.000 description 1
- LXWYCLOUQZZDBD-LIYNQYRNSA-N csfv Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LXWYCLOUQZZDBD-LIYNQYRNSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940031551 inactivated vaccine Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940124590 live attenuated vaccine Drugs 0.000 description 1
- 229940023012 live-attenuated vaccine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- -1 m-maleimidobenzoyl-hydroxy succinimide ester Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/187—Hog cholera virus
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
-
- 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
- C12N2770/24011—Flaviviridae
- C12N2770/24311—Pestivirus, e.g. bovine viral diarrhea virus
- C12N2770/24322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- 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
- C12N2770/24011—Flaviviridae
- C12N2770/24311—Pestivirus, e.g. bovine viral diarrhea virus
- C12N2770/24334—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- the present invention relates to a vaccine prepared by bioengineering technology and a preparation method thereof, and particularly to a swine fever virus vaccine and a preparation method thereof.
- Swine fever is a malignant infectious disease caused by classical swine fever virus ( ⁇ Classical Swine fever virus, CSFV or Hog Cholera virus, HCV). Once an outbreak, it often causes huge economic losses within a short period of time.
- CSFV Classical Swine fever virus
- HCV Hog Cholera virus
- the swine fever virus subunit vaccine is a swine fever vaccine currently being developed at home and abroad.
- the vaccine uses genetically-recombined viral envelope proteins to induce immune protection.
- this vaccine can cope with the mutation of classical swine fever virus to a certain extent, the vaccine contains only one genetic information of the virus. When the virus mutates, the vaccine will lose its effectiveness, and the production cost of the vaccine is still relatively low.
- the antigenic region sequence of envelope protein E2 of swine fever virus (amino acid residues 690-866) has been shown to induce immune protection, that is, to protect swine fever virus from infection (Vaccine 2000, 18: 2351; Vaccine 1999, 17: 433; J. Virology 1995, 69: 6479; Vaccine 2000, 18: 1374; J. Virology 1993, 67: 5435).
- the object of the present invention is to provide a synthetic peptide classical swine fever virus vaccine capable of coping with mutations of classical swine fever virus.
- Another object of the present invention is to provide a method for producing the above-mentioned synthetic peptide swine fever virus vaccine.
- a synthetic peptide swine fever vaccine comprising at least one of the swine fever virus envelope protein E2 coupled to an IJ carrier protein or carrier polypeptide to form a conjugate.
- the neutralizing epitope or variant epitope on the swine fever virus envelope protein E2 is located in the antigenic region on the swine fever virus envelope protein E2.
- the antigenic region is amino acids 690-866 on the swine fever virus-coated phosphin protein E2. Acid residues.
- neutralizing epitope and variant epitope polypeptides can be selected from the following 14 polypeptide sequences and their variant sequences:
- the above 14 polypeptides and their conjugates formed by the mutated sequence polypeptide and the carrier can be added to the vaccine.
- the vaccine should also include acceptable pharmaceutical adjuvants.
- a method for preparing the above-mentioned synthetic peptide swine fever vaccine basically includes the following steps:
- Example 1 Preparation of polyclonal swine fever polypeptide (synthetic peptide) based on classical protein of swine fever virus E2 1. Synthesize 11 synthetic peptides (polypeptides) that contain one of the neutralizing epitopes of the antigen region of the classical swine fever virus E2 protein (amino acid residues at positions 690-866). The sequences of these 11 peptides partially overlap each other. 11 The sequence of each polypeptide is:
- MBS nrmaleimidobenzoyl-N-hydroxy succinimide ester
- One or more of the above 11 conjugates are respectively formulated with an adjuvant (such as oil adjuvant, etc.) and mixed to prepare a multiple swine fever vaccine.
- an adjuvant such as oil adjuvant, etc.
- the fraction ratio of various conjugates can be adjusted according to the probability of variation of each point obtained by statistical processing in different years.
- Example 2 Preparation of anti-variation-multiple-one swine fever polypeptide based on E2 protein of classical swine fever virus
- MBS nrmaleimidobenzoyl- N-hydroxy succinimide ester
- the above 3 conjugates were formulated with Shan adjuvant to prepare a multiple swine fever polypeptide vaccine. Its In the three conjugates, the proportions of the conjugates can be adjusted according to the variation probability of each point obtained by statistical processing in different years.
- a synthetic peptide containing the neutralizing epitope of the antigenic region of the classical swine fever virus E2 protein the sequence is:
- the above conjugate is formulated with an oil adjuvant to prepare a swine fever polypeptide vaccine.
- MBS m-maleimidobenzoyl-hydroxy succinimide ester
- the present invention utilizes the neutralizing epitope on envelope protein E2 of classical swine fever virus to induce pigs to produce stronger, longer-lasting immune protection characteristics.
- a multiple vaccine is used to produce pigs.
- a variety of antibodies to classical swine fever virus that is, when one or several epitopes of classical swine fever virus are mutated, the vaccine-injected pigs are still sufficient to deal with the mutant classical swine fever virus corresponding to other unmutated epitopes Antibodies.
- the vaccine of the present invention has the following advantages: 1.
- the vaccine is a highly efficient multiple vaccine that can stimulate the production of a variety of neutralizing antibodies, which can effectively deal with the mutation of the virus, thereby overcoming the shortcomings of the existing swine fever vaccines, which are poor or even ineffective. .
- the active ingredient of the vaccine is an epitope polypeptide comprising a neutralizing epitope or a variant epitope on envelope protein E2 of swine fever virus coupled to a carrier protein or carrier polypeptide to form a conjugate.
- epitope polypeptides Does not require attenuated or inactivated pathogens or natural proteins of pathogens, nor does it require genetically engineered protein antigens and pathogen nucleic acids, which can directly induce a predetermined, multiple neutralizing epitope and variant epitope-specific immune response, No genetic material and activity of classical swine fever virus, no side effects induced by genetic material of classical swine fever virus, no danger of reactivation of inactivated or attenuated vaccines, and the use of attenuated classical swine fever vaccine (such as Swine fever rabbit attenuated attenuated vaccine) infection and replication of live swine fever attenuated live virus induced in breeding pigs, sows and pigs, thereby overcoming the potential, current Unknown hazard.
- attenuated classical swine fever vaccine such as Swine fever rabbit attenuated attenuated vaccine
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002223384A AU2002223384A1 (en) | 2000-08-10 | 2001-07-20 | Synthetic peptide hog cholera vaccine and method producing it |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN00121291A CN1338309A (zh) | 2000-08-10 | 2000-08-10 | 一种合成肽猪瘟疫苗及其制备方法 |
CN00121291.5 | 2000-08-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002032453A1 true WO2002032453A1 (fr) | 2002-04-25 |
Family
ID=4588704
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2001/001188 WO2002032453A1 (fr) | 2000-08-10 | 2001-07-20 | Vaccin de synthese pour la lutte contre le virus de la peste porcine classique et son procede de preparation |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN1338309A (fr) |
AU (1) | AU2002223384A1 (fr) |
WO (1) | WO2002032453A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007098717A2 (fr) | 2006-02-28 | 2007-09-07 | Centro De Ingeniería Genética Y Biotecnología | Antigènes vaccinaux chimères utilisés contre le virus de la peste porcine classique |
CN110652583A (zh) * | 2018-06-29 | 2020-01-07 | 西北民族大学 | 猪口蹄疫二价灭活抗原与猪瘟弱毒株二联苗 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101144818B (zh) * | 2007-10-19 | 2011-04-27 | 清华大学 | 检测猪瘟病毒特异性抗体的方法及其酶联免疫试剂盒 |
CN101152570B (zh) * | 2007-10-19 | 2010-11-24 | 清华大学 | 一种猪瘟病毒表位疫苗及其制备方法 |
CN103880932B (zh) * | 2009-10-09 | 2015-09-23 | 中牧实业股份有限公司 | 猪瘟合成肽疫苗及其制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0236977A2 (fr) * | 1986-03-07 | 1987-09-16 | Biotechnology Research Partners, Ltd. | Vaccins contre la diarrhée bovine virale et le choléra porcin |
EP0389034A1 (fr) * | 1989-03-19 | 1990-09-26 | Akzo Nobel N.V. | Vaccin et test de diagnostic pour le virus du choléra porcin |
WO1995035380A1 (fr) * | 1994-06-17 | 1995-12-28 | Instituut Voor Dierhouderij En Diergezondheid | Sequences nucleotidiques de souches de pestivirus, polypeptides codes par ces sequences, et leur application au diagnostic et a la prevention des infections par pestivirus |
WO1996019498A2 (fr) * | 1994-12-20 | 1996-06-27 | Akzo Nobel N.V. | Proteine de virus de la peste stimulant les cellules t |
EP0982402A1 (fr) * | 1998-08-14 | 2000-03-01 | Stichting Instituut voor Dierhouderij en Diergezondheid (ID-DLO) | Vaccination contre les Pestivirus |
-
2000
- 2000-08-10 CN CN00121291A patent/CN1338309A/zh active Pending
-
2001
- 2001-07-20 WO PCT/CN2001/001188 patent/WO2002032453A1/fr active Application Filing
- 2001-07-20 AU AU2002223384A patent/AU2002223384A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0236977A2 (fr) * | 1986-03-07 | 1987-09-16 | Biotechnology Research Partners, Ltd. | Vaccins contre la diarrhée bovine virale et le choléra porcin |
EP0389034A1 (fr) * | 1989-03-19 | 1990-09-26 | Akzo Nobel N.V. | Vaccin et test de diagnostic pour le virus du choléra porcin |
WO1995035380A1 (fr) * | 1994-06-17 | 1995-12-28 | Instituut Voor Dierhouderij En Diergezondheid | Sequences nucleotidiques de souches de pestivirus, polypeptides codes par ces sequences, et leur application au diagnostic et a la prevention des infections par pestivirus |
WO1996019498A2 (fr) * | 1994-12-20 | 1996-06-27 | Akzo Nobel N.V. | Proteine de virus de la peste stimulant les cellules t |
EP0982402A1 (fr) * | 1998-08-14 | 2000-03-01 | Stichting Instituut voor Dierhouderij en Diergezondheid (ID-DLO) | Vaccination contre les Pestivirus |
Non-Patent Citations (2)
Title |
---|
MOORMANN R.J. ET AL., VIROLOGY, vol. 177, no. 1, July 1990 (1990-07-01), pages 184 - 198 * |
VAN RIJN P.A. ET AL., VIROLOGY, vol. 237, no. 2, 27 October 1997 (1997-10-27), pages 337 - 348 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007098717A2 (fr) | 2006-02-28 | 2007-09-07 | Centro De Ingeniería Genética Y Biotecnología | Antigènes vaccinaux chimères utilisés contre le virus de la peste porcine classique |
CN110652583A (zh) * | 2018-06-29 | 2020-01-07 | 西北民族大学 | 猪口蹄疫二价灭活抗原与猪瘟弱毒株二联苗 |
Also Published As
Publication number | Publication date |
---|---|
CN1338309A (zh) | 2002-03-06 |
AU2002223384A1 (en) | 2002-04-29 |
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