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WO1991003255A1 - Vaccins polypeptidiques contre le virus de la fievre aphteuse - Google Patents

Vaccins polypeptidiques contre le virus de la fievre aphteuse Download PDF

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Publication number
WO1991003255A1
WO1991003255A1 PCT/GB1990/001329 GB9001329W WO9103255A1 WO 1991003255 A1 WO1991003255 A1 WO 1991003255A1 GB 9001329 W GB9001329 W GB 9001329W WO 9103255 A1 WO9103255 A1 WO 9103255A1
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WIPO (PCT)
Prior art keywords
polypeptide
amino acid
sequence
acid residues
protein
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Application number
PCT/GB1990/001329
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English (en)
Inventor
Nigel Richard Parry
Elizabeth Jane Ouldridge
David John Rowlands
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The Wellcome Foundation Limited
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Publication date
Application filed by The Wellcome Foundation Limited filed Critical The Wellcome Foundation Limited
Publication of WO1991003255A1 publication Critical patent/WO1991003255A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • 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
    • C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32122—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
    • C12N2770/32011—Picornaviridae
    • C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to peptides suitable for use as vaccines against foot-and-mouth disease.
  • Foot-and-mouth disease is the most important parameter to Foot-and-mouth disease.
  • a polypeptide suitable for use as a vaccine against foot-and-mouth disease virus (FMDV) serotypes O and A which polypeptide presents an epitope comprising the amino acid sequence from residue 142 to residue 158 of the VP1 capsid protein of FMDV O 1 Kaufbeuren, or the corresponding sequence of another FMDV strain of serotype 0, with the proviso that the amino acid residue 148 is serine; the said polypeptide being
  • a chimaeric protein comprising the sequence of a carrier protein and a foreign sequence of not more than 50 amino acid residues which comprises the sequence of a said epitope.
  • the polypeptides of the invention comprise a defined antigenically effective sequence. This sequence is composed of VP1 residues 142 to 158 of FMDV O 1 Kaufbeuren (Kurz et al. Nuc. Acids Res. 9, 1919-1931, 1981) or the corresponding residues of another strain of FMDV serotype O. However, the residue at VP1 position 148 is serine rather than the natural leucine. In this way, the polypeptides can raise neutralising antibody not only against FMDV serotype O but also against FMDV serotype A.
  • the epitope of interest comprises residues PNLRGDSQVLAQKVART. Amino acid residues are shown using the one letter code (Eur. J.
  • a first type of polypeptide according to the invention is composed of up to 50 amino acid residues, for example up to 40 or up to 30 or up to 20 amino acid
  • amino acids may therefore be added to one or both ends of the epitope.
  • One, two, three, four or five amino acids may therefore be added to one or both ends of the epitope.
  • One, two, three, four or five amino acids may therefore be added to one or both ends of the epitope.
  • flanking sequences for the epitope are therefore the flanking sequences which naturally occur either side of the amino acid sequence for the epitope in the overall sequence of the VP1 protein.
  • a cysteine residue may be provided at the N-terminus or C-terminus. In particular, a cysteine residue may be added to the
  • a preferred polypeptide starts with a VP1 residue numbered from 138 to 142 and ends with a VP1 residue
  • polypeptide may therefore correspond to, for example, VP1 residues 138-162, 138-160, 140-162, 140-160, 141-162 or 141-160.
  • a preferred polypeptide may therefore correspond to, for example, VP1 residues 138-162, 138-160, 140-162, 140-160, 141-162 or 141-160.
  • polypeptide based on FMDV O 1 Kaufbeuren and including a non-natural C-terminal cysteine residue, has the sequence VPNLRGDSQVLAQKVARTLPC.
  • the polypeptide may have a free C-terminal carboxy group. Alternatively, it may be in the form of a C-terminal amide. Pharmaceutically acceptable salts of the polypeptide may be employed.
  • the polypeptide may be coupled to a carrier in order to creature an immunogen which is
  • any appropriate physiologically acceptable carrier may be employed.
  • a conjugate between the polypeptide and the carrier may be formed.
  • the carrier may be for example bovine serum albumin, thyroglobulin,
  • ovalbumin ovalbumin
  • KLH keyhole limpet hemocyanin
  • hepatitis B core antigen ovalbumin
  • a second type of polypeptide according to the invention is a chimaeric protein which presents the defined epitope.
  • the chimaeric protein is typically a carrier protein which has been modified so that its amino acid sequence comprises a foreign sequence of up to 50 amino acids which includes the sequence of the desired epitope. Some amino acids of a protein may be replaced by the foreign amino acid sequence. Alternatively, the foreign amino acid sequence is fused to a protein. An intervening linker of up to 10 amino acids, for example of up to 5 amino acids, may be provided between the epitope and the carrier.
  • the foreign amino acid sequence may vary in length as described for the first type of polypeptide according to the
  • the epitope is exposed on the surface of the chimaeric protein so that it is presented to the immune system.
  • the chimaeric protein may take the form of a particle or form part of a particulate aggregation. Such an aggregation may comprise plurality of chimaeric proteins and/or may be a viral particle.
  • a protein to which a foreign amino acid sequence comprising the epitope may be fused may be a particle-forming protein such as hepatitis B surface antigen (HBsAg, EP-A-0175261) or hepatitis B core antigen (HBcAg, JP-A-63196299).
  • the foreign sequence may be inserted into the sequence of a viral protein exposed on the surface of the virus (GB-A-2125065).
  • the viral protein may be a capsid protein of a virus.
  • the foreign sequence may therefore be provided at one of the antigenic sites of a picornavirus such as
  • poliovirus (EP-A-0302801).
  • the epitope may be presented at one of the antigenic sites, for example site 1, 2 or 3, on a capsid protein of an attenuated strain of type 1 poliovirus, or at an antigenic site of type 2 or 3 poliovirus.
  • Other picornaviruses suitably modified, may be used, e.g. Bovine enterovirus.
  • amino acid sequence of an antigenic site of a picornavirus may be replaced completely or partly by the foreign amino acid sequence.
  • the foreign amino acid sequence is provided in place of some or all of
  • the attenuated strain is typically the Sabin 1 vaccine strain.
  • Antigenic site 1 of a type 1 poliovirus is composed of amino acid residues 91 to 102 of the VP1 capside protein.
  • polypeptides of the invention are synthetic polypeptides. They may be prepared by chemical synthesis, in particular the first type of polypeptide of up to 50 amino acid residues long. Solid-phase or solution methods of peptide synthesis may be employed. A polypeptide can be built up therefore by a process comprising condensing single amino acids and/or preformed peptides or two or more amino acids in the order in which amino acids occur in a
  • polypeptide of the invention may be synthesised so as to possess a free C-terminal carboxy group or a C-terminal amide group. If desired, the polypeptide may be converted into a pharmaceutically acceptable salt.
  • the amino acid sequence of the desired polypeptide is built up sequentially from the C-terminal amino acid which is bound to an insoluble resin.
  • the desired polypeptide is cleaved from the resin.
  • the polypeptide may again be built up from the C-terminal amino acid. The carboxy group of this acid remains blocked throughout by a suitable protecting group, which is removed at the end of the synthesis.
  • each amino acid added to the reaction system typically has a protected ⁇ -amino group and an activated carboxy group.
  • An amino group may be protected by the fluoren-9-ylmethoxycarbonyl (Fmoc) or t-butoxycarbonyl (Boc) group.
  • a carboxy group may be activated as a
  • Side chain functional groups are typically protected too, for example the side chain amino group of a lysine, the side chain hydroxy group of a threonine or the side chain sulphydryl group of a cysteine. After each step in the synthesis, the ⁇ -amino protecting group is removed.
  • any side-chain protecting groups are generally only removed at the end of the synthesis although they may be retained if desired.
  • the polypeptides may be prepared with a C-terminal carboxy or amide group as desired. In solid phase peptide synthesis, this may be determined by how the C-terminal amino acid is linked to the resin support and/or how the final peptide is cleaved from the resin.
  • the resin is a styrene and/or divinylbenzene polymer.
  • C-terminal amino acid may be linked to the resin via an ester linkage which can be cleaved by a strong acid such as HBr in trifluoroacetic acid or HF to give the peptide with a C-terminal carboxy group.
  • Ammonolysis can give the
  • An alternative method of obtaining a polypeptide amide by solid phase synthesis is to arrange for the
  • C-terminal amino acid of the polypeptide to be linked to the resin via a peptide aminobenzhydryl bond This can be formed by coupling with dicyclohexylcarbodiimide and can be cleaved with HF, typically in the cold.
  • HF typically in the cold.
  • C-terminal amino acid is blocked and, at the end of the synthesis, unblocked.
  • a polypeptide with a C-terminal carboxy group can be converted into one with a C-terminal amide group and vice versa.
  • Both types of polypeptide according to the invention may be prepared by recombinant DNA methodologies.
  • a DNA sequence encoding the desired polypeptide is provided.
  • An expression vector is prepared which
  • DNA sequence incorporates the DNA sequence and which is capable of expressing the polypeptide when provided in a suitable host.
  • the DNA sequence is located between translation start and stop signals in the vector.
  • Appropriate transcriptional and translational control elements are also provided, in particular a promoter for the DNA sequence and a
  • the DNA sequence is provided in the correct frame such as to enable expression of the polypeptide to occur in a host compatible with the vector.
  • a DNA fragment encoding the foreign amino acid sequence is inserted into a vector at a location which enables the epitope of interest to be expressed, as part of the chimaeric protein, exposed on the surface of the protein.
  • the chimaeric protein is then expressed.
  • Cells harbouring the vector are cultured so as to enable expression to occur.
  • the protein may self-assemble into particles.
  • the vector may be plasmid.
  • a bacterial or yeast host may be used for example E.coli or S. cerevisiae.
  • the vector may be a viral vector. This may be used to transfect cells of a mammalian cell line, such as CHO cells, in order to cause polypeptide expression.
  • An epitope according to the invention may be linked to one or more helper T-cell (Th-cell) epitopes.
  • Th-cell epitope is a site capable of eliciting help for antibody production.
  • a Th-cell epitope is capable of binding class II major histocompatibility (MHC) molecules on the surface of host antigen-presenting cells and B-cells subsequently interacting with the T-cell receptor in the form of a trimolecular complex in order to induce B-cells to differentiate and proliferate.
  • MHC major histocompatibility
  • Th-cell epitope may be linked to the first type of polypeptide of the invention in a variety of ways.
  • Glutaraldehyde polymerisation may be used, in which the polypeptide of the invention is copolymerised with a
  • polypeptide which presents a Th-cell epitope via their amino groups.
  • polypeptide presenting the Th-cell epitope may be conjugated together via a heterobifunctional cross-linking agent such as m-maleimidobenzoyl-N-hydroxy-succinimide ester (MBS).
  • a heterobifunctional cross-linking agent such as m-maleimidobenzoyl-N-hydroxy-succinimide ester (MBS).
  • the polypeptide of the invention may alternatively by linked at its C-terminus or N-terminus to a polypeptide presenting a Th-cell epitope via a peptide bond. This may be achieved by co-linear synthesis of the polypeptide of the invention and the polypeptide presenting the Th-cell epitope or by use of recombinant DNA technology as above to express a fusion protein in which the two polypeptides are fused together. In any of the methods, any suitable Th-cell epitope may be used.
  • a preferred polypeptide presenting Th-cell epitopes is hepatitis B core antigen (HBcAg).
  • a first type of polypeptide of the invention may be chemically coupled to HBcAg.
  • Recombinant DNA technology can be used to produce a fusion protein according to the second type of polypeptide of the invention, comprising HBcAg to the amino terminus of which is linked the sequence of a polypeptide of the
  • the epitope of interest may be fused directly to the amino terminus of HBcAg.
  • the sequence may be fused to the HBcAg via an intervening linker.
  • a linker may be composed of one or more, for example up to ten, amino acid residues.
  • polypeptides of the invention are useful as vaccines against FMD, in particular FMDV serotypes O and A.
  • An effective amount of the polypeptide is administered to a host animal such as a cow or pig.
  • the polypeptide may be administered orally or parenterally, for example
  • a polypeptide is administered orally or parenterally in an amount of 50 to 1000 ⁇ g per dose, more preferably from 50 to 250 ⁇ g per dose.
  • a single dose may be given or several of doses may be administered over a period of time .
  • polypeptide of the invention is typically formulated with a veterinarily acceptable carrier or diluent.
  • a veterinarily acceptable carrier or diluent Conventional formulations, carrier, adjuvants and diluents may be
  • Aluminium hydroxide or any other acceptable adjuvant may be used.
  • a polypeptide could be linked to an immunostimulating complex (iscom: Morein et al, Nature 308, 457-460, 1984) or incorporated into liposomes.
  • peptide 148 L : VPNLRGDLQVLAQKVARTLPC
  • peptide 148 R : VPNLRGDRQVLAQKVARTLPC
  • peptide 148 S : VPNLRGDSQVLAQKVARTLPC
  • peptide 148 T : VPNLRGDTQVLAQKVARTLPC
  • peptide 148 I : VPNLRGDIQVLAQKVARTLPC
  • Peptide 148 L is the natural sequence without any substitution at position 148.
  • Peptide 148 S is a peptide according to the invention. Each peptide was synthesised on a p-methylbenzhydrylamine divinylbenzene resin. The ⁇ -amino
  • the O 1 BFS 1860 and C 3 Indaial viruses used in this study are FMDV vaccine strains from Coopers Animal Health Ltd, Pirbright, Surrey.
  • the low and high passage O 1 Kaufbeuren strains are the 7th and 64th passage isolates described by Strohmaier et al. (J. gen. Virol. 59, 295-306), 1982).
  • the B and C variants of A 12 119 virus are those identified by Rowlands et al. (Nature, London 306, 694-697, 1983). 0 Colombia 9834 virus was obtained from the VECOL Laboratories, Colombia.
  • the remaining type O viruses are primary field isolates obtained from the FMDV World Reference Laboratory, Institute for Animal Health,
  • Antibody preparations Antisera were raised in Dunkin-Hartley guinea-pigs. Anti-virus serum was obtained by two inoculations 28 days apart of 20 ⁇ g of
  • acetylethyleneimine-inactivated virus particles purified by the method of Brown & Cartwright (Nature, London 199. 1168-1170, 1963). Antisera were raised to two inoculations of 500 ⁇ g of peptide 35 days apart, blood being collected 28 days after the second inoculation. All antigens were emulsified with an equal volume of incomplete Freund's adjuvant just prior to intramuscular injection. Equal volume pools of five guinea-pig antisera to each antigen were used for specificity testing.
  • Neutralization assay This was performed as a two-dimensional micro-cpe test using BHK21 cells as the indicator of residual virus infectivity as described by Rweyemamu et al. (J. Hygiene, Cambridge 81, 107-123, 1978).
  • Antibody titres are expressed as log 10 of the reciprocal serum dilution giving 50% neutralization of 100 tissue culture infective doses of virus (log 10 SN 50 /100 TC1D 50 ).
  • the antigencic relationship of viruses based on their neutralization by each serum is given by the ratio:
  • anti-peptide antisera showed some neutralization of A 12 119C virus. Antiserum to the L - R peptide also did not
  • guinea-pigs were also challenged with each virus. All eight of the non-immune animals developed lesions, whereas only one guinea-pig, that with the lowest serum titre, from each of the immunized groups developed lesions (Table 3).

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  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

Un polypeptide adapté pour être utilisé en tant que vaccin contre le sérotype O ou A du virus de la fièvre aphteuse (FMDV), présente un épitope comprenant la séquence d'acides aminés allant du résidu 142 au résidu 158 de la protéine de la capside VP1 de O1Kaufbeuren de virus de la fièvre aphteuse, ou la séquence correspondante d'une autre souche de sérotype O du virus de la fièvre aphteuse, à condition que le résidu 148 d'acides aminés soit la sérine; ledit polypeptide étant (i) d'une longueur ne dépassant pas celle de 50 résidus d'acides aminés, ou (ii) une protéine chimérique comprenant la séquence d'une protéine porteuse et d'une séquence étrangère ne dépassant pas 50 résidus d'acides aminés, laquelle comporte la séquence dudit épitope.
PCT/GB1990/001329 1989-09-08 1990-08-28 Vaccins polypeptidiques contre le virus de la fievre aphteuse WO1991003255A1 (fr)

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GB898920357A GB8920357D0 (en) 1989-09-08 1989-09-08 Peptides
GB8920357.4 1989-09-08

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471457A2 (fr) * 1990-07-24 1992-02-19 Novagene, Inc. Vecteur herpesviral exprimant un épitope du virus de la fièvre aphteuse
WO1997035008A1 (fr) * 1996-03-21 1997-09-25 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Procedes et composition de polypeptides chimeres pour des vaccins antigeniques tumoraux
US6048538A (en) * 1997-10-03 2000-04-11 United Biomedical, Inc. Peptides derived from the non-structural proteins of foot and mouth disease virus as diagnostic reagents
CN1054544C (zh) * 1993-10-21 2000-07-19 复旦大学 家畜口蹄疫病毒多肽疫苗及其制备方法
US6107021A (en) * 1998-06-20 2000-08-22 United Biomedical, Inc. Synthetic peptide vaccines for foot-and-mouth disease
CN1320116C (zh) * 2002-10-18 2007-06-06 中国人民解放军军需大学军事兽医研究所 O型口蹄疫病毒o_ny00株基因组序列
CN100425291C (zh) * 2005-04-06 2008-10-15 中国农业科学院兰州兽医研究所 O型口蹄疫病毒多基因复制缺陷型腺病毒活载体疫苗及制备方法
CN108761093A (zh) * 2018-07-19 2018-11-06 河南百奥生物工程有限公司 一种口蹄疫病毒抗体评价试纸条
CN108931644A (zh) * 2018-07-19 2018-12-04 河南省农业科学院 一种口蹄疫病毒免疫抗体评价及感染与免疫鉴别诊断二联试纸条
US10420832B2 (en) 2012-11-16 2019-09-24 United Biomedical, Inc. Synthetic peptide-based emergency vaccine against foot and mouth disease (FMD)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4544500A (en) * 1982-04-14 1985-10-01 Scripps Clinic And Research Foundation Synthetic foot and mouth disease antigen

Patent Citations (1)

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US4544500A (en) * 1982-04-14 1985-10-01 Scripps Clinic And Research Foundation Synthetic foot and mouth disease antigen

Non-Patent Citations (8)

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Title
Arzneim.-Forsch./Drug Res., Vol. 37, No. 1, 1987 E. Pfaff et al: "Peptide Vaccine - a New Approach to a Safer Foot-and mouth Disease Virus Vaccine ", *
Immunology, Vol. 61, 1987 M.J. Francis et al: "Immune response to uncoupled peptides of foot-and-moutn disease virus ", *
J.gen.Virol., Vol. 70, 1989 N.R. Parry et al: "Neutralizing Epitopes of Type O Foot-and-Mouth Disease Virus. II. Mapping Three Conformational Sites with Synthetic Peptide Reagents ", *
National Library of Medicine, Database Medline, File Med 86, Accession no. 87224810, Xie QC et al: "Neutralization of foot-and-mouth disease virus can be mediated through any of at least three separate antigenic sites", J Gen Virol 1987 Jun;68 (Pt 6): 1637-47 *
NATURE, Vol. 306, 1983 D.J. Rowlands et al: "Chemical basis of antigenic variation in foot-and-mouth disease virus ", *
NATURE, Vol. 330, 1987 B.E. Clarke et al: "Improved immunogenicity of a peptide epitope after fusion to hepatitis B core protein ", *
Prog.Vet.Microbiol.Immun., Vol. 3, 1987 F. Brown: "Progress and Perspectives in the Development of a Foot-and-Mouth Disease Vaccine by Recombinant DNA Technology ", *
UCLA Symp.Mol.Cell Biol. new ser., Vol. 84, 1988 Olga Volpina et al: "Novel foot-and-mouth disease protective peptides; mechanism of immunostimulation ", *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471457A2 (fr) * 1990-07-24 1992-02-19 Novagene, Inc. Vecteur herpesviral exprimant un épitope du virus de la fièvre aphteuse
EP0471457A3 (fr) * 1990-07-24 1992-03-04 Novagene, Inc. Vecteur herpesviral exprimant un épitope du virus de la fièvre aphteuse
CN1054544C (zh) * 1993-10-21 2000-07-19 复旦大学 家畜口蹄疫病毒多肽疫苗及其制备方法
WO1997035008A1 (fr) * 1996-03-21 1997-09-25 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Procedes et composition de polypeptides chimeres pour des vaccins antigeniques tumoraux
US6048538A (en) * 1997-10-03 2000-04-11 United Biomedical, Inc. Peptides derived from the non-structural proteins of foot and mouth disease virus as diagnostic reagents
US6107021A (en) * 1998-06-20 2000-08-22 United Biomedical, Inc. Synthetic peptide vaccines for foot-and-mouth disease
CN1320116C (zh) * 2002-10-18 2007-06-06 中国人民解放军军需大学军事兽医研究所 O型口蹄疫病毒o_ny00株基因组序列
CN100425291C (zh) * 2005-04-06 2008-10-15 中国农业科学院兰州兽医研究所 O型口蹄疫病毒多基因复制缺陷型腺病毒活载体疫苗及制备方法
US10420832B2 (en) 2012-11-16 2019-09-24 United Biomedical, Inc. Synthetic peptide-based emergency vaccine against foot and mouth disease (FMD)
CN108761093A (zh) * 2018-07-19 2018-11-06 河南百奥生物工程有限公司 一种口蹄疫病毒抗体评价试纸条
CN108931644A (zh) * 2018-07-19 2018-12-04 河南省农业科学院 一种口蹄疫病毒免疫抗体评价及感染与免疫鉴别诊断二联试纸条
CN108761093B (zh) * 2018-07-19 2020-12-25 河南百奥生物工程有限公司 一种口蹄疫病毒抗体评价试纸条
CN108931644B (zh) * 2018-07-19 2021-09-10 河南省农业科学院 一种口蹄疫病毒免疫抗体评价及感染与免疫鉴别诊断二联试纸条

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