WO1994029439A1 - Virus de la grippe a rendement eleve - Google Patents

Virus de la grippe a rendement eleve Download PDF

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Publication number
WO1994029439A1
WO1994029439A1 PCT/US1994/006541 US9406541W WO9429439A1 WO 1994029439 A1 WO1994029439 A1 WO 1994029439A1 US 9406541 W US9406541 W US 9406541W WO 9429439 A1 WO9429439 A1 WO 9429439A1
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Prior art keywords
virus strain
host
reassortment
chimeric
influenza virus
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PCT/US1994/006541
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English (en)
Inventor
Peter Palese
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Peter Palese
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Application filed by Peter Palese filed Critical Peter Palese
Priority to AU71041/94A priority Critical patent/AU7104194A/en
Priority to EP94920139A priority patent/EP0711340A4/fr
Priority to JP7502116A priority patent/JPH08511424A/ja
Publication of WO1994029439A1 publication Critical patent/WO1994029439A1/fr

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    • 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
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16151—Methods of production or purification of viral material

Definitions

  • the present invention relates to influenza virus strains which may reliably be propagated to high titer in hosts such as embryonated eggs.
  • Anti-viral vaccine production presents many challenges. For example, an ever-changing group of
  • influenza virus subtypes such as, say, influenza
  • influenza A(H3N2) and A(H1N1) , and influenza B circulate within the general population. Further, due to antigenic drift, a large amount of variation quickly develops within each influenza A subtype and within influenza
  • reassortment viruses with high growth characteristics usually derive six genomic RNA segments from the high- yield parental virus strain and the hemagglutinin (HA) and neuraminidase (NA) segments from the newly isolated parental strain (Kilbourne, E.D. and Murphy, J.S., 1960, J. Exp. Med. 111:387: Kilbourne, E.D., 1969, WHO Bull. 4JL:643; Baez, M.
  • HA hemagglutinin
  • NA neuraminidase
  • the present invention relates to influenza strains which may consistently and reliably be propagated to high titer in hosts which include, but are not limited to embryonated eggs and embryo-derived tissue culture cells, and may be used in the production of anti-viral vaccines.
  • the invention further relates to methods for the production of such high yield viruses. More specifically, the high-yield influenza viruses of the invention contain portions of viruses which are virulent in Mx hosts, (i.e.. hosts containing the Mx allele) .
  • the invention is based in part, on the surprising finding that Mx mouse resistant influenza virus strains grow to higher titers in embryonated eggs than do specifically egg- adapted viral strains.
  • the methods presented for the production of high yield viral strains include, first, the production of reassortment strains developed by crossing a low titer virus strain with a virus resistant to (i.e. , virulent in) an Mx host. Second, methods for the production of high yield virus strains are presented wherein high yield viruses are constructed which exhibit chimeric viral surface molecules, such as chimeric HA and/or NA surface molecules.
  • the chimeric surface molecules contain the cytoplasmic or cytoplasmic and transmembrane portions of the HA or NA molecules of a viral strain in an Mx host, and at least the extracellular antigenic portion of the HA or NA molecule from the newly isolated low titer virus strain. These methods may be utilized for the production of high yield influenza A, B, or C virus strains.
  • FIG. 1 Diagram depicting reassortment between a high yield Mx resistant parental strain (non-hatched) and a recently isolated, low yield virus isolate (hatched) .
  • the resulting reassortment virus shown contains HA and NA surface proteins derived from the low yield parent and the rest of the viral components derived from the high yield viral parent.
  • FIG. 5 Diagram depicting the interaction of viral surface proteins (HA and NA) with the core structure of influenza viruses.
  • FIG. 3 Diagram depicting the construction of a 0 high yield virus exhibiting a chimeric HA surface protein.
  • the two viruses shown contain extracellular or extracellular and transmembrane domains derived from a low yield viral strain (hatched) while the remaining components of the virus are derived from a 5 high yield strain developed in a Mx host strain.
  • the present invention is based, in part, on the surprising discovery that viral stains developed in Mx o mice grow to higher titers in embryonated eggs than do specifically egg-adapted viral strains. Lindenmann (Lindenmann, J. et al.. 1963, J. Immunol. 90:942) discovered that the A2G strain of mice is resistant to influenza A and B viruses. The resistance was later 5 found to be associated with the presence of the dominant Mx allele present in several mouse lines, including the A2G strain. Only a few influenza viruses have been reported to be virulent in this strain of mice (Haller, 0. , 1981, in "Current Topics 0 in Microbiology and Immunology £2., Henle, W. et al.
  • influenza strains which are virulent in Mx-containing A2G mice surprisingly behave as high yield viruses 5 when propagated in embryonated egg hosts. Therefore, as discussed further below, instead of the A/PR/8/34 influenza strain currently used for generating potentially high yield reassortment strains, viruses which are virulent in Mx hosts are utilized as parent strains for the high yield reassortment virus strains of the invention. Further, as described in detail below, portions of the viral surface proteins, such as HA and/or NA proteins, derived from viral strains developed in Mx hosts are utilized as part of the chimeric high yield virus strains of the invention. Also described below are methods for the production of the high yield reassortment and chimeric virus strains of the invention.
  • the high yield influenza viruses of the invention are capable of growing to high titer in hosts which include, but are not limited to such hosts as embryonated eggs, preferably embryonated hens eggs, and tissue culture cells derived from embryos such as chick embryos.
  • the high yield viruses of the invention may be capable of growing to high titer in a large number of other cells, including, but not limited to mammalian and avian cell lines.
  • At least a portion of each high yield influenza virus is derived from components of viral strains which have been developed in hosts which contain and express the dominant Mx allele.
  • Mx hosts are preferably Mx mice or Mx mouse cell lines.
  • Mx hosts may include, but are not limited to any mammalian animal, ferret for example, any mammalian cell line, any avian animal, or avian cell line, which contains and expresses the Mx allele.
  • the Mx allele in these appropriate hosts may be endogenous to the host or may, alternatively, be introduced into the host using standard recombinant DNA techniques well known to those of ordinary skill in the art.
  • the high yield influenza viruses of the invention may include, but are not limited to, reassortment viruses and viruses exhibiting chimeric viral surface proteins, preferably chimeric HA and/or NA proteins.
  • the high yield reassortment influenza viruses of the invention grow to high titer in both Mx hosts and in embryonated egg and embryo-derived tissue culture cell hosts.
  • the high yield reassortment viruses should exhibit on their surfaces viral surface proteins, preferably HA and/or NA proteins, derived from the low titer parent because these proteins are major targets of the host immune response after infection.
  • the reassortment viruses should contain, therefore, at least the gene(s) derived from the low titer viral parent encoding one or more viral surface proteins, such as the HA and/or NA surface proteins.
  • the high yield reassortment viruses of the invention include and express at least those portions of the genome of the Mx host-derived strain which allow the strain to grow to high titer in the Mx host.
  • Such portions of the viral genome may include, but are not limited to, all or any of the genes encoding the components of the RNA-directed-RNA polymerase complex (PB1, PB2, and PA), the gene encoding the nucleoprotein (NP) , which forms the nucleocapsid, the genes encoding the matrix proteins (Ml, M2) , and/or the genes encoding the nonstructural proteins (NS1, NS2) .
  • the portion of the Mx host-derived parental strain's genome contained within the high yield reassortment virus of the invention may, but is not required to, induce a lower host interferon response than the host interferon response elicited by the low titer viral parent, or viruses currently used to prepare high yield reassortment.
  • the high yield viruses of the invention may include viruses which exhibit chimeric viral surface proteins, such as chimeric HA and/or NA surface proteins. Because the core structures of influenza viruses are thought to interact with the cytoplasmic domains of the surface proteins, such as the HA and NA surface proteins, chimeric viral surface proteins containing cytoplasmic domains derived from a high yield Mx resistant strain may provide more favorable protein-protein interactions with a core structure derived from a Mx resistant virus strain than unaltered viral surface proteins would, thus providing a higher growth potential (See FIG. 2 for a diagram depicting this concept) . At least the extracellular portions of the chimeric viral surface proteins should be derived from the extracellular portions of the viral surface proteins of the low titer strain.
  • the cytoplasmic or the cytoplasmic and transmembrane rec ons of the chimeric viral surface proteins should be derived from the viral surface proteins of a viral strain which was developed in the Mx host. Accordingly, the portions of the viral genome encoding the extracellular domain(s) of the chimeric viral surface proteins should be derived from the genome of the low titer viral strain, and the portions of the viral genome encoding cytoplasmic or cytoplasmic and transmembrane domains of the chimeric viral surface proteins should be derived from the genome of a viral strain which was developed in a Mx host.
  • the high yield influenza viruses of the invention may consist of a virus derived almost exclusively from a viral strain which was originally developed in a Mx mouse strain, and contains only the extracellular domain of a viral surface protein, such as HA and/or NA, derived from a low titer viral strain. Portions of the low titer strain-derived domains of the chimeric viral surface proteins of the chimeric viruses of the invention may be modified such that the chimeric virus strain is capable of growing to a higher titer in hosts such as embryonated eggs.
  • a viral surface protein such as HA and/or NA
  • the portions of the low titer strain-derived domains which may be modified include, but are not limited to the extracellular domain's receptor-binding sites and/or those domains which affect the cleavability of the surface proteins. Modifications may include, but are not limited to amino acid insertions, deletions, or substitutions. In all cases, the modifications do not effectively change the antigenicity of the virus strains of the invention which is important for a protective host immune response. Amino acid substitutions may be of a conserved or non-conserved nature.
  • conserveed amino acid substitutions consist of replacing one or more amino acids of the low titer strain-derived domains of the viral surface proteins with amino acids of similar charge, size, and/or hydrophobicity characteristics, such as, for example, a glutamic acid (E) to aspartic acid (D) amino acid substitution.
  • Non-conserved substitutions consist of replacing one or more amino acids of the low titer strain-derived domains of the viral surface proteins with amino acids possessing dissimilar charge, size, and/or hydrophobicity characteristics, such as, for example, a glutamic acid (E) to valine (V) substitution.
  • Amino acid insertions may consist of single amino acid residues or stretches of residues ranging from 2 to 15 amino acids in length.
  • One or more insertions may be introduced into the low titer strain-derived viral surface proteins so long as the insertions do not effectively change the antigenicity of the virus strain which is important for a protective immune response.
  • Deletions of portions of the low titer strain- derived viral surface proteins are also within the scope of the invention. Such deletions consist of the removal of one or more amino acids from the protein sequence, so long as the resulting deletion protein does not exhibit an effectively changed antigenicity which does not elicit a protective immune response from the host. Deletions may involve a single contiguous or greater than one discrete portion of the peptide sequences.
  • the high yield influenza viruses of the invention may be used as anti-viral vaccines.
  • Such vaccines may be used in human as well as non-human hosts, including, but not limited to equine, porcine, and avian hosts.
  • Vaccine administration is performed according to techniques well known to those of ordinary skill in the art. (See Palese, P. et al.. 1992, U.S. Patent No. 5,166,057, which is incorporated herein by reference in its entirety, for such techniques.)
  • a low titer parent influenza strain is 5 crossed, in a standard mixed infection, with a parent virus strain developed in a Mx host. Mixed infections are performed by coinfecting Mx resistant virus with various dilutions of a low titer virus strain.
  • high titer virus strains may include, but 0 are not limited to the PR8 strain (Haller, O., 1981, in “Current Topics in Microbiology and Immunology", Henle, W. et al.. eds., Springer-Verlag: New York, pp. 25-51) .
  • Other high yield influenza A, B, or C parental strains may be developed by passage though Mx 5 hosts and by selecting those strains which exhibit virulence and high growth characteristics in Mx hosts.
  • Mx hosts may include, but are not limited to Mx mouse cell lines such as the A2G cell line, and Mx mouse strains, such as the A2G mouse strain (Lindenmann, J. o et al. f 1963, J.
  • Mx hosts may include, but are not limited to any mammalian animal, ferret, for example, mammalian cell line, any avian animal, or avian cell line which contains and expresses the Mx allele.
  • the Mx allele 5 in these appropriate hosts may be endogenous to the host or may, alternatively, be introduced in the host using standard recombinant DNA techniques well known to those of ordinary skill in the art.
  • Animals or monolayers of cells may be coinfected using standard 0 techniques well known to those in the art. In the case of whole animal infections, hosts may, for example, be coinfected by intranasal or aerosol routes.
  • Progeny reassortment viruses resulting from mixed 5 infections may be passaged through Mx hosts or may be used to infect hosts such as embryonated egg hosts or embryo-derived cell hosts. The growth characteristics of the reassortment virus strains are then evaluated and those exhibiting high titer growth capabilities may act as reassortment viruses of the invention.
  • the high yield reassortment virus strains of the invention must exhibit on their viral surfaces at least one viral surface protein, such as HA or NA, which has been derived from the low titer parental viral strain (See FIG. 1 for a diagram depicting one embodiment of the reassortment virus strains of the invention) .
  • RT reverse transcriptase
  • PCR polymerase chain reaction
  • pairs of primers may be used which specifically hybridize to nucleotide sequences present in the low titer-derived viral surface protein genes but do not hybridize to sequences present in the high yield parental virus strain-derived viral surface protein genes.
  • PCR amplification using standard techniques Innis, M.A. et al.. eds., 1990, PCR Protocols, Academic Press, NY) , therefore, will only yield an amplified fragment when RNA from a reassortment strain containing low titer-derived viral surface protein genes is used as the starting material in the assay.
  • RNA gene segments When developing reassortment strains, one may select against the presence of high yield parental strain derived viral surface proteins, instead of relying on completely random reassortment of RNA gene segments.
  • progeny viruses obtained after an initial mixed infection may be pretreated with an antiseru raised against the viral surface proteins of the high yield parental strain. Such treatment will neutralize those viruses exhibiting the high yield parental strain derived surface proteins, inhibiting their ability to infect host cells.
  • the antiserum- treated virus sample which now contains a population of infectious viruses which are enriched for viruses that exhibit low yield parental strain-derived viral surface proteins, may then be used to infect appropriate host cells. This is an especially useful technique when utilized in the construction of the viruses of the invention, in that neutralizing antibodies against surface proteins may readily be made.
  • the resulting reassortment virus strain may then be used to infect hosts such as embryonated egg or embryo-derived cell hosts, at which time growth characteristics of the reassortment strain in the host may be evaluated. Such growth characteristics may be evaluated by determining, for example, the number of PFUs per volume of viral sample or by assaying the hemagglutinin titer of the viral sample, using techniques well known to those of ordinary skill in the art.
  • RNA segments encoding the viral surface protein(s) of interest (such as the HA and/or NA proteins) from both a high yield strain which was originally selected in an Mx host, and from a low yield strain must be obtained.
  • Procedures for obtaining these RNA segments utilize standard techniques well known to those of ordinary skill in the art. See, for example, Palese and Schulman, 1976, J. Virol. 1/7:876-884, which is incorporated herein by reference in its entirety.
  • RNA segment encoding these genes is then reverse-transcribed into cDNA, using techniques well known to those of skill in the art (Sambrook, et al.. 1989, Molecular Cloning: A Laboratory Manual, Vols. 1-3, Cold Spring Harbor Press, NY).
  • the appropriate portions of each gene may be isolated and combined using standard recombinant DNA techniques.
  • the region of the HA gene which encodes the extracellular domain of the HA protein of a low yield strain may be isolated by, for example, the use of a convenient restriction enzyme site endogenous to the sequence or engineered into the sequence by recombinant means (see, for example, Kunkel, 1985, Proc. Natl.
  • the region of the HA gene encoding the cytoplasmic and transmembrane domains of the HA protein may be isolated using the same types of procedures.
  • the region of cDNA encoding the extracellular domain of the low yield strain and the cDNA encoding the cytoplasmic and transmembrane domains of the high yield strain may then be joined, using standard enzymatic means.
  • the chimeric viral genes of the invention may be synthesized using chemical means well known to those of skill in the art.
  • the chimeric gene constructs should include those sequences, such as viral polymerase binding site/promoter, RNA polymerase-binding sites, and the appropriate 3' and 5' regulatory sequences well known to those of skill in the art which will allow efficient transcription of the chimeric RNA segments.
  • cDNA chimeric constructs may then be introduced into a system whereby the cDNA may be transcribed into RNA of a negative polarity.
  • Such systems are well known to those of skill in the art and include, but are not limited to the T3, T7, and SP6 in vitro transcription systems and the like.
  • RNA chimeric constructs may be utilized directly.
  • the negative polarity RNA encoding the chimeric viral surface NA proteins may then be combined with viral RNA polymerase complex, which may be isolated or may be produced using recombinant techniques, both of which are well known to those of skill in the art, to form infectious RNP (ribonucleoprotein) complex.
  • RNPs comprise viral RNA-directed RNA polymerase proteins (the P proteins) and nucleoprotein (NP) .
  • the RNPs may then be used together with a "parent" virus to coinfect host cells.
  • Appropriate host cells may include, but are not limited to Mx mouse cells, such as those of the mouse A2G cell line, or, alternatively, embryonated egg or embryo-derived host cells.
  • the "parent” in this instance is a high yield virus strain originally developed in a Mx strain.
  • the techniques utilized for the production of infectious RNPs containing genes encoding chimeric proteins may be found in Palese et al. (Palese, P. et al.. 1992, U.S. Patent No. 5,166,057). After coinfection, techniques essentially identical to those described above in Section 5.2.1 may be utilized to select for and characterize those progeny viruses which exhibit chimeric viral surface proteins and whose remaining components are derived from the original high yield Mx resistant "parental" strain. 6.
  • a reassortment influenza virus developed in a Mx mouse host which grows to high titer in embryonated egg hosts.
  • the high yield Mx resistant parent virus used was the PR8 virus strain (Haller, O. , 1981, in "Current Topics in Microbiology and Immunology;
  • a recent influenza A virus isolate was used as the low titer parent virus strain.
  • Host Strains The A2G Mx mouse strain
  • Table I results which demonstrate that the reassortment virus produced in this study grows to high titer in embryonated egg hosts.
  • the growth characteristics of the virus strains were assayed using standard hemagglutinin titer measurements.
  • the recently isolated low yield influenza A virus was successfully used together with a high yield PR8 virus to produce a reassortment strain which, surprisingly, acts as a high yield virus strain in an embryonated egg host.

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Abstract

Cette invention concerne des souches de virus de la grippe qu'on peut propager de manière fiable afin d'obtenir une concentration élevée chez des hôtes tels que des ÷ufs fécondés. Des souches à rendement élevé comprenant des virus de la grippe de réassortiment et des virus de la grippe présentant des molécules de surface virales chimériques, telles que des molécules de surface HA chimériques et/ou des molécules de surface NA sont décrites, ainsi que des procédés de production de ces souches de virus de la grippe A, B, et/ou C à rendement élevé. On peut utiliser ces virus à rendement élevé dans la production de vaccins antiviraux et la production de virus de la grippe chimériques.
PCT/US1994/006541 1993-06-11 1994-06-10 Virus de la grippe a rendement eleve WO1994029439A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU71041/94A AU7104194A (en) 1993-06-11 1994-06-10 High yielding influenza viruses
EP94920139A EP0711340A4 (fr) 1993-06-11 1994-06-10 Virus de la grippe a rendement eleve
JP7502116A JPH08511424A (ja) 1993-06-11 1994-06-10 高収量性インフルエンザウイルス

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US7566093A 1993-06-11 1993-06-11
US075,660 1993-06-11

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WO (1) WO1994029439A1 (fr)

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WO2012032482A1 (fr) * 2010-09-07 2012-03-15 Novartis Ag Tests génériques pour la détection de réovirus de mammifères
WO2021099419A1 (fr) * 2019-11-18 2021-05-27 Seqirus UK Limited Procédé de production de virus de la grippe réassortis

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US8715940B2 (en) 1999-04-06 2014-05-06 Wisconsin Alumni Research Foundation Method of making recombinant influenza virus

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BIOLOGICALS, Volume 20, issued 1992, ROBERTSON et al.: "High growth reassortant influenza vaccine viruses: New Approaches to their control", pages 213-220. See entire article. *
CELL., Volume 59, issued 22 Decmber 1989, LUYTJES et al.: "Amplification, expression, and packaging of a foreign gene by influenza virus", pages 1107-1113. See entire article. *
CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY, Volume 92, issued 1981, HALLER: "Inborn resistance of mice to orthomyxoviruses", pages 25-51. See especially page 47. *
See also references of EP0711340A4 *
THE JOURNAL OF INFECTIOUS DISEASES, Volume 141, Number 3, issued March 1990, BAEZ et al.: "Gene composition of high-yielding influenza vaccine strains obtained by recombination", pages 362-365. See entire article. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012032482A1 (fr) * 2010-09-07 2012-03-15 Novartis Ag Tests génériques pour la détection de réovirus de mammifères
EP3012330A1 (fr) * 2010-09-07 2016-04-27 Novartis AG Dosages génériques de détection de réovirus de mammifère
US9657359B2 (en) 2010-09-07 2017-05-23 Novartis Ag Generic assays for detection of mamalian reovirus
WO2021099419A1 (fr) * 2019-11-18 2021-05-27 Seqirus UK Limited Procédé de production de virus de la grippe réassortis

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CA2164946A1 (fr) 1994-12-22
AU7104194A (en) 1995-01-03
JPH08511424A (ja) 1996-12-03
EP0711340A1 (fr) 1996-05-15
EP0711340A4 (fr) 1998-02-04

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