WO1990000597A1 - Virus et antigenes d'hepatite serique non a et n b - Google Patents

Virus et antigenes d'hepatite serique non a et n b Download PDF

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Publication number
WO1990000597A1
WO1990000597A1 PCT/US1989/002817 US8902817W WO9000597A1 WO 1990000597 A1 WO1990000597 A1 WO 1990000597A1 US 8902817 W US8902817 W US 8902817W WO 9000597 A1 WO9000597 A1 WO 9000597A1
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WO
WIPO (PCT)
Prior art keywords
nanb
virus
sequence
antibodies
viral
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PCT/US1989/002817
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English (en)
Inventor
Gregory R. Reyes
Daniel W. Bradley
Linda Rabin
Kirk E. Fry
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Genelabs Incorporated
THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES AND HIS SUCCESSORS
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Application filed by Genelabs Incorporated, THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES AND HIS SUCCESSORS filed Critical Genelabs Incorporated
Publication of WO1990000597A1 publication Critical patent/WO1990000597A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1081—Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
    • C07K16/109—Hepatitis C virus; Hepatitis G virus
    • 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
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • C12Q1/707—Specific hybridization probes for hepatitis non-A, non-B Hepatitis, excluding hepatitis D
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2770/24011—Flaviviridae
    • C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
    • C12N2770/24221—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • 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
    • C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
    • C12N2770/24222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • PT-NANB viruses and antigens have been re ⁇ ported. See for example, U.S. Patent Nos. 4,464,474, and 4,542,016.
  • the PT-NANB virus has been reported to be a togavirus. See, for example, U.S. Patent No. 4,464,474.
  • Genetic engineering of hepatitis viral genes, identified as hepatitis C virus, is reported in European Patent Application 88310922.5 (publication number 0 318 216 Al).
  • Figure 5 shows a series of 7 fragments of PT- NANB virus genetic material. Only the cDNA sequences are shown in this Figure. DESCRIPTION OF THE SPECIFIC EMBODIMENTS
  • fragments derived from entire molecules of the homogeneous peptide or DNA sequence if present in no more than 5% by weight, preferably 1% by weight, and more preferably 0.2% by weight, is not to be consi- dered in determining homogeneity since the term "homo ⁇ geneous" relates to the presence of entire molecules (and fragments thereof) that have a single defined structure as opposed to mixtures in which several mole ⁇ cules of similar molecular weight are present but which differ in their primary molecular structure.
  • isolated refers to pure peptide, DNA, or RNA separated from other pep ⁇ tides, DNAs, or RNAs, respectively, and being found in the presence of (if anything) only a solvent, buffer, ion or other component normally present in a biochemi ⁇ cal solution of the same. "Isolated” does not encom- pass either natural materials in their native state or natural materials that have been separated into compo ⁇ nents (e.g., in an acrylamide gel) but which have not been obtained either as pure substances or as solu ⁇ tions.
  • pure as used herein preferably has the same numerical limits as “substantially" immediate ⁇ ly above.
  • Salts of any of the biological molecules de ⁇ scribed herein will naturally occur when such molecules are present in (or isolated from) aqueous solutions of various pHs. All salts of molecules having the indica ⁇ ted biological activity are considered to be within the scope of the present invention. Examples of salts that can occur with peptides include alkali, alkaline earth, and other metal salts of carboxylic acid residues, acid addition salts (e.g., HCl) of amino residues, and zw;itterions formed by reactions between carboxylic acid and amino residues within the same molecule.
  • a second strategy for preparing gene libraries is to make complementary DNA (cDNA) copies of the total RNA of the virus and to clone these as recombinant molecules in expression vectors.
  • cDNA complementary DNA
  • Use of a cDNA library to obtain genetic information for use in the present invention is preferred.
  • Such a library has been generated from NANB-infected human plasma and screened with serum from a NANB-infected human.
  • the re ⁇ combinants expressing determinants reactive with the serum are those described in Figures 1 to 4.
  • Polyclonal antisera to NANB can be used to screen a cDNA library in order to locate the desired genetic material.
  • virus particles may be isolated by lysing the cells and subjecting the lysate to the technique of fractionating samples according to buoyant density, as described below, without additional purification techniques that might disrupt virus particles.
  • the isolated particles will reproduce the virus-related cell change when uninfected hybrid cells are exposed to virus particles.
  • the antigen may be present on an intact virus particle, a partially degraded virus particle, a protein- or carbohydrate-containing molecule in solution, or any other physical form, including an antigen that has been combined either chemically or physically with particle or solid surfaces, such as by attaching antigens to the surface of a test tube or to suspended particles, such as red blood cells or latex particles.
  • An antigen of the invention is defined as a substance containing at least one epitopic site of a virus particle.
  • antigens of the invention may be separated from undesired water-soluble materials after gross contamination is removed. Where it is desired to recover either intact virus particles or their water- insoluble fragments, it is convenient to simply remove all water soluble constituents from the sample.
  • Suit ⁇ able techniques include ultrafiltration through a membrane, use of selective flocculating or protein- precipitating agents (such as polyethylene glycol and ammonium sulfate), and chromatography. Chromatography is the most versatile method since it can be -readily scaled up for commercial manufacture of antigen. Gel chromatography systems using cross-linked dextran beads are typical of the materials used.
  • a column of a suit- able gel can be selected which will permit diffusion of proteins and low molecular weight substances into the void volume of the gel beads, thereby retarding the progress of these contaminants through the column, while allowing whole virus particles to pass through virtually unimpeded.
  • other gel sizes can be selected to provide for isolation of an antigen of any particular size. The gel which is selected will thus be a matter of routine experimentation. Any of the techniques described herein can be combined as desired.
  • Vaccination can be conducted in conventional fashion.
  • the antigen whether a viral particle or a protein
  • a suitable diluent such as water, saline, buffered salines, complete or incomplete adjuvants, and the like.
  • the immunogen is administered using standard techniques for antibody induction, such as by subcutaneous administra ⁇ tion of physiologically compatible, sterile solutions containing inactivated or attenuated virus particles or antigens.
  • An immune response producing amount of virus particles is typically administered per vaccinizing injection, typically in a volume of one milliliter or less.
  • the composi ⁇ tions can be used to prepare antibodies to NANB virus particles.
  • the antibodies can be used directly as antiviral agents.
  • anti-NANB-virus antibodies can be induced by administering anti-idiotype antibodies as immunogens.
  • a purified anti-NANB-virus antibody preparation prepared as descibed above is used to induce anti-idiotype antibody in a host animal.
  • the composition is administered to the host animal in a suitable diluent. Following administration, usually repeated administration, the host produces anti- idiotype antibody.
  • antibodies produced by the same species as the host animal can be used or the Fc region of the administered antibodies can be removed.
  • serum or plasma is removed to provide an antibody composition.
  • the composition can be purified as described above for anti-NANB-virus antibodies, or by affinity chromatography using anti-NANB-virus antibodies bound to the affinity matrix.
  • the anti- idiotype antibodies produced are similar in conforma ⁇ tion to the authentic NANB antigen and may be used 'to prepare an NANB vaccine rather than using a NANB particle antigen.
  • the manner of injecting the antibody is the same as for vaccination purposes, namely intramuscularly, intraperitoneally, subcutane- ously or the like in an effective concentration in a physiologically suitable diluent with or without adju ⁇ vant.
  • One or more booster injections may be desirable.
  • the anti-idiotype method of induction of anti-NANB- virus antibodies can alleviate problems which may be caused by passive administration of anti-NANB-virus antibodies, such as an adverse immune response, and those associated with administration of purified blood components, such as infection with other as yet uncharacterized agents.
  • analyte is an antibody or an antigen
  • either a labelled antigen or antibody, respectively can be used to bind to the analyte to form an immunological complex, which can then be detected by means of the label.
  • methods for detecting analytes such as surface antigens and/or whole particles are based on immunoassays.
  • Immunoassays can be conducted either to determine the presence of antibodies in the host that have arisen from infection by NANB hepatitis virus or by assays that directly determine the presence of virus particles or antigens. Such techniques are well known and need not be described here in detail. Examples include both heterogeneous and homogeneous immunoassay techniques.
  • Heterogeneous assays for viral antigens typically use a specific monoclonal or polyclonal antibody bound to a solid surface. Sandwich assays are becoming increas- ingly popular. Homogeneous assays, which are carried out in solution without the presence of a solid phase, can also be used, for example by determining the difference in enzyme activity brought on by binding of free antibody to an enzyme-antigen conjugate. A number of suitable assays are disclosed in U.S. Patent Nos. 3,817,837, 4,006,360, 3,996,345.
  • Monoclonal anti-virus particle antibodies or anti-idiotype antibodies can be produced as follows.
  • the spleen or lymphocytes from an immunized animal are removed and immortalized or used to prepare hybridomas by methods known to those skilled in the art.
  • a human lymphocyte donor is selected.
  • a donor known to be infected with a NANB virus (where infection has been shown for example by the presence of anti-virus anti ⁇ bodies in the blood or by virus culture) may serve as a suitable lymphocyte donor.
  • NANB hepatitis was centrifuged at 30,000 rpm for 2-1/2 hrs at 5°C in an SW40 rotor (Beckman). The supernatant was removed and discarded and the pellet solubilized in 50 mM sodium acetate buffer, pH 4.8, containing 1% sodium dodecylsulfate (SDS). The RNA was selectively extracted using phenol equilibrated in the same buffer without SDS. The nucleic acid in the aqueous phase was then precipitated using two volumes of absolute ethanol.
  • NANB virus particles originally derived from human plasma were isolated as follows: A plasma inoculum from a chimpanzee inoculated with infected plasma comprising NANB virus particles originating from a patient diagnosed as having NANB hepatitis but carried in chimpanzees was layered onto the top of a linear 20-55% sucrose gradient in Tris HCl 0.01 M, pH 8.0, containing 0.001 M EDTA, 0.1 M sodium chloride. The gradient was prepared using a Hoefer gradient maker. The chimpanzee inoculum contained 10° chimpan ⁇ zee infectious doses (CID) of NANB virus particles.
  • CID chronic chimpanzee infectious doses
  • Clone #30 (obtained as in Example 1; sequence as in Figure 1) was radiolabeled using 2 P nucleotides and a random primer kit according to the instructions provided by the kit manufacturer (Boehringer-Mannheim Biochemicals, Indiannapolis, Indiana). The radio- labeled clone #30 was then used as a hybridization probe against a filter containing the amplified cDNAs from the fractionated virus particles. Specific hybridization, as detected by autoradiography, was evident only with the cDNA prepared from the NANB- infected chimpanzee.
  • molecular clone #30 isolated from a NANB-infected human source detected homologous sequences present in cDNA prepared from an enriched source of documented infectious NANB particles passaged in chimpanzees, but originating in an infected human.
  • Clones PT'2, PT'8 and PT'9 also hybridized specifically to cDNA prepared from the NANB-infected chimpanzee.
  • Goat anti-human IgG and IgM conjugated with fluorescein isothiocyanate were obtained from a commercial source (Zymed Labs). They were each diluted with PBS to a final concentra- tion of about 1 ug antibody/ml. Either anti-IgM or anti-IgG FITC-conjugated antibody (70 ul) was added to the washed cells, and the slides were incubated at room temperature for 30 minutes. After washing with PBS and distilled water as above, the slides were mounted with one drop of 50% glycerol in PBS and observed under a fluorescence microscope. The cells were scored for weak (+), intermediate (++), and strong (+++) fluorescence.
  • NANB Virus Particles Propagated in Hybrid Liver Cells Molecular clones from NANB-infected cells are isolated to determine if in vitro passage leads to the generation of defective viral particles, with resultant attenuation of viral infectivity. The method is as follows:

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Abstract

L'invention concerne des particules de virus purifiées, des antigènes, des anticorps réagissant avec des antigènes viraux et une matière génétique virale associée à l'hépatite non A et non B. Elle concerne également une matière génétique clonée utile à la fois pour identifier des particules de virus intactes de l'invention et utilisée dans des techniques de diagnostic et/ou la production d'antigènes.
PCT/US1989/002817 1988-07-06 1989-06-28 Virus et antigenes d'hepatite serique non a et n b WO1990000597A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US21572888A 1988-07-06 1988-07-06
US215,728 1988-07-06
US22833488A 1988-08-04 1988-08-04
US228,334 1988-08-04
US33470189A 1989-04-06 1989-04-06
US334,701 1989-04-06
US35057089A 1989-05-11 1989-05-11
US350,570 1989-05-11

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WO1990000597A1 true WO1990000597A1 (fr) 1990-01-25

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EP (1) EP0423239A4 (fr)
JP (1) JPH04501203A (fr)
CN (1) CN1041005A (fr)
AU (1) AU4046489A (fr)
WO (1) WO1990000597A1 (fr)

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EP0388232A1 (fr) * 1989-03-17 1990-09-19 Chiron Corporation Diagnostics et vaccins de NANBV
GB2239245A (en) * 1989-12-18 1991-06-26 Wellcome Found Post-transfusional non-A non-B hepatitis viral polypeptides
WO1991015574A1 (fr) * 1990-04-03 1991-10-17 Southwest Foundation For Biomedical Research Virus purifies de l'hepatite c et proteines et peptides de ces virus
EP0461863A1 (fr) * 1990-06-12 1991-12-18 Immuno Japan Inc. Amorces oligonucléotidiques et leur utilisation pour la détection de non-A, non-B virus d'hépatite à haute fidélité
EP0464287A1 (fr) * 1990-06-25 1992-01-08 The Research Foundation for Microbial Diseases of Osaka University cADN génomique du virus de l'hépatite non-A non-B et antigène polypeptidique
US5106726A (en) * 1990-02-16 1992-04-21 United Biomedical, Inc. Synthetic peptides specific for the detection of antibodies to HCV
WO1992021759A1 (fr) * 1991-06-06 1992-12-10 Institut Pasteur Sequences nucleotidiques et peptidiques d'un isolat de virus de l'hepatite c, applications diagnostiques et therapeutiques
WO1993025662A2 (fr) * 1992-06-12 1993-12-23 Hiroshi Yoshikura Replication du genome du virus de l'hepatite c et identification des virus a haut pouvoir infectieux
WO1994014974A1 (fr) * 1992-12-29 1994-07-07 Akzo Nobel N.V. Anticorps monoclonaux et anticorps anti-idiotypes diriges contre le virus de l'hepatite c
US5350671A (en) * 1987-11-18 1994-09-27 Chiron Corporation HCV immunoassays employing C domain antigens
WO1994025064A1 (fr) * 1993-05-04 1994-11-10 THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMANSERVIC ES Propagation de cellules virales de l'hepatite c et procedes associes
US5372928A (en) * 1989-09-15 1994-12-13 Chiron Corporation Hepatitis C virus isolates
US5436318A (en) * 1990-04-06 1995-07-25 Genelabs Technologies, Inc. Hepatitis C virus epitopes
US5436126A (en) * 1990-02-16 1995-07-25 United Biomedical, Inc. Synthetic peptides specific for the detection of antibodies to HCV, diagnosis of HCV infection and prevention thereof as vaccines
WO1995032291A2 (fr) * 1994-05-20 1995-11-30 Genelabs Technologies, Inc. Virus de l'hepatite g et son clonage moleculaire
US5635346A (en) * 1991-03-26 1997-06-03 Dade International Inc. Assay for Non-A Non-B hepatitis
US5683864A (en) * 1987-11-18 1997-11-04 Chiron Corporation Combinations of hepatitis C virus (HCV) antigens for use in immunoassays for anti-HCV antibodies
US5709997A (en) * 1995-08-14 1998-01-20 Abbott Laboratories Nucleic acid detection of hepatitis GB virus
US5712087A (en) * 1990-04-04 1998-01-27 Chiron Corporation Immunoassays for anti-HCV antibodies employing combinations of hepatitis C virus (HCV) antigens
US5747239A (en) * 1990-02-16 1998-05-05 United Biomedical, Inc. Synthetic peptides specific for the detection of antibodies to HCV, diagnosis of HCV infection and preventions thereof as vaccines
US5766840A (en) * 1994-05-20 1998-06-16 Genelabs Technologies, Inc. Hepatitis G virus and molecular cloning thereof
US5807670A (en) * 1995-08-14 1998-09-15 Abbott Laboratories Detection of hepatitis GB virus genotypes
US5843450A (en) * 1994-02-14 1998-12-01 Abbott Laboratories Hepatitis GB Virus synthetic peptides and uses thereof
US5859230A (en) * 1992-07-30 1999-01-12 Genelabs Technologies, Inc. Non-A/non-B/non-C/non-D/non-E hepatitis agents and molecular cloning thereof
US5866139A (en) * 1992-06-04 1999-02-02 Institut Pasteur Nucleotide and peptide sequences of a hepatitis C virus isolate, diagnostic and therapeutic applications
US5874563A (en) * 1994-05-20 1999-02-23 Genelabs Technologies, Inc. Hepatitis G virus and molecular cloning thereof
US5955318A (en) * 1995-08-14 1999-09-21 Abbott Laboratories Reagents and methods useful for controlling the translation of hepatitis GBV proteins
US5981172A (en) * 1994-02-14 1999-11-09 Abbott Laboratories Non-A, non-B, non-C, non-D, non-E Hepatitis reagents and methods for their use
US5998130A (en) * 1990-06-25 1999-12-07 The Research Foundation For Microbial Diseases Of Osaka University Non-A, non-B hepatitis virus genomic cDNA and antigen polypeptide
US6051374A (en) * 1994-02-14 2000-04-18 Abbott Laboratories Non-A, non-B, non-C, non-D, non-E hepatitis reagents and methods for their use
US6156495A (en) * 1994-02-14 2000-12-05 Abbott Laboratories Hepatitis GB virus recombinant proteins and uses thereof
US6451578B1 (en) 1994-02-14 2002-09-17 Abbott Laboratories Non-A, non-B, non-C, non-D, non-E hepatitis reagents and methods for their use
US6558898B1 (en) 1994-02-14 2003-05-06 Abbott Laboratories Non-A, non-B, non-C, non-D, non-E hepatitis reagents and methods for their use
US6586568B1 (en) 1994-02-14 2003-07-01 Abbott Laboratories Non-A, non-B, non-C, non-D, non-E hepatitis reagents and methods for their use
US6720166B2 (en) 1994-02-14 2004-04-13 Abbott Laboratories Non-a, non-b, non-c, non-c, non-d, non-e hepatitis reagents and methods for their use
US7166287B1 (en) 1989-12-18 2007-01-23 Glaxo Wellcome Inc. Viral agent

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US5191064A (en) * 1988-09-30 1993-03-02 The Research Foundation For Microbial Diseases (Osaka University) Non-a, non-b hepatitis virus antigen peptide
ATE346302T1 (de) * 1990-08-25 2006-12-15 Bioprocess Pty Ltd Nicht-a, nicht-b hepatitis virus antigen, und diagnostische verfahren.

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FR2606515A1 (fr) * 1986-11-07 1988-05-13 Pasteur Institut Procede pour l'isolement d'un nouvel agent viral et de l'antigene qui lui est associe, agent viral et antigene obtenus par ce procede et procede de detection dudit antigene a l'aide d'un reactif immunologique approprie
EP0293274A1 (fr) * 1987-03-31 1988-11-30 Mitsubishi Kasei Corporation Molécules d'ADN codants pour antigènes de non A, non B hépatite, et leur utilisation pour la production desdits antigènes
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US4464474A (en) * 1980-07-09 1984-08-07 Connaught Laboratories Limited Non-A, non-B hepatitis assay and vaccine
US4702909A (en) * 1982-05-05 1987-10-27 Louisiana State University A & M Non-A, non-B hepatitis antigen, antigen compositions, vaccine and diagnostic reagent
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CN1041005A (zh) 1990-04-04
JPH04501203A (ja) 1992-03-05

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