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WO1989000861A1 - Vaccination contre des virus apparentes a la rage - Google Patents

Vaccination contre des virus apparentes a la rage Download PDF

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Publication number
WO1989000861A1
WO1989000861A1 PCT/US1988/002529 US8802529W WO8900861A1 WO 1989000861 A1 WO1989000861 A1 WO 1989000861A1 US 8802529 W US8802529 W US 8802529W WO 8900861 A1 WO8900861 A1 WO 8900861A1
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WIPO (PCT)
Prior art keywords
rabies
polypeptide
virus
related virus
nucleoprotein
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1988/002529
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English (en)
Inventor
Bernhard Dietzschold
Hilary Koprowski
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Wistar Institute of Anatomy and Biology
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Wistar Institute of Anatomy and Biology
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Filing date
Publication date
Application filed by Wistar Institute of Anatomy and Biology filed Critical Wistar Institute of Anatomy and Biology
Priority to AU21364/88A priority Critical patent/AU608354B2/en
Publication of WO1989000861A1 publication Critical patent/WO1989000861A1/fr
Priority to NO89891355A priority patent/NO891355L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • 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
    • C12N2760/20011—Rhabdoviridae
    • C12N2760/20111—Lyssavirus, e.g. rabies virus
    • C12N2760/20122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • This invention relates to rabies virus and rabies-related viruses. More particularly it relates to methods of immunizing host animals to protect against infections with rabies and rabies-related viruses.
  • Rabies virus continues to be endemic in most areas of the world. It causes an acute central nervous system disease which is normally fatal to humans and domestic and wild animals.
  • the virus structure is bullet-shaped, consisting of a nucleocapsid core surrounded by a membrane envelope.
  • the nucleocapsid is comprised of a single, non-segmented strand of RNA together with RNA transcriptase (L), phosphoprotein (NS), and nucleoprotein (N).
  • L RNA transcriptase
  • NS phosphoprotein
  • N nucleoprotein
  • the N protein which is the major portion of the nucleocapsid, is noncovalently bound to the RNA to form the helicar ribonucleo- protein (RNP) complex.
  • G major surface antigen
  • M matrix protein
  • Virus-neutralizing antibodies raised in animals against rabies virus only recognize the G protein.
  • the level of antibody production has been thought to correlate with the degree of protection afforded against live virus infection. See Crick, Post graduate Medical Journal, Vol. 49, p. 551 (1973) and Sikes, et al., Journal of American Veterinary Medical Association, Vol. 150, p. 1491 (1971).
  • antibody alone is not sufficient to protect from viral infection.
  • passive immunization with anti-rabies antibodies without a vaccine as post-exposure therapy does not decrease the probability of infection.
  • effective vaccines which do not induce high level antibody production.
  • One such vaccine is produced by Norden Labs.
  • rabies virus may require both virus-neutralizing antibodies and effector T-eell responses.
  • G protein and the nucleoprotein (N) have been shown to stimulate proliferation of rabies antigen-specific T cell lines. Most such T cell lines respond strongly to N protein and less strongly to G protein. A minority of rabies reactive T cell lines respond to G protein, but not at all to N protein. Celis et al., Journal of Immunology, Vol. 136, pp. 692-697, ⁇ 1986). It has not been shown previously that N protein provides any protection against rabies infection in immunocompetent animals or humans. Current vaccines against rabies consist of an inactivated rabies virus.
  • the present invention provides an improved method for inducing protective immunity to rabies-related viruses comprising administering a priming injection of an antigen and one or more booster injections, the improvement comprising employing a polypeptide having amino acid sequence homology to rabies-related virus nucleoprotein as said priming injection, said polypeptide being substantially free of rabies-related virus glycoprotein, said polypeptide having the ability to induce proliferation of rabies-related virus-specific human T cells.
  • a biologically pure sample of a polypeptide capable of inducing a proliferative response in rabies-related virus-specific human T cells, said polypeptide having sequence homology with the nucleoprotein of rabies-related virus and having the ability to induce protective immunity to rabies-related viruses.
  • a method for inducing protective immunity to a rabies-related virus comprising administering an injection of a preparation comprising a polypeptide having sequence homology with the nucleoprotein of a rabies-related virus, said polypeptide being capable of inducing a proliferative response in rabies-related virus-specific human T cells, said polypeptide being substantially free of rabies-related virus glycoprotein.
  • the vaccines of this invention can be produced without growing the rabies virus and they do not cause the adverse side effects associated with inactivated virus vaccines.
  • the vaccine provides protection against heterologous rabies-related virus strains. DETAILED DESCRIPTION OF THE INVENTION
  • nucleoprotein of rabies virus a protein which is internal to the membranous envelope of the virus, can serve as an effective inducer of both humoral and cellular immune responses.
  • N protein amino acid residues 313-337
  • this isolated region of the protein (as well as two other regions, corresponding to amino acid residues 369-383 and 394-408) is able to stimulate proliferation of rabies antigen-specific human T cells in the presence of irradiated autologous mononuclear cells.
  • Suitable peptides may be found which are able to stimulate proliferation of rabies antigen-specific human T cells and which can provide protective immunity to rabies infection. Stimulation of proliferation of T cells can be tested according to the method of Celis et al, J. Immunol. 56:426-433 (1985), and in Example 6 below. Protective immunity can be tested according to standard methods known in the art and described in Example 7 below.
  • rabies prophylaxis is performed by a series of injections, the first one being termed a priming injection and subsequent ones termed boosters.
  • Methods for administering such injections including appropriate formulations, dosages, anatomical localizations and timing are generally known in the medical and veterinary sciences.
  • the dosage desired is such that will induce a protective response without causing side effects or immune tolerance.
  • Standard inactivated rabies virus vaccine for example, may be used in the practice of the present invention as a booster inoculation.
  • the inactivation of virus is generally performed by treatment with a chemical, such as beta-propiolactone.
  • a vaccine is available, for example, from Institut Merieux, Lyon, France.
  • rabies- related virus is meant to encompass both rabies as well as rabies-related viruses such as the Mokola and European bat virus (e.g. the Duvenhage 6 strain). This definition is used because of the finding that the vaccines of the present invention provide cross-protection to heterologous virus strains. This is a great benefit provided by the present invention over prior vaccines.
  • Subunits of the rabies-related virus such as N protein or RNP complex- may be prepared and purified according to known methods. See, for example, Virology 124:330 (1983) and J. Virol. 7:241 (1971). Even purer preparations of N protein can be obtained by preparative gel electrophoresis, as described in J. Virol, 44:596 (1982). Other purification steps may be used, as are known in the art.
  • the useful polypeptides of the present invention can be most easily prepared by chemical synthesis, according to the solid phase method described by Merrifield, Adv. Enzymol., 32:221-296 (1969).
  • proteolysis of N protein can be accomplished using enzymes or chemicals, e.g., trypsin, 3-bromo-3-methyl-2 [(2-nitrophenyl) thiol] -3 H-indole skatole, cyanogen bromide, or protease V8. Fragments after cleavage can be separated by gel electrophoresis, for example. Although many fragments can be found which are reactive with monoclonal antibodies raised against rabies N protein, only some fragments are also able to stimulate rabies-specific T cell proliferation.
  • N-V12b This fragment, termed N-V12b, was originally produced by protease V-8 treatment of N protein, and later chemically synthesized. Fragments N-V10c and D30 were also found to stimulate T cell proliferation, although to a lesser degree. Fragment N-V12b corresponds to the amino acids 313-337 of N protein; fragment N-V10c corresponds to amino acids 369-383; and fragment D30 corresponds to amino acids 394-405. The sequences are shown below in Table 4. The sequence of the N protein has been previously determined by Tordo et al., Nucleic Acids Research, Vol. 14, pp. 2671-2683 (1986).
  • the synthetic peptides When the synthetic peptides are coupled to a protein, e.g. keyhole limpet hemocyanin, either via thiol groups (Biochemistry 18:690-697 (1979)) or via amino groups with glutardialdehyde, they are found to stimulate anti-N protein antibodies in rabbits. However, the antibody titer was lower in anti-N-V12b serum than in anti-N-V10c serum.
  • a protein e.g. keyhole limpet hemocyanin
  • sequences of the polypeptides are defined herein with particularity (Table 4) it will be apparent to one skilled in the art that some of the amino acids can be conservatively substituted without losing the beneficial characteristics. It is also apparent to one skilled in the art that changes in length can be made without altering the antigenicity. The minimum number of amino acids necessary to comprise the epitopes has not been determined.
  • polypeptides of the present invention can also be prepared through genetic engineering. That is to say that parts or all of the N gene can be cloned into suitable expression vectors, as are known in the art. Organisms transformed with the cloned gene or portion thereof can be grown to produce the polypeptide products. Recovery of the polypeptide products is within the ordinary skill of the art. Combinations or concatemers of antigenic polypeptide fragments can also be used. These can be made by synthesis, cloning, or post-synthetic covalent bonding. Liposomes, which can be employed in the practice of the present invention, are known in the art. They are used as a macromolecular carrier for the polypeptides to ensure antigenicity.
  • Liposomes may be formed, e.g., according to the method of Thibodeau, "Genetic variation among influenza viruses," Acad. Press, N.Y. (1981) p. 587. Generally, a mixture of lipids in particular ratios, such as phosphatidyl choline, cholesterol, and lysophosphatidyl choline, are mixed under conditions to form closed lipid vesicles. Many such conditions and methods are known in the art.
  • the polypeptides are eoupled to a saturated fatty acid having from about 15 to about 21 carbon atoms, before mixing with the lipid composition to form liposomes.
  • Suitable fatty acids include, palmitic, stearic and oleic acids.
  • Conjugates may be formed by the method of Hopp, Molecular Immunology, 21:13-16 (1984), wherein peptide fragment spacers of gly-gly-lys-(NH 2 ) 2 are added to the N-terminus of the polypeptide, and the alpha and epsilon amino groups of lysine are used to couple with the fatty acids.
  • the biologically pure samples of the polypeptides of the present invention are substantially free of glycoprotein of rabies virus. They are sufficiently pure that after injection into mice, rabies glycoprotein-specific antibody or T cells are not induced. In addition, rabies glycoprotein specific T cells would not be stimulated in vitro to proliferate in the presence of the preparation.
  • This example describes the selection of a multiple variant virus of rabies virus.
  • Seven anti-glycoprotein monoclonal antibodies capable of neutralizing parent CVS-11 rabies virus were used to sequentially select antigenic variants. Serial dilutions of virus were mixed with monoclonal antibody diluted 1:100, overlayed with nutrient agar, and after 4 to 5 days of incubation at 35°C in a 5% carbon dioxide atmosphere, plaques were selected. Viruses able to replicate in the presence of the monoclonal antibodies used for their selection were recovered. The seventh generation variant CVS-V7 was not neutralized by any of 40 different rabies virus-specific neutralizing monoclonal antibody. The nucleoprotein antigen of the CVS-V7 virus remained immunologically indistinguishable from that of the CVS-11 parent virus.
  • This example shows the protection afforded by vaccination with the CVS-V7 virus, as well as the virus neutralizing antibodies it induced against parent strain CVS-11.
  • Vaccines prepared from the CVS-V7 variant viruses were used to immunize mice. Groups of nine 4-week old female ICR mice were immunized with 0.2 ml of 5 serial dilutions (2000-3 ng) of the CVS-V7 inactivated virus vaccine on days 0 and 7.
  • the inactivated virus vaccine was prepared with beta-propiolactone and adjusted to a protein concentration of 100 ug/ml. The viruses had been grown on BHK 21 cell monolayers and purified as described in Journal of Virology, Vol. 21, pp. 626-635 (1977).
  • CVS-11 On day 14, vaccinated and unvaccinated control mice were bled and infected intracerebrallv with 0.03 ml (50 MIC LD 50 ) of CVS-11. (CVS-11 parent virus was used in the challenge because the CVS-V7 variant virus was not pathogenic for adult mice.) The animals were observed for 3 weeks and mortalities were recorded daily. The effective dose was calculated for each vaccine as described in Atansiu, P., "Quantitative assay and potency test of antirabies serum," In: Laboratory Techniques In Rabies, 2nd Ed., Geneva: World Health Organization, 1966, pp. 167-72. The neutralizing activity of the mouse immune sera for CVS-11 was determined as described in Lumio et al., Lance, Vol. i, p. 378 (1986).
  • the geometric mean tighter (GMT) was calculated for each vaccination group. Multiple group comparisons for differences in GMT were tested by one way analysis of variance and two-group GMT were compared statistically by a one-tailed test.
  • This example demonstrates the protection afforded and the virus neutralizing antibody induced by means of rabies virus subunit vaccines which are formulated with liposomes.
  • the glycoprotein and ribonucleoprotein (RNP) were purified from the CVS-V7 variant virus as described in Dietzchold et al., CVS-V7-G- CVS-V7-N- some ⁇ -r ⁇ » Mortality Rat* no*)
  • the RNP incorporated into liposomes induced no detectable VNA against CVS-11 nor any detectable protection from death.
  • the CVS-V7-derived G protein incorporated into liposomes indueed low titers of VNA and poor protection from death.
  • the treatment was significantly better than either protein alone, and produced results roughly comparable to those obtained with the whole virus vaccine. This too, shows the importance of N protein in immunity to rabies.
  • rabies virus RNP can augment the function of B cells producing neutralizing antibody.
  • mice were primed with either 5 ug of N protein (from the ERA strain of rabies) plus complete Freund's adjuvant (CFA) or CFA alone. Ten days after priming both groups of animals received serial dilutions of inactivated rabies virus vaccine or isolated rabies glycoprotein. Mice that were primed with RNP plus CFA and boosted with rabies virus vaccine developed significantly higher VNA titers than those mice primed with CFA alone and then boosted with a rabies virus vaccine. The results are shown in Table 2. In addition, the effective dose of rabies virus vaccine was determined and found to be about 10-fold lower in the mice which had been primed with RNP.
  • mice which received booster vaccinations consisting of just rabies virus glycoprotein developed only low levels of VNA and were poorly protected against a lethal challenge infection with rabies virus, which can be seen in the right half of Table 2. This suggests that there must be common antigens between the priming and boosting immunizations in order to induce an effective immune response.
  • the mortality rates shown in Table 2 were determined by challenging all mice with an intracerebral innoculation with 50 MIC LD 50 of rabies virus and observing the survival up to 3 weeks post-infection.
  • RNP of the ERA strain of rabies or of the rabies-related strain Mokola was used to immunize Balb/c mice against an (I.M.) challenge with the rabies strain CVS-24.
  • the RNP was isolated and purified according to the method of Schneider, et al., J. Virol., Vol. 11, pp. 748-755 (1973). Groups of 10 to 20 mice were immunized intraperitoneally (I.P.) with ERA-or Mokola-RNP plus CFA, or with CFA alone, or subcutaneously (S.C.) with ERA-RNP alone. Four weeks after immunization, the mice were challenged (I.M.) with eight mouse I.M. LD 50 of CVS-24 rabies virus
  • CFA complete Freund Adjuvant
  • Peptides were cleaved and deblocked with HF/thioanisol (10:1) at 0°C for 30 min, and the peptide was extracted with 0.1 M NH 4 HCO 3 and lyophilized. The crude peptide was then dissolved in 0.1 M NH 4 HCO 3 and purified on a BioGelTM P4 column calibrated with 0.1 M NH 4 HCO 3 . The eluted peptide was then applied to a Vydac RP C18 reverse-phase column and eluted with methanol- water (8:2). The elution of the peptide was monitored with a UV detector at 214 nm. To verify the amino acid sequence, aliquots of the peptide were subjected to amino acid analysis and amino acid sequencing.
  • the peptides were tested for the ability to stimulate T-cell proliferation in the presence of antigen-presenting populations of cells of the same HLA-DR type.
  • concentrations of 0.4 ug/ml to 25 ug/ml of protein, fragments N-V12b and N-V10c, and N protein isolated from ERA strain virus stimulated proliferation of the T-cells.
  • N-V12b was more stimulatory than N protein, whereas at higher concentrations the reverse was true.
  • mice Groups of 5 to 10 mice were immunized intraperitoneally with N-V12b-liposomes plus CFA, N-V10c-liposomes plus CFA, or liposomes plus CFA. The mice were then challenged with various amounts of CVS-24 virus.
  • the liposomes were formed by the method of Thibodeau, Genetic Variations Among Influenza Viruses, Acad. Press, N.Y., 587 (1981).
  • the peptides were incorporated into liposomes as described above in Example 3.
  • palmitic acid was linked to the amino terminal end of the peptide as described by Hopp, Mol. Immunol., Vol. 21, pp. 13-16, 1984.
  • two times the mouse LM. LD 50 was used as challenge.
  • Table 6 88% of the mice that received the N-V12b-liposome vaccine survived while none of the mice immunized by N-V10c-liposome survived three weeks after the challenge.
  • mice immunized with peptide N-V12b-liposome vaccine survived while only 12% of the mice which received the control vaccine of liposomes plus CFA survived the challenge.
  • mice immunized with the N-V12b-liposome vaccine survived the challenge, while only 10 and 20 percent respectively of the mice immunized with N-V10 liposomes plus CFA and liposome control vaccine plus CFA survived.
  • peptide N-V12b provides good protection from rabies virus challenge when incorporated into liposomes and administered with CFA.
  • Peptide N-V10c does not provide good
  • Peptides consisting of 15 amino acids were synthesized which together correspond to the entire amino acid sequence of the ERA-N protein. These were synthesized as described above in Example 6. Each peptide was screened for T cell proliferative activity in vitro and for protective activity in vivo as described above for peptides N-V12b and N-V10c.
  • Peptide number 30D demonstrated both significant T cell stimulatory activity as well as partial but significant protection against rabies virus challenge.
  • Peptide D30 protected 60% of the immunized mouse population from a challenge of 8 times the mouse I.M. LD 50 of CVS-24 virus.

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Abstract

Sont décrits des procédés de vaccination destinés à produire une immunisation protectrice contre la rage et les virus apparentés à la rage, mettant en oeuvre des polypeptides synthétiques mis au point génétiquement ou dérivés de la rage. La séquence des polypeptides est dérivée de la protéine N. Les cellules à la fois B et T sont stimulées par ces polypeptides antigéniques, afin de produire une immunisation contre la rage et autres infections apparentées.
PCT/US1988/002529 1987-07-30 1988-07-29 Vaccination contre des virus apparentes a la rage Ceased WO1989000861A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU21364/88A AU608354B2 (en) 1987-07-30 1988-07-29 Vaccination against rabies-related viruses
NO89891355A NO891355L (no) 1987-07-30 1989-03-30 Vaksinasjon mot rabis-beslektede virus.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7963987A 1987-07-30 1987-07-30
US079,639 1987-07-30

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WO1989000861A1 true WO1989000861A1 (fr) 1989-02-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011358A1 (fr) * 1989-03-29 1990-10-04 Institut Pasteur Procede de detection et/ou d'identification des infections a lyssavirus, clonage et expression de genes codant pour des peptides et/ou des fragments de peptides du lyssavirus mokola, vaccin contre le virus mokola et/ou l'ensemble des lyssavirus ainsi que procede d'obtention dudit vaccin par genie genetique
US6129921A (en) * 1994-04-19 2000-10-10 Thomas Jefferson University Viral ribonucleocapsid as an immunological enhancer
WO2003048198A3 (fr) * 2001-12-07 2004-04-22 Pasteur Institut Polypeptides induisant l'apoptose, polynucleotides les codant et leurs applications therapeutiques
US9248179B2 (en) 2010-06-24 2016-02-02 The United States of America, as represented by the Secretary of the Department of Health and Human Services, Centers for Disease Control and Prevention Pan-lyssavirus vaccines against rabies

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0203676A2 (fr) * 1985-04-19 1986-12-03 The Wistar Institute Of Anatomy And Biology Vaccin produisant une réponse en cellules T immunogènes protectrice contre un virus
EP0237686A1 (fr) * 1986-03-18 1987-09-23 Institut Pasteur Séquences d'ADN dérivées du génome du virus de la rage

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0203676A2 (fr) * 1985-04-19 1986-12-03 The Wistar Institute Of Anatomy And Biology Vaccin produisant une réponse en cellules T immunogènes protectrice contre un virus
EP0237686A1 (fr) * 1986-03-18 1987-09-23 Institut Pasteur Séquences d'ADN dérivées du génome du virus de la rage

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
J. GEN. VIROL., (1983), 64, W.H. WUNNER et al., "Rabies Subunit Vaccines", pages 1649-1656. *
J. GEN. VIROL., (1985), Vol. 66, M. LAFON et al., "Antigenic Sites on the ERA Rabies Virus Nucleoprotein and Non-Structural Protein", pages 2125-2133. *
NUCLEIC ACIDS RESEARCH, Vol. 14, No. 6, 1986, N. TORDO et al., "Primary Structure of Leader RNA and Nucleoprotein Genes of the Rabies Genome: Segmented Homology With VSV", pages 2671-83. *
PROC. NATL. ACAD. SCI. U.S.A., Vol. 84, December 1987, B. DIETZSCHOLD et al., "Induction of Protective Immunity Against Rabies by Immunization With Rabies Virus Ribonucleoprotein", pages 9165-9169. *
THE JOURNAL OF IMMUNOLOGY, Vol. 136, No. 2, 15 January 1986, E. CELIS et al., "Isolation and Characterization of Human T Cell Lines and Clones Reactive to Rabies Virus: Antigen Specificity and Production of Interferon-gamma", pages 692-96. *
VIRUS RESEARCH, 8, (1987), B. DIETZSCHOLD et al., "Localization and Immunological Characterization of Antigenic Domains of the Rabies Virus Internal N and NS Proteins", pages 103-125. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011358A1 (fr) * 1989-03-29 1990-10-04 Institut Pasteur Procede de detection et/ou d'identification des infections a lyssavirus, clonage et expression de genes codant pour des peptides et/ou des fragments de peptides du lyssavirus mokola, vaccin contre le virus mokola et/ou l'ensemble des lyssavirus ainsi que procede d'obtention dudit vaccin par genie genetique
FR2645173A1 (fr) * 1989-03-29 1990-10-05 Pasteur Institut Clonage et expression de genes codant pour des peptides et/ou des fragments de peptides du virus mokola, application a la preparation d'un v
US6129921A (en) * 1994-04-19 2000-10-10 Thomas Jefferson University Viral ribonucleocapsid as an immunological enhancer
WO2003048198A3 (fr) * 2001-12-07 2004-04-22 Pasteur Institut Polypeptides induisant l'apoptose, polynucleotides les codant et leurs applications therapeutiques
US9248179B2 (en) 2010-06-24 2016-02-02 The United States of America, as represented by the Secretary of the Department of Health and Human Services, Centers for Disease Control and Prevention Pan-lyssavirus vaccines against rabies

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EP0326598A1 (fr) 1989-08-09
CA1337115C (fr) 1995-09-26

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