Replication-deficient rabies virus-based vaccines are safe and immunogenic in mice and nonhuman primates.

Although current postexposure prophylaxis rabies virus (RV) vaccines are effective, approximately 40,000-70,000 rabies-related deaths are reported annually worldwide. The development of effective formulations requiring only 1-2 applications would significantly reduce mortality. We assessed in mice and nonhuman primates the efficacy of replication-deficient RV vaccine vectors that lack either the matrix (M) or phosphoprotein (P) gene. A single dose of M gene-deficient RV induced a more rapid and efficient anti-RV response than did P gene-deficient RV immunization. Furthermore, the M gene-deleted RV vaccine induced 4-fold higher virus-neutralizing antibody (VNA) levels in rhesus macaques than did a commercial vaccine within 10 days after inoculation, and at 180 days after immunization rhesus macaques remained healthy and had higher-avidity antibodies, higher VNA titers, and a more potent antibody response typical of a type 1 T helper response than did animals immunized with a commercial vaccine. The data presented in this article suggest that the M gene-deleted RV vaccine is safe and effective and holds the potential of replacing current pre- and postexposure RV vaccines.

[1]  M. Schnell,et al.  Immune modulating effect by a phosphoprotein-deleted rabies virus vaccine vector expressing two copies of the rabies virus glycoprotein gene. , 2008, Vaccine.

[2]  A. Traoré,et al.  Fighting rabies in Africa: the Africa Rabies Expert Bureau (AfroREB). , 2008, Vaccine.

[3]  J. Blanton,et al.  Rabies surveillance in the United States during 2007. , 2008, Journal of the American Veterinary Medical Association.

[4]  M. Meltzer,et al.  Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices. , 2008, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[5]  M. Schnell,et al.  The dynein light chain 8 binding motif of rabies virus phosphoprotein promotes efficient viral transcription , 2007, Proceedings of the National Academy of Sciences.

[6]  J. McQuiston,et al.  Human Rabies Exposures and Postexposure Prophylaxis in South Carolina, 1993–2002 , 2006, Public health reports.

[7]  L. Eisenlohr,et al.  Enhanced humoral HIV-1-specific immune responses generated from recombinant rhabdoviral-based vaccine vectors co-expressing HIV-1 proteins and IL-2. , 2006, Virology.

[8]  N. Ito,et al.  Characterization of M Gene‐Deficient Rabies Virus with Advantages of Effective Immunization and Safety as a Vaccine Strain , 2005, Microbiology and immunology.

[9]  S. Inoue,et al.  Characterization of P gene-deficient rabies virus: propagation, pathogenicity and antigenicity. , 2005, Virus research.

[10]  Nipada Ruankaew,et al.  Transmission dynamics of rabies virus in Thailand: Implications for disease control , 2005, BMC infectious diseases.

[11]  M. Meltzer,et al.  Re-evaluating the burden of rabies in Africa and Asia. , 2005, Bulletin of the World Health Organization.

[12]  I. Raw,et al.  Vero-cell rabies vaccine produced using serum-free medium. , 2004, Vaccine.

[13]  M. Schnell,et al.  In vitro growth and stability of recombinant rabies viruses designed for vaccination of wildlife. , 2004, Vaccine.

[14]  Yun Zhang,et al.  [Recombinant replication-defective adenovirus based rabies vaccine]. , 2003, Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae.

[15]  J. Orenstein,et al.  Functional Human Immunodeficiency Virus Type 1 (HIV-1) Gag-Pol or HIV-1 Gag-Pol and Env Expressed from a Single Rhabdovirus-Based Vaccine Vector Genome , 2003, Journal of Virology.

[16]  R. Pomerantz,et al.  Second-Generation Rabies Virus-Based Vaccine Vectors Expressing Human Immunodeficiency Virus Type 1 Gag Have Greatly Reduced Pathogenicity but Are Highly Immunogenic , 2003, Journal of Virology.

[17]  C. Hanlon,et al.  Rabies DNA vaccination of non-human primates: post-exposure studies using gene gun methodology that accelerates induction of neutralizing antibody and enhances neutralizing antibody titers. , 2002, Vaccine.

[18]  D. Tang,et al.  Induction of protective immunity by topic application of a recombinant adenovirus expressing rabies virus glycoprotein. , 2002, Veterinary microbiology.

[19]  E. Fèvre,et al.  Estimating human rabies mortality in the United Republic of Tanzania from dog bite injuries. , 2002, Bulletin of the World Health Organization.

[20]  C. Hanlon,et al.  One-time gene gun or intramuscular rabies DNA vaccination of non-human primates: comparison of neutralizing antibody responses and protection against rabies virus 1 year after vaccination. , 2001, Vaccine.

[21]  C. Pereira,et al.  Higher production of rabies virus in serum-free medium cell cultures on microcarriers. , 2001, Journal of biotechnology.

[22]  J. Orenstein,et al.  Expression and Immunogenicity of Human Immunodeficiency Virus Type 1 Gag Expressed by a Replication-Competent Rhabdovirus-Based Vaccine Vector , 2001, Journal of Virology.

[23]  T. Müller,et al.  Immunogenicity of an E1-deleted recombinant human adenovirus against rabies by different routes of administration. , 2001, The Journal of general virology.

[24]  D. Montefiori,et al.  Enhanced avidity maturation of antibody to human immunodeficiency virus envelope: DNA vaccination with gp120-C3d fusion proteins. , 2001, AIDS research and human retroviruses.

[25]  D. Lodmell,et al.  Post-exposure DNA vaccination protects mice against rabies virus. , 2001, Vaccine.

[26]  D. Lodmell,et al.  Rabies vaccination: comparison of neutralizing antibody responses after priming and boosting with different combinations of DNA, inactivated virus, or recombinant vaccinia virus vaccines. , 2000, Vaccine.

[27]  R. Pomerantz,et al.  Recombinant rabies virus as potential live-viral vaccines for HIV-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  N. B. Ray,et al.  DNA vaccination of mice against rabies virus: effects of the route of vaccination and the adjuvant monophosphoryl lipid A (MPL). , 2000, Vaccine.

[29]  R. Kennedy,et al.  Comparison and Characterization of Immunoglobulin G Subclasses among Primate Species , 1999, Clinical Diagnostic Laboratory Immunology.

[30]  K. Conzelmann,et al.  Matrix Protein of Rabies Virus Is Responsible for the Assembly and Budding of Bullet-Shaped Particles and Interacts with the Transmembrane Spike Glycoprotein G , 1999, Journal of Virology.

[31]  C. Hanlon,et al.  DNA immunization protects nonhuman primates against rabies virus , 1998, Nature Medicine.

[32]  Z. Fu,et al.  Rabies virus quasispecies: implications for pathogenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  N. B. Ray,et al.  Gene gun particle-mediated vaccination with plasmid DNA confers protective immunity against rabies virus infection. , 1998, Vaccine.

[34]  T. Strine,et al.  Rabies surveillance in the United States during 1994. , 1995, Journal of the American Veterinary Medical Association.

[35]  C. Dolea,et al.  World Health Organization , 1949, International Organization.