Development of an effective genital herpes vaccine

Summary

Principal Investigator: William P Halford
Abstract: DESCRIPTION (provided by applicant): For 30 years, an effective vaccine has been sought to prevent genital herpes caused by herpes simplex virus 2 (HSV-2). Most of the research has focused on the development of non-replicating HSV-2 vaccine agents such as the glycoprotein D subunit or replication-defective HSV-2 viruses. Such approaches merit consideration. However, it is unclear that non-replicating HSV-2 vaccines elicit the type of life-long immunity against genital herpes that is sought. For each year that elapses without an effective vaccine, another 10 to 20 million people contract HSV-2 infections. Given the scope of the problem, perhaps it is time to consider a second possibility: a live, replicating HSV-2 vaccine strain may be more effective. Most of our successes in controlling viral disease in the human population have been based upon live, replicating viruses. Live vaccinia virus (the original vaccine) was used to end smallpox epidemics. Poliomyelitis, mumps, measles, rubella, and chickenpox are prevented with childhood vaccines that contain live, replicating viruses that occur in nature, but are attenuated in their disease-causing potential. This, our most successful vaccination modality, has not been adequately considered for its potential to control genital herpes. In large part, this is due to the misconception that a live HSV-2 vaccine strain would be dangerous. The P.I.'s published studies and preliminary data establish that genetic engineering combined with current knowledge of HSV biology may be applied to derive live, replicating HSV-1 and HSV-2 viral vaccines that are safe and immunogenic. In principle, attenuation of HSV is readily achieved because ~30 of 75 HSV genes are not essential for viral replication. Many of these genes, such as the ICP0 gene, are required for HSV to resist repression by the host immune response. The P.I. has worked with interferon-sensitive HSV-1 ICP0- viruses for 10 years. Disruption of the ICP0 gene renders HSV-1 and HSV-2 hypersensitive to repression by interferon-1/2, avirulent in animals, and yet these viruses may serve as powerful immunogens. Mice immunized with a live, replicating HSV-1 ICP0- virus are immune to lethal challenge with 1000 times the LD50 dose of HSV-1 (McKrae strain) or HSV-2 (MS strain). Likewise, mice in which an HSV-2 ICP0- virus replicates at the site of immunization are immune to lethal challenge with HSV-2 MS. A systematic effort has not been made to develop a live and appropriately attenuated HSV-2 virus that may establish an inapparent infection at the site of immunization. The P.I.'s data indicate that HSV-1 or HSV-2's full immunogenic potential is only realized when viral replication occurs in the host. If this hypothesis is correct, then live, replicating HSV vaccine strains may be far more protective than any non-replicating HSV vaccine considered to date. Two years of R21 funding is requested to test this hypothesis, and to begin developing HSV-2 ICP0- viruses that may later be used in human clinical trials if a live HSV-2 vaccine strain proves to be safe and effective in protecting mice, guinea pigs, rabbits, and hamsters against genital herpes. PUBLIC HEALTH RELEVANCE: Interferon-sensitive herpes simplex virus-2 (HSV-2) ICP0- viruses are proposed as a live, replicating HSV-2 vaccine strain. Such live HSV-2 vaccine strains may be capable of preventing the spread of genital herpes, a disease that currently afflicts ~50 million people worldwide. The work proposed herein will test a hypothesis that live, replicating HSV-2 ICP0- viruses provide superior protection against exogenous HSV-2 infections relative to non-replicating HSV-2 vaccines that have been the focus of research for 30 years. It is anticipated that a new live HSV-2 ICP0- vaccine strain will emerge from these studies that warrants advancement to human clinical trials.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Griffithsin protects mice from genital herpes by preventing cell-to-cell spread
    Briana Nixon
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA
    J Virol 87:6257-69. 2013
  2. pmc Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 8:e65523. 2013
  3. ncbi Antigenic breadth: a missing ingredient in HSV-2 subunit vaccines?
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
    Expert Rev Vaccines 13:691-710. 2014
  4. pmc Investigation of the mechanism by which herpes simplex virus type 1 LAT sequences modulate preferential establishment of latent infection in mouse trigeminal ganglia
    Yumi Imai
    University of California at San Francisco, 94143 0412, USA
    J Virol 83:7873-82. 2009
  5. pmc ICP0 antagonizes ICP4-dependent silencing of the herpes simplex virus ICP0 gene
    Mingyu Liu
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 5:e8837. 2010
  6. pmc ICP0 dismantles microtubule networks in herpes simplex virus-infected cells
    Mingyu Liu
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA
    PLoS ONE 5:e10975. 2010
  7. pmc Herpes simplex virus 2 ICP0 mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 5:e12251. 2010
  8. pmc A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 6:e17748. 2011

Scientific Experts

  • William Halford
  • Mingyu Liu
  • Briana Nixon
  • Edward E Schmidt
  • Yumi Imai
  • Martha Stefanidou
  • Lisa Rohan
  • Esra Fakioglu
  • Kenneth E Palmer
  • Betsy C Herold
  • Theodore Segarra
  • Pedro M M Mesquita
  • Carla M Weisend
  • Olivier Lucas
  • Brandon Rakowski
  • Edward Gershburg
  • Todd P Margolis
  • Kathleen Apakupakul
  • Philip R Krause

Detail Information

Publications8

  1. pmc Griffithsin protects mice from genital herpes by preventing cell-to-cell spread
    Briana Nixon
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA
    J Virol 87:6257-69. 2013
    ..These findings demonstrate that griffithsin inhibits HSV-2 by a unique mechanism of blocking cell-to-cell spread and support its further development for HIV and HSV-2 prevention...
  2. pmc Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 8:e65523. 2013
    ..Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes...
  3. ncbi Antigenic breadth: a missing ingredient in HSV-2 subunit vaccines?
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
    Expert Rev Vaccines 13:691-710. 2014
    ..S. clinical trials for 25 years. ..
  4. pmc Investigation of the mechanism by which herpes simplex virus type 1 LAT sequences modulate preferential establishment of latent infection in mouse trigeminal ganglia
    Yumi Imai
    University of California at San Francisco, 94143 0412, USA
    J Virol 83:7873-82. 2009
    ..Additional mapping studies with the HSV-1 LAT deletion viruses dLAT371, 17DeltaSty, and 17Delta348 indicate that most of the LAT 5' exon is not required for HSV-1 to preferentially establish latent infection in A5-positive neurons...
  5. pmc ICP0 antagonizes ICP4-dependent silencing of the herpes simplex virus ICP0 gene
    Mingyu Liu
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 5:e8837. 2010
    ..Therefore, our findings appear to add to the growing list of inexplicable similarities that point to a common evolutionary ancestry between the herpesviruses and tailed bacteriophage...
  6. pmc ICP0 dismantles microtubule networks in herpes simplex virus-infected cells
    Mingyu Liu
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA
    PLoS ONE 5:e10975. 2010
    ....
  7. pmc Herpes simplex virus 2 ICP0 mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 5:e12251. 2010
    ..Based on their avirulence and immunogenicity, we propose that HSV-2 ICP0(-) mutant viruses merit consideration for their potential to prevent the spread of HSV-2 and genital herpes...
  8. pmc A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine
    William P Halford
    Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America
    PLoS ONE 6:e17748. 2011
    ..Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if it contained a live-attenuated HSV-2 virus rather than a single HSV-2 protein...