Most cases of genital herpes are due to herpes simplex virus (HSV)-2. The rate of HSV-2 infections increased by 30% from 1988 to 1994. In addition to genital herpes, transmission of HSV-2 to neonates causes severe life-threatening infections. Recent studies demonstrate a link between genital herpes and increased rates of transmission of HIV and elevated levels of HIV in the blood. HIV causes a number of opportunistic infections and is associated with increased rates of several cancers including lymphomas. Therefore, an effective HSV-2 vaccine is needed. Several HSV-2 vaccines have tested in humans for prevention or reduction genital herpes disease. A vaccine containing a single viral protein (HSV-2 glycoprotein D) reduced the rate of HSV-2 disease in women who were not previously infected with HSV-1 in two randomized, controlled clinical trials. The HSV-2 glycoprotein D vaccine, however, showed no efficacy in women previously infected with HSV-1 or in men. We postulated that the limited efficacy of the HSV-2 glycoprotein D vaccine is likely due to inadequate induction of cellular immune responses. We have been evaluating a candidate HSV-2 vaccine deleted for two essential genes, termed HSV-2 dl5-29, which was developed by David Knipe at Harvard University. As noted above, while an HSV-2 candidate vaccine consisting of glycoprotein D (gD2) in alum and monophosphoryl lipid A (MPL) reduced genital herpes disease in HSV-1 seronegative women, it was not effective in men or HSV-1 seropositive women. This year, we compared the ability of dl5-29 versus gD2 in alum/MPL to protect guinea pigs from HSV-2 infection. In HSV-1 seronegative animals, dl5-29 induced higher titers of neutralizing antibody, and after vaginal challenge with wild-type virus, dl5-29 resulted in lower rates of vaginal shedding, lower levels of HSV DNA in ganglia, and a trend for less acute and recurrent genital herpes than the gD2 vaccine. In HSV-1 seropositive animals, all three vaccines induced similar titers of neutralizing antibodies and showed similar levels of protection against acute and recurrent genital herpes after vaginal challenge with wild-type virus, but dl5-29 reduced vaginal shedding after challenge more than the gD2 vaccine. Thus, dl5-29 was an effective vaccine in both HSV-1 seropositive and seronegative guinea pigs, and was superior to the gD2 vaccine in reducing virus shedding after challenge in both groups of animals and therefore might help to reduce transmission of HSV-2.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2010
Total Cost
$469,752
Indirect Cost
City
State
Country
Zip Code
Cohen, Jeffrey I (2018) Herpesviruses in the Activated Phosphatidylinositol-3-Kinase-? Syndrome. Front Immunol 9:237
Wang, Kening; Tomaras, Georgia D; Jegaskanda, Sinthujan et al. (2017) Monoclonal Antibodies, Derived from Humans Vaccinated with the RV144 HIV Vaccine Containing the HVEM Binding Domain of Herpes Simplex Virus (HSV) Glycoprotein D, Neutralize HSV Infection, Mediate Antibody-Dependent Cellular Cytotoxicity, and Protect Mice J Virol 91:
Cohen, Jeffrey I (2017) Vaccination to Reduce Reactivation of Herpes Simplex Virus Type 2. J Infect Dis 215:844-846
Odegard, Jared M; Flynn, Patrick A; Campbell, David J et al. (2016) A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and guinea pigs. Vaccine 34:101-9
Wang, Kening; Goodman, Kyle N; Li, Daniel Y et al. (2016) A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2. J Virol 90:562-74
Lamers, Susanna L; Newman, Ruchi M; Laeyendecker, Oliver et al. (2015) Global Diversity within and between Human Herpesvirus 1 and 2 Glycoproteins. J Virol 89:8206-18
Çuburu, Nicolas; Wang, Kening; Goodman, Kyle N et al. (2015) Topical herpes simplex virus 2 (HSV-2) vaccination with human papillomavirus vectors expressing gB/gD ectodomains induces genital-tissue-resident memory CD8+ T cells and reduces genital disease and viral shedding after HSV-2 challenge. J Virol 89:83-96
Newman, Ruchi M; Lamers, Susanna L; Weiner, Brian et al. (2015) Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2. J Virol 89:8219-32
Knipe, David M; Corey, Lawrence; Cohen, Jeffrey I et al. (2014) Summary and recommendations from a National Institute of Allergy and Infectious Diseases (NIAID) workshop on ""Next Generation Herpes Simplex Virus Vaccines"". Vaccine 32:1561-2
Ben-Sasson, S Z; Wang, K; Cohen, J et al. (2013) IL-1? strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol 78:117-24

Showing the most recent 10 out of 15 publications