Globally, an estimated 16.2% of the human population is infected with HSV-2 including >17% of the U.S. adult population. Genital herpes is associated with an increased risk of HIV acquisition and transmission and HSV-2 infection can cause neonatal herpes with high infant mortality. HSV-2 infection in the adult population has increased substantially in the past two decades despite the availability of antiviral drugs. Although long-term antiviral drug treatment can lower the frequency of viral shedding and severity of recurrences, compliance and potential decreases in HSV-specific immune responses are problematic. The failure of antiviral drugs to prevent the spread of HSV-2 and the sheer magnitude of the public health problem associated with HSV-2 infection indicates a need for a safe and effective vaccine. The consensus of experts who attended the HSV workshop (Bethesda, October 2012) is that antibody response alone is not sufficient for protective immunity;mucosal and T cell responses are considered very important. HSV-2 is a very unique virus able to escape from immune surveillance, and inhibit immune responses in order to successfully infect host and establish latency. We made a significant finding in our preliminary data that HSV-2-infected and/or reference vaccine-immunized guinea pigs are not able to elicit vaginal IgA. Unlike others, our technology employs a patented heterologous prime-boost strategy consisting of a DNA vaccine prime given intramuscularly (i.m.) and a protein- encapsulated liposome (Lip) vaccine boost delivered intranasally. The two step protocol that we have developed as a mucosal vaccine regimen results in a broad and potent Th1 cellular and humoral immune response that includes critical CTLs protective responses and mucosal IgA and. To advance the vaccine candidate to clinical trials in this proposal, we request funding to accomplish these following specific research aims, necessary regulatory affair activities for ultimate IND filling and preparation for clinical trial by finalizing a clinical trial team, plan ad assays. " GMPManufacture key mucosal HSV-2 vaccine components. " Develop a cell bank to produce the gD protein using an advanced Glyco-Switch expression system. " Perform GMP manufacturing of HSV-2 gD protein for stability and liposome formulation purposes. " Scale up the production of liposome vaccine from research grade to GMP grade " Conduct a definitive toxicology study and thereby evaluate the safety of the DNA prime and protein- liposome boost vaccine formulations. " Study the immunogenicity and prophylactic efficacy of the mucosal HSV-2 vaccine in both male and HSV-1 sero-positive female guinea pigs. The net result of these research efforts will be to alleviate pain risk and suffering in the 35-40 million Americans with genital Herpes.

Public Health Relevance

Advancing a mucosal HSV-2 vaccine candiate to clinical trials described herein would clearly have an impact on the greater than $1.6 billion spent annually on direct medical costs associated with HSV-2. The Public Health Service (PHS) has recognized the significant public health issues caused by herpes simplex virus. The PHS publication, Healthy People 2010, has set sexually transmitted diseases as a national priority with a goal to reduce the number of adults infected with human papilloma virus and HSV-2.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-IMM-N (12))
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David, Hagit S
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Biomedical Research Models, Inc.
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Yang, Kejian; Varga, Steven M (2014) Mucosal vaccines against respiratory syncytial virus. Curr Opin Virol 6:78-84
Tirabassi, Rebecca S; Ace, Christopher I; Levchenko, Tatyana et al. (2011) A mucosal vaccination approach for herpes simplex virus type 2. Vaccine 29:1090-8