This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) cause frequent human infections. Common manifestations of HSV-1 infection are fever blisters around the nose and/or lips, while those of HSV-2 are irritating or painful genital ulcers, although locations of infections by the two herpesvirus types are occasionally reversed. Asymptomatic infection and severe disease can occur with either herpesvirus type, and both viruses migrate to the central nervous system where they can remain latent and cause reactivation of infection at the original site following periods of stress or other stimuli. Although sexual abstinence and condoms can reduce transmission of genital herpes and antiviral therapy can temporarily suppress local infection, the incidence of seropositivity for HSV-2 has continued to rise. The present study is a Phase III evaluation of the ability of a vaccine, gD-Alum/MPL, to reduce the incidences of genital herpes disease and infection in the most susceptible population, young adult women who are seronegative against both HSV-1 and HSV-2. The primary objective of this study is evaluation of the efficacy of the investigational herpes vaccine in the prevention of genital herpes disease caused by either HSV-1 or HSV-2 between months 2 (post 2nd dose) and 20 in healthy, adult women who were initially seronegative against both HSV-1 and HSV-2 (HSV 1-/2-). Secondary objectives include evaluations of vaccine efficacy for prevention of: 1. Genital disease caused by HSV-1 or HSV-2 between months 7 (post 3rd dose) and 20; 2. HSV-2 infection (confirmed by either culture or seroconversion) between months 2 and 20; and, 3. HSV-2 infection occurring between months 7 and 20. Other objectives include evaluation of: 1. The safety and reactogenicity of the candidate vaccine; 2. Vaccine efficacy at reducing the frequency and quantity of HSV shedding 3-6 months following HSV-2 seroconversion in infected vaccinees versus infected control vaccine recipients; 3. Vaccine efficacy in the prevention of HSV-1 or HSV-2 infection between months 2 and 20 in healthy adult women who were initially HSV 1-/2-; 4. Vaccine efficacy in the prevention of genital herpes disease caused by HSV-2 between months 2 and 20 in healthy adult women who were initially HSV 1-/2-; 5. Vaccine immunogenicity in a subset of randomly selected herpes vaccine recipients (gD ELISA antibodies, HSV neutralizing antibodies, CMI assessments [such as gamma IFN]); 6. Correlates of immune protection against HSV-2 genital herpes disease and against HSV-2 infection (gD ELISA antibody, HSV-2 neutralizing antibody, and measures of CMI such as gamma-IFN production among matched subjects with and without breakthrough genital HSV-2 disease or infection); 7. The impact of the herpes vaccine on the frequency of recurrent genital HSV-2 disease; 8. The efficacy of vaccine against primary oro-labial HSV-1 and HSV-2 disease in HSV 1-/2- women; 9. The efficacy of vaccine against primary other non-genital HSV disease (excluding oro-labial) in HSV 1-/2- women; 10. Vaccine efficacy against genital herpes (types 1 or 2) or HSV-2 infection after 2 doses (months 2-6) and after 3 doses (months 7-20); and, 11. Vaccine efficacy in the prevention of culture-confirmed genital herpes disease caused by either HSV-l or HSV-2 between months 2 (post 2nd dose) and 20 in healthy adult women who were initially HSV 1-/2-.
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