Having completed over a decade of work on antiviral treatment of genital herpes, we turned to studies of disease prevention and immunotherapy. We completed an open 2 year phase 1 assessment of a new recombinant HSV-2 glycoprotein D vaccine in alum in 24 adults, some with and without prior HSV-1 and/or 2 infection. Vaccinations of 30 ug or 100 ug were given at 0, 1, 2, and 12 months and were associated with minimal local or systemic reactions. The vaccine induced excellent primary antibody in cellular immune responses and augmented preexisting humoral and cellular responses significantly. We studied antibody and T cells from previously uninfected subjects and showed that the gD2 epitopes that the antibody and cell recognize correspond to those in genital herpes patients. On the basis of these excellent responses we enrolled patients with recurrent genital herpes into a placebo-controlled vaccine trial in collaboration with the University of Washington. The goal was to determine whether boosted immunity leads to less frequent recurrences. Upon completing the study we documented that of 98 subjects, those who received the gD2 vaccine in alum experienced 1/4 - 1/3 fewer recurrences than those receiving alum alone. This is the first trial to demonstrate efficacy in the immunotherapy of a chronic viral infection. Rates of disease improvement, though, were lower than would be expected with acyclovir suppressive therapy so we began a dose seeking study and an efficacy study using gD2 combined with gB2 in a lipid adjuvant MF59. This was completed in FY1993. Based on the data we initiated 2 further controlled trials, one for immunotherapy, the other for prophylaxis. We completed enrollment of the immunotherapy trial in which patients are vaccinated with gB2/g02/MFSG at 0, 2, 12, and 14 months and followed for recurrence of rats and severity for 18 months. The study will close in October 1995. We also completed enrollment of a multicenter study of gB2/gD2/MF59 for prevention of genital herpes.