Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection - Two randomized controlled trials

Context In the last 3 decades, herpes simplex virus type 2 (HSV-2) infectio n seroprevalence and neonatal herpes have increased substantially. An effec tive vaccine for the prevention of genital herpes could help control this e pidemic. Objective To evaluate the efficacy of a vaccine for prevention of HSV-2 inf ection. Design Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 mu g each of 2 major HSV-2 s urface glycoproteins (gB(2) and gD(2)) against which neutralizing antibodie s are directed, administered at months 0, 1, and 6. Control subjects were g iven a citrate buffer vehicle. Participants were followed up for 1 year aft er the third immunization. Setting and Participants We enrolled 2393 persons from December 10, 1993, t o April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegati ve. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of H SV-2-infected persons; the other, with 22 centers, enrolled 1862 persons at tending sexually transmitted disease clinics. A total of 2268 (94.8%) met i nclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. Main Outcome Measure Time to acquisition of HSV-2 infection, defined by ser oconversion or isolation of HSV-2 in culture during the study period by ran domization group. Results Time-to-event curves indicated a 50% lower acquisition rate among v accine vs placebo recipients during the initial 5 months of the trial; howe ver, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%) . Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P = .58). Follow-up of vaccin e recipients acquiring HSV-2 infection showed vaccination had no significan t influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P > .10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placeb o, 0.3; P > .10). The vaccine induced high levels of HSV-2-specific neutral izing antibodies in vaccinated persons who did and did not develop genital herpes. Conclusions Efficient and sustained protection from sexual acquisition of H SV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving expos ure over a prolonged period will require a higher degree of vaccine efficac y than that achieved in this study.