Efficacy results of a trial of a herpes simplex vaccine

Abstract

Background: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women.

Methods: We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20.

Results: The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26).

Conclusions: In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.).

Figure 1. Randomization of Study Subjects

Both modified intention-to-treat and per-protocol analyses of efficacy were performed. Before the treatment assignments were revealed, an audit showed serious protocol violations at a single site; the sponsors declared that data from subjects at this site could not be evaluated for efficacy. The intention-to-treat analysis included all vaccinated subjects except those at the site with serious protocol violations, those who were found to be HSV-seropositive at study entry, and those who did not return to the clinic after vaccination. The per-protocol analyses were further restricted to subjects who received either two doses of vaccine (per-protocol cohort for months 2 through 20) or three doses (per-protocol cohort for months 7 through 20) within protocol-specified windows, were uninfected at the start of each respective risk period, and did not have prespecified protocol deviations that might have confounded assessment of exposure, immunogenicity, or efficacy. Immunogenicity was evaluated in a random sample of subjects in the per-protocol cohort for months 7 through 20, with censoring of results after infection. A total of 31,770 women were screened by Western blot analysis for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) antibodies for the Herpevac Trial, of whom 39% were seronegative for both and 26% were vaccinated in the trial. The target treatment-assignment ratio was 1:1, but owing to a programming error, the initial subjects were randomly assigned at a 3:1 ratio in favor of the HSV-vaccine group. The data safety and monitoring board identified the problem, and randomization was corrected to a 1:1 ratio for the balance of the trial, resulting in a final ratio of 55:45 in favor of the HSV-vaccine group.

Figure 2. Cumulative Incidence of Genital Disease Caused by HSV in the Per-Protocol Cohort from Month 2 (1 Month after Dose 2 of Vaccine) through Month 20

Panel A shows the incidence of genital disease caused by either HSV-1 or HSV-2. Panel B shows the incidence caused by HSV-1 only. Panel C shows the incidence caused by HSV-2 only.