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Two Randomized Controlled Trials

Lawrence Corey, MD; Andria G. M. Langenberg, MD; Rhoda Ashley, PhD; Rose E. Sekulovich, PhD; Allen E. Izu, MS; John M. Douglas, Jr, MD; H. Hunter Handsfield, MD; Terri Warren, NP, RN; Lisa Marr, MD; Stephen Tyring, MD, PhD; Richard DiCarlo, MD; Adaora A. Adimora, MD, MPH; Peter Leone, MD; Cornelia L. Dekker, MD; Rae Lyn Burke, PhD; Wai Ping Leong, MS; Stephen E. Straus, MD; for the Chiron HSV Vaccine Study Group

JAMA. 1999;282:331-340.

Context  In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic.

Objective  To evaluate the efficacy of a vaccine for prevention of HSV-2 infection.

Design  Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 µg each of 2 major HSV-2 surface glycoproteins (gB₂ and gD₂) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization.

Setting and Participants  We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2–seronegative partners of HSV-2–infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion 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 seroconversion or isolation of HSV-2 in culture during the study period by randomization group.

Results  Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, 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 vaccine recipients acquiring HSV-2 infection showed vaccination had no significant 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 placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2–specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes.

Conclusions  Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.

Author Affiliations: University of Washington (Drs Corey and Ashley), Harborview Medical Center (Dr Handsfield), and Children's Hospital & Regional Medical Center (Dr Ashley), Seattle; Denver Disease Control Service, Denver, Colo (Dr Douglas); Westover Heights Clinic, Portland, Ore (Ms Warren and Dr Marr); University of Texas Medical Branch, Galveston (Dr Tyring); Louisiana State University, New Orleans (Dr DiCarlo); University of North Carolina School of Medicine, Chapel Hill (Dr Adimora); Wake County Health Department, Raleigh, NC (Dr Leone); National Institutes of Health, Bethesda, Md (Dr Straus); and Chiron Corporation HSV Vaccine Study Group, Emeryville, Calif (Drs Langenberg, Sekulovich, Dekker, and Burke and Mr Izu and Ms Leong).

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RELATED LETTER

Immunologic Strategies for Herpes Vaccination
Harvey M. Friedman, Christopher Hartley, Lawrence Corey, Andria G. M. Langenberg, Rae Lyn Burke, Stephen Straus, and John R. Mascola
JAMA. 2000;283(6):746.
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