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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).

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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