STD Quarterly: Herpes vaccine research may hold key to stemming STD

Researchers enrolling some 8,000 women in pivotal efficacy trial

You have just finished counseling a young woman who is frightened and confused after hearing she has contracted genital herpes. While you are able to offer her daily suppressive therapy to help reduce the frequency of outbreaks, you discuss the fact that there is no cure for this sexually transmitted disease (STD).

What if there were a vaccine available that would offer protection against the types of herpes simplex virus (HSV) that lead to genital herpes, HSV-2, and in some cases, HSV-1? Researchers may be closer to delivering such a vaccine, as a major pivotal efficacy trial of an experimental vaccine has just begun following the publication of Phase III trial results indicating that an experimental vaccine reduced the incidence of genital herpes by more than 70% in uninfected women.1

The pivotal trial eventually will enroll 7,550 women in at least 16 sites in the United States. It is the result of a partnership between the Bethesda-based National Institute of Allergy and Infectious Diseases (NIAID) and the vaccine’s manufacturer, GlaxoSmithKline Biologicals, with headquarters in Rixensart, Belgium.

Finding thousands of HSV-negative women for the new trial will be a significant challenge, says Pamela McInnes, DDS, MSc, deputy director of NIAID’s Division of Microbiology and Infectious Diseases.

"In the adult population as a whole, it is estimated that one in four women has HSV-2, and an estimated 66% of adults have HSV-1," she states. "Depending on the population being screened, we anticipate screening at least three women for every one determined to be both HSV-1- and HSV-2-negative."

The need for a vaccine is great: More than 1 million new cases of genital herpes are diagnosed in the United States each year. According to two national surveys between the 1970s and the 1990s, genital herpes increased fastest among white teens ages 12-19.2 Herpes prevalence in that population was five times greater than the prevalence in the 1970s. Among young white adults ages 20-29, herpes prevalence increased twofold over that same time period.

While genital herpes infection often manifests itself in subtle symptoms, it can be a devastating illness in newborns, and it also has been identified as a risk factor for the spread of HIV/AIDS in adults.

Examine new results

Results of the latest research stem from two trials of the vaccine, reported in the same paper.1 The initial study analyzed the effects of the three-dose vaccine in a total of 268 women and 579 men free from infection with HSV-1 and HSV-2. In the second study, researchers looked at 710 women and 1,157 men who had not been infected with HSV-2. In both groups, the study subjects’ regular sexual partners had a history of genital herpes. As in the first study, the recipients were injected with the vaccine followed by a second dose a month later and a third dose after six months.

In the first group of women tested, the vaccine proved 73% effective in protecting against genital herpes disease for 19 months, the duration of the study. In the second group, which was designed to focus on those not previously infected with HSV-2 alone, analysis showed that the vaccine was 74% effective in preventing genital herpes in women who had not been infected with HSV-1 or HSV-2.

Why was the vaccine more effective in women than in men? Researchers believe there may be two explanations, which may not be mutually exclusive, says Lawrence Stanberry, MD, PhD, chairman of the Department of Pediatrics at the University of Texas Medical Branch at Galveston (UTMB) and lead author of the paper.

The vaccine under research uses a genetically altered snippet of the HSV-2 virus called HSV-2 glycoprotein-D-subunit and a new type of adjuvant, a substance that causes a nonspecific immune response to boost the effectiveness of the vaccine. The adjuvant contains a combination of alum and 3-O-deacylated-monophosphoryl lipid A (3d-MPL), which Stanberry describes as a very potent substance in inducing T cell responses. Given that the vaccine elicited a better response in women, it may be possible that the adjuvant system just works better in women than in men, he says.

The other possible explanation for the vaccine’s increased protection for women may lie in the way women and men get infected with genital herpes, he suggests. Women most likely get infected on a mucosal surface, he notes. When women are vaccinated, their bodies make immune responses that go to that mucosal surface. Men, on the other hand, probably get infected through breaks in the skin, and not on mucosal surfaces, Stanberry notes.

"When you think about the vaccines being at the portal of entry, it would require that the vaccine in a man produce immune responses that are just sort of sitting just under the skin waiting for the virus to gain entry," explains Stanberry. "So it could be that just because of the differences in the way men and women get infected, the vaccine works better in women, because it can prevent that first step."

Enrollment under way

The new vaccine trial is being conducted at multiple sites across the United States as a double-blind, randomized, controlled Phase III efficacy trial. The study will be coordinated by St. Louis (MO) University; other sites include Baylor College of Medicine, Houston; Children’s Hospital, Cincinnati; Harborview Medical Center, Seattle; Harbor — University of California Los Angeles Medical Center, Torrance, CA; Indiana University, Indianapolis; Johns Hopkins University, Baltimore; Louisiana State University, New Orleans; Primary Physicians Research, Pittsburgh; University of Alabama, Birmingham; University of Colorado Health Sciences Center, Denver; University of Maryland, Baltimore; University of North Carolina, Chapel Hill; University of Rochester (NY); University of Utah Medical Center, Salt Lake City; and Westover Heights Clinic, Portland.

Volunteers will be assigned randomly to receive the candidate vaccine or a vaccine against hepatitis A, which will allow all participants a chance to be protected from disease. Volunteers will be vaccinated at the start of the trial and at one and six months after the first injection. The women will be followed for 20 months after the initial vaccination to determine whether the candidate vaccine prevents HSV infection or disease. Women between the age of 18 and 30 who wish to be evaluated for possible inclusion in the trial should visit the NIAID’s web site at www.niaid.nih.gov/dmid/stds/herpevac/.

While it is too early to predict the outcome of the new trial, Stanberry says he is encouraged by the results of the research that has been completed in looking toward an effective weapon against the STD.

"These are very exciting findings," he notes. "These new studies suggest that a comprehensive campaign to vaccinate girls and women not infected with either type of herpes simplex virus could significantly reduce the spread of the herpes epidemic in the general population."

References

1. Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med 2002; 347:1,652-1,661.

2. Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States. 1976 to 1994. New Engl J Med 1997; 337:1,105-1,111.