IAVI Report - July / September 2001
Patricia Kahn

After years without success in efforts to make a vaccine against herpes simplex virus type 2 (HSV-2), which causes chronic bouts of painful genital sores—and is present in over 20% of US adults—last year finally brought some progress. Results from two Phase III trials showed that a vaccine developed by SmithKline Beecham (now GlaxoSmithKline, or GSK) appears to offer some protection against disease. But the good news contained a shocker: it worked only in women—the first report of a vaccine that is effective in one gender only.

The vaccine, called Simplirix^®, contains a recombinant form of the HSV-2 envelope glycoprotein, D2, together with a new adjuvant called SBAS4. The two double-blind, multi-center trials collectively enrolled 2714 uninfected people from heterosexual serodiscordant couples (with one uninfected and one HSV-2-infected person). In the first study, which ran from 1995 to 1999, all 847 subjects (268 women) were seronegative for both HSV-2 and the closely-related HSV-1 virus, which causes fever sores in the mouth; the second study, begun later with 1867 participants (720 women), included participants with HSV-1. Volunteers were immunized three times (0, 1 and 6 months) and followed for 19 months, with monitoring for HSV-2 infection and clinical signs of genital herpes disease (GHD).

In both trials, the vaccine proved to be 73-74% effective against GHD in HSV-1-negative women, although it did not consistently prevent infection; effectiveness against infection was 48% in the first study and 39% in the second. But it showed no efficacy in men or in women infected with HSV-1. Transmission of GHD in the placebo group was about 11%, compared with 3% in vaccinees. The study did not determine whether protected women shed virus, and therefore whether they still transmit.

Coming after other (sometimes similar) HSV-2 candidate vaccines failed to show efficacy, Moncel Slaoui, GSK senior vice president for business and new product development, attributes this vaccine's partial success to the adjuvant. SBAS4 contains two components: QS21, which is known from other studies to enhance antibody responses (and was modified in this formulation to reduce its strong reactogenicity) and components from bacterial cell walls, which stimulate Th1-type responses, including cellular immunity. "We think that antibody responses are not enough, and that's why we use an adjuvant which induces cellular responses," he says. Slaoui adds that the adjuvant has proven safe in thousands of people, including those in an ongoing malaria vaccine trial in the Gambia, and that it will be used in GSK's planned Phase I trial of its protein-based HIV vaccine.

But there are no explanations for the apparent gender difference in efficacy. Vaccinated men and women both made HSV-2-specific antibodies, including the IgG form commonly associated with Th1-type responses; there were no direct measurements of T-cells or mucosal responses. Nor did pre-clinical studies yield any insight, since these were carried out exclusively in female guinea pigs so that HSV could be introduced into the genital tract more easily than in males. 

Turning to speculation, Spotswood Spruance of the University of Utah, a principal investigator of one of the trials, offers a few. HSV-2-transmission to women initially exposes virus to the vaginal secretions, where it is accessible to immune players such as IgA and IgG antibodies, whereas men are probably exposed through tiny breaks in the skin of the penis that bring virus directly into contact with cells it can infect. Alternatively, the explanation could relate to broader immunological differences, such as those behind women's far greater tendency to develop autoimmune diseases. Slaoui's speculation is that the gender difference could reflect the speed and ease with which immune T-cells home to the genital mucosa in females versus males immediately after HSV-2 infection.

Some answers may come from a new trial of Simplirix^® slated to begin next year. This time the study will involve a more general population of young people, rather than serodiscordant couples, and will include enough women to be statistically powered for a licensable result. Collaborators in academic groups will analyze the immune responses, says Slaoui, and hopefully give some insight into the mechanisms at work—which may then suggest a strategy for making an HSV-2 vaccine that also works in men. "We don't know what that strategy would be, but the present vaccine gives us a toehold," says Spruance.

What are the chances of a similar outcome for an HIV vaccine? While any answer is only a guess, it can't be ruled out, says Slaoui. On the other hand, he notes that the hepatitis B vaccine—the only licensed vaccine against a sexually transmitted disease—is used for both men and women and, like HIV (but not HSV), the virus causes systemic disease after being acquired via the genital tract. But he also says that GSK will be prepared for a gender difference with its HIV vaccines. "We will set up our trials for HIV so we can detect efficacy in women only," he says.

010710
IAVI2001-0709

©2001. The IAVI Report.

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1990, 2001. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.