AIDSWEEKLY Plus; Monday, April 12, 1999
Daniel J. DeNoon, Senior Editor

In a presentation to the Second Annual Conference on Vaccine Research, held March 28-30 in Bethesda, Maryland, Johns Hopkins researcher Clayton Harris laid out the rationale behind the study. The vaccine is comprised of HIV envelope glycoproteins produced in mammalian cells. It is a bivalent vaccine: Phase III tests in the U.S. include envelope from two strains of the clade B virus prevalent in North America and Central Europe; Phase I II tests in Thailand include envelope from a clade B virus and a clade E virus prevalent in Southeast Asia.

Human studies, Harris noted, show that antibodies raised by the vaccines can bind HIV envelope elements believed to be important in attaching to cells. These antibodies can neutralize both laboratory and primary strains of HIV and also induce antibody-dependent cellular cytotoxicity (ADCC) against the virus. The vaccine has elicited mucosal antibodies and delayed-type hypersensitivity (DTH) skin tests show that some vaccinated individuals retain HIV specific immune responses for at least two years after their final booster immunization.

All of these immune responses can be demonstrated only against viral strains similar to those used in the vaccine. Whether they will have any real-world relevance is the exact point of the Phase III trials. The vaccine has minimal reactogenicity, although adjuvants that boost the vaccine also boost this adverse event. Most importantly, vaccination does not appear to enhance disease in cases of breakthrough infection. But a major safety issue remains.

Despite counseling to practice safe sex, trial subjects may believe themselves protected and, over time, increase risk behavior. Trials in the U.S., Canada, and in Amsterdam, Netherlands, will enroll 5,000 men who have sex with men at 50 sites in a 2:1 vaccine:placebo ratio. It began in June 1998 and will continue for three years. Based on community rates of HIV spread, investigators anticipate that over the course of the trial placebo recipients will have a 1.5 percent infection rate. Harris said that this would be sufficient to permit detection of 30 percent vaccine efficacy.

Trials in Thailand have enrolled the first 35 of a planned 2500 subjects (1:1 vaccine:placebo ratio); the Bangkok cohort is made up of intravenous drug users. Anticipated HIV incidence in the Thai placebo recipients is expected to be 6.0 percent per year. This 17-site study is expected to continue for three years. The trials' main endpoints are, of course, prevention of HIV infection. Their secondary endpoints may prove more interesting: ability to prevent chronic HIV infection, and ability to reduce viremia during acute and/or chronic infection. In addition to following vaccine-associated adverse events, the trials will follow two other safety issues of great interest to future trials of candidate HIV vaccines: whether trial participation results in societal harm to participants, and whether participants reduce or increase their risk behaviors.

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