Death of a Vaccine

CROI update on the unexpected failure of the STEP Study
by Enid Vázquez

Late breaker reports at CROI discussed the astonishing failure of the most promising HIV prevention vaccine in development. The analysis presented of what went wrong is still early, and much more work is in progress.

The STEP Study of MRKAd5 (or the Merck vaccine, as it is commonly called) continues, but vaccination was stopped in September 2007 when an early interim analysis found failure to either stop infection or to lower the amount of virus if an individual did become infected, the two primary goals of the study.

One of the lead researchers, Susan Buchbinder, M.D., of the San Francisco Department of Health, said the study then moved rapidly into post hoc analysis. She stressed that the vaccine did not cause HIV infection.

Although a third of the participants were women, the multivariate analysis—looking at multiple variables—looked solely at men because there was only one female infection, and that was in the group not given the vaccine.

The biological mechanism for the increased risk remains a mystery.

Several of the variables were associated with an increased risk of infection; however, when comparing the vaccinated group to the placebo group, only two of them were associated with increased risk. Furthermore, participants had to have both variables for a statistically significant difference. There was no increased risk if the individual had one or the other risk factor.

The two factors were lack of circumcision and having high levels of immunity to adenovirus-5 at the start of the study (see sidebar for details of the trial).

The other variables examined were age (30 or under), race, region (this is an international study in the U.S., the Caribbean, and Brazil), number of male sex partners, unprotected receptive anal sex, unprotected insertive anal sex, substance use, or self-reported sexually transmitted infection. The study continues to look at other variables that may have been associated with increased risk of infection.

The biological mechanism for the increased risk remains a mystery. For more information, see October 1, 2007 Exclusive Online News Briefs at www.positivelyaware.com.

Editor’s note: The author is a member of the Community Advisory Board (CAB) of the STEP Study at the University of Illinois at Chicago site.

The STEP Study of the Merck vaccine

Vaccines activate the immune system so that it can provide greater protection against diseas es.

But at the first early interim analysis of the STEP Study (in September), its Data Safety Monitoring Board (DSMB) found a higher risk of becoming infected with HIV in one group of vaccinated participants (compared to placebo) and vaccination was stopped.

STEP enrolled 3,000 high-risk individuals around the world, primarily men who have sex with men. Participants were divided by their natural levels of adenovirus-5 (Ad5), a version of the common cold virus that rarely causes serious disease. Participants were separated by four Ad5 levels, from no exposure to the virus detected to three levels of Ad5 antibodies. Participants were then randomized to receive either three doses of the experimental vaccine or a placebo (“fake” or inert vaccine).

Ad5 is a vector in vaccine research—one of the harmless substances used to deliver a vaccine being studied into the human body. The virus was replication-defective (it could not reproduce—or grow—in the body). In this case, the vaccine was carrying synthetic (created in the lab) gag, pol, and nef. These are three of HIV’s genes, unable to cause an infection but used to stimulate the immune system to recognize and fight the virus if it ever enters the body.

The vaccine succeeded in doing that—in getting an immune response. But inexplicably, it may also somehow have increased the risk of infection in the highest Ad5 group. This was contrary to the two main goals of the study—to decrease the risk of HIV infection or lower viral load if infected. The study continues.—Enid Vázquez

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