Vaccine Failure Is Setback in AIDS Fight

The leading theory is that activation of the immune system, a cascade of events that occurs naturally when a person is infected with a virus or bacterium or gets a vaccine against one of them, in some way increased the risk of HIV infection.

Activation causes cells called CD4 T-lymphocytes (among many other things) to proliferate. CD4 cells are the targets of choice for HIV. In their activated state, they are coated with molecules called CCR5 co-receptors, which HIV needs to attach itself to a cell.

The hypothesis is that people who received the vaccine had greater-than-normal activation and consequently produced more and fatter cellular targets for HIV. That then increased their chances of becoming infected should they encounter the virus in unprotected intercourse.

Two things undercut this idea.

People have been suffering immune-activating infections and getting vaccines for years, and there has never been evidence that those events increased a person's risk of acquiring HIV. These vaccine trials would be odd places to first notice such a thing. Furthermore, people in the STEP study who got the vaccine did not have more activated CD4 cells than people who got placebo -- something that Merck vaccine executive Mark B. Feinberg called "kind of an interesting and unexplained observation."

"There is something very, very peculiar" going on in the vaccine trials, said Anthony S. Fauci, head of the National Institute of Allergy and Infectious Diseases, which sponsored them.

The multiple surprises have reminded researchers how much they still do not know about HIV's biology. It has also focused attention on questions they never asked.

For example, none of the monkey experiments with the Merck vaccine subjected animals to the kind of sexual exposure that people in the trial had -- namely, repeated encounters with low doses of HIV, with no single exposure being especially high-risk.

Why not?

The researchers did not have any reason to believe the vaccine might be harmful (although they acknowledged it might not be effective), and in any case such a study would have required quite a large number of monkeys, which are expensive to acquire and maintain for research.

Instead, researchers vaccinated a relatively small number of monkeys with the Merck vaccine and then injected them with the monkey equivalent of HIV in a manner that guaranteed they would become infected. Those animals did much better over the long run than infected but unvaccinated ones.

That was once enough to move a vaccine into human trials. But it probably never will be again.