June 13, 2006

HIV Vaccines: They're Not Perfect But...

June 13, 2006 (AIDSmeds)—Even if an HIV vaccine is incapable of preventing infection, new studies suggest that it may confer a significant survival advantage for those who are infected with the virus. The research, conducted by investigators at Harvard Medical School and that National Institute of Allergy and Infectious Diseases (NIAID), also introduced a rapid method of determining an HIV vaccine's effectiveness, which could potentially speed up the development of promising vaccine candidates.

Attempts to develop an HIV vaccine the triggers the production of antibodies – the mechanism responsible for vaccine protection against other viruses, including polio and hepatitis B – have been unsuccessful. According to Dr. Norman Letvin, Professor of Medicine at Harvard Medical School and a lead investigator of one of the studies, "HIV mutates so quickly it can evade antibody immunity." In turn, researchers – including Dr. Letvin and Dr. Mario Roederer of NIAID's Vaccine Research Center (VRC) – have been focusing on developing a vaccine that results in cellular immunity. Such vaccines would program T cells in the body to recognize cells that have been infected by HIV and to destroy them so that the virus cannot continue reproducing.

Some experts suggest that it may not be feasible to develop a vaccine that is effective in preventing HIV infection. But experts also argue that a vaccine providing imperfect protection may still be an important achievement, especially if it confers some survival advantage to people who do become infected with the virus.

Such a survival advantage was observed in monkey studies conducted by research teams headed by Drs. Letvin and Roederer. The researchers found that monkeys vaccinated against simian immunodeficiency virus (SIV) – a close relative of HIV that causes an AIDS-like disease in monkeys – and then exposed to the virus survived significantly longer than unvaccinated animals exposed to SIV.

"Although our ultimate goal is to have a vaccine that completely blocks HIV infection, this research suggests a potential benefit of even a partially effective vaccine," said NIAID Director Dr. Anthony S. Fauci.

Published in recent issues of Science and the Journal of Experimental Medicine, the studies also identified a measurable marker of SIV vaccine effectiveness in monkeys – something known as an immune correlate of vaccine efficacy. Further study is needed to determine if the immune correlate could predict the effectiveness of a vaccine against HIV in humans.

"Having an immune correlate of vaccine efficacy could markedly reduce the time it takes to evaluate whether a candidate HIV vaccine works in people," says VRC Director Dr. Gary Nabel. "The significance of this discovery is clearly worth evaluating in humans and may considerably accelerate future efficacy trials."

The SIV vaccine regimen used in the two studies was a simplified version of a preventive HIV vaccine strategy currently being evaluating in clinical trials being conducted in the United States, the Caribbean and sub-Saharan Africa. Current plans call for testing the efficacy of the vaccine in large-scale human clinical trials some time next year.

To examine the theory that some imperfect HIV vaccines may still allow infected people to live longer and healthier lives, Dr. Letvin's and Roederer's groups set out to determine if SIV vaccines confer such a survival advantage to monkeys.

They found that the best way to predict survival after a vaccinated monkey is infected with SIV is by measuring, early in infection, levels of a specific subset of immune cells known as the memory CD4+ T cells. Memory CD4+ T cells are T cells that have been activated by bacteria and viruses upon first exposure and are primed to act more quickly upon reinfection. Of the approximately one trillion T cells in the average adult, more than half are memory cells.

Normally, a rapid and significant loss of these memory CD4+ T cells occurs early on in SIV infection. Approximately ten days into the infection, when the levels of virus in the bloodstream are at their peak, up to 80% of the memory CD4+ T cells in some tissues became infected. Most of these cells subsequently die.

But Dr. Roederer's group found that vaccinating the monkeys lessened this damage to the immune system. In their study comparing six vaccinated monkeys to six unvaccinated monkeys – all of which were exposed to SIV in the study – the vaccinated monkeys had about three to five times fewer memory CD4+ T cells infected and destroyed. "If the virus wipes out only a fraction of the memory CD4+ T cells that it might otherwise destroy, that should allow [the animals] to live longer," Dr. Roederer said. Likewise, he adds, if HIV vaccines can prevent the destruction of these memory cells in humans, it may be possible to provide people with longer, healthier lives.

Dr. Letvin's study looked at the effect of preserving the memory CD4+ T cells over the long term. A total of 30 monkeys – 24 vaccinated and six unvaccinated controls – were infected with SIV and followed for nearly three years. The vaccine helped control the infection for the first 112 days, but thereafter, the virus levels and total CD4+ T-cell counts in the vaccinated and unvaccinated animals did not differ significantly. However, the vaccine protected the memory CD4+ T cells from the virus early on, and the levels of memory CD4+ T cells remained at significantly higher levels in the vaccinated animals for the 850 days they were studied.

"This [early protection] had huge consequences for the development of disease," said Dr. Letvin. "When infection did occur, the monkeys preserved their memory CD4+ T cells better and lived longer."

Moreover, the researchers found that measuring a subset of the memory CD4+ T cells, so-called central memory CD4+ T cells, could help predict how the monkey would fare in the long run. Since these new studies indicate that the central memory CD4+ T cell counts appear to be a crucial predictor of long-term health, blood samples from human clinical trial participants might now be examined for this marker. That way, says Dr. Letvin, scientists can gauge how well a vaccine will perform simply by measuring the central memory cell levels in the first few months after infection.