June 9, 2006
Such a survival advantage was observed in monkey studies conducted by two teams of researchers, one led by Norman L. Letvin, M.D., of Beth Israel Deaconess Medical Center, Harvard Medical School and the NIAID Vaccine Research Center (VRC), and the other by Mario Roederer, Ph.D., of the VRC. 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.
"The worldwide need for an HIV vaccine is profound," says Elias A. Zerhouni, M.D., director of the NIH. "In 2005, more than 11,000 people became infected with HIV every day. If that rate continues unchecked, the virus is going to infect another 40 million people during the coming decade."
"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," says NIAID Director Anthony S. Fauci, M.D.
Published in this week's issue of Science and this month's issue of 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 Gary J. Nabel, M.D., Ph.D. "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 human HIV vaccine strategy developed by VRC scientists and currently undergoing Phase II human clinical trials in the United States, the Caribbean and sub-Saharan Africa. This vaccine regimen has two parts: a primer vaccine consisting of noninfectious HIV DNA; and a booster vaccine made from several HIV proteins delivered in a harmless adenovirus vector. Current plans call for testing the efficacy of the vaccine regimen 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, Drs. Letvin and Roederer and their colleagues sought 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 T 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: about ten days into the infection, when the levels of virus in the bloodstream are at their peak, up to 80 percent of the memory CD4+ T cells in some tissues became infected, and ultimately, nearly all of those memory CD4+ T cells are lost.
But vaccinating the monkeys can lessen this damage to the immune system, Dr. Roederer and his colleagues found. In their study of six vaccinated monkeys and six unvaccinated monkeys exposed to SIV, the vaccinated group had about 3 to 5 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 says. 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.
In Dr. Letvin's study, he and his colleagues 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+ counts in the vaccinated and unvaccinated animals did not differ significantly.
But the vaccine protected the memory CD4+ T cells from the virus early on, and this gave the vaccinated monkeys a long-term survival advantage. 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," says 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.