June 13, 2006 (AIDSmeds)—Even if an HIV vaccine is incapable of preventinginfection, new studies suggest that it may confer a significantsurvival advantage for those who are infected with the virus. Theresearch, conducted by investigators at Harvard Medical School and thatNational Institute of Allergy and Infectious Diseases (NIAID), alsointroduced a rapid method of determining an HIV vaccine’seffectiveness, which could potentially speed up the development ofpromising vaccine candidates.

Attempts to develop an HIVvaccine the triggers the production of antibodies – the mechanismresponsible for vaccine protection against other viruses, includingpolio and hepatitis B – have been unsuccessful. According to Dr. NormanLetvin, Professor of Medicine at Harvard Medical School and a leadinvestigator of one of the studies, “HIV mutates so quickly it canevade antibody immunity.” In turn, researchers – including Dr. Letvinand Dr. Mario Roederer of NIAID’s Vaccine Research Center (VRC) – havebeen focusing on developing a vaccine that results in cellularimmunity. Such vaccines would program T cellsin the body to recognize cells that have been infected by HIV and todestroy them so that the virus cannot continue reproducing.

Someexperts suggest that it may not be feasible to develop a vaccine thatis effective in preventing HIV infection. But experts also argue that avaccine providing imperfect protection may still be an importantachievement, especially if it confers some survival advantage to peoplewho do become infected with the virus.

Such a survivaladvantage was observed in monkey studies conducted by research teamsheaded by Drs. Letvin and Roederer. The researchers found that monkeysvaccinated against simian immunodeficiency virus (SIV) – a closerelative of HIV that causes an AIDS-like disease in monkeys – and thenexposed to the virus survived significantly longer than unvaccinatedanimals exposed to SIV.

“Although our ultimate goal isto have a vaccine that completely blocks HIV infection, this researchsuggests 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 vaccineeffectiveness in monkeys – something known as an immune correlate ofvaccine efficacy. Further study is needed to determine if the immunecorrelate could predict the effectiveness of a vaccine against HIV inhumans.

“Having an immune correlate of vaccine efficacycould markedly reduce the time it takes to evaluate whether a candidateHIV vaccine works in people,” says VRC Director Dr. Gary Nabel. “Thesignificance of this discovery is clearly worth evaluating in humansand may considerably accelerate future efficacy trials.”

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

Toexamine the theory that some imperfect HIV vaccines may still allowinfected people to live longer and healthier lives, Dr. Letvin’s andRoederer’s groups set out to determine if SIV vaccines confer such asurvival advantage to monkeys.

They found that the bestway to predict survival after a vaccinated monkey is infected with SIVis by measuring, early in infection, levels of a specific subset ofimmune cells known as the memory CD4+ T cells. Memory CD4+ T cells areT cells that have been activated by bacteria and viruses upon firstexposure and are primed to act more quickly upon reinfection. Of theapproximately one trillion T cells in the average adult, more than halfare memory cells.

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

ButDr. Roederer’s group found that vaccinating the monkeys lessened thisdamage to the immune system. In their study comparing six vaccinatedmonkeys to six unvaccinated monkeys – all of which were exposed to SIVin the study – the vaccinated monkeys had about three to five timesfewer memory CD4+ T cells infected and destroyed. “If the virus wipesout only a fraction of the memory CD4+ T cells that it might otherwisedestroy, that should allow [the animals] to live longer,” Dr. Roederersaid. Likewise, he adds, if HIV vaccines can prevent the destruction ofthese memory cells in humans, it may be possible to provide people withlonger, healthier lives.

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

“This[early protection] had huge consequences for the development ofdisease,” said Dr. Letvin. “When infection did occur, the monkeyspreserved their memory CD4+ T cells better and lived longer.”

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