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June 13, 2006
HIV Vaccines: They're Not Perfect But...
by Tim Horn
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.
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
"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."
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.
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.
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.
[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."
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