|Monkeys Vaccinated Against SIV Survive Longer After Infection
Results of two new studies sponsored by the National Institute of Allergy and
Infectious Diseases (NIAID), a component of the National Institutes of Health
(NIH), suggest that even if an HIV vaccine offers imperfect protection against
the virus, it might provide vaccinated individuals with an important benefit:
a significant survival advantage after infection.
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
“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
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 immuneT 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.
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID supports
basic and applied research to prevent, diagnose and treat infectious diseases
such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related disorders,
including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.