Assessing a Failed AIDS Vaccine

After 20 years of defeat, it appeared that science may have finally
developed a viable vaccine against AIDS. Merck’s new drug, V520, was
being tested in a huge clinical trial, involving 3,000 people in 15
cities, and it was widely considered the most promising new candidate
in the field. But last September, when Merck analyzed its initial trial
data, it found that the vaccine had failed — and failed miserably. On
Wednesday, the company issued its first report on the V520 trials,
revealing that the drug did not protect against HIV, and more
disturbingly, actually increased some people’s susceptibility to the
virus. “I don’t think anyone imagined the results would be so
definitively negative so quickly,” says Dr. Gary Nabel, director of the
Vaccine Research Center at the National Institutes of Health.

V520 may have failed, but somewhere in the details of the drug’s
nonsuccess, scientists hope to find insight into what will make future
vaccines work. After all, V520 is just one of about 50 experimental HIV
vaccines that are currently being tested in clinical trials, and almost
all of them are designed to function the same way. While most vaccines
expose the body to weakened or killed viruses, or pieces of them, to
boost production of antibodies — proteins that recognize invading cells
and flag them for destruction — that tack alone was too feeble to fend
off HIV. The new class of vaccines, including V520, takes a more direct
route: They trigger cell-mediated immunity, which marshals killer T
cells that both recognize and destroy viruses and bacteria, and can
lead to a more robust, specific and longer-lived immune defense.

It’s not yet clear why V520 didn’t work, but one theory involves its
vector, or delivery vehicle. Like almost every other AIDS vaccine in
development, Merck’s drug used the common cold virus to transport its
payload — three synthetic HIV genes — into the body’s cells. What makes
the adenovirus ideal for the task is precisely the reason colds make us
so miserable — once inside a host, the cold virus infects cells and
starts to replicate quickly. The down side to that efficiency, however,
is that cold viruses are so common that most people have developed a
certain level of tolerance to them; if the adenovirus fails to excite
the immune system, then any bugs piggybacked on the virus, such as HIV
genes, will also slip past immune defenses. That’s exactly what appears
to have happened in the Merck trial: People with the highest
pre-existing immunity to the common cold also had the highest rates of
infection with HIV.

“It could be due to chance, or to differences in the populations we
studied, or to something related to the vaccine itself,” says Dr. Keith
Gottesdiener, vice president of Vaccine and Infectious Disease Clinical
Research at Merck. “The ‘why’ is still not well known.”

Researchers have already set about trying to figure it out. “We have
to remember that Merck’s was a single product testing a vaccine
concept, which is that T cell immunity can protect against HIV
infection,” says Nabel. “And we know there are other ways to stimulate
T cell immunity.” Nabel is ready to test one such method, a vaccine
similar to Merck’s that uses different HIV genes and a “prime-boost”
approach that involves two injections spaced a few months apart,
instead of one shot, to maximize the stimulation of the body’s T cells.
Other researchers, like Dr. David Ho, director of the Aaron Diamond
AIDS Research Center in New York City and the recipient of a $25
million grant from the Gates Foundation to study novel vaccine
strategies, think that the cold virus isn’t the best way to deliver
HIV. Ho is exploring the possibility that a different vector, such as
the chicken pox virus, or perhaps no vector at all — simply injecting
snippets of naked HIV DNA — could yield stronger immune responses.

At the International AIDS Vaccine Initiative (IAVI), a non-profit
group of public and private partners focused on funding and
accelerating AIDS vaccine research, scientists are studying the use of
crippled, live strains of HIV — based on the success of other such live
attenuated vaccines against polio and measles — which they think might
be critical to waking up the right immune system defenses. “There is
something magical about the replicating virus, because it has virtually
its entire genome,” says Dr. Seth Berkley, president of IAVI. His group
is also investigating ways to stimulate so-called neutralizing
antibodies, a special class of antibodies that appear to be able to
defuse HIV.

Despite the ongoing study, experts argue that none of it will
succeed without some basic changes in the way it’s conducted. Most
research occurs in isolation; there’s little coordination among labs
and no network through which data can be shared, making it difficult
for scientists to learn from each other’s missteps. Worse, it takes
years to get regulatory approval to start a human trial for a new
vaccine — not to mention enrolling the volunteers and training the
right personnel — so, by the time experiments get underway, the science
around which the vaccine was built has long since become outdated. “The
trials are not informing science at the moment,” says Dr. Alan
Bernstein, executive director of the Global HIV Vaccine Enterprise, an
alliance of independent organizations dedicated to accelerating HIV
vaccine research. “Science — and vaccine development — is an iterative
process, except that in HIV vaccine research, there isn’t a lot of
iteration going on.”

The Enterprise, which was founded in 2005, intends to change that.
With funding from the Gates Foundation, Wellcome Trust, National
Institutes of Health and the European Union, it will serve as a hub for
guiding worldwide HIV vaccine research. �We want to ensure that the
trials are done faster, better and smarter,� says Bernstein. And
hopefully, with more success.