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PORTSIDE  September 2011, Week 3

PORTSIDE September 2011, Week 3

Subject:

Clues Emerge to Explain First Successful HIV Vaccine Trial

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Portside Moderator <[log in to unmask]>

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Date:

Fri, 16 Sep 2011 22:52:11 -0400

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text/plain (169 lines)

Clues Emerge to Explain First Successful HIV Vaccine
Trial

     Immune responses of patients could point way
     forward for future vaccines.

Ewen Callaway
Published online 16 September 2011 |
Nature | doi:10.1038/news.2011.541
http://www.nature.com/news/2011/110916/full/news.2011.541.html

After decades of dashed hopes, AIDS vaccine developers
are allowing themselves some cautious optimism. At a
conference this week in Bangkok, Thailand, scientists
reported molecular clues that help to explain the first-
ever success of an HIV vaccine trial in humans (see
'Vaccine protects against HIV virus'). The results could
point the way forward for designing future vaccines.

"You might say this is the most successful experiment
we've had so far," says Adriano Boasso, an immunologist
at Imperial College London.

The study analyzed clinical samples from a previous HIV
vaccine trial of more than 16,000 people that has been
dubbed the 'Thai trial' but is officially called RV144.
In 2009, scientists leading that trial reported that,
after three years, people who received the vaccine were
about 30 percent less likely to contract HIV than those
who got a placebo1.

The modest results marked the first successful human
trial of an AIDS vaccine, two years after the high-
profile failure of a vaccine produced by the
pharmaceutical company Merck. But Thai trial results
also left many researchers scratching their heads.

Greater than the sum of its parts

The vaccine regimen consisted of two components that had
each failed on their own: a primer vaccine called ALVAC-
HIV vCP1521 from Sanofi Pasteur of Lyon, France,
containing several HIV proteins, followed by a booster
called AIDSVAX from VaxGen of Brisbane, Australia, made
of a protein on HIV's surface. Moreover, two of the
three measures the researchers used to determine whether
the vaccine prevented HIV infection did not reveal
differences between vaccinees and controls that reached
statistical significance (see 'HIV vaccine trial under
fire').

"We have clues as to why it might have worked. That's
something we haven't had over the past 30 years."
In the latest study, researchers involved with the trial
at Mahidol University in Bangkok and the U.S. Military
HIV Research Program in Washington DC assembled a team
to scour the blood of trial participants for immune
indicators that differed between 41 people who received
the vaccine and contracted HIV and 205 participants who
did not become infected.

Their work isn't complete, but so far the team has found
two molecular clues to explain why the vaccine prevented
HIV for some but not others. Subjects whose blood
contained a Y-shaped immune molecule called an
immunoglobulin G (IgG) antibody that recognises a
portion of a HIV's outer envelope called the V2 loop
were 43 percent less likely to become infected with HIV
than subjects whose immune systems did not make these
antibodies.

Meanwhile, participants who churned out another kind of
antibody, called IgA, that recognises different parts of
the HIV envelope fared worse in the trial - they were 54
percent more likely to become infected than people who
did not make these antibodies. However, this immune
reaction did not make people more susceptible to the
virus than trial participants who got a placebo.

The researchers are still studying these results. But
Nelson Michael, director of the U.S. Military HIV
Research Program, says they reassure him that the
vaccine did protect some participants from HIV and that
its success was not a statistical fluke. "This lends
biological credence to the initial clinical study
results," he says. "It suggests that what happened in
RV144 was related to vaccination."

A way forward

Barton Haynes, the director of the Duke Human Vaccine
Institute in Durham, North Carolina, who coordinated the
follow-up study, said at a press conference that the
results will generate hypotheses for further study.
"What we now have are clues as to why it might have
worked. That's something we haven't had over the past 30
years. That's very important for the field."

Researchers are already planning to test whether
antibodies like those found in trial participants have
the same effect in primates infected with a virus
related to HIV. These experiments will determine whether
these immune responses are responsible for the vaccine's
success or failure in particular people or merely linked
to other underlying factors.

Ultimately, the new findings should guide future
clinical trials and vaccine development, Michael says.
The team is planning follow-up trials of a similar
vaccine in homosexual men in Thailand, a group at high
risk of HIV infection, as well as a trials in South
Africa that will require a vaccine that recognizes a
different sub-type of HIV.

On the basis of the latest results, these new vaccines
may be re-engineered to spark the production of IgG
antibodies that recognize HIV's V2 loop, Michael says.
"This is certainly going to focus a lot of people's
efforts, and that's a good thing."

Other research presented in Bangkok support the idea
that attacking the V2 loop may be one way to defeat HIV.
Viruses collected from the RV144 participants who became
infected with HIV possess mutations in this region,
suggesting the V2 loop was being targeted by the immune
system, Michael says. Meanwhile, tests of a different
vaccine in monkeys suggest that animals who make
antibodies that recognize the V2 loop tend not to
succumb to SIV, a virus related to HIV that infects
monkeys.

Dan Barouch, an immunologist from Harvard Medical School
in Boston who led the monkey study, says seeing a
similar immune response in humans and monkeys given
different vaccines reassures him that the V2 loop is
worth targeting. But he says vaccine researchers
shouldn't stop pursuing other chinks in HIV's armour.

For instance, Wayne Koff, senior vice president for
research and development at the International AIDS
Vaccine Initiative based in New York, points to virus-
neutralizing antibodies recovered from patients
chronically infected with HIV as another encouraging
lead for AIDS vaccines. "This really is a renaissance
period in HIV vaccine development," he says.

References

1 Supachai, R. et al. N. Engl. J. Med. 361, 2209-2220
(2009).

___________________________________________

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