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U.S.-Backed AIDS Vaccine Trial in Thailand Is Questioned
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By David Brown
Washington Post Staff Writer
Monday, January 19, 2004; Page A02
Nearly two dozen well-respected AIDS researchers are publicly questioning the
value of a U.S.-sponsored AIDS vaccine trial just starting in Thailand,
suggesting the huge experiment is a waste of money that offers little
prospect of
benefiting Thais.
The study, which has been planned for seven years, is by far the largest AIDS
vaccine trial ever undertaken. It is testing a two-component vaccine in
16,000 volunteers in two provinces in Thailand. One of the vaccine's
components,
however, has twice failed to offer any protection against the AIDS virus.
While
the usefulness of the second component is not known, its ability to stimulate
the immune system has proved extremely disappointing in preliminary testing.
Defenders of the Thai trial -- designed by the U.S. Army but turned over to
the National Institutes of Health in 2002 -- believe the vaccine may prove to
be better than the sum of its parts. In any case, some argue, the trial is
likely to provide scientific insights useful to future AIDS vaccine research
and
is thus worth it.
"At the time they [Army vaccine researchers] made the decision, it was
arguably the best product there was," said Anthony S. Fauci, director of the
National Institute of Allergy and Infectious Diseases. "It's entirely
conceivable it
might not be the right decision in 2004. But we can't just stop the trial.
That would completely destroy the credibility of the United States government
to
collaborate with scientists in developing nations."
The critique of the trial, which has already enrolled 500 people, appears in
the current issue of the journal Science. While the arguments are largely
technical, they indirectly raise thorny ethical and political issues about
medical
research.
These include questions of who should benefit from research financed by the
United States but conducted in developing countries, who "owns" such projects
and what the social cost of research failure may be. As more vaccine
"candidates" move from the laboratory toward testing in whole populations,
these are
questions both scientists and policymakers will face with increasing
frequency.
The principal investigators for the vaccine trial are Thai scientists. The
trial will be run by about 450 Thais and fewer than a dozen Americans. But
much
of the $119 million cost will be borne by the United States.
"I find it incredibly discouraging to be going forward with something that I
see as having virtually no hope of any efficacy," said Douglas D. Richman, a
prominent AIDS researcher at the University of California at San Diego who
signed the Science critique. He believes there is an unseen cost "of having
this
as the frontispiece of the U.S. government's [vaccine] testing program."
When negative results -- which he believes are inevitable -- finally arrive
"in five years or seven years, there will be a price to pay. There will be a
lot of questions to answer. One of them will be 'What have you been doing
with
all your money?' " Richman said last week.
Others believe that even if a trial with negative results proves
scientifically useful, such an outcome may make it harder to recruit
volunteers to test
far more promising vaccine candidates in the future.
"The negative effects of a negative trial will far outweigh the positive
effects of a negative trial," said R. Gordon Douglas Jr., former head of
vaccines
at Merck & Co.
Both Richman and Douglas are members of the AIDS Vaccine Research Working
Group, a committee that advises the NIH and met last week to discuss the Thai
experiment, among other things.
The search for an AIDS vaccine has proved unusually difficult and
frustrating. Part of the reason is that nobody knows which parts of the human
immune
system's elaborate response to the virus might be sufficient to prevent
infection
could they be marshaled before first contact -- which is the general strategy
of vaccination.
The Thai trial vaccine -- which will be given as multiple injections -- aims
to stimulate two "arms" of the immune system. A substance called gp120, which
is part of the virus's outer shell, is designed to trigger formation of
antibodies, small proteins that attack the virus directly. A live canarypox
virus
engineered to express several HIV proteins is intended to stimulate
production
of cells called CTLs that hunt down and kill cells that HIV manages to infect.
The main complaint of the 22 scientists signing the Science declaration is
that neither of the strategies works very well.
A trial of gp120 in 5,000 high-risk people in the United States, Canada and
the Netherlands last year found the substance offered no protection. Just
under
6 percent of people who either got the real vaccine or a placebo became
infected with HIV over a three-year period. A similar trial of gp120 in 2,500
intravenous drug users in Thailand finished in the fall also found no
protection.
Two years ago, the canarypox vaccine (called ALVAC) and gp120 were tested in
330 Americans to see if they stimulated enough of a cell-killing response to
warrant a large trial that would determine whether that response led to
actual
protection against the virus. But the preliminary immune-response study was
so
disappointing that the larger study was canceled.
By then, planning for the Thai trial was nearing completion, and the study
had been approved by more than half a dozen oversight boards in the United
States, Thailand and at the World Health Organization. On Oct. 20, the first
volunteer was vaccinated.
Half of the volunteers will receive "active" vaccine and half placebo shots.
All, however, will be counseled extensively on how to avoid infection and
will
be told not to count on the shots to enhance the protection that comes from
their own behavior. For that reason, scientists expect the infection rate
among
trial participants to be lower than that of people like them not in the
study.
The critics, however, say the cumulative evidence suggests that gp120 and
ALVAC are poor bets, alone or in combination. They point out that even if the
combination vaccine turns out to be moderately effective -- for example,
protecting 50 percent of people from infection -- that would not be good
enough to
qualify it for approval by the Food and Drug Administration.
The defenders answer that nobody can say how the vaccine will perform until
it is tested in the real world. They also say that even though a vaccine that
is only 50 percent effective would not be licensed in the United States,
Thailand and other places that have high rates of HIV infection might deem it
useful
and approve it. Furthermore, even if it fails, it will be informative.
"There is no doubt that there is important information that will come out of
this if it is done right. It is a complicated immune response. If it [the
trial result] is negative, then we will know this constellation of responses
will
not work," said John McNeil, an AIDS vaccine scientist formerly in the
military who is overseeing the study for the NIH.
The study has divided AIDS activists as well as AIDS scientists.
Treatment Action Group, which regularly analyses the U.S. government's AIDS
research portfolio, said there is "little hope this vaccine combination will
be
able to offer any protection against HIV" and called the trial "a waste of
human and financial resources."
The AIDS Vaccine Advocacy Coalition, however, supports the study. In a
statement released last week, it said: "A well-done trial, with results
reported
accurately and without hyperbole, will have a positive impact on
AIDS-affected
communities even if the vaccine proves not to work. No matter what the
outcome,
the Thai trial is increasing public awareness about AIDS vaccines,
stimulating
community participation, and improving HIV prevention activities."
The signers of the Science article do not explicitly call for cancellation of
the trial. One of them, John P. Moore, of Weill Medical College of Cornell
University, said the group knows that wound not happen "so calling for it . .
.
would just be wasted words." But Moore said he hopes the study's design will
be revised so that more data will be gathered and early termination of the
trial will be permitted if it is proving futile.
In many ways the Thai trial is a victim of being first. It made a lot more
sense seven years ago than it does today.
"When you are starving for information, then whatever reasonable trial you
can do to get some information is something that you want to pursue," Fauci
said.
© 2004 The Washington Post Company
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