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U.S.-Backed AIDS Vaccine Trial in Thailand Is Questioned
  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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