Here is an article published at the very begining of the Phase 3
trials by JAMA HIV/AIDS Information Center in July 1998:
Vol. 280, pp. 8-9, Jul. 1, 1998
Medical News & Perspectives
AIDS Vaccine Moves Into Phase 3 Trials
The world's first wide-scale efficacy testing of a vaccine to prevent AIDS received the go-ahead from the Food and Drug Administration last month, although some scientists remain skeptical about its prospects for success.
The approval allows VaxGen, Inc, a South San Francisco, Calif, biotechnology company that developed the experimental vaccine, called AIDSVAX, to go forward with a 3-year, placebo-controlled phase 3 efficacy trial involving 5000 volunteers at high risk for HIV infection in as many as 40 clinics in the United States and Canada. Once the necessary approvals are secured from Thai health officials, the company expects to begin enrolling 2500 volunteers in 16 clinics in Thailand later this year in a similar trial involving a slightly different vaccine formulation.
VaxGen planned to begin recruiting US volunteers this month in Chicago, Ill, Denver, Colo, Los Angeles, Calif, Philadelphia, Pa, and St Louis, Mo, extending efforts to other cities later in the year. Prospective participants will be people who are not infected with the human immunodeficiency virus (HIV) but who are at high risk for the disease, such as homosexual men and women who have HIV-infected sexual partners. In Thailand, researchers will enroll HIV-negative volunteers from methadone clinics, who are considered at risk for the infection.
Because the vaccine cannot be presumed to be completely effective and because some participants will receive a placebo, all participants will receive extensive counseling on how to reduce potential exposure to HIV. While such counseling is necessary for ethical reasons, if study volunteers practice the recommended risk-reduction measures, the likelihood that investigators will be able to determine the vaccine's effectiveness is sharply reduced.
No Unanimity
While many researchers and AIDS advocacy groups are pleased that a potential vaccine is finally being evaluated in large-scale trials, opinions about its prospects for success are by no means unanimous. Scientists, for example, speculate whether a vaccine such as AIDSVAX, which activates the antibody-producing arm of the immune response but does not elicit the killer T cells of cell-mediated immunity, will be able to eliminate or contain the virus.
"The dogma—which is purely dogma and not necessarily verified by absolute knowledge—is that you need both antibodies and cell-mediated immunity to get a good protective response," said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, which oversees the federal government's HIV research effort. "That's a reasonable assumption, but it still remains an assumption."
Skeptics also point to concerns that the immune response induced by the VaxGen vaccine will, at best, offer only narrow protection against some subtypes of the virus.
"It can neutralize lab strains and maybe a small range of primary isolates, but it's not a broad, cross-reactive neutralizing antibody response," said Gregg Gonsalves, policy director of the Treatment Action Group (TAG), an AIDS activist organization dedicated to efforts to find effective therapies for HIV disease. "If this trial were publicly funded, I'd describe it as problematic, to say the least, and I think it's a distraction in moving us forward toward an effective vaccine."
VaxGen's candidate vaccine is made from a protein called gp120 that is part of HIV's outer coat. Unlike an earlier gp120 vaccine that an advisory panel rejected for a federally funded wide-scale efficacy trial 4 years ago because of skepticism about its likelihood of success, the new "bivalent" vaccine has a new, additional molecular component that its developers believe will contribute to a broader range of protection against subtypes of HIV found in North America, Europe, Australia, Central America, and South America. A different molecular component has been added to the bivalent vaccine to be used in the Thai trial to target antigens of HIV subtypes found in Thailand and other Asian countries, particularly among injection drug users.
In tests involving 1200 volunteers beginning in early 1992, the VaxGen vaccine elicited neutralizing antibodies against HIV in more than 99% of the vaccinated participants, the company said. The new trial is intended to determine just how effective the vaccine will be in protecting people whose behavior—either risky sexual practices or needle sharing in injection drug use—puts them at high risk of becoming infected.
"There aren't very many vaccines out there, and we need to move this forward in a stepwise fashion," said Donald P. Francis, MD, DSc, president of VaxGen. "All indications from the chimpanzee data and the human data are that a vaccine will work—the question is how well it will work and for how long. That's what the study is designed to do."
Philosophical Differences
The debate over the new trial illustrates sometimes contentious philosophical differences about which experimental HIV vaccines to test and when studies should advance from smaller trials assessing safety to large, costly efficacy trials.
During the last decade or so, researchers have tested at least 25 experimental vaccines in studies involving small numbers of volunteers. Until now, however, none has advanced to a phase 3 trial.
Some researchers say that, given the magnitude of the AIDS epidemic, any experimental vaccine that shows promise should be tested in large-scale clinical trials. Others, however, say wide-scale clinical studies of a candidate vaccine should occur only after investigators have a good understanding of how the vaccine works.
"There are major ends of the spectrum—as well as gradations between those 2 extremes," said Fauci. "There's 1 end of the spectrum saying that you shouldn't move ahead with the vaccine trial unless you dot all the i's and cross all the t's, and the other end [advocating] pure empiricism, saying you might as well test any kind of product you have, as long as it's safe."
Francis, who says his most vocal critics lack direct experience in vaccine development and that empiricism has played an essential role in vaccine development, insists that VaxGen's vaccine shows sufficient promise in earlier trials to warrant wider testing—particularly considering the stakes involved in not moving forward.
"You've got,16,000 people infected each day with HIV, and some people are saying that maybe we shouldn't go ahead with the vaccine trial," he noted. "This is a major league bug, and we should pull out all the stops to get a vaccine, because a vaccine is the only thing that's going to stop this epidemic."
"I don't think it will be a home run, but very few vaccines, if any, are ever a home run the first time at bat," said Fauci. "What I'm hoping for is that, at best, there will be partial protection [by the vaccine], and at worst, even if it's totally ineffective, we may learn something that may help us with the next generation of vaccines."
For example, researchers may find that some aspect of the vaccine-elicited immune response helps rein in viral replication, and then use that information to "emphasize that component or aim toward that particular effect," he said.
A vaccine under development at the National Institutes of Health that appears to induce both neutralizing antibodies and a cytolytic T-cell response is currently in phase 2 trials. This approach involves a "prime-boost" strategy, using a vaccine constructed by adding genetic material from HIV to the canarypox virus as a primary vaccination to evoke a T cell cytolytic response, followed by a "boost" with a different vaccine to elicit an antibody response.
"Sometime within the next year, we'll make a decision about whether we'll move ahead with efficacy trials," said Fauci. "There are also many other things that look conceptually promising, but nothing that is really at that stage of development."
—by Joan Stephenson, PhD
(JAMA. 1998;280:7-8)
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