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Jubilation, and Skepticism, Greet Announcement of First Phase III Trial of an AIDS Vaccine

Watershed — or Waterworld?

This June, the FDA gave the go-ahead to VaxGen, Inc., a subsidiary of Genentech, the biotechnology firm, to conduct the first phase III efficacy trial of a vaccine to prevent HIV infection. The story made the front page of almost every major newspaper in the country. The International AIDS Vaccine Initiative (IAVI)’s president Seth Berkeley heralded the trial’s approval as “a watershed event in the AIDS crisis.” The trial’s go-ahead is a victory for VaxGen virologist Donald Francis who has been pushing for wide-scale testing of this product for several years. TAG’s Gregg Gonsalves reports.

Media hoopla notwithstanding, not everyone is quite as excited about VaxGen’s initiative as Drs. Berkeley and Francis. Leading HIV researchers including John Moore of the Aaron Diamond AIDS Research Center, Arthur Ammann of the American Foundation for AIDS Research and Nobel laureate David Baltimore of the California Institute of Technology and chair of the NIH’s AIDS Vaccine Research Committee placed little or no hope in VaxGen’s product in statements made to the press. Indeed, the NIH decided back in 1994 not to pursue phase III studies of a similar VaxGen product based on unpromising preliminary data on the vaccine (see TAGline, vol. 1, no. 5). Over fifty AIDS researchers wrote a letter to Science magazine in May of this year reaffirming the NIH’s decision and criticizing further testing of the class of vaccines which include VaxGen’s product.

There is a clear split in the AIDS research community over the FDA’s decision. Many clinical vaccine researchers support the phase III study of AIDSVax, VaxGen’s product. Meanwhile, many basic researchers working on vaccines support the NIH’s 1994 decision not to go-ahead with phase III testing of Genentech/VaxGen’s product and don’t think the new generation of AIDSVax merits further testing.

There are two formulations of AIDSVax. Both immunogens are based on the envelope of HIV, or gp120. One of the formulations is based on the envelope of strains common in North America and Europe and the other formulation is based on the envelope of strains common in Asia. Earlier generations of VaxGen’s product were shown to be safe when administered to over 1,000 volunteers.

VaxGen and their supporters argue that since the vaccines are safe and the earlier generation of AIDSVax induced antibody responses to the immunizing strain of HIV we should go ahead and test the efficacy of these products. They also contend that the only way to finally know if these products have any efficacy at all is to put them to the test to see if they can prevent HIV transmission in humans. If AIDSVax is only partially effective, we will have made great strides in preventing HIV infection. If AIDSVax turns out to be a dud, VaxGen and their supporters contend that we will be able to draw upon the results of the study to construct better vaccines in the future.

The AIDSVax skeptics see the upcoming trials as a waste of time and money. They point to the fact that none of the subunit envelope vaccines including the earlier generation of AIDSVax has been able to generate strong and broadly reactive neutralizing antibody responses to primary isolates of HIV and are even worse at inducing strong and relevant CD8+ cytotoxic T-lymphocyte (CTL) responses. They also point to studies of trial participants who have been infected with HIV despite vaccination with these products (see Steve Wolinsky’s analysis of vaccine ‘failures’ in the 2/98 Journal of Virology). Those infected with HIV had no difference in their immune responses to the virus than did vaccine recipients that remained uninfected. Viral loads in the infected and immunized individuals were also no different than in unvaccinated HIV+ subjects.

From looking at the data, the AIDS skeptics are probably right. While we still don’t know what the correlates of protection against HIV are, it seems at least reasonable that an effective vaccine will generate strong and broadly cross-reactive neutralizing antibodies and/or CTLs to primary isolates of virus. Ten years ago, we didn’t have great surrogate markers for antiretroviral drug efficacy, but it at least seemed reasonable then to base phase III go-ahead decisions on whether or not a drug could modestly boost CD4+ T-cell numbers. If a drug didn’t raise CD4+ cells back then, it generally didn’t make its way further along in the pipeline. If a vaccine can’t induce antibody or CTL responses that reflect our latest understanding of HIV pathogenesis, what is the real scientific basis for going ahead with a large-scale trial?

Just announced results from sophisticated X-ray crystallography of HIV’s glycoprotein spikes, due out in the weekly journals Nature and Science, cast still further doubt on the envelope-based vaccine approach. “The much-hyped antibodies produced by this vaccine,” Aaron Diamond’s John Moore writes in the Nature commentary, “play into the virus’s hands because they attack its defenses head on.” Dana-Farber’s Joseph Sodroski, an author on one of the papers, is more brutal still: “One doesn’t need the crystal structure [of the virus’ envelope] to put a nail in that [gp120] coffin. The virus has evolved so as to evade immune responses and to make gp120 a not very effective provoker of antibody responses.” But Genentech’s crusading Francis (now the president of VaxGen) remains undeterred, “It works in a chimp, it’s safe in humans, and it produces a better immune response in humans than in chimps,” Dr. Francis argues. “To sit back and wait for more lab tests would, I think, be unconscionable.”

We can at least be grateful that no public funds are being used for VaxGen’s trial. A trial of this size would eat up a major portion of the NIH’s vaccine budget and take precious resources away from more important research. There are still lingering concerns about study participants in VaxGen’s trial. Any participating trial sites should make sure that participants in the study are told of the scientific skepticism about AIDSVax. With little chance of trial enrollees being protected by the vaccine, a truly informed consent would include discussions of the scientific debate surrounding this product. Many of the domestic trial sites will be at institutions that have already been preparing for phase III studies of a vaccine through programs supported by the NIH. These sites have developed strong relationships with communities at high risk of HIV infection. We can only hope that if VaxGen’s trial bombs, the important relationships between these research sites and the community won’t be negatively affected.

A truly effective vaccine is our only hope of stemming the tide of this epidemic in the U.S. and abroad. It is truly tragic that we don’t have a vaccine candidate right now that is more promising than AIDSVax. The real headline for the newspapers is that after almost two decades of this epidemic there isn’t more commercial interest in developing a vaccine and that the NIH has only recently decided to make AIDS vaccine development a priority.

The real challenge for those involved in AIDS vaccine development right now is to build on our current knowledge about HIV and the immune response to manufacture new immunogens that may have a better chance of protecting people against HIV infection. If industry is not going to pick up the slack, the NIH and private research organizations like IAVI and AmFAR have to jump start this effort by developing and producing new candidate vaccines that can quickly be pushed into phase I studies in humans. While the NIH has been increasing its investment in AIDS vaccine development, it’s time for the agency to streamline its vaccine efforts. In addition to ramping up its capacity to develop and produce new candidate vaccines, the agency should better coordinate the evaluation of new immunogens in non-human primates. Right now, monkeys studies of new vaccines are small and employ different routes and viral strains to challenge vaccinated animals. Assays of the immune response to vaccine candidates are similarly varied. The NIH to its credit has established the AIDS Vaccine Research Committee that has begun to guide the NIH’s efforts in vaccine research and has brought some needed focus to the program.

A little over a year ago, President Clinton, in a speech at Morgan State University, committed the nation to the goal of developing an AIDS vaccine within the next ten years. The achievement of this goal will not be easy, but it is not impossible. The VaxGen trial is no great leap forward; it’s a great distraction from the difficult tasks ahead.

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