"No Go": NIAID Scraps Large Scale Vaccine Trial -- And A Chastened Genentech Takes Its Case to The Hill
On April 21-22, the HIV Vaccine Working Group (VWG), formed by NIAID in December 1992, met to evaluate whether or not the current scientific data from on-going vaccine studies warrant expanding clinical trials of one or both the candidate HIV vaccines (Genentech and Chiron/Ciba-Geigy gp120). The group's evaluation unanimously supported advancing such trials, which would have meant proceeding to a large phase III trial (although half the size of the original plan) enrolling some 4,500 new volunteers over 2 years' time.
But little more than one month later, at a joint meeting June 17th of the congressionally mandated AIDS Research Advisory Committee (ARAC) and a special NIAID AIDS advisory council, members recommended that the Institute not expand the current vaccine trials of the two gp120 candidates, and NIAID director Anthony Fauci was quick to agree -- more or less scrapping the recombinant envelope approach altogether. In the director's own words, "If a recommendation is made to not proceed with an expanded trial at this time with these products, we may never get the answers concerning the soluble envelope concept." In the meantime, NIAID will continue to evaluate data from new and on-going HIV vaccine studies, awaiting a candidate vaccine suitable for large scale trials. According to the Institute's own estimates, that could take up to 3 years.
"The bottom line," explains TAG's Garance Franke-Ruta, a member of the VWG and an active participant in all of the vaccine deliberations, "is that we won't have a marketable vaccine or anything that looks like a marketable vaccine for at least a decade. It will be 1-3 years before we have new data from the Genentech and Biocine vaccines and 3-5 years before we have data on any of the new products."
Part of the problem with the scaled-down 4,500 person plan, (itself a compromise reached at the April meeting in response to earlier discouraging neutralization data) was that in the best of worlds it would only have the statistical power to determine that a vaccine was "extremely effective" (> 70%) or simply didn't work at all (
Genentech's Don Francis (cloyingly rendered by a generously Brylcreemed Matthew Modine in HBO's adaptation of Randy Shilt's illora culpa docudrama thriller, ATBPO) says he doubts the "no go" decision will stand. In fact, Genentech, with some 200,000 doses of vaccine now in cold storage, plans to take its case both to Congress and the White House, according to Science writer and vaccine chronicler Jon Cohen. "We've got a vaccine that deserves to be tested," Francis says, "and this vaccine works in chimps."
Francis refers to a recent experiment where a small number of vaccinated chimpanzees successfully resisted infection when injected with live HIV. But the 11th-hour chimp data that was supposed to save the day didn't exactly bowl anyone over. Although challenged with relatively high doses of heterologous virus, the challenge was performed 4 weeks "post-last-boost" when antibody titers are highest. And the challenge was done intravenously -- not mucosally. In order to prevent the cases of HIV infection acquired sexually, it is mucosal protection that will be the key.
There are still many unanswered questions which greatly impede the vaccine effort, particularly in the areas of pathogenesis and correlates of protection. Opening the 7-hour day of deliberation, Dr. Fauci explained that, "While it is true that other non-HIV vaccines have been developed and tested without total understanding of either of these areas, the majority of infected people in those situations spontaneously recovered and were protected thereafter, essentially establishing that protective immunity was attainable, even though scientists could not always formally prove it. We have no such luxury with HIV infection. We still are uncertain about the precise correlates of immunity."
"Correlates of immunity." That phrase has hovered menacingly over the vaccine effort since day one, becoming something of an ever-present gadfly to those working in the field. And recent developments have further sharpened the pique of its bite. In studies last fall with sera from vaccinees, researchers were devastated to learn that antibodies produced by the immune system cells of volunteers failed to neutralize viral isolates obtained from infected persons. As Duke University vaccine researcher and VWG co-chair Dani Bolognesi explained, "If your vaccine strategy is based on neutralizing antibodies against the virus, and what you're inducing by a particular vaccine really doesn't neutralize the virus -- and you're sure of that, what's the rationale for that vaccine? What's the point in going ahead ?"
More recently, 5 vaccine trial volunteers who became infected made headlines across the country (Chicago Tribune, May 29) and threatened to turn the tide of public opinion against any vaccine trials at all. So-called "high-risk" vaccine trial participants, even though their bodies were shown to have produced abundant levels of HIV-specific neutralizing antibodies, apparently could not resist subsequent infection with HIV. As NIAID's Jack Killen explained, "Scientists do not understand why vaccine-induced antibodies, which represent a potent weapon against nearly every other known virus, apparently failed to neutralize the AIDS virus."
At last count, at least 11 people vaccinated in various trials, and 2 people who received placebo immunizations, have become HIV-infected. (Six of them, however, became infected before completing the series of boosters typically needed for a vaccine to work.) Fauci readily admits that the "infection story absolutely tilted the political framework for deciding whether NIH should soon launch large trials." Nature reporter Colin Macilwain's sober summation: "The US decision leaves AIDS with no immediate prospects for either a preventive vaccine, a therapeutic vaccine, or a satisfactory drug therapy."