WASHINGTON _ Despite a host of unanswered scientific and ethicalquestions, researchers from Genentech Inc. and Chiron Corp. said thatthe time has come to begin a large-scale efficacy trial of theirpreventive vaccine candidates. But government officials won't decideuntil June at the earliest whether to give the green light for what couldbe the most complex and controversial trials."Scientifically, we must know whether our current approaches work, orequally important, if they don't work," said Don Francis, clinicalscientist for South San Francisco-based Genentech, during an HIVvaccine conference Monday and Tuesday. The conference wassponsored by the AIDS Action Council, a Washington-based AIDSlobbying group. "Over three-quarters of the worldwide HIV vaccineeffort is using recombinant techniques using the Genentech and Chironapproach . . . To wait, in my opinion, would be unwise and unethical."Francis, a former government epidemiologist whose work helped trackdown the virus, was one of several dozen speakers discussing thescientific, social and ethical considerations for a domestic efficacy trialfor a HIV preventive vaccine. Seen as an important first step ingarnering community support needed to successfully implement a largevaccine trial, the meeting comes exactly 10 years after then Secretaryof Health and Human Services Margaret Heckler announced thediscovery of the virus, proclaiming a preventive vaccine would beready for testing within two years.Chiron, of Emeryville, Calif., also believes that the time has come for alarge efficacy trial (which would include 2,000 to 12,000 participants),said Anne Marie Duliege, associate director for Biocine ClinicalResearch, Chiron's joint venture with Ciba-Geigy to develop vaccines."We share very much the same position as Genentech. We areconvinced it is the only way now to know more about this vaccine,"she said.Of the 12 HIV vaccine candidates that are being evaluated in humantrials, none have advanced to Phase III. Phase II double-blind placebotrials enrolling about 300 volunteers began two years ago for theGenentech and Chiron vaccines, which are engineered from two of themost common HIV strains in the U.S. Recombinant gp 120 (rgp 120)made by Genentech, uses the HIV-1 MN strain; rpg 120, made byBiocine, uses the closely related HIV-1 SF-2 strain.Although those trial results will not be unblinded until later this year,the vaccines appear to be safe. They also have demonstrated they canachieve immunologic memory and neutralize antibodies, researcherssaid. Nonetheless, the functional significance of these findings isunknown. Without a correlative HIV immunity to hang its hat on andfaced with other scientific and ethical ambiguities that set HIV vaccinesapart from past vaccines, the vaccine community has reached a majorcrossroads: it can try to reduce the ambiguity by enrolling thousands ofvolunteers in efficacy trials or it could wait for Phase I and II resultsfrom a new generation of vaccine candidates that could take up to fiveyears."There is no more data to be squeezed out that would convince you thatyou should or shouldn't go forward," said Anthony Fauci, director ofthe National Institute of Allergy and Infectious Diseases, in Bethesda,Md.As science and industry become increasingly dismayed by attempts todevelop an effective vaccine, the virus continues to infect an estimated45,000 Americans per year.Taking another step toward making a decision, a broad-based HIVvaccine working group for the National Institutes of Health has urgedthat clinical efficacy trials be undertaken. They fell short, however, ofendorsing a large-scale efficacy trial for the two lead vaccinecandidates.After it is presented with NIH's input on how the trial might bedesigned as well as its social and legal implications, the AIDSAdvisory Research Council is scheduled in June to make arecommendation to Fauci whether or not to go ahead.Fauci avoided stating his leanings, saying only that if the council madea recommendation to begin an efficacy trial, he would first hold apublic hearing before making the final decision."We don't take this lightly and I have concerns with going ahead witha trial in which we don't have the classic correlatives of immunity. Butthen again we have never been in this situation before with anothervaccine," he said.If Fauci would approve the trial, it would take at least the rest of theyear before the trial gets off the ground. Using the endpoint ofprotection against HIV infection rather than HIV disease, the trialwould probably last about three years, he added.What is certain is that, given the low level of protection expected fromthe vaccine candidates (most estimates range from 30 percent to 50percent), a vaccine trial would have to be linked to a behavioralmodification program, Fauci said.Indeed, issues raised by a large trial are daunting. What high-riskgroups should be targeted for the trial, what prevention messages theyshould receive and what inducements and follow-up services should beoffered are just a few of the difficult questions that need to beaddressed.However, a trial using bioengineered vaccines is seen as the safestoption. Live attenuated vaccines have been shown to protect monkeysfrom the virus, but the ethical and safety issues of injecting a livevaccine into humans "could have us in a conference for years andyears," Fauci says.

-- By Skip Connett

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