The results of test-tube trials pitting current HIV vaccinecandidates against variants of the virus actually isolated fromAIDS patients have led National Institutes of Health topostpone Phase III HIV vaccine trials.
The in vitro results were reported last week at the SixthAnnual Conference on Advances in AIDS Vaccine Development.The Alexandria, Va., meeting was sponsored by the NIH'sNational Institute of Allergy and Infectious Diseases (NIAID).
As summarized in the current issue of Science by newswriterJon Cohen, of four trials, only one showed any measurablesuccess. Duke University, Walter Reed Army Institute ofResearch, Biocine (a joint venture between Chiron Corp. andCiba-Geigy) and United Biomedical Inc. all reported trialresults. They measured how well vaccines developed againstHIV raised in the lab were able to neutralize real-life viruses PPso-called "primary field isolates" PP infecting the blood of AIDSpatients.
Only United Biomedical was able to report any success againstprimary isolates, and that against just a single primary isolate.In the other three trials, not one of the 79 aggregate patientsamples showed vaccine activity.
"The implication is that the immunogens used to date don'tinduce the breadth of response needed to neutralize primaryfield isolates," Duke researcher Thomas Matthews concluded."Efficacy trials need to be put on hold right now until thisprimary-isolate question is sorted out."
The crucial Phase III clinical trials -- originally scheduled tobegin in December, Science reporter -- would immunize peopleat high risk of contracting AIDS with candidate vaccines to seewhich, if any, can prevent infection.
But John Killen, acting head of NIAID's AIDS division, said atthe Alexandria, Va., meeting that his agency will conduct "aformal and thorough review" next spring of the field-isolateissue and will decide whether to launch Phase III efficacy trialsin the U.S. by the end of 1994.
These caveats left two of the major AIDS vaccine playersaghast. Chiron and Genentech Inc. are currently in a large-scale,competitive Phase II trial of their front-running vaccinesconducted by NIAID's AIDS Vaccine Evaluation Group. Thisdouble-blinded study has about 290 people enrolled, of atarget 360, with one arm placebo-controlled, said molecularbiologist Jack Obijeski, who directs Genentech's AIDS vaccineprogram.
Both companies have entered their native-antigen subunitgp120 formulations, but with different adjuvants. Participantswill be immunized upon entry in the trial, and again at one, sixand 12 months before the code is broken.
Obijeski insisted that Phase III field studies should go forwarddespite failing in vitro to neutralize street viruses. He recalledto the meeting that the history of past vaccine developmentsupports this idea. "Take hepatitis B," he said. "What did wereally know about that vaccine? It never grew in culture; youhad to rely just on animals. And yet people went forward totest it (in humans) and found that it was efficacious."
Noting that there are 5,000 people getting infected with AIDSevery day worldwide, Obijeski declared: "You're going to learna lot more from clinical studies than you're ever going to learnfrom the laboratory. And we've got to realize that it's theclinical data that lead to approval and licensure, not how wellyou do in a peripheral blood monocyte cell assay."
He decried NIAID's reluctance as "one step forward and twosteps back," and observed that "people like Kirk Raab(Genentech's president and chief executive officer) are going toget very very nervous, and they are going to say, 'Why are wedoing this, when there are six other projects at Genentech thatcould be going into Phase III trials?' "
Obijeski told BioWorld that Genentech's financial commitmentto fighting AIDS, including its vaccine effort, is in the range of$100 million. It has already manufactured 200,000 doses of thegp120 vaccine against the MN strain of HIV, which represents60 percent of the strains that threaten the American public.
Chiron's AIDS vaccine research project leader, KathelynSteimer, told BioWorld that she regrets the "flashy headline" onScience's story because "those of us who are doing the workdon't feel quite as discouraged." She finds that "this smallsnapshot of what we're measuring in vitro is being blown outof proportion," and declared, "We have to understand whatwe're measuring before we throw in the towel and fold up ourlawn chairs."
She added that part of the reason why everybody decided topresent their negative findings at the conference is because"we wanted the scientific community to think about it, not tobehave like Chicken Little, saying the sky is falling."
NIAID's Director Anthony Fauci, told BioWorld that the Sciencearticle is "somewhat overdetermined and may leave peoplewith a false sense of anxiety and hopelessness.
"Although we expected the antibody responses to neutralizethe laboratory isolates and are disappointed that they did notneutralize the wild-type as well, they did not elicit cytotoxic Tcell responses either," he said.
As a result, Fauci said, we cannot "jump ahead tomorrow, butmust wait a little longer" despite "some people making amajestic leap" in favor of launching efficacy trials now.
Fauci suggested that the failures just reported could possiblybe corrected by relatively slight modifications, such aspackaging the epitope in a pox vector or altering the adjuvants.He painted a hypothetical scenario in which individualsvaccinated with the current candidate vaccines may not onlyfail AIDS protection, but actually fare worse than the controls,"which might well lead to claims of malpractice."
Fauci said he empathizes with the concerns of thebiotechnology companies involved. He added that he iscounting on their continued collaboration in coming up with avaccine product that does neutralize street virus, and thus can,following next spring's audit, activate the Phase III trials.
Meanwhile, plans for assembling the infrastructure of thesevery large-scale protocols are continuing, he said, "so that thestage will be set and we can all proceed." (See BioWorld for Oct.14)
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.