AIDSWEEKLY Plus; Monday, April 19, 1999
Daniel J. DeNoon, Senior Editor

"There has been good immunogenicity with some candidate vaccines," Johnston said. "I say good, not excellent. We don't know if good is good enough, and we must turn to efficacy trials to evaluate this."

Johnston delivered the first Mary Lou Clements-Mann Memorial Lecture in Vaccine Sciences to the Second Annual Conference on Vaccine Research, held March 28-30, 1999, in Bethesda, Maryland.

While there is of course room for improved vaccines, Johnston pointed out that the NIAID AIDS Vaccine Evaluation Groups (AVEG) program has enrolled 3000 volunteers in 32 clinical trials, two of which have reached the Phase II stage.

These trials are testing 26 immunogens and a wide range of adjuvants. The major questions these trials must answer, aside from vaccine efficacy, concern the breadth of neutralization of elicited antibodies; vaccine ability to stimulate cytotoxic lymphocyte (CTL) responses; and vaccine ability to stimulate mucosal immunity.

Johnston noted that the Phase III trial of the AidsVax gp120 recombinant envelope peptide vaccine is being undertaken by VaxGen, the manufacturer.

"In three years or so we should have information on whether there is any efficacy," she said.

Various other vaccine approaches are being tested in the AVEG system. Perhaps the one farthest along the development pipeline is the prime/boost model using canarypox-vectored HIV proteins for priming immunizations and a recombinant gp120 envelope peptide for boosting immunizations.

The canarypox prime/boost strategy has succeeded in eliciting HIV specific CTL responses that have lasted for at least two years in some subjects. But only a cumulative 50 to 70 percent of all vaccinees ever show HIV specific CTL responses - and only 20 to 30 percent have such responses at any given trial timepoint. And whether the elicited CTL truly are functional remains unknown. "When I look at these results I don't know whether to jump up and down or bury my head in the pillow and cry," Johnston said. "I guess this will depend on whether these CTL turn out to be functional."

Work is underway to define the specificity of HIV CTL epitopes. Johnston noted that empiric trials of candidate vaccines have been enormously valuable in this work.

"What's most interesting is that these epitopes would not ever have been predicted from studies of HIV," she said. "These are previously undefined CTL epitopes."

The scientific highlight of the past year, Johnston noted, was the finding at Jack Nunberg's University of Montana laboratory that by killing HIV at the moment it begins infecting a cell it is possible to obtain fusion-competent HIV that exposes crucial epitopes normally hidden by the virus. A single vaccine prepared from fusion-competent killed clade B HIV was able, in the transgenic mouse model, to elicit antibodies capable of neutralizing primary isolates from HIV genetic clades A through E (see AIDS Weekly Plus, January 25, 1999).

"I must hesitate and remind people that this work has yet to be repeated," Johnston said. "I will feel better when this work has been replicated in a primate model."

At last year's first annual Conference on Vaccine Research, the late Mary Lou Clements-Mann offered a passionate defense of empiric testing of HIV vaccine candidates. In this year's first memorial lecture named for Clements-Mann, Johnston returned to the theme.

She scoffed at critics who warn that testing of suboptimal vaccines will use up the pool of people willing to serve as subjects.

"With 16,000 new HIV infections every day there is really no shortage of people at risk," she said.

She took up Clements-Mann's theme that basic science can only gain from ongoing, advanced clinical trials.

"We believe that we need not only to focus on basic science but also to focus on empiric testing of candidate vaccines now: because empiric testing will inform science about what needs to be done," she said. "Promising results from primate studies show we must progress to clinical trials as fast as we can."

Johnston closed her remarks by reminding researchers that the NIAID has redesigned its AIDS vaccine program.

"There is a program here for everyone," she said.

More information is available at NIAID's website: http://www.nih.gov/aidsvaccine.

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