AIDSWEEKLY Plus, 22 July 1996
Daniel J. DeNoon, Senior Editor

Those who say no point to the scanty amount of evidence that current vaccines will be able to induce meaningful immunity outside of the test tube. They also argue that to test now would be a great waste of valuable resources.

Those who say yes point to the enormous need for a vaccine to slow the inexorable advance of the AIDS pandemic. They passionately argue that more resources will be wasted by waiting than by moving forward.

These and other issues were brought forward in a formal but poignant debate at the XI International Conference on AIDS, held July 7-12, 1996, in Vancouver, British Columbia, Canada.

Arguing in favor of proceeding with HIV vaccine trials was Edward K. Mbidde, director of the Uganda Cancer Institute. In cooperation U.S. and U.N. health agencies, Uganda has already mobilized to create an infrastructure and to identify subject cohorts for HIV vaccine trials.

Central to Mbidde's argument is the overwhelming velocity of the AIDS epidemic in the developing world.

"Over the next five years 18 million people worldwide will be infected despite the current interventions," he said. "On average about 10,000 people daily will be infected with HIV, 90 percent of them from the developing countries."

Mbidde noted that AIDS information, education, and communication can effectively prevent new AIDS infections, but these interventions are unlikely to have any immediate impact on the epidemic.

"Provision of adequate information depends on the availability of trained staff, use of appropriate messages, high literacy rates, and the availability and affordability of public media," he said. This preventive approach is not accessible to those that need it the most.

"Given that about 90 percent of the population in Africa lives in the rural areas, this intervention benefits only a small segment of that society. ... Risk perception is not well perceived in some parts of Uganda and possibly in many other developing countries. Thus HIV prevention programs based on risk perception may not be effective."

As for condom use, Mbidde noted that condoms are not always available in poor nations - and that they are unaffordable when they are.

Similarly, programs to limit the spread of HIV by treating sexually transmitted diseases have not been effective.

But given their current state of development, could HIV vaccines do any better? Mbidde admitted that this is an open question.

"Phase I and II trials give evidence that an AIDS vaccine just might work, but we will never know unless we try," he said. "Other vaccines have been developed without having all the scientific information we wished we had."

Mbidde pointed to the successful efforts to develop vaccines against smallpox and polio. In the latter case, he observed, Jonas Salk was criticized for the lack of a scientific basis for his vaccine.

"The Sabin vaccine designed with a lot of science behind it was not available for seven years after Salk's vaccine had protected 72 percent of the vaccinees," Mbidde noted.

Advanced efficacy trials of intermediate size, Mbidde said, could make substantial achievements:

• They could rapidly identify vaccines with efficacy rates of at least 60 percent.
• They could once and for all eliminate ineffective vaccines from consideration.
• They could point to the need for improvement and further testing of vaccines with intermediate (30 to 60 percent) efficacy.
• They would require fewer years of follow-up than Phase II trials.
• They would contribute valuable information on the correlates of immunity to HIV.
• They would show whether vaccines can lower HIV viral load in previously infected individuals.

"Efficacy trials fill critical knowledge gaps," Mbidde said. "The completed intermediate-sized trial would permit public discussion of the results such that improvements in the vaccine product could be incorporated into subsequent studies."

The distinguished Ugandan physician also argued that advanced HIV vaccine trials will have a positive psychological impact.

"Developing countries are mentally, politically, and scientifically ready to move to human trials," he said. "Failure is inconclusiveness, not low or no efficacy. ... We do not need 100 percent efficacy. For us, anything that would make a dent in the epidemic is a benefit.

"We need more basic science. But the question is, should it be limited to Western countries? ... If we just wait for other people to act, I don't think we are doing justice to our own people."

Arguing against Phase III clinical trials of existing candidate HIV vaccines was John Moore of the Aaron Diamond AIDS Research Center, New York.

Moore admitted that the need for an AIDS vaccine is great, but he insisted that neither an effective vaccine nor a coherent plan to develop one now exists.

"We do not have an HIV vaccine today, and we are probably not even close to having one," he said. "Neither do we have near implementation a concerted long-term plan to make one."

Moore argued that in the absence of such a plan, little could be gained from advanced clinical trials - and much could be lost.

"We rely on hope rather than judgment, hype rather than planning, empiricism rather than science," he said. "This must change, or in a decade's time we will still be debating how to make an HIV vaccine, not celebrating the creation of one. And millions will have become infected and died in the intervening period."

To the argument that it would be a shame to waste the existing infrastructure now available for advanced testing of candidate HIV vaccines, Moore said that the purpose of HIV vaccine research is not to conduct clinical trials but to make an effective vaccine.

"At some stage efficacy trials will be essential, but that time is not now, not in 1996 or 1997," he said.

"Without strong basic research programs, any plan for making an HIV vaccine is like a house built on sand - it has no foundations. ... For the next few years, the emphasis should be on analysis of the consequences of immunization, including breakthrough infections, and not on definitive endpoints of efficacy."

Moore strongly objected to suggestions that current HIV subunit vaccines are promising. He noted that several of the 19 breakthrough infections in vaccinees occurred at times of peak antibody response. And there is no evidence, he said, that viral load is in any way reduced in vaccine recipients.

"Vaccines are not selecting wimpy viruses," he said. "There is no evidence that the vaccines put selection pressure on the virus. ... New human trials [of gp120 subunit vaccines] will not provide any new information."

Moore suggested that researchers should currently be testing as many HIV vaccine approaches as possible in carefully controlled Phase I and Phase II trials.

"Hitting a home run is great, but most games are won by accumulated base hits," he said. "Ten vaccinees carefully analyzed may teach us more than 100 studied perfunctorily."

Noting that vaccine manufacturers might be reluctant to have government agencies deem their product less promising than another, Moore recommended that federal agencies should buy vaccine immunogens from industry or make them in publicly owned facilities.

"If federal agencies shouldered the responsibility for initial testing, they would have the right to conduct experiments with a product and to discard it without fuss if necessary," he said. "Any concept that looks promising could be returned to the private sector for final development as a product, which is what industry does best."

Moore admitted that this program would be expensive, but he blasted the U.S. National Institutes of Health for allocating less than 10 percent of its AIDS budget to vaccine development.

"We need to focus our efforts on making the vaccines of the next decade rather than testing the vaccines of the past decade ad nauseam," he concluded. "Just because something can be done does not mean something must be done: product availability should not dominate any decision to conduct an efficacy trial."

But Moore is apparently no enemy to empirical studies: in a press conference he appeared to take the controversial position that live attenuated HIV vaccines should be tested in humans.

"We could have a vaccine today if there was the will in the world to test an attenuated HIV vaccine," he said. "People call for courage, and they are right to do so - but some country is going to have to find the courage to test this concept."

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