Newsday - June 15, 1998
Laurie Garrett - Staff Writer

With HIV treatments proving toxic to many Americans and unaffordable to others around the globe, President Bill Clinton in May, 1997, ordered the National Institutes of Health to have a vaccine by the year 2007. For Nathanson and many others, the order has become a life's mission.

"All I care about is making a vaccine," insists Nathanson, 71, a viral epidemiologist named to his new job last month. "And if it requires stepping on some toes to do it, so be it. My obsession is on making a vaccine."

With an estimated 40,000 Americans and 6 million other individuals worldwide becoming infected this year alone, the search for a vaccine has gained Holy Grail overtones for many within the AIDS science community.

Husband and wife team Dr. Jonathan Mann, of the School of Public Health at Allegheny University, and Mary Lou Clements, of Johns Hopkins School of Medicine in Baltimore, insist the need for a global vaccine is so large that the ongoing failure to produce one is, in Mann's words, nothing less than a "human rights violation."

Immunologist John Moore fears "there will be no `quick fix' to the HIV vaccine problem," but nonetheless concentrates all his working hours to vaccine research at the Aaron Diamond AIDS Research Center in Manhattan. And Nobel laureate David Baltimore mixes his duties as president of the California Institute of Technology in Pasadena with running a committee of America's leading scientists who eye the same vaccine goal, by order of President Clinton.

As scientists gather later this month in Geneva for the 12th International Conference on AIDS, the schisms will be sharp and the rhetoric heated among a growing number of top scientists who have, in just the past few years, become fixated on pursuit of the elusive AIDS vaccine.

The goal is shared. Next year the National Institutes of Health's AIDS budget will increase spending on vaccine research by 17.5 percent. That can be compared with only a 5.2 percent increase in funding for research on new forms of treatment. Yet individual enmity reigns.

Discussions with many key players show there is little agreement about how best to carry out the pursuit of an AIDS vaccine, and the arguments are being pursued with equal parts vision and venom.

The vitriol has been particularly sharp since June 3, when the U.S. Food and Drug Administration gave VaxGen, a San Francisco-based biotechnology company, approval to conduct the first Phase 3 clinical trial of an AIDS vaccine. The experiment, which will involve 5,000 mostly gay men in the United States and 2,100 intravenous drug users in Thailand, has become a lightning rod for the debate, pitting laboratory immunologists and leading scientists against public health advocates, researchers and the Presidential AIDS Advisory Council.

On March 18, the presidential council passed a resolution decrying the U.S. government's annual $153 million AIDS vaccine program, calling it "stalled in paralyzing scientific debate and bureaucratic delay." And it supported going ahead with large-scale field trials, "even before the scientific correlates of protection have been fully deciphered."

In other words, use an experimental vaccine even if scientists remain uncertain about how, exactly, to measure success - or even precisely what elements of the immune system must be mobilized to muster an effective reaction against HIV.

But while the policy side of the Clinton administration seems to be telling science to charge ahead hopefully at full speed, the scientific side of the administration sees a different situation. Baltimore insists that none of the vaccine candidates - including VaxGen's - is on the right track. Though the roughly three dozen potential vaccines developed to date promote production of antibodies, Baltimore says they are the wrong antibodies.

"All of the antibodies produced by all the vaccines not only don't neutralize virus, they don't even bind" to HIV, Baltimore said in a recent speech. "The likelihood that any such protein will work is very low . . . there is deep knowledge necessary if we're going to fully understand development of an AIDS vaccine."

One problem facing scientists is that they are dealing with an agent, HIV, unlike any other for which there is a vaccine.

"I have a sense that a lot of people have not caught on to a simple observation," Nathanson says, pointing to patients who are apparently doing well on anti-HIV drugs. "These patients' opportunistic infections melt away, almost miraculously. The patients do recover their innate ability to cover these infections, immunologically. But what they don't recover is their ability to control HIV.

"Clearly," he adds, "this factor presents a major challenge to immunology: Why don't HIV patients ever muster an effective [immune] response against the virus?"

HIV is almost unique among human diseases in that there don't appear to be any people who possess an immune response against the virus. There are people who are genetically capable of resisting infection, but their asset is not a strong immune system. Rather, they lack certain receptors on their cells that the virus uses to infect human or monkey cells.

But after 18 years of the AIDS pandemic, no one has found a human who can do the same for HIV.

"The most fundamental question to ask about an HIV vaccine is: `What evidence exists that protection against disease after exposure to HIV is possible?' " John Moore wrote last month in the scientific journal Nature Medicine. After reviewing all available scientific evidence gleaned from human and monkey experiments, Moore concluded that no "quick fix" vaccine should be expected.

That is certainly not the sort of news Mann, VaxGen stockholders, the Presidential Council or developing country governments want to hear.

The Presidential Council decision was reached following a March 20 speech to the group by Mann. The public-health advocate told the council "it is unethical and violative of human rights to hold AIDS vaccine development hostage to a requirement for scientific exactitude which is unreasonable and may well be unattainable."

In an interview, Mann clarified his remarks, saying, "The commonality among the groups most at risk of being infected [such as African Americans] . . . are they are marginalized from the rest of society. So that's the basis of a concern. It doesn't say that [NIH director] Harold Varmus or David Baltimore are torturers. It says that delay - that waiting to know more than has ever been raised about other vaccines - that raises important ethical and human-rights concerns."

Earlier this year the International Association of Physicians in AIDS Care, using somewhat less inflammatory language, also declaimed the government's vaccine efforts. And to back up their protest, several members of the association publicly injected themselves with a vaccine.

But no one has been as vocal as Dr. Donald Francis, director of VaxGen. His tiny biomedical company has only one product, an HIV vaccine originally developed by genetic engineering giant Genentech, but abandoned by that company and given to VaxGen three years ago.

Since then, Francis has worked tirelessly to gain popular support for the vaccine, gather venture capital to conduct an estimated $30-million field trials and elicit FDA approval for the project. On all three points, he has been successful. And field trials in the United States are scheduled to begin today.

The vaccine VaxGen is testing in the United States is made of the outer protein coats, called gp120, of two B-type viruses. These are the strains most commonly found in the United States. Later this year, Thai volunteers will receive a vaccine made of gp120s from a B-strain and E, the strain most widespread in that country.

Some of the volunteers will get the VaxGen vaccine; others will receive a placebo, Francis said in an interview.

Boosters will be given one month after the primary inoculation, and then every six months thereafter for three years. Success will be judged, Francis said, by measuring the presence of HIV in the blood of all volunteers three years from now, comparing infection rates in placebo recipients with those who got the VaxGen product. And among the VaxGen recipients who get infected, Francis' team will look to see how rapidly they get AIDS, compared with infected placebo recipients.

"I don't think there's any doubt that the vaccine is effective," Francis said.

And he says his company is having no trouble finding Americans who want to give it a try, particularly uninfected spouses and partners of HIV-positive individuals. "They're lining up," he added. "I think we're going to have to turn them away."

In its original safety trials, more than five years ago, the vaccine proved safe, but two people became infected with HIV, demonstrating that the vaccine did not protect them.

Dr. Margaret Johnston, director of the private International AIDS Vaccine Initiative (IAVI), is less sanguine about VaxGen's prospects. She says VaxGen's vaccine "clearly is not the answer. I don't think anyone thinks so. The question is whether it will have any efficacy at all. I think it will have some . . . but regardless, the global situation is so great, we need an answer. We cannot afford even the least bit of guesswork. We have to test it."

For that matter, Johnston thinks every AIDS vaccine candidate that has proven safe in small Phase 1 and 2 trials should, like VaxGen, be tested in large field trials.

"We are a unique species," compared with test animals, Johnston says, "and we always learn something in clinical trials."

As for criticism from research scientists, Johnston shrugs. "David Baltimore? He might be right," she says. "And I think he could be wrong."

Mann's public comments last month drew vehement attack. Seventy-five top scientists and AIDS activists signed a critical letter that appeared in the journal Science. Moore and Mann exchanged volleys of mutal criticism. And Baltimore said in the IAVI newsletter that "making vaccine testing a human-rights issue is the ugliest form of rhetoric I can imagine."

FDA approval of the VaxGen trial only added more fuel to an already well-stoked fire of anger in scientific circles. The original Genentech product was rejected for NIH-funded clinical trials four years ago by the National Institute of Allergy and Infectious Diseases Director Dr. Anthony Fauci.

"The decision we made was based on the priorities and resources we had," Fauci said in an interview. "If the company wants to invest their resources to do that, I have no problem at all. I'm actually looking forward to seeing their data."

NIH Director Varmus agreed with Fauci's assessment, adding, "I'd rather see the first vaccine trial carried out by the NIH involve something that can work."

And few scientists, including Varmus and Fauci, think the VaxGen product has any chance. Why? Because it is made from gp120, as were nearly all the first generation of HIV vaccines developed in the 1988-93 period. And research since that period has demonstrated a variety of problems with creating antibodies to gp120.

For example, a new study published this month by Dr. Steven Wolinsky of Northwestern University Medical School in Chicago has demonstrated that HIVs mutate and evolve radically when they are under attack from antibodies directed to gp120.

Dr. Joseph Sodroski of Harvard University recently made an enormous breakthrough, elucidating the three-dimensional structure of gp120. His X-ray analysis shows that gp120 "presents a challenge for vaccine-makers," Sodroski said, because the most important components of the viral envelope are hidden deep in folds and loops of gp120. That means, he says, they "evade antibodies."

David Ho, director of the Aaron Diamond AIDS Research Center in Manhattan, agrees wholeheartedly. And based on those and other observations, he opposes clinical trials of VaxGen or any of the first generation of anti-gp120 vaccines. Former Office of AIDS Research Director Dr. William Paul is dubious of the rationale for the trial, as well, as is his successor, Nathanson.

"If we knew with certainty all the things we need to make a vaccine, then the [Mann] critique would be a correct one," Paul said. But right now, he adds, research is stymied by evidence from monkey studies that the only effective anti-HIV responses involve not antibodies but T-cells, specifically, CD8 types of T-cells. There is no currently conceivable way of permanently boosting CD8 responses through vaccination, Paul insists.

Activist Gregg Gonsalves of the Treatment Action Group in New York said he is offended by the comments made by Mann, Francis and their supporters.

"All I hear from the other side," Gonsalves said, "is even if it's a dud, we'll learn something from it. And they never say what they'll learn. What? That it's a dud, that's what."

As Nathanson prepares to take the reins of the Office of AIDS Research, tough obstacles lie ahead. Varmus has yet to name a director for the new AIDS Vaccine Research Institute, fueling concern in some circles and providing Mann with evidence of what he calls "government incompetence." Furthermore, Nathanson says, the entire vaccine effort is bogged down in the pursuit of political correctness.

"We're talking about a vaccine, not a politically correct process," Nathanson says in disgust.

Nathanson vows he will set up a powerful, centralized vaccine program, to be audited by the Baltimore Committee. And it will draw from the entire spectrum of scientific expertise in the United States.

"Making a vaccine is like putting a man on the Moon, and you don't do that by passively issuing requests for research proposals," Nathanson said.

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