Newsday - Tuesday, June 5, 2001
Laurie Garrett, Staff Writer

That approach is echoed at the clinical level, where the physician who has led AIDS care in San Francisco since the disease's advent, Dr. Paul Volberding, says if he had to choose how to spend HIV research funds, "I'd invest heavily in basic immunology research to develop a vaccine." Yet those seemingly obvious statements mask scientific and political problems that have stymied HIV vaccine efforts. The word "invest," for example, is a charged one in the vaccine field, which only in the past five years has had considerable financial resources.

Many in the field argue that funding remains far too low. And the phrase "basic immunology research" is code for another frustration. Though breakthroughs have been reported recently in monkey vaccine studies, and some products are reaching the stage of large-scale clinical trials, most AIDS experts aren't impressed. They want research to return to basics, focusing on fundamental questions: how HIV eludes the human immune response, and how - if ever - the cells, chemicals and antibodies of the immune system can control HIV.

Today there is evidence of creative approaches, as 17 vaccines have reached small clinical trials, and dozens more are in various stages of research in monkeys and other animals. They deploy a wide range of types of antigens - the substances that are injected to elicit an immune response. Some are little more than segments of HIV genes, called "naked DNA." Others couple HIV proteins with crippled versions of viruses that cause common colds, exotic African diseases, even smallpox.

With them has come a bit of optimism.

But the one vaccine nearing a large clinical trial, and another private sector effort already in such trials, have not been greeted with enthusiasm in the scientific community. And researchers generally expect their results to be dismal.

Jon Cohen, author of the new book "Shots in the Dark: The Wayward Search for an AIDS Vaccine," is part of a growing constituency of scientists, policy-makers and activists who say that the National Institutes of Health has failed in its leadership.

"This field remains a free-for-all," he says. "And I'm amused that when it comes to a real-world test of a vaccine, researchers start pretending as though this is an organized enterprise that moves in a logical fashion." He and others advocate parallel, even competitive, efforts in the private and pharmaceutical sectors. Cohen suggests that the March of Dimes' 1950s campaign against polio be used as a model: It raised money privately, funded several scientists and was responsible for both Jonas Salk's injectable polio vaccine and Albert Sabin's oral one. The then-nascent NIH played no role.

The private International AIDS Vaccine Initiative, located on a top floor of a Wall Street skyscraper, is the closest thing to an AIDS March of Dimes. With support from the Bill and Melinda Gates Foundation, the Rockefeller Foundation and a number of smaller scale donors, the vaccine initiative, founded in 1996, has raised cash reserves in the neighborhood of $230 million, about half of the targeted sum the organization says it needs to execute its scientific blueprint for vaccine development.

The initiative is backing trials of would-be vaccines and is willing to bankroll even corporate research - provided vaccine developers sign agreements that give the organization partial control of the product for low-cost distribution in poor countries.

Dr. Seth Berkley, the group's peripatetic and energetic leader, acts as a sort of global cheerleader of the effort, alternatively rooting for one initiative, then leading the booing of others. But the word most commonly found in Berkley's vernacular is "urgent." "If tomorrow this virus mutated and were airborne, what would we be doing, huh? What would we be doing?" Berkley asks rhetorically. "We'd be operating 24 / 7, state of emergency, cutting corners and trying everything . . . "When IBM wants to move a product quickly, what do they do? They throw money at it. Who's working 24 / 7 on an AIDS vaccine? Nobody!" Most of the $800 million in government funds spent over the past 20 years on finding a vaccine has been overseen by Dr. Anthony Fauci's National Institute of Allergy and Infectious Diseases.

When Fauci hears Berkley's talk of an airborne version of HIV, he groans. "That's a modern day version of 'How would the government respond if it wasn't a gay disease,' " he says. "Is the level of urgency behind our effort OK? I think so. If you look at the fastest-growing sector of our [NIH AIDS] budget, it's the vaccine area. It's the hottest area." In 1996, for example, the entire NIH budget for AIDS vaccine research was $111 million. Last year it reached $239 million, or 10 percent of the total NIH budget for HIV research. President George W. Bush's budget proposal for 2002 would put $357 million into vaccine research.

In the pharmaceutical industry only one company - Merck - has a large HIV vaccine program. The company won't specify how much money or personnel is devoted to the program, but last year's expenditure was far larger than the combined efforts of the NIH and International AIDS Vaccine Initiative, topping $2.4 billion. Merck, in fact, has bought most of the available supplies of research monkeys. The company's effort, led by Dr.

Emilio Emini, draws awe from even traditionally critical outsiders, such as activist Gregg Gonsalves, policy director for the Gay Men's Health Crisis in Manhattan. "Emilio's first vaccine is just not going to be it," Gonsalves says. "But at least he says, 'I want to find something that looks promising. I don't have to prop up a [NIH] vaccine network that has no product to test. I don't have to prop up the NIH.' That's where it's [a vaccine] going to come from - big pharmaceutical." Basic research scientists complain of getting caught in the crossfire between these competing forces. If collaborating with Merck, for example, they cannot speak to other scientists about the specifics of their research without violating proprietary secrecy agreements. If involved with the International AIDS Vaccine Initiative, they say, there's a healthy dose of NIH-bashing to be heard regularly. And the NIH insists that researchers abide by what many consider odious bureaucratic rules and committee meetings.

But they agree that a degree of competition is a good thing.

The competition, coupled with a rising sense of urgency, has led to tension between those who believe that even third-rate vaccine candidates ought to get into human arms as soon as possible, vs. more cautious scientists who insist that only products that prove strong in monkey studies should move into human trials.

"Rational empiricism must lead the way," argues Dr. Margaret Liu of the Bill and Melinda Gates Foundation. "In other words, we cannot wait for all the answers before moving candidates through to the clinic. But neither should we allow the huge need for a vaccine to cause us to push entities into clinical trials if the data supporting them are marginal. And we must make decisions . . . based upon science, not upon biases or politics." Until the mid-1990s, the AIDS vaccine effort appeared particularly grim, with most top immunologists disdaining involvement in what was seen as an applied-science problem. Then the NIAID directed more cash into the effort, a few breakthroughs raised optimism levels, President Bill Clinton in 1997 set a 10-year target for discovery of a vaccine and Congress set aside funds for construction of a vaccine research center at the NIH.

So there was reason for hope. But it remains coupled with disappointment and skepticism.

"The AIDS vaccine 'success' is just that the bar is lowered," argues Dr. Wayne Koff, the international vaccine initiative's scientific director.

What Koff is worried about is a trend supported by Dr. Jay Levy of the University of California in San Francisco: lowering the goal to be achieved.

Levy suggests that it will be impossible to make a vaccine that actually keeps HIV from infecting people's cells.

He calls for setting a less ambitious target for the next 10 or 20 years: developing an agent to "limit the spread of HIV after entering" the body. So an infection would occur, but the amount of virus in the blood - the "viral load" - would remain low. The result: Individuals would not develop AIDS, and they would be less infectious to others.

He calls the strategy "population protection." "As with other viruses, a successful HIV vaccine even if it does not protect the host from infection could protect the individual from disease development - perhaps even for a lifetime," Levy wrote in the British medical journal Lancet in January.

Such an approach does not preclude the need for a preventive vaccine, which he says "should certainly remain the primary goal of vaccine research" in the long run.

With "population protection" as its target, Merck is moving ahead with a naked DNA vaccine designed by Dr. Norman Letvin of Harvard Medical School. In monkey tests it has boosted only one of the immune system's two arms, the cellular response. Historically, disease vaccines have triggered the other arm, the antibody response. The latter provides long-lasting protection.

Letvin says there's a short-term role for a vaccine that triggers cellular responses, because it "may buy the time we need" to develop a better, lifesaving product.

A number of groups are pursuing the idea. Dr. Judy Lieberman, also at Harvard Medical School, has put HIV genes into bacteria, Listeria monocytogenes. When the bacteria infect an animal, the immune system attacks both bacterial and HIV antigens. Dr. David Ho of the Aaron Diamond AIDS Research Center has another HIV DNA virus, mixed with a harmless smallpox strain called MVA, that he hopes to get into clinical trials - funded by the international vaccine initiative - in Xinjiang, China, early next year.

Harriet Robinson of Emory University and her collaborators are also working on a naked DNA vaccine aimed at cellular immunity. Like Ho, Robinson has used the MVA smallpox vaccine in monkey studies. A year after vaccination, she rectally exposed the animals to a virulent, laboratory-made virus that combines the most powerful components of simian immunodeficiency virus SIV and HIV-1.

"You can see all of the animals are responding," Robinson told virologists gathered last month at Cold Spring Harbor Laboratory. "All of the animals got infected. But all of the vaccinated group pulled their viral loads down." And after eight months of infection, 23 of the 24 animals are "doing very well." Robinson is ready to try her vaccine in people. She too concedes that cellular immunity alone is unlikely to be the answer.

The first generation of vaccines, prototypes made during the late 1980s, did raise antibodies, but not ones with the power to destroy HIV. They targeted proteins found on the outer envelope of HIV, called gp120. One of those gp120 vaccines, made by a private California company named VaxGen, has survived the first two stages of clinical trials in humans and has moved on to Phase III, a test of its effectiveness in a large population. The results of those trials - which most scientists expect will be dismal - won't be known for at least a year.

Robinson tried adding gp120 to her vaccine in hopes of eliciting both cellular and antibody responses, but her results were worse than those produced by the original agent alone. That's no surprise to John Moore, a vaccine researcher at Cornell's Weill Medical College in Manhattan. Several years ago Moore proved that gp120 immune responses were ineffective in control of HIV.

Today, efforts are under way to find something else on the outside of HIV that will be effective in provoking neutralizing antibody responses.

"There are perhaps five or six laboratories doing serious work," Moore says.

"None of us is making spectacular progress. But there's little or no coordination at present . . . Sure, we could all probably spot a home run if one happens, but right now we are all wandering randomly around the diamond wondering in which direction first base actually is." Koff, of the private vaccine initiative, thinks there is a need to standardize the research on neutralizing antibodies - have everybody work in the same systems, with the same chemicals, so they can compare results. But scientists are a contrary and independent lot and don't take kindly to such enforced research regimens, Fauci says.

Meanwhile, though few scientists believe it is going to prove effective, the NIAID is preparing to take a gp120 vaccine coupled with a canarypox virus into its first large-scale Phase III clinical trials.

Dr. Larry Corey of the University of Washington in Seattle, a major proponent of the gp120 / canarypox vaccine trial, argues that it is "the first vaccine that has produced a consistently detectable [cellular] response to HIV after vaccination." Whether or not the vaccine is effective, the clinical trials will offer information on human responses.

Gonsalves, who has written a critique of the NIH's vaccine efforts for Gay Men's Health Crisis, takes issue with Corey's analysis.

"If you want to know what's wrong with the vaccine field, look no further than what's going on with the canarypox. It's practically useless," he says. "What kind of a response does it get? And what kind of crap is it to say we'll never know until we put it in people? . . . Merck isn't going to waste their time and money with a canarypox vaccine." As disparate as their approaches are, there is one thing the various parties to the vaccine pursuit have in common: Baseball is their metaphor.

"I think everyone now is sophisticated enough to know that we're not going to hit a home run on the first time" in clinical trials, Fauci says. "If we don't get a home run the first time we'll go back up to the plate and keep swinging." "If nine out of 10 of our products don't strike out then we haven't tried," says Berkley. "We haven't taken risks, we haven't done our job."
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