An Aids Vaccine Is No Longer A Dream

"Huge progress" is spurring human trials on several fronts

The waiting is hard for Dr. Donald P. Francis. The former government virologist who helped eradicate smallpox in the 1970s is now conducting the first advanced-stage trial of a vaccine against a tougher foe--the virus that causes AIDS. The vaccine or a placebo has been given to 5,400 people in the U.S., and 2,400 more are being recruited in Thailand. Francis already knows through monitoring that some of the volunteers are infected with the dreaded virus. But he won't know if the vaccine is working until the fall of 2001, when he finds out who got the real thing or the placebo. "We're in this frustrating interval," he says.

Francis and his company, VaxGen Inc., are also way out on a limb. Many scientists believe his vaccine doesn't have a prayer of working. But even skeptics see the Phase III trial as an important milestone in the long battle against a microbe that has struck more than 40 million people around the world. "It's our first chance to know if we're on track to have a vaccine in the next 10 years," says Dr. Jose Esparza of the Joint United Nations Program on HIV/AIDS (UNAIDS) in Geneva. Even more encouraging, second and third chances are waiting in the wings.

Indeed, after hundreds of animal experiments and dozens of small-scale human trials, researchers are confident that new vaccine attempts are promising enough to put to the ultimate test in people. The advances range from innovative ways to prod the immune system into attacking HIV to studies identifying vulnerable targets on the virus itself. "I've been the ultimate cynic and pessimist," says Dr. Norman L. Letvin, professor of medicine at Harvard Medical School. "But I've become very optimistic. The truth of the matter is that huge progress has been made in the last couple of years."

Progress is desperately needed--and long overdue. While new drugs are helping keep AIDS at bay in the U.S. and other industrialized countries, around the world, 16,000 people are being infected with HIV each day. Some 95% of these new victims are in the developing world, where treatments are unavailable or far too expensive. That's why "the only answer will be a vaccine," says California Institute of Technology President David Baltimore.

NO PROFIT PAYOFF. That answer has been slow in coming. "We're 18 years into the epidemic, and we've got only one Phase III trial," says Francis. "You have to ask whether we are committed to developing a vaccine or not." Part of the problem has been that drug companies can't profit from an HIV vaccine the way they can with, say, AIDS drugs or Viagra, which must be taken over and over. For tiny AlphaVax Human Vaccines Inc. in Durham, N.C., "at first blush, it seems we are on a suicidal path," says Chairman Robert Johnston. "We picked a target for which no one has managed to make a vaccine, for a third-world market in which no one can pay."

A few big pharmaceutical companies, such as Merck, Wyeth-Ayerst, and Rhone-Poulenc's Pasteur Merieux Connaught unit, are supporting HIV vaccine research efforts. But there remains the sheer difficulty of the task. In its ability to evade the immune system, "HIV is especially nasty," says Baltimore.

The basic theory of vaccination is simple. First, give the body something that looks like an invading microbe. That stimulates the immune system to respond--and remember. Then, if the actual microbe does invade, the immune system is primed for a massive attack. Its response can take two forms. One is like a naval battle, where the immune system makes torpedo-like antibodies: They search for, bind to, and neutralize microbes navigating through the bloodstream. The other response resembles an army going door to door in a city of cells, seeking enemies that are hidden indoors. The immune system's killer T-cells destroy the microbe-infected cells.

Scientists believe most vaccines follow the first method, stimulating antibodies. So when HIV appeared, researchers rushed to design vaccines to do just that. The main tack: inject a big chunk of the protein that forms an envelope around the AIDS virus, stimulating antibodies against the virus' own coat. But human trials in the early 1990s failed. The antibodies stimulated by the envelope vaccines turned out be about as effective as popguns against a rhino. "We quickly learned that most antibodies that are elicited against the virus are notoriously incapable of neutralizing it," says Merck's AIDS vaccine chief, Dr. Emilio Emini.

VaxGen is trying to generate more potent antibodies with a vaccine that includes envelope proteins from two viral strains instead of one. But many scientists hold out little hope--and some see financial motives behind the trial. With VaxGen coming off a successful IPO on June 30, "the investors and founders will recover their investment before the efficacy data are published," says Jack H. Nunberg, director of the University of Montana Biotechnology Center. VaxGen's Francis retorts that vaccine trials have often proved the experts wrong. "All this gum-gnashing of whether ours will work or not has been true of most vaccines," he says.

Perhaps. But past disappointments with the antibody approach have led most AIDS scientists to focus on the other arm of the immune system--killer T-cells. They're trying to design a vaccine that mimics an actual infection so the body's cells will make viral proteins. That prods the T-cells into action.

One approach is to genetically modify a benign virus to carry a few HIV genes. During a brief, harmless infection period, cells will make HIV proteins along with those of the carrier virus, thus stimulating the immune system against both. The best human results have come from studies using a canary-pox virus developed by Pasteur Merieux Connaught.

REWRITING THE CODE. The pox-virus vaccine has protected some monkeys from getting the simian equivalent of AIDS--and has stimulated the T-cell response in humans. "So far, this is the only [vaccine] injected into humans that can do that," says Dr. Michel H. Klein, Pasteur's vice-president for science and technology. "But we don't know yet if it is protective."

Other virus-based vaccines in development may be even more potent. Government and academic scientists are experimenting with a weakened version of vaccinia, the virus used to help eradicate smallpox. Based on monkey trials, "there is some enthusiasm" that it might be more effective than canary pox, says Bernard Moss, a virologist at the National Institute of Allergy & Infectious Diseases. Scientists at AlphaVax have been able to protect monkeys from simian AIDS using a vaccine based on Venezuelan equine encephalitis virus.

But virus-based vaccines aren't without flaws. The immune system reacts not only to proteins made from the HIV genes but to proteins from the carrier virus, too, thereby dividing its attention. As a result, some scientists are experimenting with vaccines consisting of DNA with HIV genes inserted. Injected into the body, the DNA is taken up by some cells, where its genetic instructions are used to make HIV proteins. The trick is getting the cells to make enough of the HIV proteins to attract the immune system's attention. Working with Apollon Inc. (acquired by Wyeth-Ayerst), David B. Weiner of the University of Pennsylvania has boosted production of HIV proteins by adding an HIV gene called REV. And Merck scientists are rewriting the genetic code of HIV genes to make them look more like human genes. The researchers are getting higher levels of HIV proteins--enough to generate impressive killer T-cell responses in monkeys.

Many experts think the best vaccine will be a combination of the various candidates. "There is every reason to believe that using these together will do better than using them independently," says Harvard's Letvin. At Emory University, the most successful monkey trials used a DNA vaccine first, followed by a pox vaccine, says Harriet L. Robinson, chief of microbiology and immunology at Emory.

ACHILLES' HEEL. Moreover, there's new hope That the antibody arm of the immune system can also play a major role. Scientists now know that the envelope protein surrounding HIV is able to resist antibody attacks. But as the Virus binds to cells and prepares to force its way in, the envelope protein changes shape. That exposes its vulnerable parts, much the way a porcupine does as it uncurls, exposing its defenseless belly. The University of Montana's Nunberg has been able to "freeze" the virus in the act of binding. When he injected the frozen bits into mice, he stimulated antibodies capable of neutralizing a broad range of virus types. At the Massachusetts Institute of Technology, Peter S. Kim has been able to pinpoint the envelope protein's precise shape change--and find a newly exposed region that could turn out to be an excellent target for antibodies.

The next large-scale trial after VaxGen's is expected to use a combination of canary-pox vaccine and another type. No one thinks it will be the ultimate answer. But scientists now can see a clear path to creating better vaccine combinations. A truly protective vaccine is still years away, but for the first time since AIDS became a global scourge, the possibility of protection seems real.

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