Wall Street Journal - Friday, 17 January 1997.
Elyse Tanouye, Staff Reporter of The Wall Street Journal

Yet the need for an AIDS vaccine has never been greater. About 23 million people world-wide carry the AIDS virus. The epidemic infects three million more people each year -- 8,500 new patients a day. New "protease inhibitor" drugs have produced promising results in beating back HIV, but only 200,000 people take them, and most AIDS patients will never get access to the $12,000-a-year therapy.

Other vaccines have wiped out previous viral scourges or brought them under control in decades past: smallpox, polio, yellow fever, measles, mumps and rubella. So why not AIDS?

About two dozen AIDS vaccines have undergone initial tests, and some are poised to move into broad patient trials. But scientists are split over whether they should proceed. Drug makers, researchers and government officials fret over the risk to test-patients, the threat of litigation and the geopolitical sensitivities of Western leaders making decisions that affect millions of people in developing nations.

"This is a very polarized field," says Peter Piot, executive director of UNAIDS, the United Nations AIDS program. "And now, the debates will become hotter."

On one side are the "empiricists," who take a "learn-as-we-go" tack and urge the start of wide-scale human tests now, even though the test vaccines don't look all that promising and little is known about how an AIDS vaccine should work. The other side, the "rationalists," argues that to begin human testing would be unethical and a waste of scarce resources until researchers discover far more about the interaction of HIV and the immune system.

"We shouldn't go just shooting things into people's arms and hope it works. If it doesn't, you're in a helluva lot of trouble," says John Moore, a researcher at the Aaron Diamond AIDS Research Center in New York.

Haunting this clash of lab coats is the history of vaccine development, marked by impressive breakthroughs and sporadic tragedy. Even the polio vaccine created by famed researcher Jonas Salk in the 1950s ended up infecting more than 200 children when a manufacturer took a shortcut, resulting in 11 deaths.

That kind of risk is especially frightening in the case of HIV. The most promising vaccine approach would involve injecting a live-virus vaccine into thousands of willing, healthy volunteers, essentially infecting them with a disabled HIV version to trigger the immune system into a counterattack against the real thing.

Even some who favor testing concede current prototypes are lacking. "The available vaccines to date don't look that great," says Robert C. Gallo, co-discoverer of the AIDS virus and director of the Institute of Human Virology in Baltimore.

One reason is that drug companies, which played a central role in past vaccine development, have largely sat on the sidelines. They spend only a paltry sum -- about $25 million a year -- on AIDS vaccine research, according to a report by a Rockefeller Foundation-led coalition that hopes to prod business into making a bigger commitment.

"Drug company research investment in AIDS vaccines is horrifically small, given the nature of the global problem," says David Gold, co-author of a survey on the subject for Amfar, the American Foundation for AIDS Research. "We all have failed. We all need to do more."

Critics charge that drug makers have dragged their heels because the most desperate need for an AIDS vaccine lies in the poorest countries, such as Uganda, India and Thailand.

Some companies, however, deny that a lackluster market outlook discourages work on an AIDS vaccine. "We may have appeared to slow down, but that's because we're groping around in the dark," says Emilio Emini, top AIDS researcher for Merck & Co. "The tools still aren't there."

Of the world's five major vaccine makers, only the Merieux Connaught unit of France's Rhone-Poulenc SA and Chiron Corp., Emeryville, Calif., have broadbased, active programs. Merck, based in Whitehouse Station, N.J.; the Wyeth-Lederle vaccine unit of American Home Products Corp., Madison, N.J.; and London-based SmithKline Beecham PLC all have limited vaccine programs, according to Amfar.

Yet AIDS experts say drug companies will drive the creation of a vaccine rather than the government, which until recently has spent less than 10% of its $1 billion-ayear AIDS budget on such efforts. "Development isn't done in a basic research lab, it's done in industry," says Dr. Piot of UNAIDS.

"Create the incentives to bring the corporate engine back," says Seth Berkley of the Rockefeller Foundation, which has joined the World Bank and UNAIDS in an effort to create a guaranteed overseas market for an AIDS vaccine. The World Bank hopes to persuade countries to commit in advance to purchase a vaccine, perhaps by offering international financing as a lure. "The more we can make a market look good for an eventual vaccine, the more the private sector will be stimulated to invest in the R&D," reasons Richard Feachem, who oversees the bank's health programs.

HIV has proved to be an unpredictable and elusive target for a vaccine. While other viruses attack human cells in the gut, nervous system and elsewhere, the AIDS virus aims directly at cells in the immune system, complicating the vaccine approach. HIV reproduces in such unimaginable quantities -- 10 billion to 30 billion new copies each day -- that it spins off mutations that can elude a vaccine. "It makes it totally unpredictable where to aim the gun," says Dani P. Bolognesi, a researcher at Duke University Medical School.

Vaccine developers usually try to mimic the natural immune process of people who have survived infections. But HIV is so deadly that no such blueprint exists for AIDS. So they must tackle the seemingly impossible task of inducing an immune response that works better than the natural one.

"This is one of the first diseases in man that for a long time didn't see protective immunity. If it isn't naturally present, it's hard to artificially create it," says R. Gordon Douglas Jr., head of Merck's vaccine business.

That is why the track record so far is riddled with failure. AIDS researchers have seen myriad approaches flop: injections of killed virus, HIV proteins, and "decoy antibodies" that mimic the virus. Most attempts have been shelved.

Vaccines work by manipulating the human immune system into jump-starting its natural defenses. The immune system can take weeks to kick into gear the first time a particular virus-type invades. The next time around, though, the defense system can "recall" the virus and counterattack much sooner. In a healthy patient, a vaccine often introduces an initial infection of a benign virus so the immune system can respond more quickly when the real threat arrives.

The patient can, however, run the risk of an inoculation turning into a full-blown infection. In fighting polio, a live-virus vaccine is used even though it typically causes eight or nine cases of the disease each year in the U.S., or about one per every 790,000 newly inoculated patients. Public-health officials decided the risk was necessary to protect possibly millions of people.

But should such a trade-off be made in the case of HIV, a virus so robust that some researchers worry that even a weakened version used in a vaccine could pose the risk of causing AIDS? Ronald C. Desrosiers, a Harvard Medical School professor, argues the answer may be yes, particularly in countries where the high rate of AIDS infection makes the risk-benefit choice clear-cut.

In his lab on a wooded hilltop outside Boston, four grayish-brown rhesus monkeys are remarkable simply for being alive: Six years ago they were injected with large amounts of the virus that causes AIDS in the species. They survived because, prior to infection, they received a test vaccine with a live, weakened version of the same virus. Test monkeys that weren't inoculated died of AIDS years ago.

Dr. Desrosiers reduced the monkey virus's ability to spread by removing one of its nine genes, known as nef. The human AIDS virus similarly has a nef gene, posing the immediate question: Might the same approach work with HIV in humans?

His tennis partner, AIDS researcher John L. Sullivan, was working with a small group of hemophiliac patients who had contracted HIV in tainted blood transfusions more than a decade earlier but hadn't gotten full-blown AIDS. In one patient, a man now in his mid-40s, Dr. Desrosiers found the virus was also missing the nef gene.

Dr. Desrosiers suspects the patient's initial exposure to the nef-deficient HIV virus acted like a vaccine, training his immune system to immediately recognize and ward off later invasions that may have happened before the blood-transfusion supply was cleaned up. In late 1995, Australian researchers reported they, too, had found similar results in another group of patients infected with nef-deficient HIV.

Dr. Desrosiers strongly advocated moving the nef-deficient vaccine into long-term human tests, but won virtually no public support. "I have been frustrated that my arguments seem so logical, and I've never heard a good argument otherwise," he says. After a while, "people didn't want to hear me talk" on the subject at scientific meetings.

Therion Biologics Corp., a small Cambridge, Mass., biotechnology firm, licensed the nef-HIV vaccine and had hoped to have begun small-scale safety trials by now. But the resistance and fear are so palpable in the research community that "we can't see this entering human clinical trials in the foreseeable future," says Dennis L. Panicali, Therion's president.

Even Dr. Desrosiers admits that he wouldn't take a live-virus vaccine himself because his risk of HIV infection is low. But if he lived in a country riddled by AIDS, where the HIV risk in some population groups is more than 50%, "I would take it in a minute," he says.

That points up what some scientists refer to as "the guinea-pig issue": Developing nations desperately need an AIDS vaccine, but questions arise about the appropriateness of testing Western-developed prototypes on patients in developing nations.

Dr. Piot of UNAIDS argues that human testing should always begin in the country where a drug was developed and expand to other countries only after its safety has been established. Yet the community groups he talks to in developing nations are demanding, rather than resisting, the testing of AIDS vaccines in their countries, he says. "We are under constant, daily pressure from colleagues in developing countries who are crying out for new AIDS vaccines," Dr. Piot says. "We can't afford to wait."

Many researchers would rather err on the side of creating an AIDS vaccine that is the safest possible, even if it isn't very effective and protects, say, only one of every three people inoculated. "Our objectives are much more modest and humble than they used to be," says Michel Klein, head of Pasteur Merieux's AIDS vaccine effort.

Pasteur Merieux has tested one version in about 100 patients thus far. It uses the canary-pox virus to carry HIV genes into the body, where the genes produce proteins that can trigger an immune-system alarm.

In early tests on people, the vaccine and a follow-on booster shot generated antibodies in all patients, a sign the immune system kicked into gear. It also triggered the mobilization of killer T-cells, the immune system's attack force, in 40% of the patients, Dr. Klein says.

If the canary-pox prototype passes current safety tests, the company would begin an efficacy trial of 3,500 people in the U.S. in 1998 and smaller trials in Uganda and Thailand over the next few years.

Merck and other companies are experimenting with DNA vaccines that involve injecting one or two HIV genes, rather than the whole virus, into muscle or other tissue. Theoretically, the genes would enter the patient's cells and produce HIV proteins, training the immune system to recognize and defend against HIV.

But many leading scientists argue that researchers need to pull back and conduct more basic science on HIV and the deepest mechanisms of the immune system itself. Designing drugs to treat AIDS was a narrower pursuit because drugs often seek to block a single viral protein. Vaccines, by contrast, activate a complex system of interacting biological processes, much of which is still poorly understood.

"Given the limited success of existing vaccines, we need to inject new concepts," says David Baltimore, a Massachusetts Institute of Technology biologist and Nobel laureate who was named last month to advise the National Institutes of Health on the AIDS-vaccine program.

That will require more funding. "If we get a candidate that really looks hot, then we will throw whatever millions of dollars at it that it takes to fund it adequately. But it really depends on having the scientific opportunities to fund," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which oversees government-funded AIDS research.

Thus the argument continues its circular path: The companies are waiting for advances in basic science; basic-science researchers are waiting for the government to ante up; government is waiting for basic breakthroughs from academic and corporate labs.

David Gilden, an official at the Gay Men's Health Crisis in New York, says plenty of people -- including himself -- would readily volunteer to test even a live-virus vaccine, if only drug companies and AIDS researchers would get their act together. "We need an AIDS vaccine," Mr. Gilden says. "Get on with it."

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