Randall Osborne

Editor

Rather quietly, the search for an AIDS vaccine forges ahead. Plodding advances made by a small cluster of biotech firms (some of them helped by government funds) offer chances for big money for shrewd investors, whose task is one of sifting, sorting and defining terms.

"Vaccine" is a simple-sounding word. For most people, it means a drug, typically injected, that blocks disease. But when the subject is AIDS, therapeutic vaccines often are spoken of hopefully.

As physicians scramble to come up with new drug cocktails for patients no longer responsive to the initially prescribed mix, the idea of a vaccine-based treatment seems not just plausible, but inviting.

The National Institute of Allergy and Infectious Diseases (NIAID), of the National Institutes of Health which last month vowed to pump $70 million into private entities through its HIV Vaccine Design and Development Teams said in its recently updated AIDS vaccine status report that "a strong interest remains in determining whether a vaccine could have therapeutic benefit in HIV infected persons."

NIAID said some researchers believe that "identifying a successful therapeutic vaccine would provide valuable information on the immune responses desired in a preventive vaccine."

Even NIAID implicitly acknowledges that the financial bonanza, when it comes, if it comes, will arrive in the form of a drug that protects against HIV somewhat confusingly, in this case, dubbed a "prophylactic" vaccine rather than one that ameliorates the disease's ravaging effects.

But the disease is devious. It mutates and recombines without ceasing, so an AIDS vaccine likely would need to guard against multiple strains many more than, say, a flu shot.

What's more, because HIV infection targets immune helper T cells, scientists are faced with the chore of stimulating the very cells that already are under fire.

Add to this the mad way HIV spreads itself (as free virus and as part of infected cells), and activating immune response becomes at least twice as difficult, especially without an ideal animal model.

Still, a preventive vaccine seems within reach. Most HIV is passed along through heterosexual contact, which is less direct than mother-child transmission. The latter, thanks to new drug approaches, is hardly the scourge it once was. Progress here has given researchers cause for optimism regarding heterosexually contracted AIDS.

Though far from perfect, animal-model tests have shown promise. Hit with viral challenges much greater than those suspected in human exposure to the disease, vaccine-treated animals develop encouraging levels of resistance. And humans apparently have biological defense mechanisms already in place. They often fight off AIDS for years.

Progress in the battle was reported in sessions last week at the XIII International AIDS Conference in Durban, South Africa. Meanwhile, in a scenario reminiscent of AIDS' early days, U.S. political pressure is building to find better treatments or a cure.

In May, the AIDS Vaccine Advocacy Coalition (AVAC) chided legislators for leaving out tax incentives for vaccine development in trade legislation. AVAC is pushing the Vaccines for the New Millennium Act. Through tax credits, the measure would spur biotech firms to spend more on AIDS vaccine development. President Clinton has called for development of an AIDS vaccine by 2007.

For investors, the time may be ripening. Here, as in most realms of biotech research, the key to profit making is likely to be found not only in those firms with the latest-stage successful trials, but also in those pursuing the technologies most apt to bear fruit that can win FDA approval in the end. In AIDS research, maybe more so than in any other disease, these are not the same things.

VaxGen Inc. is the furthest along, with Phase III trials under way in the U.S. and Thailand of its gp120 subunit HIV vaccine called AIDSVAX. Other firms with AIDS vaccines in the works are Chiron Corp. (which was among the winners of the $70 million in NIAID grant money); Aventis Pasteur; Cel-Sci Corp. (through its subsidiary, Viral Technologies Inc.); Merck & Co. Inc.; HIV-VAC Inc.; Therion Biologics Corp.; Vical Inc.; Immune Response Corp.; Progenics Inc.; Protein Sciences Corp.; Virax Ltd.; Wyeth-Lederle Vaccines, a business unit of American Home Products; Avant Immunotherapeutics Inc.; SmithKline Beecham plc; Targeted Genetics Inc.; and Epimmune Inc.

Only one prophylactic vaccine is in Phase III trials. Three are in Phase II trials, and eight are in Phase I trials. Twenty-five are being tested preclinically.

It's VaxGen's drug that could easily beat Clinton's 2007 deadline, reaching the market in the next two or three years, if data prove favorable. Aventis Pasteur, Chiron and Cel-Sci follow closely behind VaxGen.

Sharon Seiler, vice president and biotech analyst with Punk, Ziegel & Co., of New York, said AIDS vaccine scientists are divided into two camps.

One camp is occupied by NIAID and various immunologists and virologists, who "have satisfied themselves that antibodies are not sufficient to prevent infection, and what's needed is a T-cell response. That's why the VaxGen trials are funded by investors and not the government."

In fact, it was NIAID's decision not to fund experiments at Genentech Inc. that caused the company to spin out VaxGen, she said, adding that Genentech retains options to manufacture and market the vaccine. "The protein is fairly tricky to make, so they have some important intellectual property on manufacture," Seiler said.

Private-public partnerships are taking place beyond NIAID's contributions to the likes of Chiron. The International AIDS Vaccine Initiative, funded by governments, foundations and multilateral organizations, said it plans to sponsor six potential AIDS vaccines for developing countries this year, investing more than $10 million.

Members of other camp, scientists from VaxGen and the Centers for Disease Control most of them trained as epidemiologists believe "the only way we're going to find out is to do the trials," Seiler said.

"There's a lot of bad blood between them," she said. "The NIAID people think the CDC/VaxGen people are outright frauds, evil. The CDC/VaxGen people think the others are just resentful."

Yet another approach is being explored in the deal between the Institute of Human Virology (IHV) and the International AIDS Vaccine Initiative to develop an oral vaccine. IHV is a center of the University of Maryland Biotechnology Institute, founded by Robert Gallo, one of the scientists who discovered HIV.

The proposed HIV vaccine will use weakened Salmonella bacteria to deliver genetic material encoding the vaccine DNA to human cells, which translate the genes into vaccine. Oral delivery means the vaccine likely will bring on mucosal immune responses, which could head off sexually transmitted HIV.

Efforts on all fronts are expected to converge eventually. But, for now, VaxGen stands at the forefront, and seems well positioned to harvest major gains, Seiler said especially since VaxGen appears likely to get a part of its competitors' action.

"The next most advanced is the Aventis Pasteur product, Alvac," she said. "It's a canary pox vector into which they've inserted some HIV genes, and they're using VaxGen's gp120 as a booster."

And if VaxGen's product proves even partially effective, "any future trial will have to use that as a control, rather than a placebo," Seiler said. "I would think it would be unethical to do anything else."

Aventis Pasteur remains in large-scale Phase II trials with Alvac, or vCP1452, Seiler said. "They certainly have the infrastructure and resources to move forward, but they're still a good couple of years behind," she said, and others are further back. Cel-Sci, for example, has only done a pilot Phase II trial with a small number of people using its HGP 30 vaccine.

"The important data point for VaxGen is the interim analysis next October," Seiler said, "but the subsidiary points have been successfully addressed. Can you enroll people? They did that ahead of schedule. Can you retain people? Yes, they're ahead of what's expected. Does [participating in a trial] cause them to engage in more risky behavior? The answer seems to be no. Basically, everybody's doing the same thing they did before."

Such are the real issues, she said. Arguments over access to vaccine and exploitation of developing countries where some vaccines might be tested are valid, but not weighty in VaxGen's case, she added.

"Part of the problem is that HIV strains that circulate in the U.S. and Europe are the strains that circulate in most of the developing world, so to say you're testing it there first doesn't mean you don't think it's good enough [for the rest of the world]," Seiler said. VaxGen's trial "is being run in collaboration with Thai scientists, and the invitation of the government," she added.

Seiler said she ordinarily does not recommend "one-product companies," but VaxGen is a deserving exception. "The reward is so large, the risk is worth it," she said.

But that risk must be acknowledged as sizeable, she added, estimating the chance that the vaccine is "somewhat effective" at 30 percent to 40 percent, and the possibility that it works "very well" at 10 percent to 20 percent.

"There's a 50 percent chance it doesn't work at all," Seiler said. *

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