The Wall Street Journal - 26 May 1992
Marilyn Chase, Staff Reporter of The Wall Street Journal

Despite many ingenious vaccine models, successful animal studies and encouraging human safety trials, realizing the dream of a simple world-wide prevention strategy seems as distant as ever.

"What we'd like is a sugar cube that you take once in your life to prevent infection. But I don't think it's going to happen," said Philip Berman, a veteran vaccine researcher from Genentech Inc., at a meeting in Colorado last month on the acquired immune deficiency syndrome epidemic.

The human immunodeficiency virus that causes the fatal syndrome mutates so swiftly that it threatens to outrun the scientists trying to halt its spread. There are so many strains of it around the world that some researchers have all but abandoned hope for a single-shot global preventive that would stop AIDS in the way that the Salk vaccine halted polio.

"We need Indiana Jones, going around the world with a PCR gene-amplification machine to type the various virus strains," Dr. Berman says. He isn't alone in feeling daunted.

"The idea of protecting against HIV in the real world isn't feasible at this time, given the candidates {vaccines} we now have," says former federal vaccine researcher Wayne Koff, now of United Biomedical Inc. "Nine or 10 U.S. vaccines have been entered into clinical trials," he says, "but none meet the ideal criteria" -- namely, that it be long-lasting, require few booster shots and provide immunity to HIV whether it enters the blood stream directly as in needle-borne infection or through the the anogenital area as in sexual transmission.

There have been a number of encouraging studies using chimpanzees. Marc Girard at France's Pasteur Institute and, in the U.S., Dr. Berman at Genentech and Emilio Emini at Merck & Co., have used vaccines and antibodies to prevent animals from becoming infected by HIV. But such studies were "idealized," Dr. Koff says, because researchers sought to introduce the virus shortly after vaccination, when immunity was at its peak, and they used the same strain the animals had been immunized against.

Eventually, says Dr. Koff, it will be necessary to test chimps by injecting different virus strains long after vaccination. Studies also should simulate sexual transmission by releasing a dose of the virus into the animals' anogenital area. That, he says, is more "real world."

The obstacles to a home-run vaccine continue to be HIV's wide strain variation and its sexual transmission. In addition, researchers spent years investigating a strain called IIIB that they later learned is very rare in nature. Moreover, the virus wears a "bulletproof" coat.

HIV "is armored by a sugar shield which prevents even the best antibody from binding it and blocking infection," says Peter Nara of the National Cancer Institute. He says he feels there will be no single solution: "We need multistrain vaccines, and different vaccines for different strains and strain groups."

While human studies so far show several of the vaccines to be safe, most have elicited only weak and transient immune reactions, says researcher Julie McElrath of the University of Washington at Seattle. The strongest reaction was sparked when researchers put together two vaccines from Bristol-Myers Squibb Co.'s Oncogen unit and MicroGeneSys Inc. "The combination approach offers the most optimism toward an anti-HIV vaccine," she says.

Duke University vaccine expert Dani Bolognesi agrees, adding that Chiron Corp. and Genentech vaccines should be included in future combination regimens. And while scientists don't have an AIDS preventive in hand yet, he argues that more cooperation and corporate joint ventures could greatly improve the odds.

"I don't think anybody would say we're ready right now. But we have leads, and we have immune responses I didn't see a year ago," Dr. Bolognesi says. "We've got to get these companies together, to get us across the threshold, to maximize the response that we need."

Genentech's Dr. Berman worries that even if authorities decided to conduct a study of a vaccine's prevention capabilities tomorrow, "it would take two years to set it up." Some researchers regard Bangkok as a likely spot for such a study; the AIDS epidemic is relatively young there -- and fewer mutant HIV strains have cropped up to complicate the picture. The World Health Organization is preparing for vaccine studies in four countries: Thailand, Brazil, Rwanda and Uganda -- that is, when a promising vaccine candidate emerges from safety studies in the U.S. and Europe.

For now, Dr. Berman is comparing virus strains from around the world, searching for any areas of consensus in their variable genetic codes. He shows a slide of strains from Africa, America and Asia. Amid the lines of alphabet soup, one sequence of initials shows up repeatedly: GPGRAF. He thinks he is onto something. He says rabbit studies suggest the possibility of inducing broadly reactive immunity against many strains of HIV.

However, Merck's Dr. Emini seems unimpressed by the findings. "We need to drive the levels of antibody to much higher levels. This virus unfortunately isn't that easy to neutralize."

Despite the absence of a clear candidate for AIDS prevention, Dr. Koff says scientists must continue tests of effectiveness. "In the absence of any other way" of stemming the spread of HIV, he says, "the urgency of the epidemic is such that we have to take these steps.

"We're on a long curve into the next century before we have an AIDS vaccine," Dr. Koff says, and the ways to speed the curve are combination vaccines and efficacy trials.

Daniel Hoth, a researcher at the National Institute of Allergy and Infectious Diseases, says he feels "increasing respect for what a damned complicated problem AIDS is." He adds: "A lot of research is like shining a flashlight on a dark street corner. We feel good because we're looking where the light is. But who knows how big the darkness is?"

Taking solace in "the critical mass of brain power" now focused on the epidemic, Dr. Hoth says, "We need scientists in the grip of an obsession to see this through."

Both obsessed and doggedly optimistic, Robert Redfield, a researcher at Walter Reed Army Medical Center in Washington will soon have 600 volunteers enrolled in his studies of AIDS vaccines as immune-boosters. He is testing such vaccines not for purposes of prevention but as treatment for people who are already HIVinfected. He says he believes vaccines such as those of MicroGeneSys and Genentech can "redirect" the immune system, and he is eager to test the Chiron model too.

In a preview of a study he will release this summer, Dr. Redfield says that using vaccines as immune boosters shows "intriguing" hints of effectiveness by slowing the loss of infection-fighting white blood cells called T-cells. He says one patient has been on the vaccine treatment for more than 1,000 days and is maintaining his T-cell count at between 450 and 475. This is nearly half the normal level of roughly 1,000 T-cells -- good stabilization, Dr. Redfield says. Skeptics point out that controls are needed to compare how the patient would have fared without the shots, but Dr. Redfield seems confident of winning over his doubters.

"People say: `Yeah, but does it work?'" he acknowledges. "Well, we think we see intriguing signs that the viral load in patients' blood is falling and their T-cells are stabilizing."

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