Chicago Tribune (CT) - SUNDAY, November 12, 1995 Edition: CHICAGOLAND FINAL Section: NEWS Page: 1 Word Count: 2,080
John Crewdson, Tribune Staff Writer.

In the mid-1980s, many researchers said an AIDS vaccine was a decade away. Now even the revised goal set by government researchers five years ago-a workable AIDS vaccine by the year 2000-appears to have moved beyond reach.

The discouraging new data come from government-financed tests of a vaccine called gp120 on more than 250 men and women whose lifestyles place them at increased risk of infection with HIV, the virus that causes AIDS. Although no data on the infected volunteers has yet been reported in the medical literature, the findings were presented at a scientific meeting in Paris two weeks ago.

So far, at least 14 of the high-risk volunteers and three members of a low-risk group have become infected with HIV, in most cases after receiving the full course of gp120 vaccinations and boosters, according to researchers who saw the data in Paris. Two members of a high-risk control group who received a placebo instead of the vaccine have also become infected.

In addition, laboratory tests suggest that the immune response evoked by the gp120 vaccine in the infected volunteers may be insufficient to neutralize the AIDS virus. That finding, together with the HIV infections reported from the study, have strengthened the determination of the National Institutes of Health not to spend the $20 million to $60 million necessary for a three-to-five-year study of gp120's effectiveness.

"We continue to believe that such a trial is not warranted," said Dr. John Killen, an NIH official in charge of AIDS vaccine development. "For a variety of different reasons that have to do with confidence in the ultimate outcome, we are not interested in pursuing (the gp120 vaccine). We're pursuing others of higher priority."

None of the NIH's other vaccine trials, some of which involve highly tal concepts, is nearly as far along as the gp120 study. Killen believes "it will be a minimum of five years before we have a vaccine," and other researchers say an effective AIDS vaccine may be 15 to 25 years away, assuming one can be developed at all.

"We've got to get back to the drawing board," said Dr. Jay A. Levy, a veteran AIDS researcher at the University of California in San Francisco, who believes that none of the approaches now being tried will "give us the vaccine that's going to be the one we want."

Levy said that he did not foresee an AIDS vaccine before the year 2010, and that he believed the only viable concept was an attenuated live-virus vaccine like that developed by Albert Sabin for polio. A report in last week's issue of Science said seven Australians infected with an attenuated strain of HIV like that which could form the basis for a vaccine had remained well for as long as 14 years.

A lobbying effort led by the two San Francisco-area biotechnology firms that manufacture gp120, Genentech and Biocene, faltered in June of last year when the AIDS coordinator at NIH, Dr. Anthony Fauci, put off a decision to expand the vaccine trial to 10,000 volunteers nationwide. At the time of Fauci's decision, NIH officials said there were three infections among the high-risk volunteers and none in the low-risk group.

Killen noted that the vaccinated volunteers in the high-risk group had continued to become infected at the same rate as the control subjects who received a placebo. "Although the controls are smaller in number, the rates (of new infections in each group) are virtually identical," he said.

The subjects in the high-risk group include homosexual men who acknowledge having had unprotected intercourse; individuals of either sex whose partners are HIV-positive; and others at increased risk of infection, such as intravenous drug users.

Researchers emphasized that the infected volunteers had acquired the AIDS virus from unprotected sex or contaminated needles and not from the vaccine itself, which is incapable of causing disease.

Ironically, a principal appeal of gp120 has been its inherent safety. The vaccine is made from a subunit of the AIDS virus, the outer protein called gp120, rather than from the entire virus, as in some vaccines for polio and other infectious diseases.

In theory, the human immune system should produce virus-killing antibodies to gp120 that are also capable of neutralizing the AIDS virus should it appear later. But Killen said NIH had now become disillusioned with "the subunit concept in general. It's not one that we're vigorously pursuing."

Dr. Steven Wolinsky of Chicago's Northwestern University School of Medicine, who heads a research group that has been intensively studying the infected volunteers, said the antibodies found in their blood after they received the vaccine but before they were infected did not last nearly as long as those produced by a genuine HIV infection, and were incapable of killing strains of HIV isolated from other AIDS patients.

The early promise of gp120 stemmed largely from the fact that the AIDS virus failed to take hold in two chimpanzees who had been inoculated with the Genentech product several years ago. But John Moore of the Aaron Diamond AIDS Research Center in New York, who presented the Wolinsky group's data in Paris, pointed out that "chimps aren't people."

"HIV doesn't cause disease in chimps, and it replicates extremely weakly in chimps," Moore says. "The less a virus replicates, the easier it is to protect against. Secondly, the viruses they use to infect chimps are wimpier viruses than the viruses that are found in real life."

Moore and Wolinsky both said that while the vaccine studies to date have not been large enough to definitively establish or disprove the effectiveness of gp120, their own data from the infected volunteers provided no reason to convene a larger trial.

"Based on what we've seen with these 19 people, the data do not show these to be very effective vaccines," Wolinsky said. Added Moore: "These vaccines aren't doing very well. These data, looked at objectively, would give nobody any confidence these things are going to work."

According to Wolinsky's data, the AIDS viruses that infected the volunteers are not significantly different from viruses isolated from AIDS patients at random over the past several years, suggesting that gp120 is no better able to protect the general population than it did the infected volunteers.

Wolinsky added that his group could detect no difference between the virus in the blood of the vaccinated volunteers compared with ordinary AIDS patients, indicating that the vaccine had not reduced the viral burden.

Nor, he said, did the "breakthrough" viruses that infected the volunteers (so called because they broke through the vaccine shield) appear to cluster together on the genetic spectrum. Such clustering might have indicated that the vaccine was at least partly effective in suppressing some strains of virus.

A possible explanation for the vaccine failures lies in data from Wolinsky's group and the Los Alamos National Laboratory in New Mexico showing that the AIDS viruses isolated from the infected volunteers differ genetically from the decade-old AIDS virus strains used to make the two gp120 vaccines.

"Those viruses were from an earlier epidemic," Wolinsky said. "The AIDS virus is changing its genetic makeup by about 1 percent a year, so 10 years later we'd expect to find a 10 percent difference."

The Genentech version of the vaccine is made from an AIDS virus isolated from a New Jersey infant, known by the initials MN, by Dr. Robert Gallo in March of 1984. The Biocene vaccine is made from SF-2, a virus taken from a gay San Francisco man in November of 1983 by Jay Levy, and genetically quite different from MN.

A key unanswered question is why the 14 high-risk volunteers who received gp120 became infected at all. Put another way, why did they apparently continue the behavior that originally placed them at risk for HIV infection?

NIH official Killen noted that all subjects enrolled in the trial received "intensive counseling" about safe sexual practices and the use of sterile needles at the outset of the trial, but not all of them followed the advice. "If everybody totally eliminated risk, we would not be able to prove whether the vaccines worked," Killen said.

Although all volunteers sign consent forms affirming they understand there is no evidence the vaccine will prevent them from getting AIDS, some researchers worry that the volunteers, believing themselves to be protected, continued their unsafe behavior. Levy goes farther, wondering whether the gp120 vaccine, in addition to not protecting the infected volunteers, may actually have contributed to their infections.

"The real concern here," Levy said, is whether the antibodies from the vaccine are enhancing the infections with the virus." Levy noted that when horses were given a gp120-type vaccine made from an HIV-like equine virus and then inoculated with the virus itself, "they died much more quickly. This is not a subject that any drug company likes to talk about, but it's there."

Although pharmaceutical companies traditionally pay for clinical trials of prospective drugs, neither Genentech nor Biocene appears willing to finance a full-fledged trial of gp120 in the U.S.

Tim Gregory, the gp120 team leader at Genentech, said his company had manufactured only 150,000 doses of gp120, now stored in a warehouse, with the expectation that the government would pay for the large study needed to show definitively whether it worked.

"We only really had a program as long as we had public money to do the trial," Gregory said. "From a company's standpoint, the risk of failure is just too great to justify the expense of an efficacy trial. You have to look at it in the context of the other products in the portfolio of the company. Genentech doesn't have unlimited resources."

A Genentech spokeswoman said the company's only independent study at the moment was a test of gp120 on 20 volunteers in Thailand. Biocene, a joint venture of the Chiron Corp. of Emeryville, Calif., and Ciba-Geigy, is also testing its gp120 on 30 Thai volunteers in collaboration with the U.S. Army, which has a large laboratory in Bangkok.

The only Genentech employee working full time on the vaccine project is Dr. Donald Francis, whose role with the Centers for Disease Control during the first African Ebola epidemic and during the early days of AIDS was e late Randy Shilts' book, "And The Band Played On."

Francis agrees that the Genentech vaccine may not have kept pace with the moving target that is the AIDS epidemic. "What the breakthroughs are showing," he said, "is that we may need a cocktail" of genetically different viruses in addition to the original MN strain.

But Francis noted that the AIDS viruses in circulation will continue to mutate away from those being cultured in the vaccine labs. "Would you then say it's endless in terms of variation and you'll be chasing your tail?" he asked. "You could."

Francis remained adamant, however, that gp120 is worthy of a full-scale trial of its effectiveness. "We're trying to make efficacy conclusions from non-efficacy trials," Francis said. "The vaccine's not perfect, (but) you do not know the effect of a vaccine until you do an efficacy trial."

Francis said he still held out hope for such a trial, "either in this country or abroad," but not with public funds. "The partnership between me and the government is nonexistent," he said. "We are exploring doing it independently.

"The problem is not within Genentech. The problem is within society. Society does not value vaccines. If they valued vaccines, Genentech would move ahead and make one. Society values drugs.

"During the Ebola outbreak in Zaire I got probably 100 telephone calls about Ebola. How many telephone calls do I get from people interested in AIDS vaccines?"

CAPTION: GRAPHIC: Hope fades for AIDS vaccine. Disappointing results of clinical tests of gp120, an experimental vaccine to combat infection with the AIDS virus, were presented in Paris recently. Many experts had felt gp120 was the most promising chance for an AIDS vaccine by the end of the century. - 596 volunteers tested. How gp120 performed in preventing HIV infection.

951112
CT951102

ÆGIS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 1995. This material is designed to support, not replace, the relationship that exists between you and your doctor.

Copyright ©1980, 2003. AEGiS. All materials appearing on ÆGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGiS, or the party credited as the provider of the content.