Anticipation grows for AIDS vaccine

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Human trial ends; findings awaited

By Raja Mishra, Globe Staff, 12/23/2002

Scientists have finished the first human trial of an AIDS vaccine, a mammoth $200 million, 5,400-patient effort more than a decade in the making.

Within three months, the vaccine's maker, California-based VaxGen Inc., will reveal whether simple injections can protect against the world's most feared viral killer. Already, the Food and Drug Administration has granted the vaccine fast-track status that would speed it through the approval process, if it proves effective, for public availability.

Public health researchers have long believed that only vaccines can reverse the global HIV epidemic infecting more than 30 million people, most in the developing world. This trial remains the only short-term hope: The next large-scale vaccine trials will not be completed until around 2010.

The much-anticipated experiment unfolded in hundreds on North American examination rooms, including some in Boston. Doctors injected gay men and heterosexuals with numerous sex partners with a clear solution: half were given the experimental HIV vaccine, which is designed to disrupt the virus' spreading mechanism. The rest received an inert placebo.

Though critics have questioned whether the vaccine is potent enough to truly reverse the epidemic, even pessimists say a partially effective vaccine could save thousands of lives in the AIDS-ravaged developing world where few can afford treatment.

Shortly after Dec. 31, VaxGen will begin analyzing whether the vaccine protected people against HIV, with the possibility of an announcement by late March.

''I pray often for a vaccine, given the scope of the pandemic,'' said Michael Duffy, executive director of the AIDS Action Committee in Boston. ''But there's been a lot of false starts since this virus was discovered. There have been so many dashed hopes over the last 20 years.''

Beyond the trial's results, reseachers praise VaxGen and its network of private investors, including billionaire Microsoft co-founder Paul Allen, for mounting a complex, ethically delicate experiment that required 5,400 volunteers in the United States, Canada, and Puerto Rico to maintain rigorous schedules of injections, checkups, and AIDS tests over several years.

''This is a tour de force, in terms of being able to execute a complex trial with the proper ethical considerations,'' said Dr. Raphael Dolin, head of Harvard Medical School's HIV vaccine unit.

The trial unfolded at 61 locations, including Site No. 004, the Fenway Community Health center. Previous small-scale trials demonstrated that the vaccine was safe. No other AIDS vaccine trials have moved past this early stage.

Next, 5,100 gay men and 300 promiscuous women, all at risk for HIV, were recruited as volunteers. Half received the vaccine, half were given the placebo. Neither doctor nor patient knew which was which in the double-blind study: the vaccine and placebo looked identical.

Doctors told volunteers that the vaccine may not work and that they might have been injected with the placebo. Also, doctors were obligated to advise the high-risk patients to change their behavior, potentially causing them to steer clear of HIV and undermine the trial. But statistics indicate that a significant portion of them will ignore doctors' advice, allowing a scientifically meaningful test of the vaccine.

''I honestly don't know what we're going to find,'' said Dr. Kenneth Mayer, medical research director at Fenway Community Health, where he injected 122 men with either the vaccine or placebo.

Volunteers were given seven shots over 21/2 years, interspersed with HIV tests and detailed interviews asking, as Mayer put it, ''What did you do, and with whom did you do it?'' questions. Still, 90 percent of those enrolled completed the regimen and all the data - reports stacked higher than the Statue of Liberty - were electronically sent to VaxGen headquarters in Brisbane, Calif.

In January, the company will reveal who got the vaccine. Then comes a simple question: Did the vaccine group have noticeably fewer HIV cases than the placebo group?

VaxGen promises to release the data on the vaccine's effectiveness by March, an event certain to generate enormous attention. VaxGen head Dr. Don Francis refused to make predictions.

''You don't know the outcome until nature gives you the message,'' he said, adding, ''I don't think that there's any doubt, from the chimp data, that the vaccine is effective.''

The vaccine first proved itself in primates. Chimps acquired complete immunity against a version of the virus that the vaccine was precisely tailored for. A second test found similar immunity against a mutated form of the virus; HIV has various genetic strains.

In fact, five to seven months after the results from the VaxGen trial, the company is scheduled to report results from the Thailand wing of the trial, where 2,400 intravenous drug users were given a version of the vaccine designed to target the HIV strain prevalant in Asia and Africa.

HIV infects and kills immune cells (the cells that defend against disease) before the body can muster a response. The VaxGen vaccine, called AIDSVAX, induces the immune system to produce antibodies that attach to a protein called gp120 on HIV's outer layer that HIV uses to grab healthy cells. Jamming up gp120 this way will stop HIV from spreading, VaxGen scientists believe.

But recent studies have shown that fast-mutating HIV can even change its gp120 protein in ways that evade vaccines. Francis, however, remains hopeful that his vaccine will protect against some HIV strains. Even if the vaccine is only 30 percent effective, he argues, that may be enough to ''drive the epidemic into the ground.''

His hopefulness draws from mathematical studies by Dr. Ronald Gray of Johns Hopkins University, who calculated in 2001 that a vaccine with 50 percent efficacy, distributed widely, could decrease HIV caseloads. Even a lower effectiveness level would still save lives.

Francis has a large presence in AIDS research. His efforts in the early days of the epidemic figured prominently in Randy Shilts's best-selling book on AIDS, ''And the Band Played On,'' which was made into a film. He has weathered much criticism over the vaccine trial.

''People were saying it wouldn't work, but we went ahead,'' he said. ''You can't tell if it works unless you run a trial.''

But doubters remain: those who believe the vaccine cannot outwit HIV's chameleon-like nature.

''I think the feeling of most of the scientific community is one of skepticism,'' Dolin said. ''The feeling is that the likelihood of success is small. But the data will speak for themselves.''

But, despite low expectations, Dolin said that ''it would still be very disappointing if the results are negative.''

A complete failure would mean that a vaccine is, at a minimum, a decade away, when testing on the next generation of vaccines should be completed. By that time, 45 million more people are expected to be infected with HIV, mostly in the developing world. The current drug treatments, while effective at extending the life of patients in the West, remains too expensive for most in Africa and Asia. Most physicians and activists have concluded that only a vaccine can avert humanitarian disaster.

Raja Mishra can be reached at rmishra@globe.com.

-- Anonymous, December 23, 2002


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