May 22 2006

AIDS Vaccine Testing Goes Overseas

U.S. Funds $120 Million Trial Despite Misgivings of Some Researchers

Copyright 2006 The Washington Post

Inside a ramshackle Buddhist temple here on the country's southeastern coast, curious villagers gathered last fall as part of the United States' biggest gamble yet on stopping the AIDS pandemic.

The informational meeting was almost like a game show as attractive young hosts revved up the crowd, working up to the big question, boomed out over loudspeakers: Would the audience be willing to volunteer to test an experimental HIV vaccine?

The villagers hesitated. No one moved for a full 60 seconds. Then, tentatively, they approached the three stands set up at the front, marked "Join," "Not Join" and "Unsure."

For the past three years, such gatherings have been held all over Thailand, exhorting young adults to take part in the largest, most expensive, most resource-intensive AIDS vaccine trial ever. Funded by the National Institutes of Health, it ultimately will involve 16,000 people and last 31/2 years.

But as the trial moves forward, at a cost of more than $120 million, some researchers are raising questions about its validity. They disparage its science, question its ethics and doubt its efficacy.

One of the chief dissenters is Robert C. Gallo, who helped discover the human immunodeficiency virus. He scoffs at the notion that the trial will be successful. "I thought we'd learn more if we had extract of maple leaf in the vaccine," he said derisively.

NIH scientists defend the study, arguing that even if the vaccine doesn't work, the trial may reveal new things about HIV. "With 5 million new infections each year, the luxury of time is absent," four researchers wrote in the journal Science.

When scientists identified HIV as the cause of AIDS 21 years ago, they predicted that a vaccine to prevent the infection would be ready long before a treatment for the symptoms could be developed. The opposite turned out to be true. Many people today, especially in wealthy countries, are keeping the virus in check with drugs, but a vaccine, desperately needed in poor countries, has eluded modern medicine.

Despite years of effort, investment in the billions of dollars, and dozens of small tests in people around the world, there's still no scientific proof that a vaccine is even possible. HIV is a diabolical virus that disables the very immune responses a vaccine needs to trigger in order to work.

And yet the need is so urgent that scientists have gone forward with preliminary human tests of many vaccines on the basis of data they acknowledge is weak. The one in Thailand is the largest.

The fact that no one has ever been cured of AIDS increases the urgency of finding a vaccine. "In contrast to virtually every other microbe we've come across, there isn't a documented case of anyone who . . . ultimately cleared HIV from the body completely. That's why more and more research is being directed at trying to stop infection from happening in the first place," said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, part of the NIH.

The U.S. government last year spent 22 percent of its $3 billion AIDS research budget on vaccines and other preventive drugs, compared with less than 8 percent a decade ago. (Most of the rest is devoted to developing treatments or a cure for those already infected.) Meanwhile, the Bill & Melinda Gates Foundation this year designated up to $360 million for AIDS vaccine research, and Congress is encouraging more research with bills that would provide liability protection and tax benefits for drug companies.

But the science is daunting and subjects hard to come by. Scientists have been forced to travel to remote corners of the world to find communities where the infection rate is high enough to show results in a reasonable amount of time.

Thailand, where AIDS is a leading cause of death, has been among the most accommodating places. The NIH effort there involves two vaccines that individually have been disappointing in previous trials. One of them, developed by a once-revered scientist in the AIDS world, flopped spectacularly after an expensive test funded by private investors. The other showed little promise in early trials. Researchers cling to the hope that using them simultaneously will attack different aspects of the disease and prove effective.

A vaccine is basically a trick: Take a germ or part of a germ, kill it or alter it so that it doesn't cause disease, then inject it into the body. The body thinks it is being attacked and produces an immune response that will protect it when it is exposed to the real thing.

But because HIV comes in 11 subtypes that constantly mutate, it must be treated differently. Enter Donald Francis, a longtime government researcher who is credited with helping to eradicate smallpox and develop vaccines for Ebola and hepatitis B. Francis had great credibility in the AIDS community. He was immortalized as an early hero in Randy Shilts's book "And the Band Played On" because he recognized the danger of AIDS long before it became an epidemic and argued forcefully for government action.

In 1982, he left public service to work for biotechnology giant Genentech Inc. and concentrate on AIDS full time.

His idea was to try to use the protein envelope that surrounds HIV to try to trick the body into thinking the whole virus had invaded it. When he injected it into a group of chimpanzees and then exposed them to HIV, they were protected. Francis then injected the cloudy liquid into his arm and became human research subject No. 1. There were no side effects, or none that he could notice. When he drew his blood he saw something promising -- a strong antibody response. Antibodies, proteins that form in response to invaders, typically protect a person against infection.

The big question was: Would that be enough to stop HIV infection?

Based on the preliminary trials, many scientists were skeptical. Nine of the 499 U.S. volunteers who had received Francis's vaccine subsequently became infected with HIV -- not from the vaccine but from later sexual exposure to the virus. While Francis was not concerned with those "breakthrough infections," other scientists were. "It is not the fact of breakthroughs that is so disturbing," John P. Moore of Cornell University's medical college said at an international AIDS conference in 1996. "It is the individual cases where there was a good vaccine response but infection occurred nonetheless." Researchers feared that the virus mutated so quickly that antibodies were ineffective against it.

Other scientists turned to a new technique, using snippets of the virus to promote a response from another part of the immune system, which activates "T-cells" instead of antibodies to attack germs. Most vaccine candidates in human trials today use that strategy.

Jay A. Levy, an AIDS researcher at the University of California at San Francisco, said he believes that the cellular approach is the only one that will work. "You aren't going to prevent HIV infection by the classic vaccine model," he said.

But Francis was not dissuaded. He took his data to the NIH and asked for funding to test his vaccine in a large group of humans. He ran into a wall of opposition.

Moore and Dennis R. Burton of the Scripps Research Institute argued in the journal Nature Medicine that funding for vaccine trials is limited, that patient cohorts are precious resources, and that "a social and political price" would be paid for a vaccine that failed in a large-scale trial.

The NIH turned Francis down. Ever persistent, he decided to rely on private funding. He persuaded Genentech to invest $2 million in a spinoff company, VaxGen Inc., and embarked on a cross-country tour that raised $150 million from other private investors.

With that money, the trial began in 1998, mostly in gay men in the United States, Canada, Puerto Rico and the Netherlands and in intravenous drug users in Thailand -- a total of 7,500.

Punnee Pitisuttithum of Mahidol University in Bangkok, who coordinated the Thai portion of the study, remembers being holed up in a San Francisco hotel room in 2003 studying reams of data. On the fourth day, the computers spat out the final analysis. The incidence rate for those who got the vaccine was 3 percent and the incidence for those who did not get the vaccine was 3 percent. There was no difference.

Punnee, 48, ran to her room and wept. "It took us nine years to find out the VaxGen vaccine did not work," she said.

Still, Francis latched on to an interesting blip in the analysis of African Americans. Fewer of the patients who got the vaccine were infected with HIV, but there were too few volunteers to draw any conclusions. For Francis it was a signal that perhaps the vaccine was indeed doing something to help prevent infection, if only in one segment of the population.

Critics brushed off that opinion, calling it a desperate attempt to salvage something from all the years of work. Weeks after the announcement that the vaccine had failed, VaxGen was hit with a shareholder lawsuit that accused the company's officials of continuing to make positive statements about their vaccine to artificially pump up the company's stock price, despite mounting evidence that it was not effective. The suit was dismissed last year and VaxGen, under new management, remade itself into a biodefense company.

"We were naively optimistic" back then, Francis said. "Our understanding of the technology to create an AIDS vaccine is still a black box and it's going to be a long haul."

In 2005, he quit his job as president of VaxGen and founded Global Solutions for Infectious Disease, a nonprofit organization that aims to develop an AIDS vaccine. Francis works in a basement office south of San Francisco that looks more like a file room than a laboratory. After VaxGen abandoned their project, he and his researchers struck out on their own. Four of the five researchers work without pay, draining their personal savings to pay for their research as they apply for grants. Francis said recently that he expects funding from a foundation in the coming month.

Francis is no longer involved in testing the VaxGen vaccine. But the failure of the big 2004 trial did not stop its inclusion in the current trial, which was begun by the U.S. Army and subsequently taken over by the NIH. Half a world away in Thailand, that effort continues.

The Thai government has approached recruiting for the trial like the U.S. government did for the military during World War II -- with a call for patriotism and a plea for people to think of the greater good.

"You! Your family! Your community! Join your hands together to develop an HIV vaccine," said a yellow banner hoisted on storefronts and government buildings. Another sign, featuring a smiling woman, told young people to go to their nearest health center to get more information.

The recruiters in December exceeded their goal of enrolling 16,000 volunteers. Test subjects will receive either a placebo or a combination of two vaccines -- Francis's and one by Sanofi Pasteur SA of Lyon, France, that targets T-cells. The study will conclude in 2009, after all participants have been followed for 31/2 years.

The idea behind the NIH trial is that maybe vaccines need to provoke both antibody and T-cell responses to protect the body from AIDS. Critics say that the potentially confusing inclusion of Francis's vaccine muddies the issue and that it should be dropped from the study.

Nearly two dozen prominent AIDS researchers wrote an opinion piece in the journal Science in early 2004 calling Francis's vaccine "completely incapable of preventing or ameliorating" HIV infection and questioning "the wisdom of the U.S. government's sponsoring" the Thailand trial. "There are adverse consequences to conducting large-scale trials of inadequate [HIV] vaccines. . . . One price for repetitive failure could be crucial erosion of confidence by the public and politicians in our capability of developing an effective AIDS vaccine."

Last summer, Sen. Tom Coburn (R-Okla.), a physician, and other members of Congress began pressing U.S. officials to cut government funding to the trial, to no avail.

While the controversy over the trial continues in scientific and political circles in the United States, it has not been an issue in Thailand. At the Buddhist temple that evening in November, nearly all the 174 villagers eventually overcame their hesitation and said they would be open to serving as human test subjects.

Jo, a 19-year-old mechanics student with a goatee and buzz cut, signed up in the fall and brought eight friends to a clinic one morning so that they could get more information to decide whether they, too, wanted to be test subjects.

Jo said he doesn't care about the $7.50 he will be paid for each visit or any personal benefit he will get from the trial. It's important "to do something good for the community," he said.

That thought was echoed by Supachai Rerks-Ngarm, the principal investigator for the vaccine study and an official with the Thai Ministry of Public Health, who said that when it comes to researching an AIDS vaccine, there's no such thing as wasting time or money. "If we decide not to do it," he said, "we cannot explain that we have done our best to help our people."