The Waiting Game The Fenway Community Health Center has injected 33 people with a genetically engineered vaccine that mimics the "coat" of HIV. Time will tell whether it prevents infection. by Neil Miller Paul Ricciardi is a man with a mission. Four times this winter and spring, the 26-year-old program manager at the United Way arrived at the Fenway Community Health Center at eight in the morning, still a little groggy with sleep. A phlebotomist took his blood; a nurse checked his weight and temperature; a counselor talked to him about safe sex. Then, he settled back in his chair, rolled up his sleeves, and received an injection of what maybe -- just maybe -- could turn out to be a successful vaccine against HIV. A lot of his peers -- gay men in their mid-20s -- are "over the whole AIDS thing," as Ricciardi puts it. " `Been there, done that, done the HIV-prevention thing and I'm sick of it.' " But not Ricciardi. He is part of a group of 22 men in Boston and 11 women in Rhode Island who are participating in a federally funded AIDS vaccine trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), in conjunction with two vaccine manufacturers. The Boston/Rhode Island site, called Project Achieve, is one of eight centers nationwide that have enrolled 420 people, all HIV-negative but classified as "at-risk" because of sexual activity or intravenous drug use. (Project Achieve is reluctant to spell out its criteria for at-risk classification, due to concerns about confidentiality.) Before they were accepted into the trial, the participants went through a rigorous process: a complete physical exam, hours of vaccine education, lectures on risk reduction, even a test to make sure they understood what they were getting into. Ricciardi is participating in what is called a phase-two trial, designed to see whether the vaccine is safe in at-risk people and whether the participants develop an immune-system response. The first phase -- to test the safety of the vaccine in "low-risk" volunteers -- has already been successfully completed. And phase three -- to see whether the vaccine actually protects against HIV infection -- is still in the future. (Assuming that it takes place, phase three will not involve inoculating people and then injecting them with HIV, but rather vaccinating large numbers of volunteers and waiting to see how many, if any, become infected as they go about their daily lives.) Meanwhile, as Ricciardi's study continues, Project Achieve has begun vaccinating another, smaller group -- 20 low-risk people who are participating in a phase-one safety study of yet another potential AIDS vaccine. This trial, sponsored by VaxGen, a spinoff of the Bay Area biotech company Genentech, has no connection to Ricciardi's trial. Today, 16 years into the epidemic, vaccine research is still in its "early days," according to Kenneth Mayer, director of medical research at the Fenway and the principal local investigator for both the NIAID and the VaxGen studies. No one knows for sure whether a vaccine will work; even if it does, no one expects it to be 100 percent effective. So far, there has been little fanfare, little buzz. Nonetheless, "It is very exciting, probably the most exciting thing I have done in research," Mayer asserts. And Paul Ricciardi? "I feel sort of like a pioneer," he says. FROM THE very beginning, the search for an AIDS vaccine has been fraught with problems. Although testing AIDS vaccines on animals -- including chimpanzees -- has produced some success, human trials have been disappointing. Economics has been a major stumbling block. The market for a vaccine against HIV is potentially huge, particularly in Asia and sub-Saharan Africa, where the number of cases is rising at an alarming rate. But who would pay to inoculate 30 million Kenyans, or 50 million Congolese, or almost a billion Indians? With no answers forthcoming, drug companies have been reluctant to invest in HIV-vaccine development. Then there are political factors. To some, spending money on vaccine research amounts to "condoning" the very behaviors that lead to AIDS. "In some people's minds, vaccines are in the same column as needle exchange," notes Calvin Cohen, research director at Boston's Community Research Initiative (CRI). Within the gay and AIDS communities in the US, treatment -- not vaccine development -- has been the priority. Once it became clear how the virus was transmitted -- and how transmission could be prevented -- the conventional wisdom was that vaccine development was probably a waste of time and money. Behavioral changes, safe-sex education, and clean needles were more important, people believed; it seemed more sensible to put limited resources into the development of strategies for behavioral change, rather than into a vaccine that might or might not work. When there are 16,000 new cases of HIV infection every day, finding an effective vaccine seems an important goal. Yet to many activists, pursuing the vaccine option was admitting defeat on the behavioral front of the war against AIDS, says Cohen. Despite these objections, the first human vaccine trials did go forward. The man behind them was virologist Donald Francis, who had previously coordinated the Centers for Disease Control and Prevention's successful vaccine effort against hepatitis B, and whose early efforts to get AIDS taken seriously made him one of the heroes of Randy Shilts's book And the Band Played On. (Matthew Modine played Francis in the movie version.) In 1992, Francis went to work for Genentech. By synthesizing portions of the "coat," or envelope, of HIV, the company's scientists had developed a vaccine that tricks the body's immune system into believing that HIV is present and releasing antibodies that neutralize the virus. The genetically engineered vaccine, called gp120, uses the same "envelope only" principle as the hepatitis B vaccine. It does not contain "live" HIV. Francis's job at Genentech was to run trials of gp120. Large numbers of people nationwide were vaccinated with gp120 in phase-two trials, beginning in 1992. Two years later, the massive project seemed ready to proceed to the definitive phase three. In Boston and Rhode Island, Project Achieve was recruiting people in preparation for the anticipated trial. But phase three never took place. The reason: it was revealed that during phase-two trials, there had been 18 "breakthrough" infections -- cases of people who, despite being vaccinated, had contracted HIV through unsafe sex or drug use. Not only did this cast doubt on the efficacy of Francis's vaccine, but it was a public relations disaster. NIAID, which was funding the vaccine effort, decided not to go forward with the trials. But Francis, who had left Genentech to become president of VaxGen, refused to give up. He reformulated gp120 to protect against those strains of the virus that had caused the breakthrough infections. Meanwhile, scientists at the French pharmaceutical company Pasteur Merieux Connaught had come up with a new approach. Instead of generating antibodies that neutralize infection -- the basis of both the hepatitis B vaccine and Francis's gp120 -- this vaccine "primes" cytotoxic T lymphocyte cells (CTLs) to kill HIV. Once again, no live virus is used. And once again, the concept involves some high-tech trickery: convincing the killer CTLs that HIV is present when it really isn't. In this case, bioengineered copies of three HIV genes are inserted into a weakened canary pox virus; the virus, which infects birds, can enter human immune-system cells but is unable to multiply in them. The canary pox virus functions as the vaccine's "delivery system," and the copies of the HIV genes inside it make proteins that resemble proteins produced by the real HIV. In response, the T lymphocyte disease-fighters swing into action, primed to attack any new HIV. By late 1997, NIAID was ready to blend both approaches by mounting a major vaccine trial -- the trial that Paul Ricciardi is in. A third of the 420 participants nationwide received a double-barreled combination of the CTL-priming vaccine (made by Pasteur Merieux) and a new version of gp120 (made by Chiron Vaccines of San Francisco). Another third of the participants received only the CTL-priming vaccine. The remaining third received a placebo. It's a "blind" study -- the participants don't know which of the three treatments they are getting, and neither do the investigators at the local site. The current configuration of the vaccine trials reflects a dose of politics. NIAID's director, Anthony Fauci, who canceled the phase-three trials of gp120 back in 1994, is suspicious of the gp120 approach, especially after the 1994 fiasco. So the NIAID trials include reformulated gp120 only in conjunction with the CTL-priming vaccine, not alone. And Fauci elected to use another vaccine manufacturer, not Francis's VaxGen. That left the company and Francis, who has been researching AIDS vaccines since 1992, out in the cold. So Francis and VaxGen are testing their revamped vaccine on their own, without NIAID funding -- hence the phase-one study under way at Project Achieve and other sites around the country. MAYER EMPHASIZES that neither study is intended to prove whether a vaccine can prevent HIV. If enough participants in the NIAID trial demonstrate immune response to a significant degree, then a larger, phase-three trial of the vaccine or vaccine combination will be in order. That trial would require the participation of at least 5000 people in the US, according to Mayer. Such large numbers are essential. Studies have shown that in the United States, an average of fewer than 2 percent of at-risk individuals recruited for a study would become infected each year if there were no vaccine. Out of 5000 at-risk people, that would mean 100 would become infected. If, in a large efficacy trial in which half the participants received a placebo and half received a vaccine, 50 people became infected -- and all the infections occurred in the placebo group -- the vaccine would be considered 100 percent effective. In the real world, however, most vaccines are not 100 percent effective, so some participants who received the vaccine would most likely become infected. You need a large cohort in order to sort through the numbers. In the meantime, Project Achieve is doing everything possible to make sure its volunteers do not become infected. "We are not about getting at-risk people in and getting them to be risky and sitting back to see if they become infected," says Mayer. Study participants are bombarded with safe-sex counseling and risk-reduction education. Tom LaSalvia, the director of Project Achieve, suggests that, because of all the support and education during phase two, the infection rate could actually decline from 2 to 1 percent, thanks to awareness alone. "That is why we need a big phase-three trial," he says. In part, the emphasis on education in Project Achieve grows out of concerns that people enrolled in vaccine studies might be lulled into a false sense of security and feel tempted to have unsafe sex. That may have helped account for the "breakthrough" infections back in 1994. But it is a temptation that Paul Ricciardi hasn't struggled with. For one thing, he's in a long-term relationship. "I haven't thought that because I'm getting the vaccine, `Maybe I'll put myself at risk just once,' " he says. "That hasn't crossed my mind." ALTHOUGH THESE studies are totally safe, there is one major drawback. Being in a vaccine trial means that, in some cases, your antibody status will change from negative to positive. It's purely a vaccination response that doesn't mean you're infected with HIV, of course. However, on the relatively crude ELISA test -- usually the first blood test used to detect HIV -- it might appear that way. This may leave participants open to the same kinds of problems HIV-infected people can face -- job discrimination, health insurance worries, social stigma. Ricciardi and others haven't let that stop them. Before he took his current job at the United Way, Ricciardi worked as a program manager at a number of small AIDS service organizations. One of the reasons he had originally decided to work in the area of AIDS was that he felt HIV touched him only in theory. "I wanted to connect with it," he says. Two years ago he enrolled as a participant at Project Achieve, which, after signing up a number of people in anticipation of the original, ill-fated gp120 trials, had kept them on for several behavior and risk-reduction studies. Then the new vaccine came along. In December 1997, Ricciardi received the first of his four doses. "If my sacrifice is to go to the Fenway every now and then and get a vaccine and talk to a counselor, that's fine," he says. "There is no risk. There is no big deal in terms of my time. The balance between what I have to give out and what might be the end result is amazing." Other vaccine study participants see it similarly. Martin Sabol, a 40-year-old, gay public health worker from Bangor, Maine, signed up for the phase-one study of Don Francis's vaccine after reading about it on the Internet. "I thought it was a good thing to do," he says. Syd Smith, a 42-year-old married man who lives in North Weymouth and is enrolled in the same study, says simply, "I wanted to make a small contribution." Another participant, a 30-year-old veterinarian in a small Massachusetts community, puts it this way: "As a woman in a low-risk group, this is a way I can make a difference," she says. "AIDS is in my daily life, but it's not. I'm a spectator. And I don't like being a spectator." Project Achieve's LaSalvia says that most participants are people with altruistic motives -- "The woman who says, `My hairdresser was my best friend. He died of AIDS and I want to do something in his memory.' Someone else who says, `I can't afford to write a big check, but this is something I can do.' Others are just good-deed doers and want to help people. Really, what other motivation is there?" Before he joined the study, Ricciardi felt he had to get the approval and support of his partner and his friends. There was a "low-grade level of fear," he felt, partly because of misinformation that the vaccine study involved having live HIV injected into one's body. "That was completely false," he says, "but hearing it over and over again, that set the tone. Once I could get around that, I didn't have a problem." Although Syd Smith was confident that the vaccine was safe, his wife needed some reassurance. So the two sat down with a friend who works in genetics research to convince her of the vaccine's safety. As someone who works for the state of Maine's immunization program, Martin Sabol wasn't worried about whether the vaccine was safe. But he was concerned about the issue of antibody status. He imagined a scenario of "being in a car accident in North Carolina and I'm rushed to the hospital. And someone says, `Maybe we should screen him for HIV -- he has an earring!' I test positive. Am I going to get as good care? It's the whole homophobia thing." Then there was issue of overseas travel. China, for example, requires a negative HIV antibody test for anyone living or working in the country. How would a Chinese immigration officer react to a letter from the Fenway Community Health Center in Boston explaining that positive antibody status was the result of being in a vaccine trial? But Sabol wasn't planning a trip to China anytime soon. In the end -- after talking with his partner -- he decided that these kinds of potential problems were outweighed by the benefits of taking part in the study. For his part, LaSalvia thinks that, as a result of the vaccine trials, we will soon have to change the way we talk about HIV, discarding the term antibody-positive and using HIV-infected instead. "Beginning to test preventive vaccines challenges us to think about the language we use and how we talk about infection status," he says. He suggests that the FDA may have to change the way HIV testing is done, as well, discarding the ELISA test in favor of the more precise Western Blot. Now, the Western Blot is used mainly to confirm the results of an ELISA test. Once participants get beyond the initial hesitation, there is that strange feeling when the moment actually comes to get the vaccine. Those four mornings this winter and spring that Ricciardi rolled up his sleeves at the Fenway, things came into sharp relief. "It's a moment when your mind can take you anywhere," he says. Even to a world without HIV. WHAT HAPPENS next is anyone's guess. Ricciardi and the other participants in his study received their last dose of vaccine this month. By summer, NIAID investigators will determine which vaccine or combination of vaccines in the trials resulted in the greatest immune reaction. Mayer says that if the current trial seems "really stellar," that will "build a hue and cry" and encourage NIAID to initiate the larger phase-three trials. Still, it is a complicated process, in which politics and bureaucratic maneuvering play a role. And thus far, there hasn't been the same kind of pressure for a vaccine that ACT UP used so effectively to bring about quicker release of AIDS drugs. (A group called VACT UP was recently established, however, to press for vaccine development). Even if NIAID does decide to go on to phase three, it isn't clear that would happen this year. According to Mayer, Pasteur Merieux has already said that, whatever the results, it may want to "retool" its vaccine before it is ready to go on to the definitive study. The future of VaxGen's back-to-the-drawing board version of gp120 is also in doubt. A phase-two trial of this vaccine is currently under way in Thailand, and Don Francis hopes to gather enough data on phases one and two to do efficacy studies with thousands of people in the US and Thailand next year. Francis's passion on the subject of vaccines may make an important difference here. Although he needs FDA approval to do a phase-three study, his trial would be privately funded and wouldn't face the same bureaucratic problems as a federally funded study. If a viable vaccine emerges -- and that could take five years at least -- it won't be 100 percent effective. The vaccine manufacturers are hoping for 60 to 80 percent; the hepatitis B vaccine is about 90 percent effective. But many would settle for half that. "If this vaccine is only 40 percent effective, it will still save millions of lives worldwide," Steve Boswell, executive director of the Fenway Community Health Center, said recently. One thing is clear: vaccine or no vaccine, there isn't much chance of returning to the good old days before AIDS. "Even if this is a home run -- that is, 80 percent effective -- we are still going to have to tell people to be careful," says LaSalvia. "We are never going to go back to the days when HIV infection was not part of our lives." As for Paul Ricciardi, like all pioneers, he can't be anything but optimistic. "The bottom line is that I am part of something that is pretty intense and pretty amazing," he says. "I do have hope. I think this might be something. And I'm part of it!" Neil Miller can be reached at MrNeily@aol.com.

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