Gambling On an AIDS Vaccine With Sudhir Paul

Last summer, while watching a news program about a possible AIDS vaccine, Zach Barnett had a "Eureka!" moment. The show was describing a Texas scientist's unorthodox approach to vaccine-making, a strategy that involved superantigens and covalent bonds and a lot of other words that weren't in Barnett's vocabulary. That didn't matter; the science turned him on anyway. "It was just so cool," he says. "I was like, 'lightbulb!' "

For years, Barnett, a fashion publicist, had been trying to get involved in AIDS activism, but mainstream organizations had told him there wasn't much for him to do, save passing out brochures. "That was a waste of my talent," he says. Here he saw a use for his skills. He wrote to the scientist, Dr. Sudhir Paul of the University of Texas, to tell him that "if what he was saying was true, he was doing a bad job of publicizing it." To show he was serious, he offered Paul $50 out of his own pocket to support the research.

Scientific inquiry isn't often funded in double-digit increments—the average amount the National Institutes of Health puts toward a given project is about $350,000—but for Paul, the meager offering was welcome. In the past, Paul had won NIH grants easily, but by last summer he was running up against resistance from peer reviewers who found his ideas for an AIDS vaccine "too novel," which is to say too out-there. In Barnett, though, he had a fan, and, as it turned out, there was more where that $50 came from.

Barnett is now in charge of development for the Covalent Immunology Foundation, a grassroots group that raises money for Paul's research. This fall it hosted a flashy fundraiser full of drag queens, indie musicians, and well-dressed young hipsters, and for World AIDS Day, Dec. 1, it has student groups called W.A.D. Squads fanning out across 15 university campuses to raise money for a phase-one trial of Paul's vaccine. (The most successful squad will win prizes from American Apparel and AriZona, the beverage company.) It's developed a commercial with celebrities like Wilson Cruz, the Broadway actor and former star of My So-Called Life. In the past six months, the group has raked in $50,000, with thousands more promised, and Paul is finding himself in a new and slightly odd position for a scientist—something akin to an artist with a patron.

In the past decade, private groups have started funding not just causes but specific researchers. The phenomenon may have started with autism—private organizations raise $78 million each year, or 35 percent of the country's funding, some of it for research that isn't completely in line with mainstream thinking—but it's seeping into other fields too, including AIDS research. It's tempting to write off Paul's supporters: what makes them think they know something the NIH doesn't? On the other hand, if they're right and Paul really does have a way to vaccinate against HIV, they're funding one of the most important projects in contemporary medicine. The question they have to ask themselves is whether they're wasting their money or shifting a paradigm.

The AIDS vaccine field could use a shift. For more than two decades, scientists have mounted campaigns to vaccinate against the virus, only to lose each one, watching as their vaccine candidates have failed (and, in one case, may have made people more susceptible to the disease). In September, researchers announced some of the most encouraging results in years, but even that success was quickly undercut by an argument over how the data were analyzed. "It's been so tough to solve this problem," says David Montefiori, director of the Laboratory for AIDS Vaccine Research and Development at Duke University. "That may be because a lot of the approaches have just been the same old, same old. People keep repeating the same tactics over and over again with minor variations."

At first glance, Paul's HIV vaccine looks familiar; it uses the "neutralizing antibody" strategy, which calls on the body's B cells to make proteins that fight the virus. This approach is how all existing vaccines for other diseases work, but it hasn't succeeded against HIV. The virus is too smart to fall victim to the human immune system. It hides many of the identifying proteins on its outer coat, cloaking them from the prying eyes of B cells, and thus no antibodies are made.

A few proteins on the outside of the HIV virus remain naked and exposed. They have to, in order to bind to human cells and kill them. Paul has his eye on one of these proteins, called gp120. According to his theory, it is a superantigen, a protein related to a fragment of a retrovirus that wormed its way into the human genome hundreds of thousands of years ago and stayed there.

Paul says that because gp120 is a superantigen, it's similar to something the body has seen before. That means the immune system can make antibodies against it—just not enough of them, because after infection, the viral protein sabotages the B cells' assembly line. This is where Paul's vaccine comes in. By chemically manipulating gp120 and administering it as a vaccine, he says, he can cause the B cells to ramp up their production of unusually powerful antibodies, thwarting the virus's attempts at sabotage, arming the immune system, and protecting the body against HIV.

There are two possible reactions to a theory like this. If you're not an expert in virology or immunology, it just sounds, as Barnett puts it, "cool." It's a classic war story, with offensives and counteroffensives and sneak attacks on both sides.

If you know more about science, it still sounds cool, but also a little outlandish. What Paul is proposing is very different from any other vaccination strategy. Some scientists take issue with his fundamental claims about the virus; not all of them believe that gp120 stops B cells from being made. Others doubt his technology. The manipulation Paul wreaks on gp120 is not used in any other type of vaccine. His antibodies work differently than traditional, monoclonal types too. Paul's antibodies don't show up in blood samples when tested with the measurement techniques that scientists typically use to determine whether a vaccine is working. "That has raised some doubts in some scientists' minds as to whether or not [Paul's] work is real," says Montefiore, who has examined Paul's samples for antibodies—successfully—using other, more boutique techniques.

To Paul, the unconventional nature of his work is its greatest strength. But even he admits that the project is a hard sell, especially to scientists who by nature and training are cautious and slow, sometimes to a fault. "People have been trying to achieve for many, many years what we are claiming we can achieve," he says. "Some of the resistance we are seeing now is because it's a competitive field—but the doubt is also because what we've done is revolutionary. If our vaccine worked by conventional methodologies, I think there would be much less doubt."

The final, and perhaps most daunting, problem with Paul's work is that so far, the only published research has been conducted in test tubes and mice. (Paul says he also has some promising data from rabbits, but it's unpublished.) The NIH has funded his work lavishly until recently, contributing almost $30 million, but now, just as he's getting ready to move to trials in monkeys, it's balking. "Sometimes when things don't fit with the mainstream work, it's harder to get them funded," says Montefiori, who has assessed an enormous number of AIDS-vaccine candidates. "Sudhir's approach is novel, so it's exciting—but that's also why it hasn't really caught on in the field." This is Paul's Catch-22: the basic science behind his work is so strange that he needs primate research to prove its potential, but without successful primate research already in hand, his peers are wary of his claims about the basic science.

Outside the scientific establishment, there are plenty of people willing to take a chance on a wild but potentially groundbreaking idea. There are several of them running the Covalent Immunology Foundation, including Barnett and a Ph.D. turned patent lawyer named Ben Adler who says he recognized the "revolutionary quality" of Paul's work as soon as Paul came to his office for help with a patent three years ago. When Paul's NIH funding started to dry up, Adler first considered going the biotech route to raise money for him, "but given the economic problems in the last year, venture capital in biotechnology had fallen off a cliff," he says. Instead, he started listening to his wife, who runs a small business and was fascinated with social media. Going "outside the system" for funding, "taking it to the people," would be a novel approach, he thought—perhaps just the kind that equally novel science demanded.

CIF has a lot more money to raise: Paul will need about $2.5 million to move into monkey research. But Barnett and Adler seem optimistic. Barnett says he has no trouble getting donors on board with the science; "if they give me five minutes," he says, "they can usually wrap their heads around it." He does try to keep Paul's work in perspective, for his donors and himself. He knows it may not ultimately succeed. But, he says, given the failure of traditional science to create an HIV vaccine, "I think risks are justified at this point."

Are Paul and Barnett and Adler chasing after an impossible dream, not just an improbable one? It's hard to say. Yes, the NIH may be reluctant to support Paul, and the NIH is full of smart people—but it's not the kind of institution that gambles, and sometimes a gamble is necessary to move science along. Vaccines in general must have seemed like a ludicrous idea when they were first being developed, but they're often now described as the biggest boon to public health of the 20th century. They owe their existence not to a lumbering government agency, but to a small group of people—including the brave family who offered their son as the first test case for the smallpox vaccine—who believed in a radical idea. Maybe Sudhir Paul isn't the second coming of Edward Jenner, but wouldn't it be a shame if we never got to find out?

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