In the absence of an AIDS cure, prevention gains prominence

As vaccine research retrenches, scientists seek to provide a stopgap with new approaches to HIV prevention that were first explored with help from the Bill and Melinda Gates Foundation.
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The human immunodeficiency virus (HIV). (Centers for Disease Control and Prevention)

As vaccine research retrenches, scientists seek to provide a stopgap with new approaches to HIV prevention that were first explored with help from the Bill and Melinda Gates Foundation.

For several years, failure has been the dominant theme of AIDS vaccine initiatives. Most recently, an upcoming AIDS vaccine trial was substantially pared back in size and scope after a similar vaccine appeared to make recipients more susceptible to HIV infection. After committing nearly half a billion dollars in 2006 and 2007, the Seattle-based Bill and Melinda Gates Foundation this year has committed no new funding to AIDS vaccine research.

However, the foundation pursues multiple paths in seeking to eradicate infectious diseases. In fighting malaria, the foundation leaves no stone unturned, from low-tech mosquito netting to research into new vaccine technologies. As Regina Rabinovich, the foundation's director of the Infectious Disease Program, said of these many approaches: "We are supporting all of them. ... We just want something that works." In the fight against HIV, the Gates Foundation pioneered funding research into pre-exposure prophylaxis, or "PrEP," alongside a broad array of other initiatives.

In 2002, the foundation backed a study of whether daily doses of Tenofovir, an antiretroviral used to treat HIV, might prevent infection. The study was inconclusive because not enough volunteers were recruited. On the idea that herpes increased susceptibility to infection, in 2003 the foundation supported a study conducted by the University of Washington into whether acyclovir, a treatment for genital herpes, could cut HIV transmission. That didn't work. But giving antiretrovirals to pregnant women to prevent transmission to their infants has been more successful. Also encouraging are recent tests with primates. According to researchers, "the PrEP treatment created conditions in which infection was prevented, eliminated, or controlled by unknown mechanisms."

The National Institutes of Health and the Centers for Disease Control and Prevention joined as funders of PrEP research in 2003. Gates Foundation support ballooned in 2007. Investments in the strategy now total $93 million. "If you ask me what will come first," Bill Gates told The Wall Street Journal, "something like PrEP has a good chance of becoming available before we have a 100 percent efficacious vaccine. The challenges are a little less daunting. If we have that tool, it could have a very big impact."

Amid the dejection coming from vaccine trials, PrEP now represents hope for many. The two main vaccine approaches have fallen from favor. Both the failed trial that seemed to increase infection susceptibility and the scaled-back, upcoming candidate are attempts to provoke a "cell-mediated" immune response, specifically producing the T cells thought to be effective in battling HIV. The other main research thrust, neutralizing antibodies, has likewise lost its sheen. Obvious successors, however, have yet to emerge. Instead, as Alan Bernstein, head of the Global HIV Vaccine Enterprise, observed [PDF], there is an "urgent need for a diversity of new approaches to HIV vaccine design."

The Gates Foundation shares this view. Last fall, the foundation announced its Grand Challenges Explorations program. Among the objectives is to explore radical new ways to prevent or cure HIV infection. Researchers with "approaches to creating neutralizing antibodies or T-cell-mediated protective immune responses" need not apply.

The foundation already backs multiple projects under earlier Grand Challenges grants awarded in 2005. Several teams are using genetic engineering and human stem cells in an effort to create a mouse with a human-like immune system, which would speed up and reduce the costs of lab tests that currently are conducted using primates. Another Grand Challenges researcher, Francis Plummer, has been questing since the 1980s for how a group of sex workers in Nairobi, Kenya, have remained HIV-free despite intense exposure to the virus. A related Grand Challenges project seeks to create a low-cost vaginal gel or ring which would provide mucosal immunity. However, numerous topical microbicides have failed, with some actually increasing infection rates.

A very small percentage of the global HIV-infected population, sometimes known as "elite controllers," is able to contain the virus without medication. One of the last Gates Foundation grants targeting an AIDS vaccine went to Massachusetts General Hospital to study these biological outliers, in hopes of discovering mechanisms that can control the virus. However, as with the HIV resistance among sex workers, simple explanation remains elusive. Steven Deeks, who studies elite controllers at the University of California-San Francisco, estimated that there are "probably 20 to 30 known, possible, or theoretical mechanisms of control."

The Grand Challenges also fund a vaccine effort that targets the dendritic cells in the immune system, although this project falls into the quasi-discredited realm of T cell vaccines. Neither the researchers nor the Gates Foundation have commented on whether Phase I human trial will proceed as planned. Finally, the Grand Challenges are funding an audacious project to mathematically model the immune response to HIV infection.

One AIDS advocacy group has called for the outright abandonment of HIV vaccine research in favor of an exclusive focus on prevention. A prominent AIDS researcher likened the latest vaccine trial failure to the Challenger disaster, which grounded the space shuttle program for years. As long ago as 2004, Richard Horton, editor of the British medical journal The Lancet, claimed that "a vaccine against AIDS is becoming little more than a pipe dream." Contrarily, as the Gates Foundation and others have pointed out, developing vaccines take time, from as little as 10 years for measles to 105 years for typhoid. Gates has described stopping AIDS as "the top priority of our foundation." He's highly optimistic that vaccines for the top 20 diseases will emerge in the next 10 to 15 years, but Gates acknowledged that "the toughest, the hardest, will actually be AIDS."

Roughly a dozen out of the 3,000 volunteers in the failed vaccine trial showed enhanced T cell immune responses and lower viral load, which one researcher characterized as "sort of the glimmer of hope" in an otherwise falling sky. Today, Gates is undaunted, but the contest with AIDS will perhaps represent the severest test of his faith in the efficacy of modern science and technology.


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