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Promising AIDS Vaccine's Failure Leaves Field Reeling

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Science  05 Oct 2007:
Vol. 318, Issue 5847, pp. 28-29
DOI: 10.1126/science.318.5847.28

On Tuesday 18 September, AIDS vaccine research suffered one of its most devastating setbacks.

That day, an interim safety analysis that no one expected would reveal anything significant showed that the vaccine widely thought to have the best shot at success had failed in a large human trial. “We were all in shock and devastated,” says Peggy Johnston, who heads AIDS vaccine research at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, which was one of three partners conducting the multicountry trial of the vaccine, made by the pharmaceutical giant Merck.

Three days later, Merck, NIAID, and an academic consortium known as the HIV Vaccine Trials Network (HVTN) announced that the trial, dubbed STEP, had been halted. Started in December 2004, the trial involved 3000 HIV-negative men and women from North and South America, the Caribbean, and Australia who were at high risk of becoming infected.

AIDS researchers around the world were stunned by the trail's results. “This was the first AIDS vaccine clinical trial in history where most people thought they'd at least see something positive,” says John Moore, an AIDS researcher at Weill Cornell Medical College in New York City. “It's very dispiriting for the field,” says Lawrence Corey, an AIDS researcher at the University of Washington, Seattle, who also heads HVTN. “It will take time to unravel where this leaves us and how we move forward.”

Knocked out.

Disappointing interim results abruptly ended a Merck vaccine trial that used this recruiting poster.

CREDIT: COURTESY OF HVTN

Researchers had pinned their hopes on Merck's vaccine because it uses a novel strategy. Instead of trying to trigger antibodies to HIV, as most other candidates do to some degree, this one relies exclusively on another arm of the immune system that stimulates what are known as killer T cells. HIV has so many mutant types that it's easy for the virus to dodge antibodies. Killer T cells, in contrast, appear to work against a wide array of variants, selectively targeting and destroying cells that the virus has managed to infect. Although only antibodies can actually prevent infections, the hope was that a T-cell vaccine might beat back HIV before it could get a foothold, or at least keep levels of the virus (the viral load) in check.

To trigger the T-cell response, the vaccine uses a modified adenovirus, or cold virus, as a vector to shuttle three HIV genes into the body. But many people have strong immunity to that adenovirus, which theoretically could cripple the vector and render the vaccine ineffective. To assess the magnitude of this problem and increase chances that the vaccine would work, half of the people enrolled in the study had to have low antibody levels against that adenovirus. The interim analysis focused on only those 1500 people, most of whom were men who have sex with men.

In participants who received at least one dose of the vaccine, 24 of the 741 vaccinated people became infected, compared with 21 of the 762 participants who received a dummy shot. More discouraging still, there was virtually no difference in viral loads between the two groups. “I was hopeful we'd see some dampening of viral replication,” says Norman Letvin, an AIDS vaccine researcher at Harvard Medical School in Boston, Massachusetts, whose earlier monkey studies with the vaccine did show such a decline.

Letvin and his colleagues vaccinated monkeys and then challenged them with a lab virus, SHIV, which combines HIV with its simian cousin SIV. But when another group later tested the Merck vaccine against a more potent SIV, it failed. To Ronald Desrosiers, head of Harvard's New England Primate Research Center in Southborough, Massachusetts, that failure should have raised more red flags. “Everything protects against SHIVs,” says Desrosiers.

Anthony Fauci, NIAID's director, worries that the Merck failure will give the broader T-cell vaccine concept a bad rap. “Clearly this indicates the failure of a product. Whether or not it indicates the failure of a concept, we don't know at this point,” Fauci says. NIAID researchers have developed another T-cell vaccine that has more HIV genes and differs in several other key features. A large-scale trial was slated to start this fall but has been delayed pending a more thorough analysis of the STEP results. HVTN has also put on the back burner its plans for a trial of the Merck vaccine in South Africa.

Fauci worries, too, that the failure could have reverberations throughout the pharmaceutical industry, which already is wary of investing in AIDS vaccine research and development. “There's certainly a danger of industry scratching its head and saying before we put substantial resources in, we need more sound scientific data,” says Fauci.

Merck, based in Whitehouse Station, New Jersey, would not speculate about the future of its AIDS vaccine program. “The best thing we can contribute to the field overall is a thorough analysis of the data,” says Mark Feinberg, the company's vice president of medical affairs. Many intriguing questions remain, he notes, such as what happened in the other 1500 participants, what was the immune responses in the “breakthrough” infection cases, and are there differences in heterosexual transmission (so far, only one woman out of the 1000 volunteers became infected). “It's not like we're not interested in the questions anymore, but it's unclear where the next breakthrough will come from,” he says. “And that's not just a question for Merck. It's a question for the entire field.”

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