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An AIDS vaccine has been shown to reduce the risk of HIV infection in humans for the first time, a significant advance in a field of research that has long been stymied by failure.

The $105 million, six-year trial, which involved more than 16,000 people in Thailand — the largest AIDS-vaccine trial ever conducted — found that an experimental vaccine was 31% effective in preventing HIV infection. The volunteer group in the study was representative of the general Thai adult population, including low-risk, heterosexual adults. Calling the results of the trial a "significant scientific advance," officials at the World Health Organization said the results reinvigorated the stalled quest for a vaccine against AIDS, which is estimated to kill some 2 million people globally each year.

The vaccine, called RV144, combined two older vaccines that had each proved unsuccessful in previous tests: ALVAC, from Sanofi Pasteur, the vaccine division of French drugmaker Sanofi-Aventis; and AIDSVAX, originally developed by VaxGen Inc. and now held by the nonprofit Global Solutions for Infectious Diseases.

The vaccine was administered in two stages. First the ALVAC vaccine, which uses a Frankenstein virus of canarypox and HIV, was used as a primer dose, then AIDSVAX was administered as a "booster" to improve the body's immune response to the first shot. Half of the trial's participants received the combination vaccine, while the other half received a placebo. In the final analysis, 74 of the 8,198 placebo recipients became infected with HIV, compared with 51 of 8,197 participants who received the vaccine regimen.

"The efficacy is a modest one. But it's the first time we've seen a positive signal of efficacy in a human trial of any HIV vaccine. That's an exciting result in a field that has been characterized by disappointments for two decades," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), which provided major funding and other support for the Thai trial.

The scientists working on the trial, led in Thailand by the U.S. Army and the Thailand Ministry of Public Health, said they were baffled as to why the two seemingly ineffective vaccines appeared to work together. Another mystery was that the people who became infected with HIV developed roughly the same amount of virus in their blood whether they got the vaccine or the placebo. Typically a protective vaccine would lower a patient's so-called viral load, a criterion that physicians use as the main indicator of HIV infection. The outcome of the trial of RV144 suggests that scientists do not fully understand what constitutes a successful immune response to the AIDS virus.

"We don't know whether our current measures of the human immune response are even relevant to the protection that we see in this trial. [That is] a humbling reminder of how little we know, and how much work remains to be done in our search for an optimal HIV vaccine," Fauci says.

But Jonathan Weber, a professor of communicable diseases and an HIV expert at Imperial College in London, says the consistency of the viral load across the placebo and vaccine groups was not a surprise. "It's a fair assumption that this vaccine works through antibody production," he says. "We've known for years that antibodies don't seem to affect the course of an HIV infection. Antibodies can be preventive, but they can't modify the disease."

Colonel Jerome Kim, who helped lead the study for the U.S. Military HIV Research Program, says other unknowns remain about the vaccine, such as the duration of its effect, the potential need for additional boosters, its efficacy in higher-risk populations like intravenous drug users and, most crucially, whether it might work on other subtypes of the virus. "The vaccine was tested in Thailand against types of HIV that circulate in Thailand," Kim says, pointing out that a different strain of the virus causes high infection rates in Africa.

Both Kim and Fauci emphasize that it will probably be a "significant period of time" before the trial results lead to a vaccine that can be submitted for approval for use in the general public, if such a breakthrough occurs at all. Most licensed vaccines have an efficacy rate of at least 70%, although it's possible that an HIV vaccine with lower efficacy may gain approval, Kim says. "The efficacy threshold may be a consideration that is specific to individual countries, the nature of their HIV-AIDS epidemics and the performance characteristics of the vaccine," Kim says.

Ade Fakoya, a London-based clinician and senior adviser to the British nonprofit AIDS Alliance, tells TIME that a 30% efficacy rate is still very low. By comparison, studies in Africa suggest that male circumcision can cut the risk of HIV infection in men by up to 60%. Still, in a field that has been beset by a series of high-profile failures in the past 20 years — in 2007, for example, two international trials of a promising Merck vaccine in about 4,000 people were stopped early, and later analysis suggested that the vaccine may have increased people's risk of infection — the results of the Thai trial are a turning point. "In terms of where the vaccine world was even a few weeks ago, this is huge news and a proof of concept, finally, that vaccines can work," says Fakoya.

• Eben Harrell
• A large six-year trial conducted in Thailand finds that an AIDS vaccine has for the first time significantly lowered the risk of infection with HIV