Published online 16 September 2011 | Nature | doi:10.1038/news.2011.541

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Immune responses of patients could point way forward for future vaccines.

Combining two vaccines that failed on their own has led to success in protecting against HIV. Thomas Deerinck/Visuals Unlimited/Corbis

After decades of dashed hopes, AIDS vaccine developers are allowing themselves some cautious optimism. At a conference this week in Bangkok, Thailand, scientists reported molecular clues that help to explain the first-ever success of an HIV vaccine trial in humans (see 'Vaccine protects against HIV virus'). The results could point the way forward for designing future vaccines.

"You might say this is the most successful experiment we've had so far," says Adriano Boasso, an immunologist at Imperial College London.

The study analyzed clinical samples from a previous HIV vaccine trial of more than 16,000 people that has been dubbed the 'Thai trial' but is officially called RV144. In 2009, scientists leading that trial reported that, after three years, people who received the vaccine were about 30 percent less likely to contract HIV than those who got a placebo1.

The modest results marked the first successful human trial of an AIDS vaccine, two years after the high-profile failure of a vaccine produced by the pharmaceutical company Merck. But Thai trial results also left many researchers scratching their heads.

Greater than the sum of its parts

The vaccine regimen consisted of two components that had each failed on their own: a primer vaccine called ALVAC-HIV vCP1521 from Sanofi Pasteur of Lyon, France, containing several HIV proteins, followed by a booster called AIDSVAX from VaxGen of Brisbane, Australia, made of a protein on HIV's surface. Moreover, two of the three measures the researchers used to determine whether the vaccine prevented HIV infection did not reveal differences between vaccinees and controls that reached statistical significance (see 'HIV vaccine trial under fire').

“We have clues as to why it might have worked. That's something we haven't had over the past 30 years.” Barton Haynes

Duke Human Vaccine Institute

In the latest study, researchers involved with the trial at Mahidol University in Bangkok and the U.S. Military HIV Research Program in Washington DC assembled a team to scour the blood of trial participants for immune indicators that differed between 41 people who received the vaccine and contracted HIV and 205 participants who did not become infected.

Their work isn't complete, but so far the team has found two molecular clues to explain why the vaccine prevented HIV for some but not others. Subjects whose blood contained a Y-shaped immune molecule called an immunoglobulin G (IgG) antibody that recognises a portion of a HIV's outer envelope called the V2 loop were 43 percent less likely to become infected with HIV than subjects whose immune systems did not make these antibodies.

Meanwhile, participants who churned out another kind of antibody, called IgA, that recognises different parts of the HIV envelope fared worse in the trial — they were 54 percent more likely to become infected than people who did not make these antibodies. However, this immune reaction did not make people more susceptible to the virus than trial participants who got a placebo.

The researchers are still studying these results. But Nelson Michael, director of the U.S. Military HIV Research Program, says they reassure him that the vaccine did protect some participants from HIV and that its success was not a statistical fluke. "This lends biological credence to the initial clinical study results," he says. "It suggests that what happened in RV144 was related to vaccination."

A way forward

Barton Haynes, the director of the Duke Human Vaccine Institute in Durham, North Carolina, who coordinated the follow-up study, said at a press conference that the results will generate hypotheses for further study. "What we now have are clues as to why it might have worked. That's something we haven't had over the past 30 years. That's very important for the field."

Researchers are already planning to test whether antibodies like those found in trial participants have the same effect in primates infected with a virus related to HIV. These experiments will determine whether these immune responses are responsible for the vaccine's success or failure in particular people or merely linked to other underlying factors.

Ultimately, the new findings should guide future clinical trials and vaccine development, Michael says. The team is planning follow-up trials of a similar vaccine in homosexual men in Thailand, a group at high risk of HIV infection, as well as a trials in South Africa that will require a vaccine that recognizes a different sub-type of HIV.

On the basis of the latest results, these new vaccines may be re-engineered to spark the production of IgG antibodies that recognize HIV's V2 loop, Michael says. "This is certainly going to focus a lot of people's efforts, and that's a good thing."

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Other research presented in Bangkok support the idea that attacking the V2 loop may be one way to defeat HIV. Viruses collected from the RV144 participants who became infected with HIV possess mutations in this region, suggesting the V2 loop was being targeted by the immune system, Michael says. Meanwhile, tests of a different vaccine in monkeys suggest that animals who make antibodies that recognize the V2 loop tend not to succumb to SIV, a virus related to HIV that infects monkeys.

Dan Barouch, an immunologist from Harvard Medical School in Boston who led the monkey study, says seeing a similar immune response in humans and monkeys given different vaccines reassures him that the V2 loop is worth targeting. But he says vaccine researchers shouldn't stop pursuing other chinks in HIV's armour.

For instance, Wayne Koff, senior vice president for research and development at the International AIDS Vaccine Initiative based in New York, points to virus-neutralizing antibodies recovered from patients chronically infected with HIV as another encouraging lead for AIDS vaccines. "This really is a renaissance period in HIV vaccine development," he says.