Study Explains How the First Effective HIV Vaccine Worked

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In 2009, researchers reported that an AIDS vaccine had for the first time protected people against HIV. Since then, the researchers have been wondering, How did it work?

One of the biggest black boxes in AIDS research remains the important question of what actually protects the body from HIV. Is it antibodies to the virus? Or is it immune cells that are targeted to recognize and eliminate HIV?

AIDS researchers have only been able to guess at what these critical weapons against HIV could be, which is partly why their efforts to create a vaccine have thus far been marked by a long line of failed attempts. But when the RV144 trial in Thailand showed promise in 2009, scientists finally had something to work with. The vaccine was only modestly effective — protecting just 31% of heterosexual adults from infection — especially compared with inoculations against other common infectious agents like measles or mumps, which are 95% to 98% effective. But it was a start.

(MORE: AIDS Vaccine: The Promise of HIV Antibodies)

Studying blood samples from the original Thai trial, Dr. Barton Haynes, director of the Duke Human Vaccine Institute of Duke University, and his colleagues report this week in the New England Journal of Medicine that they have begun to understand how the vaccine worked. Two HIV-binding antibodies may play an important role in determining whether the virus can gain a foothold in healthy cells and start an infection, the researchers say.

The scientists began with blood samples from 246 trial participants who were vaccinated; 41 people later became infected with HIV and 205 did not. After a two-year search for the right antibodies or other factors that could be responsible for protection against HIV, they zeroed in on 17 assays that were “sensitive, specific and could pick up something this vaccine did to allow us to compare before and after,” says Haynes.

The researchers then focused on six of the strongest variables, and then compared those who got infected with those who did not. The groups differed in levels of two antibodies. One, called V1V2, is made by the immune system to bind to HIV’s outer coating; part of the immune cell family called IgG, this antibody may be critical in preventing the virus from attaching to and then gaining entry into a healthy cell. Those with higher levels of V1V2 antibodies were less likely to become infected with HIV than those with lower levels.

The other antibody, however, had the opposite effect. Part of the IgA family of immune cells, these antibodies, which bound to a different part of HIV, seemed to increase the risk of infection: higher levels of IgA binding to HIV were linked with higher rates of infection, which suggested that rather than protecting against the virus, the vaccine was actually helping HIV to do its pathogenic duty. “Our first thought was, Oh, my gosh, this vaccine is inducing antibodies that enhance infection,” says Haynes.

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But that didn’t make sense, since the vaccine was 31% effective in warding off infection. When the researchers compared IgA levels among those who were vaccinated and became infected with those who didn’t get the vaccine, they found the two groups had similar infection rates. That provided some relief, since it suggested that the IgA antibodies were not enhancing infection. Rather, the antibodies appeared to be countering the effect of the V1V2 antibodies that were fending off HIV and undoing their protection.

That’s an important finding, since it hints at how complex any successful HIV vaccine must be in order to protect people from infection. Unlike viral infections such as influenza, measles and mumps, AIDS is caused by a much wilier virus that survives and replicates by inserts itself into its host’s genome and becoming a part of the cell. To be protected against such an intrusion, says Haynes, it may take an exquisite balance of both turning up defensive immune cells that target and destroy viruses, as well as turning down the body’s natural suppression systems that keep the immune system from overreacting — much like regulating a vehicles speed by using both the accelerator and the brakes.

That understanding could also clarify why previous vaccine candidates have failed. Some might have been successful in eliciting the proper antibodies or immune responses, but failed to provide an overall protective effect because they were washed out by the counteracting antibodies. “We have a direction now, with tools and clues to check out in previously completed trials, why they might have worked or might not have worked,” says Haynes.

(MORE: HIV Drugs May Prevent Infection in Healthy Individuals)

“This analysis has produced some intriguing hints about what types of human immune responses a preventive HIV vaccine may need to induce,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which helped fund the study, along with the U.S. Army Medical Research and Materiel Command and the Bill and Melinda Gates Foundation, in an statement. “With further exploration, this new knowledge may bring us a step closer to developing a broadly protective HIV vaccine.”

And because of the way HIV works, that vaccine needs to be able to protect people immediately and powerfully. “For this vaccine, we have got have all our antibodies and killer cells and armamentarium upfront,” says Haynes. “The person has to be completely protected from infection at the time they are challenged by HIV.”

And now, with the first clues about how to develop that protection, a more effective anti-HIV vaccine might actually be possible in coming years.

Alice Park is a writer at TIME. Find her on Twitter at @aliceparkny. You can also continue the discussion on TIME’s Facebook page and on Twitter at @TIME.

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