Published online 20 July 2009 | Nature | doi:10.1038/news.2009.707

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Mystery of HIV vaccine failure deepens

Heightened immune response to cold virus may not be to blame.

HIV virusThe failure of the STEP vaccine trial remains a mystery.Getty

Two groups of scientists have cast doubt on a leading explanation for the failure of a key HIV vaccine.

In September 2007, researchers halted a trial of the vaccine made by Merck & Co. of Whitehouse Station, New Jersey, because it seemed to increase the risk of HIV infection. The failure of the trial — known as STEP — was a serious setback for AIDS researchers, who were at a loss to explain its disappointing results.

One theory was that some people responded more strongly than others to a component of the vaccine tested in the STEP trial, making them more vulnerable to HIV, which attacks immune cells that are actively responding to a pathogenic threat. Research teams led by immunologists Dan Barouch at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Michael Betts of the University of Pennsylvania School of Medicine in Philadelphia, decided to test this idea in independent studies1,2, both published in Nature Medicine today.

The two teams examined immune cells from volunteers who received the vaccine used in the STEP trial. The vaccine was built on a backbone made from a modified cold virus — adenovirus 5. In the STEP trial, people who had been infected with adenovirus 5 before receiving the experimental vaccine were more likely to become infected with HIV than people who had not. So the researchers asked whether people whose immune systems had 'seen' adenovirus 5 before the trial responded more strongly to the vaccine than the other volunteers.

“We hope that these papers will be positive messages for the field, which has been quite depressed over the past year and a half.”

Dan Barouch
Beth Israel Deaconess Medical Center

The researchers examined particular immune-system cells, called T cells, from the blood of those who had received the vaccine. They found that people with previous exposure to adenovirus 5 did not have more T cells that recognized adenovirus 5. They did not make more T cells after vaccination, and did not make more 'activated' T cells — those specifically targeted by HIV — than those who had no previous exposure to the cold virus.

"The bottom line is that, immunologically, there do not appear to be any substantial differences" between those who were and were not exposed to adenovirus 5, "so this would not explain the differences in HIV susceptibility seen in the STEP trial", Betts said.

Positive messages

Larry Corey, principal investigator of the HIV Vaccine Trials Network, which conducted the STEP trial, said that researchers within the network had seen similar results. But he cautioned that these latest studies do not examine T cells from specific tissues where HIV enters the body, such as the rectum and the penis foreskin, and so do not rule out the possibility that previous adenoviral immunity made tissues at those sites more vulnerable. "The hypothesis doesn't go away totally," he said.

However, Corey also notes that continuing analyses suggest that previous adenoviral exposure is not as important as was thought at the time the STEP trial was stopped. Investigators continue to follow volunteers both from STEP and from a sister trial, and to reanalyse their original data. These analyses have highlighted the role of circumcision and of infections with genital herpes in susceptibility to HIV in these trials. In particular, uncircumcised men who received the vaccine were at least three times more likely than circumcised men to become infected with HIV. As time goes on, Corey adds, differences in HIV-infection rates between the vaccine and placebo groups are narrowing.

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"The role that [adenovirus 5] immunity plays has taken a back seat to the role that lack of circumcision has played, and also, to some extent, to the role that genital herpes plays," Corey said. "The issues are getting increasingly more complex as time goes on."

Although there is still no answer as to what caused the increased HIV-infection rates in the STEP trial, Barouch says the new data are a positive development for the field, meaning that other vaccines built on backbones made from viruses may not necessarily be harmful. Many scientists, including Barouch, are developing such vaccines.

"We hope that these papers will be positive messages for the field, which has been quite depressed over the past year and a half, and will provide a path for testing of future HIV vaccine candidates," Barouch says. 

  • References

    1. Hutnick, N. A. et al. Nature Medicine advance online publication doi:10.1038/nm.1989 (2009).
    2. O'Brien, K. L. et al. Nature Medicine advance online publication doi:10.1038/nm.1991 (2009).
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