Adenovirus targeted as cause of 2007 HIV vaccine failure

Kathleen Blanchard's picture
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Researchers from the Imperial College of London release findings that adenovirus, the same virus that causes the common cold, used to make HIV vaccine in the 2007 STEP trial, was the likely cause of increase in HIV infections associated with administration of the vaccine. The findings serve as a warning to scientists about the use of adenovirus for malaria and tuberculosis vaccines that is now targeted for failure of the HIV vaccine.

The STEP trial began in late 2004 and included 3,000 uninfected people in North and South America and Australia. Researchers hoped they could prevent replication of HIV, preventing its development into full blown AIDS.

The HIV vaccine used during the STEP trial relied on the adenovirus that causes the common cold to deliver the vaccine throughout the body. Scientists halted the study after discovering that individuals given vaccine had a higher chance of becoming infected with HIV, compared to placebo. Scientists injected HIV genes into the adenovirus shell used in the vaccine trial.

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The findings, published today in the Proceedings of the National Academy of Sciences, cite the “shell” of the adenovirus as responsible for failure of the HIV vaccine. That means researchers need to use other methods for developing vaccines for malaria and tuberculosis which also rely on the adenovirus to distribute vaccines throughout the body. It also means that using all subtypes of adenovirus for developing a vaccine for HIV could pose dangers.

According to Dr Steven Patterson, corresponding author of the study from the Division of Investigative Science at Imperial College London, "HIV is a huge threat to global health, with 2.7 million people becoming infected every year. We were all hopeful that the STEP trial would be a success, so when the researchers published their results and the trial was halted, we were all very surprised and disappointed. Scientists use adenoviruses in all sorts of vaccines and we did not expect this result. It was vital to discover what caused this increase in HIV infection risk so we could avoid the same problem in future trials."

For the STEP trial, researchers measured immunity against adenovirus type 5 (Ad-5) and adenovirus type 11 (Ad-11) in twenty volunteers. The scientists used immune cells from the volunteers, growing them in the lab to see if immune cells, called CD4 cells recognized Ad-5 and Ad-11. The addition of adenovirus to the tissue cultures caused CD4 cells to replicate and migrate to mucosal membranes – the exact places HIV would be introduced.

Dr. Patterson explains, "Our research suggests that the adenovirus-based HIV vaccine effectively instructs the cells that HIV infects to gather round exactly where HIV is likely to be introduced. This is clearly worrying for this kind of vaccine." The STEP trial for HIV vaccine failed because CD4 cells recognized and reacted to adenovirus used in the vaccine. Mucous membranes in the nose, mouth, vagina and gut infected the CD4 cells that were activated from the introduction of the adenovirus in the HIV vaccine. The scientists warn against the use of adenovirus for the development of other vaccines that could result in increased risk of infection from using the "shell" of adenovirus that activated CD4 cells during the STEP HIV vaccine trials.

PNAS

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