One of the biggest disappointments in AIDS research was the failure of Merck & Co.'s STEP trial of an experimental AIDS vaccine, which was terminated prematurely in 2007 when it became apparent that the vaccine seemed to increase the number of people who contracted HIV. Now, British scientists believe they have an explanation for why the vaccine failed, and it has little to do with HIV itself and more to do with the adenovirus that was used to produce the vaccine. The findings may have implications for other experimental vaccines, such as those against malaria and tuberculosis, that also used the adenovirus, as well as for gene therapy.
The adenovirus is what is known as a vector. It is used to carry genes from, in this case, the AIDS virus into cells in the body, where they can produce proteins that stimulate immunity to HIV. Merck used a vector called adenovirus serotype 5 (Ad5), from which they removed genes that could cause disease. Ad5 is very similar to adenoviruses that cause colds, and there's the rub, according to Dr. Steven Patterson of Imperial College London, who led the new study, appearing this week in the Proceedings of the National Academy of Sciences. Many of the patients in the study had previously been exposed to closely related adenoviruses and had built up immunity to the virus.
But that immunity did not simply destroy the vaccine vector. In addition, it attracted T cells that were meant to kill the virus to the mucosal membranes in the nose, mouth and genital areas. Those cells are the primary targets for HIV. "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," Patterson said. "This is clearly worrisome for this kind of vaccine. Scientists are currently developing adenovirus-based vaccines to protect people from TB and malaria as well as HIV, but they may have to rethink those vaccines if the effect we describe in our new paper is a problem for all of them."
Patterson and his colleagues studied the phenomenon in laboratory dishes using samples obtained and frozen during the initial trials of the vaccine. Two other recent studies in humans concluded that the adenovirus was not the problem. But such negative results, Patterson said, can be difficult to interpret. In particular, those earlier studies looked for the T cells in the blood, and Patterson believes the simplest explanation is that the cells migrated out of the blood into mucosal tissues.
Merck responded that the researchers may be jumping to unwarranted conclusions. "It would be premature to suggest that this provides an explanation for the STEP results, and the implications for other vaccines or gene therapy are unclear," Dr. Michael Robertson, director of vaccines clinical research for the company, said in a statement.
— Thomas H. Maugh II