A new study has shed light on why Merck & Co.’s a once-promising HIV vaccine actually made people in a clinical trial more likely to become infected. A phase II clinical trial for the HIV vaccine, known as STEP, was halted in September 2007 after researchers realized it put participants at a higher risk of contracting HIV.
The Merck vaccine was the first of a new class of HIV vaccines to get to an advanced stage in human testing. It consisted of a modified form of a common cold virus — Adenovirus 5. Vaccine developers believed Adenovirus 5 would carry elements of HIV into the body, which would then trigger the immune system to start fighting a subsequent HIV infection.
But three years after the trial began, researchers at the Montpellier Institute of Molecular Genetics in France said that more of the recipients who had prior immunity to the Adenovirus 5 had contracted HIV than those who had not received the vaccine. Scientific analyses found that the highest risk of HIV infection among recipients of the Merck vaccine was in males who both were uncircumcised and had pre-existing antibodies to Adenovirus 5.
This new study, published in the Journal of Experimental Medicine, shows how the presence of long-lasting Adenovirus 5-specific antibodies—generated during natural infections with adenoviruses—may have altered the immune response to the Merck HIV vaccine. In the presence of antibodies from Adenovirus 5-immune individuals, HIV infection spread through cell cultures three times faster than without them. The antibodies attached the Ad5-HIV vaccine to receptors on the surface of specialized immune cells, called antigen-presenting cells (APCs), thus facilitating entry of the vaccine into the cell.
Once inside, components of the vaccine then activated these cells, allowing the APCs in turn to activate T cells. Since HIV prefers to infect active T cells, the virus was thus provided with more cells to infect.
The problem with the Merck HIV vaccine wasn’t discovered in phase I of the STEP trial because those studies were done on primates. Because these animals don’t naturally come in contact with human adenoviruses, the vaccine did not put them at higher risk for HIV.
After the Merck vaccine trial was halted, plans for a large human trial of another promising government-developed HIV vaccine in the United States were canceled by the National Institutes of Health (NIH). Officials at the NIH said that scientists realized that they did not know enough about how HIV vaccines and the immune system interact. The government vaccine — known as PAVE, for Partnership for AIDS Vaccine Evaluation — was similar to the Merck vaccine.
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