No. 5: Failure of HIV Vaccine

On September 24, interim results from a major, international, NIAID-cosponsored trial indicated that a Merck-developed vaccine does not prevent HIV infection. An independent data and safety monitoring board consequently recommended that the 3000 volunteers in the phase 2b “test-of concept” study no longer receive vaccine. It was also recommended that the vaccine not be administered to subjects in a companion South African study, which began February 2007.

In December 2004, the STEP study (also called HVTN* 502 or Merck V520-023) began enrolling uninfected volunteers to receive 3 doses of the Merck vaccine or placebo in randomized, double-blind fashion. The trivalent vaccine consisted of a replication-defective adenovirus 5 (Ad5) vector in which was inserted 1 of 3 synthetically produced HIV genes: gag, pol, or nef.^† The vaccine was intended to allow the re-establishment of nascent immunity against HIV-infected cells.

Among volunteers who received at least 1 dose of vaccine, the rate of HIV infection was 3.2% with the active vaccine and 2.8% with placebo vaccine, according to the interim results. In men who received at least 2 doses of vaccine, the infection rates were 2.8% and 1.6% with vaccine and placebo, respectively. Currently it is unclear if the vaccine fails to prevent HIV infection or actually increases the risk of infection.

Regardless, the reason for the failure of the vaccine is presently a mystery. However, investigators and observers speculate that the Ad5 vector may be responsible, by limiting the immune response in vaccinated men who have preexisting immunity to Ad5. According to a Merck press release, STEP was originally designed to include only those persons with low Ad5 antibody levels (≤200 units), with the expectation that those individuals would demonstrate the best vaccine response. However, persons with Ad5 antibody levels higher than 200 units were subsequently enrolled, because new data indicated that the vaccine was immunogenic in those subjects as well. Follow-up data from the interrupted STEP study, which may include subgroup analyses, are scheduled to be presented in February 2008 at the Conference on Retroviruses and Opportunistic Infections in Boston.

*HIV Vaccine Trials Network.

^†As a reminder, gag genes code for HIV structural components; pol codes for reverse transcriptase; and nef codes for a protein that promotes the survival of infected cells.