Immune Response May Render HIV Vaccine Ineffective

Emma Hitt, PhD

December 27, 2011

December 27, 2011 — Individuals with large numbers of T cells that were responsive to adenovirus serotype 5 (Ad5) generated a less robust immune response to HIV vaccine than those who had fewer Ad5-responsive T cells before vaccination, according to a follow-up analysis from the Step study.

Because of the similarities in epitopes among Ad-based vaccines, this finding may help explain why other Ad-based vaccines might also be ineffective in individuals with large numbers of Ad5-responsive T cells, the researchers note.

Nicole Frahm, PhD, from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, and colleagues reported their findings in the January 2012 issue of the Journal of Clinical Investigation.

"Our comprehensive investigations of Ad-specific T cell responses are, to our knowledge, the first to define the impact of vector-specific cellular immunity on HIV-specific, vaccine-induced T cell responses in the context of a clinical trial," Dr. Frahm and colleagues point out.

The Step study, which evaluated the MRKAd5 HIV-1 gag/pol/nef vaccine (n = 1494) vs a placebo (n = 1506) was discontinued after findings showed no benefit for the HIV vaccine. Furthermore, some patients receiving the vaccine, and specifically those with preexisting antibodies to vaccine component Ad5, became more susceptible to HIV than those not receiving it.

The current analysis evaluated the associations between patients' HIV-specific T cell responses and preexisting Ad5 immunity. The researchers analyzed samples from more than 400 participants in the Step study who received either vaccine or placebo, in addition to 35 recipients of the same vaccine from another trial (HVTN 071) that was conducted in parallel.

The analysis showed that higher baseline cellular immune responses to the Ad vector attenuated vaccine-induced T cell responses to HIV. In addition, epitope mapping studies and sequence analysis across serotypes showed that Ad "regions targeted by Ad-specific T cells are conserved not only between group C adenoviruses such as Ad5, but also adenoviruses outside group C that are currently under development as vaccine vectors based on their lower seroprevalence in target populations."

According to the researchers, the "cross-reactivity of Ad-specific T cell responses could potentially lead to reduced vaccine-induced immune responses in all populations with prevalent adenovirus infections of any serotype."

"These findings provide what we believe to be a new understanding of how preexisting viral immunity may impact the efficacy of vaccines under current evaluation for prevention of HIV, tuberculosis, and malaria," they add.

The Step study was supported by Merck Research Laboratories; the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the National Institutes of Health–sponsored HIV Vaccine Trials Network. Two of the study authors are employees of Merck.

J Clin Invest. 2012;122:359-367. Full text


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