HIV-1 STEP Vaccine Trial Failure Blamed on Adenovirus Shell

Becky McCall

November 18, 2009

November 18, 2009 (London, United Kingdom) — Failure of the HIV type 1 (HIV-1) STEP vaccine trial, which resulted in more HIV infections in those vaccinated with the adenovirus serotype 5 vaccine than in those who received the placebo, has been attributed to the activation and expansion of adenovirus serotype 5–specific mucosal-homing memory CD4 T cells, researchers announced here at the 12th European AIDS Conference/European AIDS Clinical Society.

Phase 2 of the STEP trial was stopped in 2007, but only now have scientists arrived at an explanation for events, announced coinvestigator Steven Patterson, PhD, from the Division of Investigative Science at Imperial College London, United Kingdom.

Results of the investigation have been simultaneously released ahead of print in an early online edition of the Proceedings of the National Academy of Sciences (published online November 16, 2009). The findings may have implications for other HIV adenovirus vectors that are currently being used in the development of tuberculosis and malarial vaccines, Dr. Patterson observed.

Individuals that were seropositive for adenovirus serotype 5 showed increased rates of HIV-1 infection on vaccination with the adenovirus 5 vaccine used in the STEP trial. Dr. Patterson explained that it was a CD4 cell response against the structural or "shell" proteins of the adenovirus that caused the problem.

"Trial individuals who had preexisting antibody against adenovirus 5 had presumably encountered the virus naturally and had probably experienced an infection by adenovirus 5. As well as inducing antibody, the virus would have stimulated CD4 T cells to divide and expand," said Dr. Patterson, forming a memory population with the capacity to expand again rapidly on meeting the adenovirus again, as in vaccination. This expanded CD4 cell population would have encouraged HIV infection uptake.

"CD4 T cells are the main target of HIV, and thus exposure to the vaccine vector would simulate rapid expansion of CD4 T cells in those individuals who were already immune to the adenovirus. Furthermore, since natural infection with adenovirus occurs through mucosal surfaces, such as the respiratory or gastrointestinal tract, the memory cells, on expansion stimulated by adenovirus, would be expected to migrate to mucosal tissues, and this, of course, is the site of HIV infection," added Dr. Patterson.

Between 40% and 60% of individuals in the Western Europe are thought to have neutralizing antibody against the adenovirus, indicating prior exposure. In sub-Saharan Africa, where HIV is highly prevalent, adenovirus 5 has stimulated immunity in up to 90% of the population.

"Scientists are currently developing adenovirus-based vaccines to protect people against tuberculosis and malaria, as well as HIV, but they may have to rethink these vaccines if the effect we describe in our new paper is a problem for all of them," Dr. Patterson commented.

At this time, HIV vaccine development is making slow progress. Françoise Barré-Sinoussi, PhD, director of the Regulation of Retroviral Infections Unit, Virology Department, Institut Pasteur, Paris, France, and joint winner of the 2008 Nobel Prize for Medicine, commented that the STEP vaccine trial "does raise several questions which are important for the future of HIV vaccine research." Dr. Barré-Sinoussi spoke at the opening ceremony of the 12th European AIDS Conference.

Dr. Barré-Sinoussi said the Thai–US vaccine, which apparently cut the risk of becoming infected with HIV by 31% in a trial of 16,000 volunteers in Thailand, showed modest vaccine efficacy for the first time, but there are concerns with HIV vaccines. "Firstly, regarding protective response in those people vaccinated who were protected, we don't actually know what kind of response they developed. Also it raises the question of why some of those vaccinated who actually acquired the virus still had a viral load which was the same as the control group, so there is a dichotomy between the response which blocks acquisition of the HIV virus and the response which blocks replication," Dr. Barré-Sinoussi told Medscape HIV/AIDS.

Dr. Patterson believes that science is still some way from producing an HIV vaccine. "Not only do we have difficulty in identifying and stimulating an immune response that can provide protection, the STEP trial has shown that some viral vectors used to carry the HIV vector genes to the immune system may themselves cause problems," he pointed out.

Dr. Patterson and Dr. Barré-Sinoussi have disclosed no relevant financial relationships.

12th European AIDS Conference/European AIDS Clinical Society: Opening Ceremony. Presented November 11, 2009.

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