HIV vaccine trial failure

 

Age-standardised disability-adjusted life year...

Age-standardised disability-adjusted life year (DALY) rates from HIV/AIDS by country (per 100,000 inhabitants). (Photo credit: Wikipedia)

 

Via the New York Times, a report has been released confirming an earlier suspicion that an HIV vaccine was actually making some recipients more susceptible to infection by the virus, as opposed to providing protection.  In the almost 30 years of research into the development of AIDS following infection by HIV, there have been a number of clinical trials, but no standout successes in that time. In 2004, a study using a recombinant-carrier mediated vaccine formulation made by Merck was begun with 3000 healthy volunteers in 9 countries. The study was halted in 2007 when it was apparent that no protection was being conferred by the vaccine. Furthermore, some individuals appeared to have an even higher incidence of HIV infection than control subjects, suggesting that they were more susceptible to infection because of the vaccine formulation.

The Merck vaccine used a weakened, or attenuated version of adenovirus as a vehicle for delivery. Adenovirus is a common, mostly innocuous virus that is responsible for 5 to 10% of human upper respiratory infections. Attenuated versions of viral serotypes are currently used as delivery vehicles for several vaccines, and are useful for this approach because they are highly infectious, yet attenuated strains do not cause disease. DNA segments encoding antigens from other pathogens are spliced into the modified adenovirus genome, creating a virus that can present the antigens from a second pathogen. The immune system then responds with antibody production to that other pathogen, hopefully conferring protection to infection by the second pathogen.

When patients were analyzed demographically in the 2004 study, there were higher numbers of HIV positive vaccine recipients  in comparison to placebo recipients. Vaccine recipients who were uncircumcised and who had previously caught common colds appeared to be 2 to 4 times more likely to become HIV positive during the trial than those who had not. The reason for the higher risk remains unknown, but further following of patients from the 2004 vaccine trial through 2009 confirmed the higher risk.

Patients were analyzed for other risk factors (number of sexual partners, type of sexual activity, IV drug use,) and these were not different between the vaccine group and the placebo group, suggesting that the immune response to the vaccine was responsible. One possible scenario proposed is this: in patients who had previously been repeatedly infected by adenovirus, a pool of preexisting CD4 T-helper cells would be primed for activation when the vaccine was administered, creating a larger than normal  pool of T cells that represent the cellular target for infection by HIV. Screening vaccine recipients by identifying whether they have a preexisting immune response to the adenovirus vehicle could help to improve efficacy and diminish increased risk of infection, however this does not help to address the other fundamental flaw which was that the vaccine formulation didn’t provide any increase in protection in any of the study participants after the high risk groups were excluded, in comparison to placebo.

The failure of this and other ongoing vaccine trials to prevent HIV infection go to demonstrate the difficulties that have been encountered over the past 3 decades. In 1984 after the identification of HIV as the etiologic agent of AIDS, Secretary of Health and Human Services Margaret Heckler said that a vaccine would be available within two years. The biology of HIV infection however makes development of a vaccine using the paradigms of viruses such as smallpox extremely difficult, including the fact that the latency of HIV infection means that it may be a long period of time from infection to the development of disease.

About ycpmicro

My name is David Singleton, and I am an Assistant Professor of Microbiology at York College of Pennsylvania. My main course is BIO230, a course taken by allied-health students at YCP. Views on this site are my own.

Posted on May 20, 2012, in Microbes in the News. Bookmark the permalink. Leave a comment.

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