[HIV/AIDS vaccines: heading for new vaccine approaches?]

The development of an HIV/AIDS vaccine faces formidable challenges related to the high genetic variability of the virus which has developed potent escape mechanisms to dodge the immune responses of the host, while maintaining the immune system in a permanent state of activation that rapidly leads to T cell exhaustion. Our total lack of knowledge on potential immune correlates of protection, our inability to elicit potent broadly neutralizing anti-HIV antibodies by active immunization added to the limitations with the existing animal models are other obstacles to overcome. The field met with its first failure 5 years ago when a gp120-based subunit vaccine showed no protection against HIV infection in two Phase III trials in the USA and Thailand. It recently met with its second failure when the Merck "STEP" trial had to be prematurely interrupted. The trial was a Phase IIb study of an Adenovirus 5 (Ad5)-HIV vaccine meant to elicit a cellular immune response, essentially HIV-specific CD8+ CTLs, to control viremia in the vaccinees who happened to become infected. Not only did the vaccine fail to control the viral loads in the HIV-infected vaccinees, but unexpectedly the number of HIV infections observed in adenovirus-pre-immune volunteers was significantly higher in the vaccine group than in the placebo group. This does not imply that T cell vaccines have no future but illustrates the limitations and risks of that approach. It also suggests that current assays that measure T cell responses are inadequate to assess CTL functionality. Taking into account the failure of these first two generations of HIV/AIDS vaccines, the development of a third generation vaccine is being considered, aiming at setting up a dual humoral and cellular immune barrier to HIV at the mucosal site of entry of the virus.