Background:  The recently announced intermediate outcome of the STEP trial of an AIDS vaccine candidate mandates a re-evaluation of the status of programs for development of a prophylactic vaccine against HIV infection. The STEP trial indicated that a non-replicating adenovirus vector that expressed many of the HIV proteins—when primed with a similar DNA construct—induced cellular immunity in a large proportion of vaccinees. However, in an efficacy trial, this prime boost vaccine regimen failed to reduce the incidence of HIV infections and failed to influence virus set-points in those immunized subjects who subsequently were infected. The disappointing inefficacy of what was widely considered a very promising vaccine candidate has led to an intense discussion about the direction of future AIDS vaccine research.

Conclusions:  I will comment on several issues relevant to this discussion, including:  What lessons is nature trying to teach us? Among the vast body of knowledge about HIV and AIDS, are there some important clues as to promising leads? How do we wrest the truth from our nonhuman primate co-workers? Although some have concluded that challenge studies with nonhuman primates misled the field, is it more logical to use the STEP trial to better calibrate monkey models to evaluate candidate immunogens? In view of the general consensus that broadly reactive neutralizing antibody is the potential key to an effective AIDS vaccine, are there alternative approaches that might help to cut this Gordian knot? If we can’t prevent or eliminate HIV infection, can we live with it? Could a vaccine that fails to prevent HIV infection sufficiently modulate the very early events to convert HIV into a chronic disease that is not necessarily fatal? Absent a vaccine, can the HIV/AIDS epidemic be controlled effectively, particularly in high prevalence settings? Is it time for another Levine report? Do we need a full-scale evaluation of the direction of AIDS vaccine research?