Past efficacy trials of HIV vaccines have attempted to generate neutralizing antibodies. With the failure of these trials to demonstrate protection, the focus for HIV vaccine development has shifted to inducing a cytotoxic T-lymphocyte response (CTL). A CTL response is not expected to produce sterilizing immunity, but may delay progression to AIDS or reduce the transmission of HIV. Adenovirus vector-based regimens that induce CTLs are currently in efficacy trial testing. These efficacy trials are using surrogate end points in an innovative Phase 2B trial design.