Future HIV vaccine research should consider the balance between responses that favor protection and those that lead to susceptibility to infection. The development of a safe and effective HIV vaccine is perhaps the most important and challenging goal remaining in HIV-AIDS research. Recent progress using a poxvirus vector prime and envelope protein boost strategy demonstrated a modest but statistically significant level of efficacy and established the concept that a vaccine could prevent HIV infection ( 1 ), and approaches to boost durability and efficacy are currently in the planning stages ( 2 ). But the results of two vaccine concepts based on recombinant adenovirus serotype-5 (rAd5) ( 3 – 5 ) pointed to a potential major problem—that such vaccines might increase susceptibility to HIV infection. This also raised the question of whether the problem extends to some or all of the other recombinant adenovirus vectors currently in development or to other vector-based vaccines.