Concerns have been raised about the safety of Ad5-vectored vaccines in populations at risk for HIV infection. One of the challenges faced by such vaccines is the presence of pre- existing Ad-specific neutralising antibodies (NAbs) in the general population. The safety of adenovirus vaccine vectors has been evaluated in a number of studies. In particular, the results of the STEP trial (which primarily recruited men who have sex with men in the Americas) 1 and the PHAMBILI trial (which recruited heterosexual men and women in South Africa) 2 were considered. Both clinical trials were designed to administer three doses of an Ad5-vectored vaccine encoding the HIV gag, pol and nef proteins. In both the STEP clinical and PHAMBILI trials, administration of an Ad5-vectored vaccine was associated with enhanced susceptibility/acquisition of HIV in men. The STEP trial was stopped in September 2007 due to lack of efficacy, but evidence quickly emerged of an enhanced risk of HIV infection in a particular subgroup of participants (uncircumcised men with high titers of pre-existing antibodies to Ad5). Over extended follow-up, the increased risk of HIV among vaccine recipients became statistically significant when the entire trial population was analysed.3 The STEP trial results led to the early cessation of the PHAMBI