Background:  Over the past several years, there has been considerable interest in the development of replication-incompetent, recombinant adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1. Recombinant Ad5 vector-based vaccines for HIV-1 have proven highly immunogenic in preclinical studies and early phase clinical trials, and phase 2b proof-of-concept studies are currently in progress to evaluate the efficacy of these vaccine candidates in high-risk populations. A potential limitation of rAd5 vectors, however, is the high frequency of pre-existing vector-specific immunity in individuals in Sub-Saharan Africa. In the United States, 30 to 50% of individuals have pre-existing Ad5-specific immunity. In contrast, more than 80% of individuals in Sub-Saharan Africa have pre-existing Ad5-specific immunity, and many have particularly high titers of Ad5-specific neutralizing antibodies (NAb). To overcome this problem, we have constructed a series of novel rAd vectors that are serologically distinct from rAd5 vectors and that circumvent pre-existing vector-specific immunity. We have taken 2 parallel approaches:  developing rAd vectors from serotypes that are rare in human populations, and developing molecularly engineered capsid chimeric rAd5 vectors in which the dominant Ad5-specific NAb epitopes have been specifically removed from the hexon major capsid protein.

Conclusions:  These rare serotype and capsid chimeric rAd vectors could potentially serve as alternatives to rAd5 vectors if the suppressive effects of pre-existing vector-specific immunity in target populations prove clinically relevant. Novel rAd vectors could also be utilized in conjunction with rAd5 vectors or other vectors in heterologous prime-boost vaccine regimens.