Several recent large clinical trials evaluated
HIV vaccine candidates that were based on recombinant adenovirus serotype 5 (rAd-5) vectors expressing HIV-derived
antigens. These
vaccines primarily elicited T-cell responses, which are known to be critical for controlling
HIV infection. In the current study, we present a meta-analysis of
epitope mapping data from 177 participants in three clinical trials that tested two different
HIV vaccines: MRKAd-5 HIV and VRC-HIVAD014-00VP. We characterized the population-level
epitope responses in these trials by generating population-based
epitope maps, and also designed such maps using a large cohort of 372 naturally infected individuals. We used these maps to address several questions: (1) Are
vaccine-induced responses randomly distributed across
vaccine inserts, or do they cluster into
immunodominant epitope hotspots? (2) Are the immunodominance patterns observed for these two
vaccines in three
vaccine trials different from one another? (3) Do
vaccine-induced hotspots overlap with
epitope hotspots induced by chronic natural
infection with HIV-1? (4) Do immunodominant hotspots target evolutionarily conserved regions of the HIV genome? (5) Can
epitope prediction methods be used to identify these hotspots? We found that
vaccine responses clustered into
epitope hotspots in all three
vaccine trials and some of these hotspots were not observed in chronic natural
infection. We also found significant differences between the immunodominance patterns generated in each trial, even comparing two trials that tested the same
vaccine in different populations. Some of the
vaccine-induced immunodominant hotspots were located in highly variable regions of the HIV genome, and this was more evident for the MRKAd-5
HIV vaccine. Finally, we found that
epitope prediction methods can partially predict the location of
vaccine-induced
epitope hotspots. Our findings have implications for
vaccine design and suggest a framework by which different
vaccine candidates can be compared in early phases of evaluation.