Abstract
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.
Highlights
The HIV epidemic is a major global health challenge leading to more than 1.8 million deaths annually, and despite significant efforts the search for an efficacious and safe vaccine continues
We analyze data from the three largest epitope mapping studies performed in three clinical trials testing two recombinant adenovirus serotype 5 (rAd-5) vaccines
We find that vaccine-induced responses tend to cluster in ‘‘epitope hotspots’’ and that these hotspots are different for each vaccine and more surprisingly in two different vaccine trials testing the same vaccine
Summary
The HIV epidemic is a major global health challenge leading to more than 1.8 million deaths annually, and despite significant efforts the search for an efficacious and safe vaccine continues. One of the leading approaches in this field focuses on vaccines that are primarily designed to elicit CD8+ T-cell responses that have been shown to be critical for controlling HIV infection [1,2,3,4,5]. These vaccines are comprised of vectored immunogens that use a modified virus (e.g. adenovirus or poxvirus) from which specific HIV genes are expressed. We analyze epitope mapping data from two candidate rAd-5 HIV immunogens that were tested in human clinical trials. The VRCHIVAD014-00VP was a multiclade, multivalent recombinant rAd-5 vaccine that contained a clade B gag-pol insert as well as envelope inserts from the three major HIV clades (A, B and C), and was tested in a phase I trial (HVTN 054) [12]
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