Immunodominance and sequence diversity are major hurdles in the development of effective HIV vaccines. We tested the hypothesis that a vaccine candidate composed of strictly Conserved Elements (CE) of the HIV proteome excluding the variable regions would help overcome problems of viral sequence diversity and potential negative effects of immunodominance. Seven CE were identified in p24gag. Vaccination of macaques with p55gagDNA failed to elicit cellular or humoral immune responses to the CE, while epitopes outside of the CE were immunogenic.
Two HIV p24gagCE DNA plasmids were generated, providing potential epitopes found in >99% of all HIV-1 M group sequences. DNA vectors, optimized for gene expression were used to immunize mice and macaques by IM injection followed by in vivo electroporation.
Vaccination with p24gagCEvac DNAs elicited potent, cross-clade cellular and humoral immune responses. Highly cytotoxic CE-specific T cells, capable of Granzyme B production and degranulation, were generated. Importantly, boosting of the CEvac-primed macaques with p55gagDNA greatly augmented the CE-specific cellular responses (up to 10-fold) as well as humoral responses, despite the failure of p55gagDNA vaccine to induce de novo CE-specific responses. CEvac DNA prime-p55gagDNA boost in mice led to similar conclusions. Interestingly, mapping analysis showed differential increase of the CE-specific responses by the p55gagDNA boost, demonstrating changed hierarchy of CE responses in macaques.
Vaccination with the p24gagCEvac DNA overcame the problem of diversity by generating strong cross-clade Gag-specific immune responses, and of immunodominance, eliciting responses to subdominant but highly conserved elements, and also by broadening the p55gagDNA induced immunity. p55gagDNA did not induce de novo responses to the CE, but was able to significantly boost pre-existing CE-induced responses and alter the hierarchy of these responses. Translation of this concept into clinical trials may elicit cross-clade cellular immune responses against components of the viral proteome with limited capacity for immunological escape.