DNA priming vaccination to induce T cell responses to subdominant conserved HIV epitopes

Abstract

Abstract Background HIV sequence diversity and epitope immunodominance exerted by the variable regions are hurdles in the development of an effective AIDS vaccine. We developed novel DNA vaccine regimens to redirect T cell responses to highly conserved regions (CE) in the HIV proteome. Methods Rhesus macaques were primed with DNA expressing CE immunogen and boosted with a combination of DNAs expressing CE and/or full-length (FL) immunogens. Different prime-boost protocols were compared. The CE prime/CE+FL boost vaccination co-delivered in the same anatomical site was compared to delivery of CE and FL DNA in contralateral sites. Results CE prime/CE+FL boost regimens induced high and broad CTL responses which cannot be achieved using FL DNAs only. Thus, priming with CE DNA profoundly alters the immunodominance exerted by the variable non-CE regions, promoting responses to subdominant CE. This vaccine regimen is currently tested in clinical trials (HVTN 119, ACTG A5369). Comparison of same site vs contralateral vaccine delivery showed that separating CE and FL DNA resulted in increased breadth of T cell responses to non-CE while maintaining CTL responses to CE. Separating the immunogens at the prime allows for induction of independent primary adaptive responses by targeting the two vaccine components to distinct lymph nodes and preventing interference. Conclusions HIV DNA vaccine regimens comprising CE as prime and native immunogens as boost induce responses to subdominant epitopes, maximizing breadth and focusing the immune response against vulnerable regions of the virus. Separating the immunogens results in broader epitope recognition. This has implications for many vaccine protocols promoting induction of protective responses.