Vaccination with self-launching RhCMV/SIV DNA vaccine vectors

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PROJECT SUMMARY/ABSRACT A prophylactic HIV vaccine would be of tremendous benefit for global health by helping to reduce the number of infected people. Similarly, new vaccine approaches are needed with the potential to reduce incidence of tuberculosis and malaria. RhCMV-vectored SIV vaccines have demonstrated tremendous potential for eliciting immune responses that can control SIV infection, but the unstable CMV genome and the relatively large proportion of non-infectious virions in vaccine stocks present major practical challenges, which have already delayed tests of CMV-vectored vaccines in human patients. Additionally, the need for a cold chain that is likely infeasible in some HIV-endemic areas is problematic. Here we describe and propose to test a vaccine platform based on delivery of the CMV- based vaccine vector genome in nucleic-acid form. We have shown that the delivered genomes are capable of initiating self-sustaining replication in vivo, and that this vector replication engenders immune responses that appear at least equal if not superior to those stimulated by (conventional) vaccination with encapsidated vaccine-vector particles. Successful completion of this R21 project will thus accelerate CMV-based vaccine development for HIV and potentially other diseases as well. Indeed, we believe that an advance such as this is required before CMV-vectored vaccines can have the positive impact on human health that is so hoped for by the field. The goal of this work is to provide a practical, cost-effective platform for cytomegalovirus-based vaccine delivery in vivo. Our hypothesis is that RhCMVdIL10-SIVgag and -SIVenv vaccines delivered as replication-competent, self-excising BAC DNA can elicit immune responses that have the unique character associated with RhCMV-vectored vaccination and that are protective against SIV. This hypothesis will be addressed in two specific aims using the rhesus macaque non-human primate model. Aim 1 will determine the optimal in vivo delivery method for replication and dissemination of, as well as host immune responses to, a novel, self-launching RhCMVdIL10-SIV vaccine. Three different methods of in vivo BAC DNA delivery will be tested for immunogenicity. Cellular and humoral immune responses, including the development of Mamu-E-restricted responses, will be assessed in addition to replication and dissemination of the vector. Aim 2 will test if RhCMVdIL10-SIVgag and -SIVenv vaccines are protective against SIV disease when delivered as self-launching BACs. We will determine the extent of protection achieved against low-dose, pathogenic SIV challenge following vaccination of macaques using the optimal delivery method identified in Aim 1. The novel vaccine vectors that are described in this proposal will solve many of the hurdles that are limiting the development of current CMV-based viral vectors and have broad applicability for other diseases that impact human health.