MEPCS (Multi-epitope protease cleavage sites) vaccine for protecting against SIV rectal transmission - Summary Novel vaccine strategies is needed to develop a safe, effective, and broadly accessible HIV vaccine to end the HIV pandemic. This proposal is built upon several innovative advancements. First, learned from natural immunity observed in a group of HIV resistant Kenyan female sex workers, we found 12 protease cleavage sites (PCS) in HIV are critical for virus maturation due to their essential function in tightly controlled cleavage of Gag, Gag-Pol, and Nef precursor proteins. Sequences surrounding the HIV PCS are immunogenic and highly conserved across global HIV subtypes, thereby a vaccine based on 12 PCS immunogens will be globally accessible and likely to prevent virus escape mutations. Further, our recent studies demonstrated that a PCS vaccine delivered by recombinant vesicular stomatitis virus (rVSV) vector and nanoformulation protected more than 80% of vaccinated female Mauritian cynomolgus macaques (MCMs) against SIVmac251 intravaginal challenges, which is associated with vaccine elicited potent PCS-specific CD8 T cell responses. However, in previous studies, 12 PCS immunogens were individually expressed in the rVSV. To improve vaccine immunogen presentation and facilitate the vaccine preparation, 12 PCS immunogens should be expressed in a single cassette, i.e., multi-epitope PCS (MEPCS). i.e., multi-epitope PCS (MEPCS). To that end, we have developed a cold-chain friendly and long-term stable MEPCS-mRNA-LNP vaccine. We found that SIV MEPCS-mRNA-LNP vaccine induced a potent PCS-specific CD8 T-cell immunity without inducing generalized inflammation and CD4 T-cell activation. Based on our strong preliminary date, we hypothesize that MEPCS vaccines would protect rhesus macaques against SIVmac251 rectal transmission. The reason we will use a rhesus macaque (RM)-SIV rectal challenge model is that the effectiveness of MEPCS vaccine needs to be validated in the most rigorous rhesus macaques and anal sex is the most common HIV transmission in the United States of America. The primary objective of this study is to evaluate the effectiveness of cold- chain friendly and long-term stable MEPCS-mRNA-LNP vaccine in comparison with rVSV-MEPCS vaccines in protecting RMs against SIVmac251 intrarectal challenge and to better understand the immune correlated protection. in this proposed study we will comparatively evaluate the effectiveness of MEPCS-mRNA-LNP with rVSV-MEPCS vaccines against SIVmac251 intrarectal challenge in RMs. The proposed study has the great potential to develop a new HIV/SIV vaccine to prevent HIV/SIV rectal transmission. The novel MEPCS immunogens plus the cold-chain friendly and long-term stable mRNA- LNP formulation makes this proposed study highly innovative and significant. .
