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.
.
