This Program-project (PPG) application is focused on conducting preclinical studies to understand the molecular basis of immune programming by the rhesus cytomegalovirus vaccine against SIV infection (RhCMV/SIV vaccine), and on defining the role and actions of IL-15 in eliciting vaccine protection against persistent SIV infection. These studies are highly relevant for HIV vaccine development. RhCMV/SIV elicits high frequency and persistent effector-differentiated T cell responses in diverse tissues. Using of this vaccine in the rhesus macaque (RM) model of Simian immunodeficiency Virus (SIV) infection has demonstrated superior efficacy against highly pathogenic SIV challenge over conventional SIV vaccines (overall 59% of RhCMV/SIV vaccinated RM with abrogation of progressive SIV infection). The RhCMV/SIV vaccine response mediates early SIV intercept and replication arrest followed by eventual viral clearance. Vaccine protection is mediated by an MHC-E-restricted immune response of effector memory-differentiated CD8+ T cells unique to CMV-vector vaccination. We have revealed also that interleukin (IL)-15 and the IL-15 response are correlates of protection by RhCMV/SIV vaccination. The IL-15 response is rapidly induced following vaccination, with low prevaccination baseline IL-15 expression/response in blood, followed by rapid induction of IL-15 response networks linked with vaccine protection. This IL-15 dynamic serves as RhCMV/SIV vaccine efficacy outcome predictor. We have defined an inclusive whole blood predictive protective signature (wbPPTS) biomarker of RhCMV/SIV vaccine efficacy, and we will monitor this wbPPTS across RM vaccina cohorts within vivo studies to define the molecular mechanisms of vaccine immune programming. We hypothesize that RhCMV/SIV vaccine and IL-15 together direct expression of specific gene networks across tissues and cells to program effective vaccine immunity and establish the wbPPTS biomarker signature of vaccine protection. To investigate this hypothesis we have designed our PPG with two projects and three service cores including: Project 1. Systemic analysis of the origin and tissue effects of the 68-1 RhCMV/SIV vaccine efficacy-predictive whole blood transcriptomic signature; Project 2: Systems vaccinology of RhCMV/SIV and IL-15 mechanisms of immune programming; Core A, Administration, Core B, Nonhuman primates, and Core C, Systems biology. We feature in vitro/ex vivo and in vivo studies within a Systems Vaccinology design using multiomics 4-platform RNAseq applications (bulk RNAseq, scRNAseq/CITEseq, GeoMx/CosMx, Nanostring) and bioinformatics and statistical modeling approaches to define the systems response across tissues and cell types revealing the molecular basis of immune programming by IL-15 and RhCMV/SIV vaccine.

The world is in need of an effective HIV/AIDS vaccine, and the cytomegalovirus (CMV) vector-based HIV/SIV vaccine featured in our studies is highly efficacious and durable to uniquely mediate viral “replication arrest” efficacy in the Rhesus Macaque-SIV model. Vaccine immunity is mediated by unconventional MHC-E-restricted CD8+ T cell responses and induction of IL-15, which correlate with vaccine protection. The work proposed in this application will reveal the molecular mechanisms of immune programming by the CMV-based vaccine and IL- 15 actions to inform human testing of this vaccine concept in ongoing and future phase I/II trials.