# Mechanisms programming Protective Immunity from RhCMV-SIV Vaccine and IL-15 actions

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2024 · $1,643,486

## Abstract

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.

## Key facts

- **NIH application ID:** 11181920
- **Project number:** 7P01AI177688-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Michael Gale
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,643,486
- **Award type:** 7
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11181920

## Citation

> US National Institutes of Health, RePORTER application 11181920, Mechanisms programming Protective Immunity from RhCMV-SIV Vaccine and IL-15 actions (7P01AI177688-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11181920. Licensed CC0.

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