# Mechanistic Exploration of cGAS-STING-Mediated Vaccine Enhancement

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $640,563

## Abstract

PROJECT SUMMARY
The goals of this R01 proposal include the molecular and immunological characterization of vaccine adjuvant
activity associated with processes mediated by the protein Stimulator of Interferon Genes (STING). Two vital
insufficiencies are currently evident regarding adjuvanted human vaccines. First, very few adjuvants are
approved for clinical use in the U.S. Second, the precise mechanistic bases of adjuvant-associated immune
augmentation are poorly understood. Effective adjuvants trigger rapid, localized innate immune responses
following their administration. Fundamentally, the innate signaling is initiated through engagement of pattern
recognition receptors (PRRs) by ligands indicative or imitative of microbial infection. This, in turn, leads to
expression of immunomodulatory and proinflammatory factors that ultimately direct adaptive immune responses
capable of eliminating infected tissues. STING represents the PRR that senses cyclic dinucleotides (CDN), a
product of the cellular enzyme cyclic GMP-AMP synthase (cGAS) following its detection of cytoplasmic dsDNA
derived from microbes, mitochondria, or the nucleus. STING-mediated phenotypes are ultimately conferred by
genes that are transcriptionally induced by the activated protein. This crucially involves the transcription factors
IFN regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB), which synthesize mRNAs of distinct ontologies yet
whose functional roles are mostly unexplored. Moreover, STING appears to control physiological processes that
differ dramatically between cell types of the immune system including stromal, myeloid, and T cells. Intriguingly,
pharmacologic induction of STING-dependent activity in murine models greatly enhances vaccine efficacy as
indicated by protective immunity elicited against diverse pathogens. Unfortunately, the precise molecular and
innate correlates of adaptive immune potentiation associated with STING activity remain largely unexamined.
Furthermore, whether STING adjuvants elicit similarly effective immunogenic outcomes in primates has not been
examined. We plan to couple these with our powerful CRISPR and transcriptomic technologies to obtain
penetrative insight into the fundamental bases of STING-mediated immune outcomes. We hypothesize that the
enhancement of antigen-directed adaptive immunity associated with STING-based adjuvants is functionally
linked to molecular and cellular processes that are discernable using these models. We have also identified a
first-in-class small molecule that activates cGAS-STING across species and enhances immunogenicity to Zika
virus antigen. Including this alongside CDN in in vitro, murine, and nonhuman primate (NHP) models will allow
us to: 1) Validate and characterize cGAS as a new immunotherapeutic target; 2) Demonstrate STING adjuvant
efficacy in a highly clinically relevant model species; and 3) Identify species-specific similarities and differences
with respect to STING-mediated immune responses.

## Key facts

- **NIH application ID:** 9852956
- **Project number:** 5R01AI143660-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** VICTOR Robert DEFILIPPIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $640,563
- **Award type:** 5
- **Project period:** 2019-01-23 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852956

## Citation

> US National Institutes of Health, RePORTER application 9852956, Mechanistic Exploration of cGAS-STING-Mediated Vaccine Enhancement (5R01AI143660-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9852956. Licensed CC0.

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