# Project 1: Neutralizing and decolonizing Clostridioides difficile using mRNA vaccines

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2024 · $311,038

## Abstract

SUMMARY- PROJECT 1 (VACCINE DEVELOPMENT)
Clostridioides difficile is a gram negative spore forming pathogen that causes mild to severe gastrointestinal
disorders and death in the elderly, immune compromised individuals and those exposed to systemic antibiotics.
Increased recurrence and difficulties treating the disease following antibiotic administration highlight the need to
develop novel therapeutic and prophylactic strategies. To date, vaccines against C. difficile demonstrated
promising results but failed to meet primary outcome criteria to mitigate/reduce primary infections. Therefore,
novel and innovative strategies/approaches are required. Our objective is to develop a clinically relevant
highly effective multivalent mRNA-LNP vaccine to prevent colonization and treat C. difficile infection.
Our strategy relies on our extensive experience with the nucleoside-modified mRNA and mRNA-LNP platforms,
large libraries of ionizable lipids, and a multipronged approach to vaccine development and novel target
discovery, as well as the unique multidisciplinary expertise and resources available to us. We hypothesize that
multivalent targeting of disease causing toxins and bacterial proteins (e.g., surface proteins) will 1)
mitigate primary infection in healthy individuals, and 2) prevent disease and promote decolonization in
infected individuals. Improving mucosal immunity following intramuscular administration of mRNA-LNP
through ligand and charge mediated tropism, oral delivery of mRNA-LNP vaccines capsulated in hydrogels
and/or the addition of immune modulators will improve the efficacy of the multivalent vaccine to decolonize C.
difficile in the gut lumen. Insight from the proposed multi-omic approach for target discovery (Project 2 and Core
B), and a better understanding of human immune responses to C difficile (Project 3 and Core C) will support a
translational workflow that leverages fundamental science and knowledge based approach for the discovery and
rational design of novel vaccine targets to treat and prevent C. difficile.

## Key facts

- **NIH application ID:** 10792895
- **Project number:** 5U19AI174998-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DREW WEISSMAN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $311,038
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792895

## Citation

> US National Institutes of Health, RePORTER application 10792895, Project 1: Neutralizing and decolonizing Clostridioides difficile using mRNA vaccines (5U19AI174998-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10792895. Licensed CC0.

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