# Development of a mucosal vaccine to prevent Clostridium difficile infection using papilloma pseudovirus as a vector.

> **NIH NIH R56** · LOYOLA UNIVERSITY CHICAGO · 2020 · $502,325

## Abstract

Abstract
Clostridium difficile is a major cause of diarrhea in health care settings, with one-half million cases of infection,
annually. Clostridium difficile infection and disease (CDI) usually occurs after antibiotic treatment, which
eliminates much of the intestinal commensal microbiota and provides C. difficile the opportunity to colonize
the gut. If the colonizing C. difficile produces toxins, many patients develop CDI and suffer from symptoms
ranging from diarrhea to life-threatening pseudomembranous colitis. The incidence of CDI is on the rise, in
large part because of increased use of antibiotics. Further, CDI recurs in ~20% of treated patients, making this
a serious and expensive disease, for which there is no cure and no effective approved vaccine. The goal of this
proposal is to develop a protective vaccine to prevent CDI and also, its transmission in the health care
environment. While a few C. difficile vaccines are in Phase II/III clinical trials, they target the toxins, but will
not prevent colonization of C. difficile in the intestinal mucosa, nor its transmission. We think that the optimal
protective vaccine would be one that generates a strong mucosal IgA antibody response against toxins, and also
one that prevents colonization of C. difficile. Papillomaviruses are small DNA viruses in which the major
capsid protein, L1, assembles with the minor capsid protein, L2 into virus-like particles (VLP). These VLPs
infect mucosal surfaces, are not infectious but are strongly immunogenic, making them ideal vectors for
mucosal vaccines. We have developed papilloma pseudoviruses (PsV) from capsid proteins L1 and L2, that
contain plasmids expressing the receptor binding domain (RBD) of the C. difficile toxins A and B, and we have
preliminary data showing that these vaccines can induce neutralizing mucosal IgA and protect mice from
challenge by C. difficile. In Aim 1, we will develop PsV expressing RBD of toxins A, B (from different strains)
and binary toxin. We will immunize them in mice and hamsters. We will identify an adjuvant that will increase
the mucosal Ab response and generate long-term immunologic memory in mice and hamsters, the gold
standard for CDI animal models. In Aim 2, we will generate PsV expressing surface molecules FliD or high
molecular weight SLP, molecules that will affect colonization, and determine if these vaccines can induce
antibodies that inhibit colonization of C. difficile. In Aim 3, we will vaccinate mice and hamsters with a
mixture of all the PsV and challenge with toxogenic C. difficile spores from different strains to determine if CDI
and colonization of C. difficile are prevented. If successful, the mucosal vaccine will generate a robust
neutralizing mucosal IgA response against both toxins and the surface antigens FliD and SLP. Such a vaccine
would make a major contribution to improving the health care of thousands of patients in health care settings,
and save billions of dollars in health care costs.

## Key facts

- **NIH application ID:** 10213890
- **Project number:** 1R56AI151138-01
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Katherine L. Knight
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,325
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213890

## Citation

> US National Institutes of Health, RePORTER application 10213890, Development of a mucosal vaccine to prevent Clostridium difficile infection using papilloma pseudovirus as a vector. (1R56AI151138-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213890. Licensed CC0.

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