# Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines

> **NIH NIH U19** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $1,570,047

## Abstract

OVERALL PROJECT SUMMARY
Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines VANDy-CdV
Clostridioides difficile is a spore-forming anaerobic bacterium that is the leading cause of hospital-
acquired gastrointestinal infection in the United States. The rising incidence of community-
acquired C. difficile infection (CDI) in otherwise healthy adults is linked to increased antibiotic use
and the emergence of new strains. CDI symptoms and pathology are mediated by two large
homologous toxins, TcdA and TcdB, and therefore the toxins represent attractive targets for
prevention and therapeutic strategies. While efforts centered around the use of toxoids for
immunization have shown promise in reducing the severity of symptoms, the toxoid approach has
not resulted in a decreased incidence of CDI in clinical trials. There are several opportunities to
improve upon existing vaccine strategies. First, large scale genomic studies show that TcdB is
undergoing rapid evolutionary change; the identification of conserved toxin epitopes can be used
to direct the immune response toward the production of broadly neutralizing responses. Second,
the identification of conserved antigens on the surface of the vegetative bacteria or spores that
can serve as immunogens will allow the host to elicit mucosal immune responses that prevent
bacterial colonization. The inclusion of mucosal immunization routes is expected to further
enhance vaccine efficacy and durability. The overarching goal of the VANDy-CdV program is to
identify toxin subunits and novel cell surface antigens that, when combined, promote durable
protection against C. difficile infection and symptoms. Among many innovative strengths, the
approach includes the use of human CDI patient samples as a resource for understanding what
antigens promote IgG, IgA, and sIgA responses in natural infection. The approach also includes
the use of powerful single B cell sorting and sequencing methods. The ability to identify paired
heavy and light chain sequences from individual memory B cells binding toxins and/or bacteria
allows for the production of unique antibodies that can then be used as tools for epitope mapping
and novel antigen discovery. A third highlight of the approach involves the use of a newly created
C. difficile transposon library which will be used to identify novel antigens in an in vivo
vaccination/challenge experiment. Other innovations include a structure-guided approach to
identifying potent, neutralizing epitopes and a systematic evaluation of how intestinal lymphocyte
responses vary with routes of immunization. Vaccine efficacy and the mucosal correlates of
protection will be evaluated in pre-clinical models of colonization, infection, and recurrence. At the
end of five years, we expect to have the pre-clinical data needed to advance a novel antigen
cocktail and immunization strategy forward into human safety and efficacy trials.

## Key facts

- **NIH application ID:** 10800713
- **Project number:** 5U19AI174999-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Dana Borden Lacy
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,570,047
- **Award type:** 5
- **Project period:** 2023-03-03 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800713

## Citation

> US National Institutes of Health, RePORTER application 10800713, Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines (5U19AI174999-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10800713. Licensed CC0.

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