Project 2: Leveraging microbial ecology to define novel Clostridioides difficile mRNA vaccine targets

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Principal Investigator: Joseph Paul Zackular
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $380,746
Funding agency: National Institute of Allergy and Infectious Diseases

SUMMARY - PROJECT 2 (ANTIGEN DISCOVERY)
Clostridium difficile is a spore-forming pathogen that causes a wide range of gastrointestinal (GI) disorders
varying in severity from mild diarrhea to fulminant colitis and death. Difficulties in treating infections with
conventional antibiotics and increasing rates of recurrent infection underscore the need for the development of
new therapeutic strategies to combat this urgent public health threat. To date vaccines for C. difficile have not
fully met this need, thus future strategies will require innovative approaches that limit disease and promote
clearance of this pathogen. Our objective is to generate a pipeline to identify novel vaccine antigens on the C.
difficile cell and spore surface and develop these as the next generation of multi-valent mRNA vaccines against
C. difficile. Antigen discovery strategy will incorporate aspects of the C. difficile life cycle, antigen variation on
the cell surface, and microbial ecology. We hypothesize that detailed characterization of C. difficile proteins and
gene systems important for fitness in the infected gut and competition with the resident microbiota will lead to
validation of highly effective new vaccine targets. Our approach will use whole genome sequence (WGS) and
surface proteome analyses on a wide array of hospital and community-associated strains and in-depth
investigation into metabolic correlates during infection. We will combine advanced imaging mass spectrometry
(IMS), mouse models of infection, and genetics to define nutritional requirements for C. difficile during infection
and target these surface exposed proteins for mRNA-LNP vaccination. Together, this work will generate a
translational workflow that leverages microbial ecology for discovery of novel vaccine targets for eradication of
C. difficile.

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