Dissertation
Identifying immune correlates of protection against Clostridioides difficile infection and the development of an optimized C. difficile toxin DNA vaccine for the elderly
Doctor of Philosophy (Ph.D.), Drexel University
May 2023
DOI:
https://doi.org/10.17918/00001855
Abstract
Clostridioides difficile is the causative agent of C. difficile infection (CDI) which is an enteric infection that leads to severe diarrhea and intestinal inflammation and is the leading healthcare-associated infection in the United States. Due to the high burden of CDI cases and lack of an FDA-approved vaccine, there is immense interest in uncovering the immune correlates of protection against CDI. Previous research has focused on the immune response to the two major pathogenic factors of C. difficile, toxins A and B. Although this research has shown that high serum antitoxin antibody titers are associated with protection from both symptomatic CDI and recurrent CDI (rCDI), there is limited data on the toxin-neutralizing abilities of these serum titers as well as a lack of understanding on the role of cellular and intestinal antitoxin antibody responses in protecting from symptomatic CDI. By recruiting hospitalized patients who were newly diagnosed with CDI, asymptomatic C. difficile carriers, or non-carriers of C. difficile, we show that, while serum and stool antitoxin titers are significantly elevated in asymptomatic carriers compared to CDI cases, the ability of serum antitoxin titers to neutralize toxins A and B does not differ between asymptomatic carriers and CDI cases. Additionally, while serum antitoxin responses in rCDI cases were significantly lower compared to single-episode CDI cases, toxin neutralization was not significantly altered in rCDI cases. Our data also show that asymptomatic carriers of C. difficile present an altered inflammatory phenotype that suggests an important role in the cellular response in protection from symptomatic CDI. Finally, as CDI is an infection that disproportionately impacts the elderly, studies seeking to improve the vaccination response in an aged murine model for CDI show the ability of a novel adjuvant, ADA-1, to improve the humoral and cellular immune responses to a toxin-based DNA vaccine. Taken together, our studies provide evidence that toxin-neutralizing antibody responses do not correlate with protection from symptomatic CDI, demonstrate the potential importance of the cellular immune response in protection against CDI, and show the ability to develop a novel adjuvanted DNA-based vaccine with enhanced immune responses in the context of advanced age.
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Details
- Title
- Identifying immune correlates of protection against Clostridioides difficile infection and the development of an optimized C. difficile toxin DNA vaccine for the elderly
- Creators
- Matthew Ryan Bell
- Contributors
- Michele Kutzler (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 317 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991020668710804721