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Improving vaccine efficacy in aging: adenosine deaminase reverses age-related immune dysfunction in a Clostridioides difficile vaccination and challenge model
Dissertation

Improving vaccine efficacy in aging: adenosine deaminase reverses age-related immune dysfunction in a Clostridioides difficile vaccination and challenge model

Emily Nicole Bitsko
Doctor of Philosophy (Ph.D.), Drexel University
May 2026
DOI:
https://doi.org/10.17918/00011329
pdf
Bitsko_Emily_202614.60 MB
PDF Embargoed Access, Embargo ends: 30 Apr 2027

Abstract

Adjuvants Immunosenescence Lymphocytes Vaccines
Biological aging drives the progressive accumulation of immune impairments giving rise to heightened disease vulnerability and reduced vaccine efficacy. As the elderly population continues to expand exponentially worldwide, efforts to elucidate and target the underlying causes are imperative. Clostridioides difficile infection (CDI) epitomizes this susceptibility, with elderly individuals representing the largest at-risk population for severe disease. However, creation of a protective, clinically approved vaccine remains elusive. Though substantial evidence defines humoral immunity against the two major virulence factors, toxins A and B, as a substantial correlate of protection, aging-specific investigations for vaccine candidates remain limited. Moreover, the reduced magnitude and function of vaccine- and infection-elicited antibody responses are distinct features of immunosenescence. These features make CDI an attractive model for adjuvant development targeting mechanisms of aging-diminished immunity. Utilizing a previously described next generation DNA vaccine platform to target C. difficile toxin (pRBD), we've incorporated plasmid-encoded murine adenosine deaminase (pADA) as a molecular adjuvant to determine the modulatory impact and mechanisms associated with immunosenescent vaccine response restoration in a murine model. Here, we show pADA reverses aging deficits in toxin-specific CD4 T cell generation and cytokine production, TFH activation, antibody neutralization, and protection against severe infection. These findings coincided with a reduction in CXCR4 expression on germinal center TFH and whole lymph node adenosine levels, suggesting pADA exerts age-specific immunomodulation by regulating adenosine metabolism in the GC microenvironment. Taken together, this work provides further support for the translational potential of ADA as a molecular adjuvant for the elderly, while positioning the adenosine axis as a therapeutically actionable pathway for overcoming age-associated cellular and humoral immunosenescence.

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