{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:00Z","timestamp":1785431340449,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,9]]},"group-title":"Immunology","reference-count":101,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["19-747-06"],"award-info":[{"award-number":["19-747-06"]}],"id":[{"id":"https:\/\/ror.org\/00ra1fg11","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Merck Sharp & Dohme LLC","award":["103166"],"award-info":[{"award-number":["103166"]}]},{"name":"National Institutes of Health\/National Institute of Allergy","award":["R01AI158830"],"award-info":[{"award-number":["R01AI158830"]}]},{"name":"National Institutes of Health\/National Institute of Allergy","award":["U19AI174998"],"award-info":[{"award-number":["U19AI174998"]}]},{"name":"National Institutes of Health\/National Institute of Aging","award":["AG071815"],"award-info":[{"award-number":["AG071815"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Older adults experience disproportionate morbidity and mortality from\n                  <jats:italic>Clostridioides difficile<\/jats:italic>\n                  infection (CDI); however, existing toxoid- and receptor binding domain (RBD)-based vaccines elicit suboptimal protection in aged hosts due to the age-associated defects in CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell function, T follicular helper (T\n                  <jats:sub>FH<\/jats:sub>\n                  ) cell activation, and antibody quality. We evaluated whether adenosine deaminase (ADA), an enzymatic immune modulator that degrades immunosuppressive adenosine, and improves GC T\n                  <jats:sub>FH<\/jats:sub>\n                  differentiation and survival, could reverse these age-related impairments when co-delivered with DNA vaccine plasmids targeting toxin A and B RBDs (pRBD). In aged mice, pRBD vaccination alone produced markedly reduced toxin-specific effector\/memory CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells, diminished T\n                  <jats:sub>FH<\/jats:sub>\n                  activation, and poor toxin A neutralization compared to vaccinated young mice. Co-immunization with plasmid-encoded adenosine deaminase-1 (pADA) restored toxin-specific CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell generation and cytokine production, activation-induced marker (AIM) T\n                  <jats:sub>FH<\/jats:sub>\n                  responses, and antibody-mediate toxin neutralization to levels comparable to young adults. Mechanistically, pADA co-immunization was associated with the reduction of CXCR4 on germinal center (GC) T\n                  <jats:sub>FH<\/jats:sub>\n                  cells\u2014an age-related defect linked to impaired GC positioning and diminished B cell help\u2014suggesting that ADA improves humoral quality by correcting GC T\n                  <jats:sub>FH<\/jats:sub>\n                  mislocalization. These immune enhancements corresponded with improved clinical outcomes in morbidity, mortality, and weight-loss following\n                  <jats:italic>C. difficile<\/jats:italic>\n                  spore challenge of aged mice. Finally, pADA significantly reduced adenosine levels in aged lymph nodes, implicating a potential enzymatic-based regulation of GC immunosenescence. Together, these findings identify ADA as a metabolic adjuvant capable of reversing key features of vaccine immunosenescence and highlight adenosine dependent CXCR4 regulation as a tractable axis for improving vaccine efficacy in older populations.\n                <\/jats:p>","DOI":"10.64898\/2026.06.04.730208","type":"posted-content","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T19:20:11Z","timestamp":1781032811000},"source":"Crossref","is-referenced-by-count":0,"title":["Adenosine deaminase co-immunization reverses age-associated immunosenescence by restoring germinal center T follicular helper cell function"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6039-8857","authenticated-orcid":false,"given":"Emily N.","family":"Bitsko","sequence":"first","affiliation":[{"name":"Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9913-3432","authenticated-orcid":false,"given":"Arden O.","family":"Edgerton","sequence":"additional","affiliation":[{"name":"Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7246-4021","authenticated-orcid":false,"given":"Matthew R.","family":"Bell","sequence":"additional","affiliation":[{"name":"Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4332-1141","authenticated-orcid":false,"given":"Christian","family":"Sell","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Perelman School of Medicine, Department of Microbiology, Philadelphia, 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