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Previous vaccine strategies against CDI failed to reduce pathogen burden, a prerequisite for preventing\n                    <jats:italic>C. difficile<\/jats:italic>\n                    transmission and recurrence\n                    <jats:sup>6\u201311<\/jats:sup>\n                    . These vaccines were administered parenterally, which induced a systemic immune response, rather than a mucosal response in the colon, the site of infection. Here we compare protection and colonization burden between mucosal (rectal) and parenteral (intraperitoneal) administration routes of a multivalent, adjuvanted vaccine combining inactivated\n                    <jats:italic>C. difficile<\/jats:italic>\n                    toxins and novel surface antigens. We found that mucosal immunization, but not parenteral, clears\n                    <jats:italic>C. difficile<\/jats:italic>\n                    from the host. Unique correlates of decolonization included faecal IgG responses to vegetative surface antigens and a colonic, T helper type 17 (T\n                    <jats:sub>H<\/jats:sub>\n                    17)-skewed tissue-resident memory T cell response against spore antigen. Importantly, mucosal vaccination protected against morbidity, mortality, tissue damage and recurrence. Our results demarcate notable differences in correlates of protection and pathogen clearance between vaccine administration routes and highlight a mucosal immunization regimen that elicits sterilizing immunity against CDI.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10138-x","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T16:02:04Z","timestamp":1771430524000},"page":"1289-1297","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mucosal vaccination clears Clostridioides difficile colonization"],"prefix":"10.1038","volume":"652","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3473-5289","authenticated-orcid":false,"given":"Audrey K.","family":"Thomas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0920-2285","authenticated-orcid":false,"given":"F. Christopher","family":"Peritore-Galve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9164-2923","authenticated-orcid":false,"given":"Alyssa G.","family":"Ehni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno B. C.","family":"Lan\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5890-1894","authenticated-orcid":false,"given":"Jonathan","family":"Coggin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2717-5532","authenticated-orcid":false,"given":"Eric J.","family":"Brady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra M.","family":"Yoder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Shrem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n Cano","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather K.","family":"Kroh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1846-1580","authenticated-orcid":false,"given":"Katherine N.","family":"Gibson-Corley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Kay Washington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyvid","family":"Olivares-Villag\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Buddy","family":"Creech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maribeth R.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5397-1028","authenticated-orcid":false,"given":"Benjamin W.","family":"Spiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2273-8121","authenticated-orcid":false,"given":"D. Borden","family":"Lacy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"10138_CR1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41579-021-00660-2","volume":"20","author":"SL Kordus","year":"2022","unstructured":"Kordus, S. L., Thomas, A. K. & Lacy, D. B. Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics. Nat. Rev. Microbiol. 20, 285\u2013298 (2022).","journal-title":"Nat. Rev. Microbiol."},{"key":"10138_CR2","unstructured":"C. diff (Clostridioides difficile) (CDC, 2022)."},{"key":"10138_CR3","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1056\/NEJMoa1910215","volume":"382","author":"AY Guh","year":"2020","unstructured":"Guh, A. Y. et al. Emerging Infections Program Clostridioides difficile Infection Working Group. Trends in U.S. burden of Clostridioides difficile infection and outcomes. N. Engl. J. Med. 382, 1320\u20131330 (2020).","journal-title":"N. Engl. J. Med."},{"key":"10138_CR4","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/cix1085","volume":"66","author":"LC McDonald","year":"2018","unstructured":"McDonald, L. C. et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 66, e1\u2013e48 (2018).","journal-title":"Clin. Infect. Dis."},{"key":"10138_CR5","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1001\/jamainternmed.2016.9045","volume":"177","author":"VW Stevens","year":"2017","unstructured":"Stevens, V. W. et al. Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection. JAMA Intern. Med. 177, 546\u2013553 (2017).","journal-title":"JAMA Intern. Med."},{"key":"10138_CR6","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00742-17","volume":"86","author":"L Quemeneur","year":"2018","unstructured":"Quemeneur, L. et al. Clostridium difficile toxoid vaccine candidate confers broad protection against a range of prevalent circulating strains in a nonclinical setting. Infect. Immun. 86, e00742-17 (2018).","journal-title":"Infect. Immun."},{"key":"10138_CR7","first-page":"193","volume":"9","author":"A Gribenko","year":"2017","unstructured":"Gribenko, A. et al. Development of a subunit vaccine for prevention of Clostridium difficile associated diseases: biophysical characterization of toxoids A and B. Biochem. Biophys. Rep. 9, 193\u2013202 (2017).","journal-title":"Biochem. Biophys. Rep."},{"key":"10138_CR8","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1099\/mic.0.066712-0","volume":"159","author":"RGK Donald","year":"2013","unstructured":"Donald, R. G. K. et al. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. 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D.B.L. has research collaborations with AstraZeneca and Pfizer that are unrelated to this work\u00a0and serves as a consultant to GSK. B.W.S. is a co-founder and owner at Turkey Creek Biotechnology, which was not involved in this work. C.B.C. receives grant support from Moderna, Pfizer, and Vedanta; serves as a consultant to GSK, Merck, CommenseBio, TDCowen, Guidepoint Global, AstraZeneca and Delbiopharm; and serves on the data and safety monitoring boards for studies sponsored by GSK and Bavarian Nordic\u2014each unrelated to this work. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}