Mucosal vaccination clears Clostridioides difficile colonization.
| Title: | Mucosal vaccination clears Clostridioides difficile colonization. |
|---|---|
| Authors: | Thomas AK; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Peritore-Galve FC; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Ehni AG; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Lança BBC; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Coggin J; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Brady EJ; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.; Yoder SM; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.; Shrem R; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Rodríguez RC; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Kroh HK; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Gibson-Corley KN; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Kay Washington M; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Olivares-Villagómez D; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.; Creech CB; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.; Nicholson MR; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.; Spiller BW; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Lacy DB; Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. borden.lacy@vanderbilt.edu.; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA. borden.lacy@vanderbilt.edu.; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA. borden.lacy@vanderbilt.edu. |
| Source: | Nature [Nature] 2026 Apr; Vol. 652 (8112), pp. 1289-1297. Date of Electronic Publication: 2026 Feb 18. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basingstoke : Nature Publishing Group; Original Publication: London, Macmillan Journals ltd. |
| MeSH Terms: | Clostridioides difficile*/immunology ; Clostridioides difficile*/growth & development ; Clostridioides difficile*/pathogenicity ; Clostridium Infections*/prevention & control ; Clostridium Infections*/immunology ; Clostridium Infections*/microbiology ; Clostridium Infections*/pathology ; Bacterial Vaccines*/immunology ; Bacterial Vaccines*/administration & dosage ; Immunity, Mucosal*/immunology ; Vaccination*; Th17 Cells/immunology ; Th17 Cells/cytology ; Spores, Bacterial/immunology ; Immunoglobulin G/immunology ; Colon/microbiology ; Colon/immunology ; Feces/microbiology ; Memory T Cells/immunology ; Immunologic Memory/immunology ; Antigens, Bacterial/immunology ; Animals ; Mice ; Female ; Mice, Inbred C57BL ; Male |
| Abstract: | Clostridioides difficile infection (CDI) is the leading cause of healthcare- and antibiotic-associated infection and has a 30% recurrence rate1-5. Previous vaccine strategies against CDI failed to reduce pathogen burden, a prerequisite for preventing C. difficile transmission and recurrence6-11. 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 C. difficile toxins and novel surface antigens. We found that mucosal immunization, but not parenteral, clears C. difficile from the host. Unique correlates of decolonization included faecal IgG responses to vegetative surface antigens and a colonic, T helper type 17 (TH17)-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.; (© 2026. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.) |
| Competing Interests: | Competing interests: A.K.T. and D.B.L. are listed as inventors on a patent application filed by Vanderbilt University Medical Center containing data published in this manuscript and covering multiple C. difficile vaccines and immunogens (US patent application 18/671,007). D.B.L. has research collaborations with AstraZeneca and Pfizer that are unrelated to this work and 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—each unrelated to this work. The other authors declare no competing interests. |
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(PMID: 24675735431213810.1038/nprot.2014.064) |
| Substance Nomenclature: | 0 (Bacterial Vaccines); 0 (Immunoglobulin G); 0 (Antigens, Bacterial) |
| Entry Date(s): | Date Created: 20260218 Date Completed: 20260429 Latest Revision: 20260504 |
| Update Code: | 20260504 |
| PubMed Central ID: | PMC13128438 |
| DOI: | 10.1038/s41586-026-10138-x |
| PMID: | 41708852 |
| Database: | MEDLINE |
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