{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:02:30Z","timestamp":1788566550103,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Military Infectious Disease Research Program","award":["OPP1112376"],"award-info":[{"award-number":["OPP1112376"]}]},{"name":"Bill &amp; Melinda Gates Foundation","award":["OPP1112376"],"award-info":[{"award-number":["OPP1112376"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Introduction: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA\/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT. Methods: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 \u00b5g) or Chimera (2.6 and 12.9 \u00b5g) with and without 0.1 \u00b5g of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses. Results. The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 \u00b5g of dscCfaE with 0.1 mcg of LT(R192G). Conclusion: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.<\/jats:p>","DOI":"10.3390\/microorganisms11112689","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T09:16:21Z","timestamp":1698916581000},"page":"2689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic Escherichia coli CFA\/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G)"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-1370","authenticated-orcid":false,"given":"Ramiro L.","family":"Guti\u00e9rrez","sequence":"first","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Riddle","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7258-1690","authenticated-orcid":false,"given":"Chad K.","family":"Porter","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"},{"name":"Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Milton","family":"Maciel","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"},{"name":"Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T.","family":"Poole","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee M.","family":"Laird","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Lane","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George W.","family":"Turiansky","sequence":"additional","affiliation":[{"name":"Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abel","family":"Jarell","sequence":"additional","affiliation":[{"name":"Walter Reed National Military Medical Center, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Savarino","sequence":"additional","affiliation":[{"name":"Naval Medical Research Command, Silver Spring, MD 20910, USA"},{"name":"Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/S1473-3099(18)30475-4","article-title":"Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: The Global Burden of Disease Study 1990\u20132016","volume":"18","author":"Khalil","year":"2018","journal-title":"Lancet Infect. 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