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Trop. Dis"],"abstract":"<jats:p>The enterotoxigenic <jats:italic>Escherichia coli<\/jats:italic> (ETEC) are a diverse and genetically plastic pathologic variant (pathovar) of <jats:italic>E. coli<\/jats:italic> defined by their production of heat-labile (LT) and heat-stable (ST) enterotoxins. These pathogens, which came to recognition more than four decades ago in patients presenting with severe cholera-like diarrhea, are now known to cause hundreds of millions of cases of symptomatic infection annually. Children in low-middle income regions of the world lacking access to clean water and basic sanitation are disproportionately affected by ETEC. In addition to acute diarrheal morbidity, these pathogens remain a significant cause of mortality in children under the age of five years and have also been linked repeatedly to sequelae of childhood malnutrition and growth stunting. Vaccines that could prevent ETEC infections therefore remain a high priority. Despite several decades of effort, a licensed vaccine that protects against the breadth of these pathogens remains an aspirational goal, and the underlying genetic plasticity of <jats:italic>E. coli<\/jats:italic> has posed a fundamental challenge to development of a vaccine that can encompass the complete antigenic spectrum of ETEC. Nevertheless, novel strategies that include toxoids, a more complete understanding of ETEC molecular pathogenesis, structural details of target immunogens, and the discovery of more highly conserved antigens essential for virulence should accelerate progress and make a broadly protective vaccine feasible.<\/jats:p>","DOI":"10.3389\/fitd.2021.709907","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T05:15:27Z","timestamp":1631596527000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":43,"title":["Confronting Challenges to Enterotoxigenic Escherichia coli Vaccine Development"],"prefix":"10.3389","volume":"2","author":[{"given":"James M.","family":"Fleckenstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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 1990-2016","volume":"18","author":"Khalil","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00459-07","article-title":"Disease Burden Due to Enterotoxigenic Escherichia Coli in the First 2 Years of Life in an Urban Community in Bangladesh","volume":"75","author":"Qadri","year":"2007","journal-title":"Infect Immun"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60844-2","article-title":"Burden and Aetiology of Diarrhoeal Disease in Infants and Young Children in Developing Countries (The Global Enteric Multicenter Study, GEMS): A Prospective, Case-Control Study","volume":"382","author":"Kotloff","year":"2013","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(19)30456-5","article-title":"Heterogeneity in Enterotoxigenic Escherichia Coli and Shigella Infections in Children Under 5 Years of Age From 11 African Countries: A Subnational Approach Quantifying Risk, Mortality, Morbidity, and Stunting","volume":"8","author":"Bagamian","year":"2020","journal-title":"Lancet Glob Health"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(18)30483-2","article-title":"Burden of Enterotoxigenic Escherichia Coli and Shigella Non-Fatal Diarrhoeal Infections in 79 Low-Income and Lower Middle-Income Countries: A Modelling Analysis","volume":"7","author":"Anderson","year":"2019","journal-title":"Lancet Glob Health"},{"key":"B6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1017\/S0950268899002526","article-title":"Outbreaks of Enterotoxigenic Escherichia Coli Infection in American Adults: A Clinical and Epidemiologic Profile","volume":"123","author":"Dalton","year":"1999","journal-title":"Epidemiol Infect"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e2705","DOI":"10.1371\/journal.pntd.0002705","article-title":"Estimating Diarrheal Illness and Deaths Attributable to Shigellae and Enterotoxigenic Escherichia Coli Among Older Children, Adolescents, and Adults in South Asia and Africa","volume":"8","author":"Lamberti","year":"2014","journal-title":"PloS Negl Trop Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"ofw003","DOI":"10.1093\/ofid\/ofw003","article-title":"Long-Term Sentinel Surveillance for Enterotoxigenic Escherichia Coli and Non-O157 Shiga Toxin-Producing E. 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