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      A bivalent vaccine confers immunogenicity and protection against Shigella flexneri and enterotoxigenic Escherichia coli infections in mice

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          Abstract

          Vaccine studies for Shigella flexneri and enterotoxigenic Escherichia coli have been impaired by the lack of optimal animal models. We used two murine models to show that a S. flexneri 2a bivalent vaccine (CVD 1208S-122) expressing enterotoxigenic Escherichia coli colonization factor antigen-I (CFA/I) and the binding subunits A2 and B of heat labile-enterotoxin (LTb) is immunogenic and protects against weight loss and diarrhea. These findings document the immunogenicity and pre-clinical efficacy effects of CVD 1208S-122 vaccine and suggest that further work can help elucidate relevant immune responses and ultimately its clinical efficacy in humans.

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          Most cited references 22

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          Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study.

          Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS).
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            Enterotoxigenic Escherichia coli EtpA mediates adhesion between flagella and host cells

            Adhesion to epithelial cells1 and flagella-mediated motility are critical virulence traits for many Gram-negative pathogens, including enterotoxigenic Escherichia coli (ETEC)2, a major cause of diarrhoea in travellers and children in developing countries3,4. Many flagellated pathogens export putative adhesins belonging to the two-partner secretion (TPS) family5. However, the actual function of these adhesins remains largely undefined. Here we demonstrate that EtpA, a TPS exoprotein adhesin of enterotoxigenic Escherichia coli 6, mimics and interacts with highly conserved regions of flagellin, the major subunit of flagella, and that these interactions are critical for adherence and intestinal colonization. Although conserved regions of flagellin are mostly buried in the flagellar shaft7, our results suggest that they are at least transiently exposed at the tips of flagella where they capture EtpA adhesin molecules for presentation to eukaryotic receptors. Similarity of EtpA to molecules encoded by other motile pathogens suggests a potential common paradigm for bacterial adhesion, while participation of conserved regions of flagellin in adherence has implications for development of vaccines for Gram-negative pathogens.
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              Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990–2016

              Summary Background Shigella and enterotoxigenic Escherichia coli (ETEC) are bacterial pathogens that are frequently associated with diarrhoeal disease, and are a significant cause of mortality and morbidity worldwide. The Global Burden of Diseases, Injuries, and Risk Factors study 2016 (GBD 2016) is a systematic, scientific effort to quantify the morbidity and mortality due to over 300 causes of death and disability. We aimed to analyse the global burden of shigella and ETEC diarrhoea according to age, sex, geography, and year from 1990 to 2016. Methods We modelled shigella and ETEC-related mortality using a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We used a compartmental meta-regression tool to model the incidence of shigella and ETEC, which enforces an association between incidence, prevalence, and remission on the basis of scientific literature, population representative surveys, and health-care data. We calculated 95% uncertainty intervals (UIs) for the point estimates. Findings Shigella was the second leading cause of diarrhoeal mortality in 2016 among all ages, accounting for 212 438 deaths (95% UI 136 979–326 913) and about 13·2% (9·2–17·4) of all diarrhoea deaths. Shigella was responsible for 63 713 deaths (41 191–93 611) among children younger than 5 years and was frequently associated with diarrhoea across all adult age groups, increasing in elderly people, with broad geographical distribution. ETEC was the eighth leading cause of diarrhoea mortality in 2016 among all age groups, accounting for 51 186 deaths (26 757–83 064) and about 3·2% (1·8–4·7) of diarrhoea deaths. ETEC was responsible for about 4·2% (2·2–6·8) of diarrhoea deaths in children younger than 5 years. Interpretation The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden. Funding Bill & Melinda Gates Foundation.
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                Author and article information

                Contributors
                phquintela@hotmail.com
                Journal
                NPJ Vaccines
                NPJ Vaccines
                NPJ Vaccines
                Nature Publishing Group UK (London )
                2059-0105
                27 March 2020
                27 March 2020
                2020
                : 5
                Affiliations
                [1 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Center for Global Health and Division of Infectious Diseases and International Health, , University of Virginia, ; Charlottesville, VA USA
                [2 ]ISNI 0000 0001 2160 0329, GRID grid.8395.7, Institute of Biomedicine, , Federal University of Ceará, ; Fortaleza, CE Brazil
                [3 ]ISNI 0000 0004 0610 3705, GRID grid.412964.c, Department of Microbiology, , University of Venda, ; Thohoyandou, Limpopo province South Africa
                [4 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Center for Vaccine Development and Global Health, , University of Maryland, ; Baltimore, MD USA
                Article
                180
                10.1038/s41541-020-0180-y
                7101394
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100006492, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID);
                Award ID: U19 AI109776
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000865, Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation);
                Award ID: OPP1137923
                Award ID: OPP1137923
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: U19 AI109776
                Award Recipient :
                Funded by: Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)
                Categories
                Brief Communication
                Custom metadata
                © The Author(s) 2020

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