measles, pertussis)

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measles, pertussis). diarrheal morbidity and mortality in this age group has been emphasized by estimates from the Global Enteric Multicenter Study (GEMS),3 the Malnutrition and Enteric Disease (MAL-ED) birth cohort study,4 and the Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2016).5 Frequent and repeated episodes of diarrhea in children living in these resource-poor areas have been associated not only with increased mortality but also with severe and lifelong health impairment, which compromises growth and cognitive ability.6,7 Current CFD1 prophylaxis to treat acute diarrheal episodes includes oral rehydration and antibiotics. While improved sanitation and access to clean water are certainly effective primary control measures, vaccination might be a more rapid and efficient preventive intervention. The success of this approach is exemplified by the rotavirus vaccine introduction, which resulted in substantial reduction in diarrhea-related hospital visits, admissions8-10 and death9,11-13 in children less than 5 years of age globally. has also been associated with diarrhea across all adult age groups, with increased incidence in the elderly.5 and Enterotoxigenic (ETEC) are the main causes of diarrhea in travelers and military personnel. The development and clinical advancement of a vaccine are seen 3-Methylcytidine as an equitable, cost-effective prevention tool that could be deployed with existing vaccination programs for effective disease control.14 Naturally acquired immunity against shigellosis and the relevance of antibodies It is known from observational epidemiological and human challenge studies that subjects repeatedly infected with acquire a natural immunity that prevents or reduces illness following subsequent infection.15-17 In endemic regions, disease incidence diminishes in older children and adults, and pathogen-specific host defenses, lacking in early infancy, progressively increase with age.17-19 This naturally acquired protective immunity tends to be serotype-specific and directed to the O-polysaccharide (OPS).15,16 Early studies involving Israeli soldiers reported associations between LPS-specific serum IgG and reduced illness during outbreaks.15,16,20 On the basis of this premise, OPS is the main antigen targeted by current vaccine approaches. Serum antibodies against plasmid-encoded antigens have been detected in individuals living in are used as indicators of robust mucosal immunity.25,26 Vaccine-induced immunity and the relevance of antibodies There is no approved vaccine to prevent shigellosis. A variety of vaccine concepts have been proposed and tested mainly for safety and immunogenicity in clinical studies (Reviewed in ref.27). Modeling natural infection, oral vaccines are among the leading candidates tested in human clinical trials during the past decade. These include the whole cell inactivated 2a Sf2aWC,28 and the live attenuated 2a CVD 1208S,29 2a SC602,30 and WRSs2 and WRSs3.31 Orally delivered whole cell organisms generally elicit high levels of LPS-specific serum IgG and 3-Methylcytidine IgA as well as fecal IgA, and are potent inducers of LPS-specific IgA ASC. OPS-protein conjugate vaccines have gained interest and support in recent years due to the record of safety and ability to elicit potent systemic immunity. The concept of a conjugate vaccine was pioneered by John Robbins and colleagues at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in the early 1990s. A candidate vaccine produced by this group consisting of OPS from covalently bound to recombinant exoprotein A of (rEPA) had an efficacy of about 70% in young adults 3-Methylcytidine in the Israeli military32 and in 3C4-year-old children in a Phase 3 clinical trial.33 Protection was associated with the presence of high levels of serum IgG against the O-antigen. Unfortunately, the vaccine had no effect in 1C2-year olds, who would be primary targets for immunization. It remains unclear whether the protection seen in adults and in older children derived solely from vaccination or from boosting of pre-existing immunity acquired through natural exposure. A newer conjugate, Flexyn2a, was engineered based on the 3-Methylcytidine same principle, except this time using an elegant and simpler bioconjugation of the 2a OPS to rEPA. Flexyn2a elicited strong serum antibody and ALS responses in young adult volunteers, and up to 50% protection against severe shigellosis in an experimental human challenge.34,35 Another glycoconjugate vaccine candidate, SF2a-TT15, featuring repeating units of synthetic O-antigen from 2a conjugated to tetanus toxoid, has been shown to be safe and strongly immunogenic in a Phase 1 study.36 An immunogenicity and efficacy study of SF2a-TT15 is ongoing at the University of Maryland in collaboration with Institut Pasteur, University of Tel Aviv, and The Walter Reed Army Institute of Research (WRAIR). vaccine candidates that leverage the potential to offer broad protection have also advanced into clinical evaluation. One.