Effects of improved water, sanitation, handwashing, and nutrition on early childhood IgG immune repertoire development against Shigella and enteroinvasive Escherichia coli (EIEC).

Abstract

We studied the effects of a combined water, sanitation, handwashing, and nutritional supplementation (WSH + N) intervention on Shigella/EIEC IgG immune development among Bangladeshi children enrolled in a cluster-randomized trial. We used a bacterial display assay to measure IgG-specific binding to Shigella/EIEC Ipa proteins (IpaA, IpaB, IpaC, IpaD, and IpaH) from a substudy of 120 children (60 intervention, 60 control) at median ages 3, 14, and 28 months. We found that the WSH + N intervention did not impact IgG seroprevalence (56% vs 53%, P = 0.6) or IgG epitope repertoire development (P = 0.15-0.97), but there were distinct age-based patterns of IgG linear epitopes and motifs charting the development of the immune repertoire. Samples from before age 6 months, reflecting predominantly maternal IgG, had higher epitope breadth and magnitude compared with samples from older ages. A modeling analysis of maternal-child IgG dynamics suggests that peak susceptibility occurs between 6 and 9 months of age. With this methodology, we found that intensive, household-based WASH interventions were insufficient to impact early childhood immune development to Shigella/EIEC. Our results motivate complementary interventions, such as vaccines, to prevent Shigella/EIEC infection in the first 2 years of life.IMPORTANCEShigella/EIEC is a leading cause of global diarrheal deaths, especially in low-resource settings. Current interventions against childhood Shigella/EIEC infection focus on reducing exposure, such as through improved water, sanitation, handwashing, and nutritional supplementation (WSH + N). It is unclear how these interventions impact childhood immune development against pathogens. In the present study, we characterize the null impact of a WSH + N intervention on IgG immune responses to Shigella/EIEC in a birth cohort and demonstrate the development of immune responses over the first 2 years of life. We found that maternal IgG wanes between 6 and 9 months, and that peak susceptibility to infection is during this time. From our findings, we provide a modeling framework that can be used to inform vaccination schedules in early childhood after 6 months.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01590095.