Our analysis of the Vellore cohort included the 373 children (of 452 newborns recruited) who completed all 36 months of follow-up, consistent with primary analyses of the studies; no differences in baseline nutritional and demographic covariates were observed between those who completed or decreased out of follow-up in Vellore [8]. Statistical Analyses Descriptive Analyses Within each cohort we calculated age-specific incidence rates of rotavirus infection, asymptomatic infection, and RVGE, as well as all-cause and rotavirus-negative L-APB diarrhea, by fitting Poisson regression models measuring the incidence rate as a continuous function of age (in months). interval [CI], 12%C41%), 69% (95% CI, 30%C86%), and 64% L-APB (95% CI, C186% to 95%), respectively, in Mexico City, and by 10% (95% CI, C1% to 19%), 51% (95% CI, 41%C59%) and 67% (95% CI, 57%C75%), respectively, in Vellore. Elevated serum immunoglobulin A and immunoglobulin G titers were associated with partial protection against rotavirus contamination. Associations between older age and reduced risk for RVGE or moderate-to-severe RVGE given contamination persisted after controlling for antibody levels. Conclusions Dissimilar estimates of protection against RVGE may be due in part to age-related, antibody-independent risk for rotavirus infections to cause RVGE. Keywords: rotavirus, gastroenteritis, immunity, natural contamination, birth cohort Rotavirus gastroenteritis (RVGE) remains a leading cause of pediatric gastrointestinal disease burden globally [1], with approximately 10 million severe cases and 193000 deaths annually among children <5 years old [2]. Live oral vaccines are being integrated into national immunization plans of developing countries following a decade of use in higher-income settings. Because immunity against rotavirus contamination is imperfect, understanding how naturally acquired and vaccine-derived protection influences rotavirus epidemiology is critical for planning interventions and assessing vaccine impact [3C6]. Birth cohort studies have sought to measure naturally acquired immune protection against rotavirus among young children [7C11]. Under comparable designs, studies have yielded near-identical estimates of naturally acquired protection against rotavirus contamination. However, protection against RVGE, and against moderate-to-severe RVGE in particular, has appeared to differ considerably. In a cohort of Mexican children, 2 infections seemed to confer complete protection KLRB1 against moderate-to-severe RVGE [9], while some children in Vellore, India, experienced severe disease following 3 infections [8]. These apparent differences in protection mirror variation in vaccine performance. Despite delivering >90% protection against moderate-to-severe RVGE in the United States and Europe [12], estimated protection has ranged from 81% in middle-income Latin American countries, including Mexico [13], to 39%C48% in low-income African and Asian settings [14, 15]. Several hypotheses have been proposed to account for differences in the epidemiology of diarrheal pathogens across settings. Nutrition-related immune L-APB deficiencies, host-genetic factors, and physiological damage to the gut from previous infections or chronic conditions may contribute to susceptibility and weak immune protection in low-resource, high-burden settings such as Vellore. Recent multicenter cohort studies have been undertaken to determine how these risk factors relate to diarrhea susceptibility [16C18] and the performance of oral polio and rotavirus vaccines [19]. A question the earlier cohort studies can answer, however, is usually whether age-dependent host responses to rotavirus contamination further confound direct comparison of estimates from studies undertaken in distinct settings. Children exposed to differing levels of rotavirus transmission are expected to acquire primary, secondary, and later infections at distinct ages, when they may experience differential risk for RVGE given contamination [20]. We revisited 2 large-scale birth cohort studies undertaken in Mexico City, Mexico and Vellore, India, to understand why protection against RVGE appeared to differ between the settings despite comparable levels of protection against rotavirus contamination [8, 9]. In side-by-side analyses of the studies, we evaluated serum antibody concentrations and age as determinants of rates at which children acquired rotavirus contamination, and as determinants of risk for rotavirus infections to cause RVGE. METHODS Birth Cohort Studies The studies followed comparable protocols [8, 9] aiming to identify all rotavirus infections among children during follow-up, and to characterize gastrointestinal symptoms associated with each contamination. Children were L-APB enrolled at birth in slum communities and followed to ages 24 and 36 months in.