ABSTRACT Sapovirus (SaV), a genus in the Caliciviridae family alongside norovirus, is increasingly recognized as an important cause of acute gastroenteritis (AGE) in childhood. SaV ranked second among all enteric pathogens in its contribution to AGE incidence in children under 24 months of age in a large multi-site birth cohort study and was associated with lower cognitive development scores. While vaccines against rotavirus have lowered the burden of childhood AGE and a pediatric norovirus vaccine will be entering Phase III trials, currently, there are no vaccines against SaV. A major challenge to SaV vaccine development is that there is little known about natural immunity to serve as a guide for vaccine-elicited immunity. For other enteric viruses, such as rotavirus and norovirus, virus-specific IgA Abs in serum, saliva, and feces have been associated with protection against disease or decreased viral load after challenge. While mucosal Abs likely also play an important role in protection against this enteric pathogen, we are unaware of any published studies reporting on humoral immunity to SaV in saliva or stool or IgA responses to SaV in any compartment, likely due to the challenge in obtaining sapovirus antigens. Our ongoing epidemiological studies of SaV show that reinfection with the same genotype is uncommon, suggesting the development of genotype-specific immunity. Heterotypic infections do occur, although they lessen with age. Our interdisciplinary team is uniquely poised to substantially advance the understanding of natural humoral immunity to sapovirus with our platform for field epidemiology research in Nicaragua and state-of-the-art laboratory techniques to elucidate memory B cell repertoires. Building on an NIH- funded birth cohort of 444 children in León, Nicaragua, this project aims to characterize the kinetics of humoral immunity to sapovirus in longitudinal serum, saliva, and stool samples collected from 67 children experiencing a SaV gastroenteritis episode during the first two years of life. In addition, we will correlate these responses in different compartments and compare responses elicited by symptomatic vs. asymptomatic infections and in first vs. subsequent infections. In addition, we will use peripheral blood mononuclear cells collected 28 days after first SaV infections to reveal important immune phenotypes and produce stable populations of memory B cells to clone monoclonal antibodies (mAbs). Using our unique resource of a panel of sapovirus antigens representing the common circulating genotypes, we will investigate the breadth of SaV-specific antibodies produced from natural infections. Together, this unique collaboration allows us to exchange analytic tools to better understand the immunology of sapovirus in children. Specifically, this project will generate new data that are fundamental for the advancement of control and prevention interventions, including pediatric sapovirus vaccines.