ABSTRACT Following the global roll-out of rotavirus vaccines, attention is now focusing on vaccination strategies against norovirus, the next leading cause of viral gastroenteritis. Several norovirus vaccine candidates are in the pipeline, including an oral GI.1/GII.4 vaccine that will soon be tested in lactating women. The main goal of this vaccination strategy is to elicit norovirus-specific antibodies in breastmilk. However, very little is currently known about norovirus immunity in breastmilk. Epidemiologic studies do not consistently find breastfeeding to protect against norovirus. Also, no prior studies have fully characterized norovirus-specific antibodies in lactating women with natural norovirus infections to understand what might be attainable with postpartum vaccines. A better understanding of maternal immunity and how it protects infants against norovirus infections could guide novel postpartum vaccination strategies. In addition, pediatric vaccines are being developed. A parenteral GI.1/GII.4 norovirus vaccine is undergoing testing in children after encouraging Phase IIb results in adults. However, vaccine-elicited immunity in naïve infants may differ from that in adults, who have experienced multiple prior infections. For example, our group demonstrated that the dominant response to the parenteral GI.1/GII.4 vaccine in adults was boosting from a previous GII.4 infection. Further, we have demonstrated that natural norovirus infections in young children elicit a narrow antibody response—typically to the infecting genotype only— suggesting that an effective pediatric vaccine would need to include multiple norovirus genotypes. These differences in the immune response in adults vs. children suggest that understanding the unique immune stage of the infant is necessary to develop an effective pediatric vaccine. This project connects a robust field site with state-of-the-art immunological approaches to inform norovirus vaccination strategies to benefit children. We will enroll 120 Guatemalan breastfed infants with acute norovirus gastroenteritis and their mothers to determine if there is an association between norovirus-specific antibodies in breastmilk and the duration of norovirus infections in infants. Next, we will characterize and compare humoral immunity to norovirus in infants and mothers infected with the same norovirus strain. Finally, we will characterize the kinetics and breadth of norovirus-specific antibodies in breastmilk in lactating women with norovirus infections. We hypothesize that a) infants receiving breastmilk with higher levels of genotype-specific norovirus antibodies will have shorter norovirus infections as compared to infants receiving lower levels of these antibodies, b) infants will mount narrow antibody responses to norovirus as compared to (previously exposed) adults, and c) in lactating women with norovirus infections, norovirus-specific antibody responses in breastmilk will be broad and short-lived, similar ...