OVERALL ABSTRACT – MATERNAL IMMUNIZATION AND DETERMINANTS OF INFANT IMMUNITY (MADI) Infectious diseases remain the leading cause of death in children under 5 years worldwide. The most affected are newborns and infants within the first year of life. Maternal and infant immunity are interrelated. Immune fitness of the mother is key to sustained health of a child. Vaccination during pregnancy enhances maternal immunity and has a tremendous potential to improve neonatal immunity to pathogens. However, major gaps remain in our understanding of how the immunologically unique setting of pregnancy influences responses to vaccination, the rules of maternal Ab transfer, and the interactions between transferred maternal Ab and the infant immune system. To fill this knowledge gap, we have proposed synergistic and multidisciplinary studies organized in three Aims that will: 1. Distinguish unique features and predictors of vaccine-induced immunity during pregnancy. 2. Define the principles governing maternal antibody transfer. 3. Identify determinants of infant immunity and responses to vaccines. MADI consists of four integrated and synergistic Projects (P) and three Cores (C): P1 will determine the influence of pregnancy on Ab biophysical and functional features and on B/T cell responses to vaccines. P2 will identify Ab-intrinsic factors underlying transfer via placenta and breast milk. P3 will identify features of transferred maternal Ab mediating immunity to pathogens and regulating vaccine responses in infants. P4 will identify cellular and molecular predictors of responses to vaccination in the mother-infant dyad. C1 will provide cutting- edge systems serology and Ab engineering technologies, training, and quality control. C2 will provide centralized management and analysis of data from all projects and will manage data dissemination. The Admin Core will provide management and programmatic support. The MADI team combines complementary expertise, access to unique and well characterized clinical cohorts, and state-of-the-art methods to dissect complex maternal-infant immune interactions. MADI has public health significance and translational value in 1) investigating the immunobiology of maternal immunization at a new breadth and depth; 2) identifying novel actionable targets to improve effectiveness of maternal immunization; 3) informing vaccine design and implementation; and 4) stimulating the field of maternal- infant immunology and vaccinology by generating new analytical tools, mechanistic insights, and rich hypothesis- generating systems immunology datasets. Such knowledge can transform the field of maternal immunization.

OVERALL NARRATIVE – MATERNAL DETERMINANTS OF INFANT IMMUNITY (MADI) Building on the premise that the maternal and infant immune states, from gestation and through the first months of life, are interconnected entities, we propose a research program aimed at transforming our understanding of the determinants of immunity against infectious agents early in life. Through coordinated, synergistic, and multidisciplinary studies, and utilizing advanced technologies and approaches, MADI will generate essential knowledge to inform the development of new and improved interventions to enhance maternal and infant health.