Pediatric Immune System Ontogeny and Development (INTEND) (R01 Clinical Trial Not Allowed)

The purpose of this Funding Opportunity Announcement (FOA) is to correlate immune system development patterns between two or more age groups - neonates, infants, and children and adolescents and further understand the impact of infectious diseases, microbiome and environmental factors on the ontogeny and development of the pediatric immune system, from birth, transitioning into adolescence and adulthood with the focus of impact during pregnancy and post-natal period.Purpose The purpose of this Funding Opportunity Announcement (FOA) is to correlate immune system in general and development patterns in particular, between two or more age groups - neonates, infants, and children and adolescents and further understand the impact of infectious diseases, microbiome and environmental factors on the ontogeny and development of the pediatric immune system, from birth, transitioning into adolescence and adulthood with the focus of impact during pregnancy and post-natal period. Background Worldwide, mortality in children under the age of 5 is predominantly due to infectious diseases and immune modulations associated with these infections. Pediatric immune system is remarkably different from adult immune system and also forms the basis for overall wellbeing and providing an adequate disease encountering status to adulthood. A protected and systematically trained pediatric immune system results in a robust and efficient adult immune system. Moreover, immune system in children responds strongly, rapidly and robustly in comparison to adult immune system to immunization, diet and environmental factors. Knowledge of development of the pediatric immune system in response to exposure to childhood infections and vaccinations, microbiome and the environmental factors can help chart pathways that provide strategies to prevent and treat infectious diseases more efficiently. These variations between pediatric and adult immune systems offer insight into better understanding strategies for developing immune-therapeutics and vaccines against infections. The research focus in the current announcement is multi-disciplinary. The focus however is in the areas of immune ontogeny and development, the mechanisms of infant and neonatal immunity or relationship between ontogeny of immunosuppression, susceptibility to infection during infancy or studies on effect of early infections or vaccinations that train the immune system. It is expected to diversify areas in existing research and draw comparisons between age groups or specific organ system development (for example, projects of interest might investigate immune cell ontogeny in lung alveoli from infancy to adult hood or immune alterations due to exposure to a specific immunogen (like measles or BCG vaccine) at infancy vs adolescence and the chronic effect of air pollution). More specifically, the aim here is to elucidate immune system development patterns in infants, children and adolescents focusing on both the innate immunity and the development of diverse antibodies or T cell maturation, with relevance to chronic infections (not limited to HIV, CMV, TB and the current SARS-CoV2 pandemic as well). Further, the intention is to expand the science to include additional internal factors like microbial metabolites and/or external factors like the environment that modulate the developing immune system so that a research program that is multi-disciplinary can be developed to address the interaction between host and pathogen. Research Scope The over-arching scope of this FOA is: to correlate immune system in general and development patterns in particular, between two or more age groups - neonates, infants, and children and adolescents to understand the evolution or immune ontogeny in human immune system development focusing on either or both, innate and adaptive immune systems with additional focus on internal factors like the microbiome and/or external factors like the environment. Further, the scope can be covered under these following topics and is not limited to: Study in young children vs adolescents vs adults, development of immunity and variations in immune system in physiology and in response to infectious diseases focusing on MTCT diseases (HIV, CMV, TB, Syphilis, SARS-CoV2 etc.), not limited to, broadly neutralizing antibodies (bNAbs), development of mucosal antibodies, germinal center formation and maturation; correlate with T cell development and identification of immunogens that activate T cells without enhancing infection. Characterize the impact of age, environmental factors, microbial metabolites and microbiome composition in relation to the immune responses against acute or chronic infectious diseases not limited to HIV, TB, CMV, SARS-CoV2 etc., and their contribution towards the development of a robust immune system development using novel technologies (RNA seq, imaging of immunogens and cellular interactions, single cell imaging). Understand cellular and soluble immune system components and the developmental pathways, including the microbiome, that regulate these components in specific age-groups. For example, developing immune profiles of HIV exposed un-infected (HEU) infants in comparison with the immune profile of an adolescent living with HIV and how these immune alterations prepare the immune system to encounter future infections. Study the contribution of increased exposure to environmental factors, pathogens, extensive or scheduled immunization early in life on enhanced cross-talk between innate and adaptive immune systems; specific inflammatory responses generated by innate immune factors and their downstream effect on cellular immune development. Delineate the role of human microbiome in health and disease and the environmental factors to observe correlation of immune responses against acute and chronic infections and focus on transfer of microbes and immune factors from human milk to infants. For example, assess alterations in immune profiles of known oral microbial clusters in CMV infected child vs immune profiles in an adolescent. Understand the impact of variations of microbiome in specific organ systems (gut vs oral vs vaginal microbiomes) in age defined profiles and their effect on immune ontogeny with emphasis on Virome . Influence of maternal microbiome on the effect of microbial composition and development of immunity in the offspring; detailed studies exploring placental microbiome and correlation with maternal oral microbial microbiome are encouraged. Projects that will be considered non-responsive for this FOA include, but are not limited to: Applications proposing vaccine advocacy. Applications proposing to focus exclusively on effects of microbiome and not studying the relevance of these effects on immune system development. Applications proposing to focus exclusively on epigenomic approaches. Applications focusing on immunization strategies in infants for altering early immune responses.