SUMMARY The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 233 million people globally. The US alone has reported ~126,000 coronavirus disease-19 (COVID-19) cases in pregnant individuals, not including many asymptomatic and unconfirmed cases. Thus, potentially millions of children worldwide may be impacted by the sequelae of prenatal SARS-CoV-2 exposure. Animal research has shown that various maternal viral infections during pregnancy are associated with impaired neurodevelopment in offspring. In line with these findings, epidemiological studies suggest that prenatal exposure to infections is linked to neurodevelopmental deviations, and an elevated risk for ASD. There is an urgent need for prospective, well-characterized birth cohorts to study the link between prenatal exposure to SARS-CoV-2 infection and risk for adverse child development, particularly in light of a global health crisis with potentially lifelong consequences for the child. Moreover, pregnant women are now being vaccinated against COVID-19 on a large scale. Vaccines elicit a brief immune response, ranging from mild to severe, with fever and increased cytokine levels. While studies have shown that these vaccines are safe during pregnancy, the long- term effects on the child's developing brain are unknown. This study aims to investigate the association of prenatal exposure to SARS-CoV-2 infection and COVID-19 vaccination with behavior, cognition, and brain functioning in the child at 3 years of age. We hypothesize that SARS-CoV-2 infection negatively impact child outcomes, mediated by changes to the fetal immune system. We further hypothesize that COVID-19 vaccines are safe, with little to no long-term effects on the child. We will leverage our on-going prospective pregnancy cohort `Generation C', which we established at The Mount Sinai Health System in New York City (NYC) in the early weeks of the pandemic (> 2,800 women enrolled). The cohort is racially/ethnically and socio-economically diverse. We obtained the following: 1) maternal blood samples during pregnancy, and at delivery; 2) maternal SARS-CoV-2 antibody titers for each blood draw; 3) demographic and clinical data; and 4) neonatal dried blood spots (DBS). In the proposed project, we will (i) follow-up SARS-CoV-2 exposed, vaccine-exposed and non-infected and non-vaccinated mother-child dyads 3 years after birth, combining (ii) existing information on maternal SARS-CoV-2 infection and COVID-19 vaccination status during pregnancy, with (iii) newly collected data on SARS-CoV-2 antibody and cytokine levels in neonatal DBS; (iv) childhood neurodevelopment including behavior, cognition, and motor development, and (iv) brain functioning using electroencephalogram (EEG).