PROJECT SUMMARY - Mandatory Component A Acute respiratory illness (ARI) and acute gastroenteritis (AGE) are the leading causes of death worldwide in young children. Established leading viral etiologies of AGE are rotavirus and norovirus and respiratory syncytial virus (RSV) and influenza virus for ARI. Our understanding of ARI and AGE epidemiology is constantly changing due to spatiotemporal fluctuations, discovery of new or re-emerging pathogens [e.g. enterovirus D68 (EV-D68) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], and use of rotavirus and influenza vaccines. Hence, surveillance efforts are imperative to define ARI and AGE disease burden, causative pathogens, outcomes, and vaccine impact. The primary influenza prevention strategy in the United States is vaccination for all individuals six months or older. There is a paucity of data regarding vaccine effectiveness (VE) against laboratory-confirmed influenza in children, and influenza viruses and vaccine antigenic components change annually. Therefore, perpetual assessments of VE are needed to monitor the impact of influenza vaccination on disease and inform strategies to improve magnitude, durability, and breadth of protection. Pediatric SARS-CoV-2 vaccines are an urgent public-health priority and likely will become available on an accelerated timeline in an effort to curb the COVID-19 pandemic. Rigorous, prospective surveillance of SARS-CoV-2 VE is crucial to support reliance on vaccines as primary prevention. Thus, the first main objective of this project is to conduct population-based active surveillance for respiratory and enteric viral pathogens in pediatric inpatient and emergency department settings and asymptomatic controls. Our team of Vanderbilt investigators is highly experienced in conducting prospective, population- based ARI and AGE surveillance. We propose to conduct ARI and AGE surveillance with the following specific aims: 1) To perform prospective, active surveillance to determine the etiology and burden of inpatient and emergency department (ED) acute viral respiratory and enteric diseases among the pediatric population. 2) To characterize the clinical and epidemiologic factors of pediatric infections (including in asymptomatic children) through active surveillance. 3) To evaluate vaccine effectiveness and impact of vaccines and other interventions (e.g., immunoprophylaxis with antiviral agents or other therapeutics) available or projected to become available during the period of performance. The second main objective of this project is to conduct surveillance and epidemiologic characterization of acute flaccid myelitis syndrome in children. Given the epidemiologic connection between EV-D68 infection and acute flaccid myelitis (AFM), it will be important to conduct rigorous, active, longitudinal surveillance for AFM across multiple consecutive seasons; carefully define AFM clinical spectrum, risk factors, incidence rates, and laboratory parameters; an...