PROJECT SUMMARY/ABSTRACT – COMPONENT A Influenza and SARS-CoV-2 are major causes of morbidity and mortality and constitute the leading causes of vaccine preventable deaths in the United States. A better understanding of vaccine effectiveness for these viral pathogens is critical to drive public health decisions and interventions. We propose utilizing a multidisciplinary approach to conduct a test-negative study to determine influenza and SARS-CoV-2 vaccine effectiveness in ambulatory patients with respiratory tract infections. The team of investigators includes experts in emergency medicine, infectious disease, pediatrics, epidemiology, information technology, molecular microbiology, virology, and genetics. This team has extensive experience in automated electronic medical record alerts, high-volume subject recruitment of ambulatory patients with respiratory tract infections, rapid escalation/de-escalation of recruitment efforts to match viral circulation patterns, respiratory and blood sample processing and shipment, quality data collection and verification, and viral genomic sequencing necessary to ensure the success of this project. The proposed study will encompass the following specific aims: 1)Utilize innovative automated alerting strategies to identify and recruit a diverse population of ambulatory patients with acute respiratory illnesses; 2) Estimate influenza and SARS-CoV-2 vaccine effectiveness using a test- negative study design in the general population as well as different demographic subgroups.; 3) Explore factors that influence influenza and SARS-CoV-2 vaccine effectiveness such as co-morbidities, vaccination type and schedule, and social determinants of health; 4) Determine effect of viral vaccination status on health outcomes in ambulatory patients with influenza and SARS-CoV-2 infection; 5) Contribute biospecimens and viral genomic sequencing data to a national repository of subjects with PCR-confirmed influenza or SARS-CoV-2 infection. To accomplish these goals, we will enroll at least 1000 ambulatory patients/year with acute respiratory tract infections in the proposed study. The subject population will be identified from the emergency departments of 3 large hospitals in the St. Louis area and their associated outpatient clinics. The available patient population at these enrolling sites is diverse with respect to race, ethnicity, age, socioeconomic status, and medical care access which will enhance the generalizability of the study outcomes to the US population.