Project Summary The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic that has currently caused over 81 million illnesses and 996,000 deaths in the United States. Variants that show changes in transmissibility (Omicron variants) and symptom severity (Delta variants) have recently emerged. The impact of these variants on immune and non-immune populations remains unknown. Within South Dakota, waves in SARS-CoV-2 infections have occurred since the pandemic began, resulting in significant stress on our healthcare infrastructure, especially in our medically underserved communities. In direct response to the Notice of Special Interest (NOSI): Urgent Competitive Revisions to IDeA and NARCH Programs for SARS-CoV-2 Surveillance Studies, the current supplement proposes expanding our efforts in SARS-CoV-2 surveillance. Specifically, next-generation sequencing will be conducted on both clinical and wastewater samples to increase our surveillance efforts, including in rural and urban areas of South Dakota. To achieve our research goals, a subset of clinical samples collected in South Dakota will be sequenced each month and this will be complemented by wastewater surveillance in these communities. These sequences will be used to determine how the incidence of variants in South Dakota counties relates to the number of cases over time. The goal is to identify SARS-CoV-2 outbreaks and variant shifts in rural and urban communities 2- 3 weeks before surges in hospitalizations. These findings will advance research on the spread and evolution of the SARS-CoV-2 virus in underserved communities throughout the state. Through these efforts, we will provide critical information regarding circulating variants in areas of the underserved Midwest that are expected to see significant increases in tourism in the coming months.