Project Summary The overall objective of this project is to continue and expand surveillance efforts to detect and monitor extant and emerging variants by sequencing the positive samples detected by the extensive university surveillance and community testing programs at Clemson University (CU). Variants of concern of SARS-CoV-2 have caused large outbreak events worldwide. As we tracked during the significant Delta and Omicron outbreaks in Upstate South Carolina, this poses a serious public health threat; the new variants can escape the coverage of COVID-19 vaccines or infect previously exposed individuals. Our sequencing surveillance program aims to continue to provide much-needed insight and guidance to inform policy decisions to help mitigate these potential threats. In response to the COVID-19 pandemic, CU established a robust high-throughput COVID-19 diagnostic testing program, which enabled the university to remain opened to in-person instruction through most of the pandemic. The CLIA-certified Clemson Research and Education in Disease Diagnosis and Intervention (REDDI) Lab has facilitated regular testing of all university personnel and free testing to members of the surrounding Upstate South Carolina community. The lab has run >10% of all the COVID-19 tests from South Carolina. In 2021, the REDDI Lab partnered with the CU Genomics and Bioinformatic Facility (CUGBF) to set up a SARS-CoV-2 genomics sequencing program, which mapped 3 major outbreak events and provided early detection of the Delta and Omicron variants in the rural Upstate South Carolina region. These data were instrumental to inform the pre- emptive COVID-19 policies and timely response for the university as well as Upstate SC cities and municipalities. In addition, the sequencing surveillance program allowed for significant scientific discovery on variant specific disease presentation, variant differences in effectiveness of vaccine and prior infection protection, surveillance testing and COVID-19 mitigation strategies, and wastewater community surveillance efforts. The results from the sequencing program also led to the development of new assays and technologies for COVID-19 diagnosis and surveillance as well as undergraduate and graduate student training and community outreach programs. To accomplish our overall goals of continued SARS-CoV-2 genomic surveillance, we propose the following aims: Aim 1: Determine the association of SARS-CoV-2 genomic variants with population demographics, outbreak events, COVID-19 symptom severity and duration, previous infection, and vaccination. Aim 2: Develop real-time workflows and data analytics platforms to meet the challenge of variant surveillance through the on-going COVID-19 situation for its inevitable transition from pandemic to endemic phase. Over the last year, we have created a unique and robust sequencing program that not only sequences samples but also ties the results to a rich university and community COVID-19 surveillance da...