The SARS-CoV-2 pandemic has challenged public health systems globally. Several variants of concern have been identified, some of which increase transmissibility, severity of disease, risk for reinfection, and/or variable responses to prior infection or vaccination. In the US—and especially in New Hampshire—the number of SARS-CoV-2 genomes sequenced has been sparse but have been substantially increased by our prior efforts. Furthermore, SARS-CoV-2 sequencing efforts have primarily been directed toward symptomatic individuals and/or contact tracing of special cases. We currently lack knowledge in several areas: (1) the temporal sequence and geolocation of the appearance of SARS-CoV-2 variants in regional communities; (2) the correlation between increases in transmissibility and SARS-CoV-2 variants; (3) differences in the distribution of variants among different racial, ethnic, gender, and age groups as well as in presentation of clinical symptoms; and (4) the extent to which previously infected and/or vaccinated individuals acquire the virus and which variants are reinfecting these individuals. In addition, wastewater surveillance of SARS-CoV-2 is a valuable public health tool but we lack an understanding of the relationship between the SARS-CoV-2 variants in human specimens and the variants detected in wastewater samples from the same geolocation. The primary objective is to continue determining the genomic sequence of a large, representative set of SARS-CoV-2 variants within the state of NH and to apply this knowledge to better understand the likelihood that specific variants increase transmissibility of the virus, evade the immune systems of those previously infected, or increase the likelihood of infected individuals to experience clinical symptoms. Our central hypothesis is that whole genome sequence analysis of SARS-CoV-2 variants will exhibit significant differences in temporal and geolocation prevalence, susceptibility of sub-populations to become infected and develop symptoms, and ability to infect individuals whose immune systems have previously been challenged. We will sequence ~5000 archived and prospectively collected SARS-CoV-2 diagnostic specimens from individuals who test positive from the University of New Hampshire, the NH Department of Health and Human Services, and the COVID-19 surveillance and clinical testing programs at Dartmouth College and Dartmouth- Hitchcock Medical Center. In addition, we will evaluate the ability of genomic surveillance of wastewater samples to serve as a sentinel for SARS-CoV-2 outbreaks in a congregate community where direct correlations can be made between wastewater samples and human specimens from the same geolocation. Understanding the distribution and infectivity of SARS-CoV-2 variants will enable public health agencies to provide more accurate and specific guidance on public health measures that need to be enacted to control COVID-19 based on the types of SARS-CoV-2 variants present in specific populations.