Write a PREreview

Understanding respiratory virus transmission requires integrating pathogen genomic data with detailed epidemiological context. We analyzed >85,000 SARS-CoV-2 genomes linked to epidemiological data collected in Massachusetts from November 2021 to January 2023. Collected in 666 settings, including schools, colleges, and skilled nursing facilities, this dataset enabled direct comparison of within-setting transmission to community-wide risk. Elevated transmission was concentrated in specific age-defined subpopulations, older adolescents in schools, undergraduates in colleges, and residents in nursing facilities, with little additional risk among other groups, notably including staff. Young adults, particularly in colleges, played a disproportionate role in spread, and new viral lineages consistently expanded first within this group. Viral spread followed reproducible urban-to-rural gradients, and vaccination was associated with reduced onward transmission. We further estimated sequencing thresholds required for timely detection of emerging variants. Together, these findings reveal consistent demographic and spatial structure in SARS-CoV-2 transmission that can inform future viral respiratory pathogen genomic surveillance.