Large-Scale Saliva-Based Clinical Surveillance Enables Real Time SARS-CoV-2 Outbreak Detection and Genomic Tracking (Arizona, 2020–2023)

<b>Background/Objectives:</b> Monitoring community health and tracking SARS-CoV-2 evolution were critical priorities throughout the COVID-19 pandemic. However, widespread shortages of personal protective equipment, the necessity for social distancing, and the redeployment of healthcare personnel to clinical duties presented significant barriers to traditional sample collection. <b>Methods:</b> In this study, we evaluated the feasibility of using self-collected saliva specimens for the qualitative detection of SARS-CoV-2 infection. Following confirmation of reliable viral detection in saliva, we established a large-scale surveillance program in Arizona, USA, to enable clinical diagnosis and genomic sequencing from self-collected samples. Between April 2020 and December 2023, we tested approximately 1.4 million saliva samples using RT-PCR, identifying 94,330 SARS-CoV-2 infections. Whole genome sequencing was performed on 69,595 samples, yielding 54,040 high-quality consensus genomes. <b>Results:</b> This surveillance approach enabled real-time monitoring of general infection trends that matched regional case counts. We monitored multiple wave-like introductions of viral lineages over the course of the pandemic. We identified three periods of S gene target failure on a commercial assay and assessed its ability to make fast, genotyping assignment during the pandemic (PPV = 0.98, 95% CI = 0.97-0.99; NPV = 0.94, 95% CI = 0.94-0.96). The co-location of clinical testing and sequencing capabilities within the same facility resulted in low turnaround time from the sample collection to the generation of sequencing data (median = 12 days, IQR: 9.0-19.75). <b>Conclusions:</b> Our findings support the use of self-collected saliva as a scalable, cost-effective, and practical strategy for infectious disease surveillance in future pandemics.