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Background: The COVID-19 pandemic is now dominated by variant lineages; the resulting impact on disease severity remains unclear. Using a retrospective cohort study, we assessed the risk of hospitalization following infection with nine variants of concern or interest (VOC/VOI). Methods: Our study includes individuals with positive SARS-CoV-2 RT PCR in the Washington Disease Reporting System and with available viral genome data, from December 1, 2020 to July 30, 2021. The main analysis was restricted to cases with specimens collected through sentinel surveillance. Using a Cox proportional hazards model with mixed effects, we estimated hazard ratios (HR) for the risk of hospitalization following infection with a VOC/VOI, adjusting for age, sex, and vaccination status. Findings: Of the 23,563 cases, 22,068 (93.7%) were sequenced through sentinel surveillance, of which 582 (2.6%) were hospitalized due to COVID-19. Higher hospitalization risk was found for infections with Gamma (HR 3.23, 95% CI 2.19-4.76), Beta (HR 3.03, 95% CI 1.68-5.47), Delta (HR 2.35, 95% CI 1.7-3.22), and Alpha (HR 1.61, 95% CI 1.28-2.03) compared to infections with an ancestral lineage. Following VOC infection, unvaccinated patients show a similar higher hospitalization risk, while vaccinated patients show no significant difference in risk, both when compared to unvaccinated, ancestral lineage cases. Interpretation: Infection with a VOC results in a higher hospitalization risk, with an active vaccination attenuating that risk. Our findings support promoting hospital preparedness, vaccination, and robust genomic surveillance.

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