mRNA COVID-19 Vaccine Effectiveness Against Severe Outcomes Among Adults Hospitalized with COVID-19 from May 2021 to January 2023

<b>Background/Objectives</b>: COVID-19 mRNA vaccines protect against hospitalization, but less is known about real-world vaccine effectiveness (VE) against other severe outcomes. <b>Methods</b>: We enrolled adults hospitalized with acute respiratory illness at two hospitals in Atlanta, Georgia, USA from May 2021 to January 2023. Participants were eligible if they had standard-of-care COVID-19 testing or provided an upper respiratory swab for analysis. Vaccination status was confirmed through the state registry. mRNA COVID-19 VE among those with severe outcomes was determined using a test-negative case-control design with stepwise logistic regression adjusting for confounding variables. <b>Results</b>: Of 1973 participants eligible for analysis, 886 (44.9%) were unvaccinated, 641 (32.5%) received a primary series, and 446 (22.6%) received a primary series plus ≥ 1 booster. A total of 734 (37.2%) were positive for COVID-19. During the pre-Delta/Delta (2 May 2021-19 December 2021) vs. Omicron (20 December 2021-31 January 2023) eras, adjusted COVID-19 mRNA VE of a primary series compared to no vaccination was 85.5% (95% CI: 77.0%, 90.8%) vs. 38.2% (95% CI: 11.5%, 56.8%) overall, 90.0% (95% CI: 82.6%, 94.2%) vs. 54.4% (95% CI: 9.0%, 77.1%) among those with radiographic pneumonia, and 94.4% (95% CI: 80.5%, 98.4%) vs. 62.5% (95% CI: 19.0%, 82.7%) among those admitted to the ICU. VE against severe outcomes was highest within the 6 months following vaccination and during the pre-Delta/Delta era. A booster dose partially restored VE against Omicron-associated hospitalization and pneumonia. <b>Conclusions</b>: COVID-19 mRNA vaccines were effective at preventing hospitalization and other severe outcomes in adults during periods of pre-Delta/Delta and Omicron variant circulation.