It is important to understand real-world BNT162b2 COVID-19 vaccine effectiveness (VE), especially among racial and ethnic minority groups. We performed a test-negative case-control study to measure BNT162b2 COVID-19 VE in the prevention of COVID-19-associated acute respiratory illness (ARI) hospitalizations at two Atlanta hospitals from May 2021–January 2023 and adjusted for potential confounders by multivariate analysis. Among 5139 eligible adults with ARI, 2763 (53.8%) were enrolled, and 1571 (64.5%) were included in the BNT162b2 analysis. The median age was 58 years (IQR, 44–68), 889 (56.6%) were female, 1034 (65.8%) were African American, 359 (22.9%) were White, 56 (3.6%) were Hispanic ethnicity, 645 (41.1%) were SARS-CoV-2-positive, 412 (26.2%) were vaccinated with a primary series, and 273 (17.4%) had received ≥1 booster of BNT162b2. The overall adjusted VE of the BNT162b2 primary series was 58.5% (95% CI 46.0, 68.1), while the adjusted VE of ≥1 booster was 78.9% (95% CI 70.0, 85.1). The adjusted overall VE of primary series for African American/Black individuals was 64.0% (95% CI 49.9, 74.1) and 82.7% (95% CI 71.9, 89.4) in those who received ≥1 booster. When analysis was limited to the period of Omicron predominance, overall VE of the primary series decreased with widened confidence intervals (24.5%, 95% CI −4.5, 45.4%), while VE of ≥1 booster was maintained at 60.9% (95% CI 42.0, 73.6). BNT162b2 primary series and booster vaccination provided protection against COVID-19-associated ARI hospitalization among a predominantly African American population.

Background/Objectives: COVID-19 mRNA vaccines protect against hospitalization, but less is known about real-world vaccine effectiveness (VE) against other severe outcomes. Methods: 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. Results: 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. Conclusions: 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.