Effectiveness of mRNA COVID-19 Vaccine Boosters Against Infection, Hospitalization, and Death: A Target Trial Emulation in the Omicron (B.1.1.529) Variant Era

Background: The effectiveness of a third mRNA COVID-19 vaccine dose (booster dose) against the Omicron (B.1.1.529) variant is uncertain, especially in older, high-risk populations. Objective: To determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization, and death in the Omicron era by booster type, primary vaccine type, time since primary vaccination, age, and comorbidity burden. Design: Retrospective matched cohort study designed to emulate a target trial of booster vaccination versus no booster, conducted from 1 December 2021 to 31 March 2022. Setting: U.S. Department of Veterans Affairs health care system. Participants: Persons who had received 2 mRNA COVID-19 vaccine doses at least 5 months earlier. Intervention: Booster monovalent mRNA vaccination (Pfizer–BioNTech's BNT162b2 or Moderna's mRNA-1273) versus no booster. Measurements: Booster VE. Results: Each group included 490 838 well-matched persons, who were predominantly male (88%), had a mean age of 63.0 years (SD, 14.0), and were followed for up to 121 days (mean, 79.8 days). Booster VE more than 10 days after a booster dose was 42.3% (95% CI, 40.6% to 43.9%) against SARS-CoV-2 infection, 53.3% (CI, 48.1% to 58.0%) against SARS-CoV-2–related hospitalization, and 79.1% (CI, 71.2% to 84.9%) against SARS-CoV-2–related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups, and primary vaccination regimens but was significantly higher with longer time since primary vaccination and higher comorbidity burden. Limitation: Predominantly male population. Conclusion: Booster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the Omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden. Primary Funding Source: U.S. Department of Veterans Affairs.