Vaccine Effectiveness of 3 Versus 2 Doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA Vaccines in a High-Risk National Population

BACKGROUND: Knowledge of the vaccine effectiveness (VE) of a third or booster vaccine dose in preventing SARS-CoV-2 infection or its consequences is critical in developing recommendations for their use. We determined relative VE of 3 vs 2 doses of an mRNA vaccine in preventing symptomatic SARS-CoV-2 infection, hospitalization, and severe/critical disease. METHODS: Among veterans who had received 2 doses of an mRNA vaccine by 30 April 2021, we identified those who received a third dose of the same vaccine between 22 September and 24 November 2021 and 1:1 matched controls who had not received their third dose by then. Using Cox proportional hazards model, we calculated adjusted hazards ratios for symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2–positive test. RESULTS: Among 2 321 366 veterans who received 2 doses of Pfizer BNT-162b2 or Moderna mRNA-1273 vaccine by 30 April 2021, we matched 395 686 persons who received a third dose of the same vaccine between 22 September and 24 November 2021 to controls who did not receive a third dose. Adjusted HRs (95% CI) were .15 (.11–.21) for symptomatic infection and .18 (.13–.26) for hospitalizations for 3 vs 2 doses, corresponding to relative VE of 85% and 82%. Five ICU admissions or deaths were observed (4 among recipients of 2 doses). There was no difference in VE between BNT162b2 versus mRNA-1273 recipients. CONCLUSIONS: A third dose of a SARS-CoV-2 mRNA vaccine is associated with high VE against symptomatic infection, hospitalization, and critical disease in the pre-Omicron era.