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 the relative VE of a three vs. two doses of an mRNA vaccine in preventing symptomatic SARS-CoV-2 infection, hospitalization, and severe/critical disease. Methods Among Veterans who had received two doses of an mRNA vaccine by April 30, 2021 we identified those who received a third dose of the same vaccine between September 22 and November 24, 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 two doses of BNT162b2 or mRNA1273 vaccine by April 30, 2021, we matched 395,686 persons who received a third dose of the same vaccine between September 22 and November 24, 2021, to controls who did not receive a third dose. Adjusted hazards ratios (95% CI) were 0.15 (0.11-0.21) for symptomatic infection and 0.18 (0.13-0.26) 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 two doses). There was no difference in VE between BNT162b2 vs. mRNA1273 recipients. Conclusion 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.