Background: Protection against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]) can limit transmission and the risk of post-COVID conditions, and is particularly important among healthcare personnel. However, lower vaccine effectiveness (VE) has been reported since predominance of the Omicron SARS-CoV-2 variant.

Methods: We evaluated the VE of a monovalent messenger RNA (mRNA) booster dose against COVID-19 from October 2021 to June 2022 among US healthcare personnel. After matching case-participants with COVID-19 to control-participants by 2-week period and site, we used conditional logistic regression to estimate the VE of a booster dose compared with completing only 2 mRNA doses >150 days previously, adjusted for multiple covariates.

Results: Among 3279 case-participants and 3998 control-participants who had completed 2 mRNA doses, we estimated that the VE of a booster dose against COVID-19 declined from 86% (95% confidence interval, 81%-90%) during Delta predominance to 65% (58%-70%) during Omicron predominance. During Omicron predominance, VE declined from 73% (95% confidence interval, 67%-79%) 14-60 days after the booster dose, to 32% (4%-52%) ≥120 days after a booster dose. We found that VE was similar by age group, presence of underlying health conditions, and pregnancy status on the test date, as well as among immunocompromised participants.

Conclusions: A booster dose conferred substantial protection against COVID-19 among healthcare personnel. However, VE was lower during Omicron predominance, and waning effectiveness was observed 4 months after booster dose receipt during this period. Our findings support recommendations to stay up to date on recommended doses of COVID-19 vaccines for all those eligible.