Hybrid Immunity Provides Protective Advantage Over Vaccination or Prior Remote Coronavirus Disease 2019 Alone

BACKGROUND: The protective efficacy of prior coronavirus disease 2019 (COVID-19) with or without vaccination remains unknown. This study sought to understand if 2 or more messenger RNA (mRNA) vaccine doses provide additional protection in patients with prior infection, or if infection alone provides comparable protection. METHODS: We conducted a retrospective cohort study of the risk of COVID-19 from 16 December 2020 through 15 March 2022, among vaccinated and unvaccinated patients of all ages with and without prior infection. A Simon-Makuch hazard plot illustrated the incidence of COVID-19 between groups. Multivariable Cox proportional hazards regression was used to examine the association of demographics, prior infection, and vaccination status with new infection. RESULTS: Among 101 941 individuals with at least 1 COVID-19 polymerase chain reaction test prior to 15 March 2022, 72 361 (71.0%) received mRNA vaccination and 5957 (5.8%) were previously infected. The cumulative incidence of COVID-19 was substantially higher throughout the study period for those previously uninfected and unvaccinated, and lowest for those previously infected and vaccinated. After accounting for age, sex, and the interaction between vaccination and prior infection, a reduction in reinfection risk was noted during the Omicron and pre-Omicron phases of 26% (95% confidence interval [CI], 8%–41%; P = .0065) to 36% (95% CI, 10%–54%; P = .0108), respectively, among previously infected and vaccinated individuals, compared to previously infected subjects without vaccination. CONCLUSIONS: Vaccination was associated with lower risk of COVID-19, including in those with prior infection. Vaccination should be encouraged for all including those with prior infection, especially as new variants emerge and variant-specific booster vaccines become available.