Risk of subsequent SARS-CoV-2 infection among vaccinated employees with or without hybrid immunity acquired early in the Omicron-predominant era of the COVID-19 pandemic

Background: Hybrid immunity, from COVID-19 vaccination followed by SARS-CoV-2 infection acquired after its Omicron variant began predominating, has provided greater protection than vaccination alone against subsequent infection over 1-3 months of observation. Its longer-term protection is unknown. Methods: We conducted a retrospective cohort study of COVID-19 case incidence among healthcare personnel (HCP) mandated to be vaccinated and report on COVID-19-associated symptoms, high-risk exposures, or known-positive test results to an employee health hotline. We compared cases with hybrid immunity, defined as incident COVID-19 during the first 6 weeks of Omicron-variant predominance (run-in period), to those with immunity from vaccination alone during the run-in period. Time until COVID-19 infection over 13 subsequent months (observation period) was analyzed by standard survival analysis. Results: Of 5867 employees, 641 (10.9%, 95% confidence interval [CI]: 10.1%-11.8%) acquired hybrid immunity during the run-in period. Of these, 104 (16.2%, 95% CI: 13.5%-19.3%) experienced new SARS-CoV-2 infection during the 13-month observation period, compared to 2177 (41.7%, 95% CI: 40.3%-43.0%) of the 5226 HCP without hybrid immunity. Time until incident infection was shorter among the latter (hazard ratio: 3.09, 95% CI: 2.54-3.78). Conclusions: In a cohort of vaccinated employees, Omicron-era acquired SARS-CoV-2 hybrid immunity was associated with significantly lower risk of subsequent infection over more than a year of observation-a time period far longer than previously reported and during which three, progressively more resistant, Omicron subvariants became predominant. These findings can inform institutional policy and planning for future COVID-19 additional vaccine dosing requirements for employees, for surveillance programs, and for risk modification efforts.