| Summary: | <h4>Background</h4>Evidence on protection of different patterns of infection- and vaccine-acquired immunity against Omicron-associated severe illness is useful in planning booster vaccination strategies. We examined protection of prior SARS-CoV-2 infection, a third or a fourth COVID-19 vaccine dose, and hybrid immunity against Omicron-associated severe illness.<h4>Methods and findings</h4>This population-based cohort study followed five million individuals with at least one SARS-CoV-2 RT-PCR test before November 21, 2021 until an Omicron-associatedhospitalization or death. We used Cox regression models to estimate risks of Omicron-associated hospitalization and a composite severe outcome (hospitalized and death), among individuals with infection- and/or vaccination-acquired immunity. Individuals who were unvaccinated and had no history of a prior infection severed as the reference group. Both adjusted hazard ratios (HR) and corresponding protection (one minus adjusted HR), with 95% confidence intervals (CIs), were reported. Three doses provided 94% (95%CI 93-95) and 93% (95%CI 91-94) protection against Omicron-associated hospitalization at 2-3 and ≥3 months post-vaccination respectively, similar to the protection conferred by three doses and a prior infection (2-3 months: 99%, 95%CI 97-100; ≥3 months: 97%, 95%CI 92-99) and four doses (1 month: 87%, 95%CI 79-92; 1-2 months: 96%, 95%CI 92-98). In individuals ≥65 years old, protection of four doses increased to 95% (95%CI 91-98) at 1-2 months, significantly higher than that of three doses over the follow-up period. Similar results were observed with the composite severe outcome.<h4>Conclusion</h4>At least three antigenic exposures, achieved by vaccination or infection, confers significant protection against Omicron-associated hospitalization and death in all age groups. Our findings support a third dose for the overall population, regardless of prior infection status, and a fourth dose for the elderly to maintain high level of immunity and substantially reduce risk of severe illness at individual level.
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