Risk of SARS-CoV-2 infection and hospitalization in individuals with natural, vaccine-induced and hybrid immunity: a retrospective population-based cohort study from Estonia

A large proportion of the world’s population has some form of immunity against SARS-CoV-2, through either infection (‘natural’), vaccination or both (‘hybrid’). This retrospective cohort study used data on SARS-CoV-2, vaccination, and hospitalization from national health system from February 2020 to June 2022 and Cox regression modelling to compare those with natural immunity to those with no (Cohort1, n = 94,982), hybrid (Cohort2, n = 47,342), and vaccine (Cohort3, n = 254,920) immunity. In Cohort 1, those with natural immunity were at lower risk for infection during the Delta (aHR 0.17, 95%CI 0.15–0.18) and higher risk (aHR 1.24, 95%CI 1.18–1.32) during the Omicron period than those with no immunity. Natural immunity conferred substantial protection against COVID-19-hospitalization. Cohort 2—in comparison to natural immunity hybrid immunity offered strong protection during the Delta (aHR 0.61, 95%CI 0.46–0.80) but not the Omicron (aHR 1.05, 95%CI 0.93–1.1) period. COVID-19-hospitalization was extremely rare among individuals with hybrid immunity. In Cohort 3, individuals with vaccine-induced immunity were at higher risk than those with natural immunity for infection (Delta aHR 4.90, 95%CI 4.48–5.36; Omicron 1.13, 95%CI 1.06–1.21) and hospitalization (Delta aHR 7.19, 95%CI 4.02–12.84). These results show that risk of infection and severe COVID-19 are driven by personal immunity history and the variant of SARS-CoV-2 causing infection.