Risk of SARS-CoV-2 Infection and Hospitalization in Individuals with Natural, Vaccine-Induced and Hybrid Immunity: A Retrospective Nationwide Study from Estonia

Currently, the SARS-CoV-2 immunity landscape is diverse, with various degrees of natural, vaccine-induced and hybrid immunity. Understanding how protection from natural and hybrid immunities compares with that from vaccine-induced immunity and understanding changes in protection against different SARS-CoV-2 variants are emergent research needs. We evaluated the real-world effectiveness of natural immunity in comparison to that of no SARS-CoV-2-specific immunity, vaccine-induced immunity and hybrid immunity against SARS-CoV-2 infection and hospitalization and evaluate epidemics stemming from Delta and Omicron variants.Methods: Individual-level linked data on SARS-CoV-2, vaccination, and health care utilization in Estonia from national health system testing for the period of February 2020 to June 2022 were used. Three cohorts were nested in these data by pairwise matching of birth year and sex to include individuals with natural immunity only and those with no immunity (Cohort 1; n=92917); those with hybrid and natural immunity (Cohort 2; n=46813); and those with vaccine-induced immunity only and natural immunity (Cohort 3; n=252414). The outcomes were laboratory-confirmed SARS-CoV-2 infection and COVID-19 hospitalization. We used adjusted Cox proportional hazards regression for modelling.Findings: In Cohort 1, in comparison to those with no immunity, those with natural immunity were at lower risk for infection during the Delta period (adjusted [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. Natural immunity conferred substantial protection against COVID-19 hospitalization (Delta period aHR 0·05 (95% CI 0·03, 0·11); Omicron period aHR 0·10 (95% CI 0·04, 0·26).In Cohort 2, in comparison to natural immunity, hybrid immunity offered strong protection during the Delta period (aHR 0·61 (95% CI 0·46, 0·80)) but not the Omicron period (aHR 1·05 (95% CI 0·93,1·19)). 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 both COVID-19 infection ((Delta aHR 4·90 (95% CI 4·48, 5·36); Omicron 1·13 (95% CI 1·06, 1·21)) and hospitalization during the Delta period (aHR 7·19 (95% CI 4·02, 12·84)).Interpretation: Our findings suggest that risk of infection (and of developing severe disease) is driven by personal history of immunity-conferring events and the variant of SARS-CoV-2 virus causing infection. Hybrid immunity seems to confer the greatest protection against SARS-CoV-2 infection and severe disease as viral variants change. This finding highlights the need for continuous vaccination programmes.Funding Information: Research was carried out with the support of the European Regional Development Fund (RITA 1/02-120), Estonian Research Council (grants PRG1197, PRG198) and European Social Fund via IT Academy program.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: The study was approved by the Research Ethics Committee of the University of Tartu.