Hybrid Immunity and SARS-CoV-2 Antibodies: Results of the HEROES–RECOVER Prospective Cohort Study

Abstract Background There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (infection with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or vaccination against coronavirus disease 2019 [COVID-19]). From a multi-site cohort of frontline workers, we examined the heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. Methods Exposures included event count and event order, categorized into 7 permutations. Outcome was level of serum antibodies against receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding immunoglobulin). Means were examined up to 365 days after each of the first to seventh events. Results Analysis included 5793 participants measured from 7 August 2020 to 15 April 2023. Hybrid immunity from infection before 1 or 2 vaccine doses elicited modestly superior antibody responses after the second and third events (compared with infections or vaccine doses alone). This superiority was not repeated after additional events. Among adults infected before vaccination, adjusted geometric mean ratios (95% confidence interval [CI]) of anti-RBD early response (versus vaccinated only) were 1.23 (1.14–1.33), 1.09 (1.03–1.14), 0.87 (.81–.94), and 0.99 (.85–1.15) after the second to fifth events, respectively. Post-vaccination infections elicited superior responses; adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated only) were 0.93 (.75–1.17), 1.11 (1.06–1.16), 1.17 (1.11–1.24), and 1.20 (1.07–1.34) after the second to fifth events, respectively. Conclusions Evidence of heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy. In this adult cohort, hybrid immunity elicited superior SARS-CoV-2 serum antibody response compared with COVID-19 vaccination alone; however, this superiority was not repeated after ≥4 immunizing events. Associations differed by permutations of immunizing events. These findings could inform vaccination strategies.