An increasing proportion of the population has acquired immunity through COVID-19 vaccination and previous SARS-CoV-2 infection, i.e., hybrid immunity, possibly affecting the risk of new infection. We aim to estimate the protective effect of previous infections and vaccinations on SARS-CoV-2 Omicron infection, using data from 43,257 adult participants in a prospective community-based cohort study in the Netherlands, collected between 10 January 2022 and 1 September 2022. Our results show that, for participants with 2, 3 or 4 prior immunizing events (vaccination or previous infection), hybrid immunity is more protective against infection with SARS-CoV-2 Omicron than vaccine-induced immunity, up to at least 30 weeks after the last immunizing event. Differences in risk of infection are partly explained by differences in anti-Spike RBD (S) antibody concentration, which is associated with risk of infection in a dose-response manner. Among participants with hybrid immunity, with one previous pre-Omicron infection, we do not observe a relevant difference in risk of Omicron infection by sequence of vaccination(s) and infection. Additional immunizing events increase the protection against infection, but not above the level of the first weeks after the previous event.
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