We assessed the protection conferred by naturally-acquired, vaccine-induced and hybrid immunity during the concomitant Omicron and Delta epidemic waves in France on symptomatic infection and severe COVID-19. The greatest levels of protection against both variants were provided by hybrid immunity. Protection against Omicron symptomatic infections was systematically lower and waned at higher speed than against Delta in those vaccinated. In contrast, there were little differences in variant-specific protection against severe inpatient outcomes in symptomatic individuals.

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Background SARS–CoV–2 continues to spread despite fast vaccine rollout, which could be attributed to waning immunity or to a reduced protection against some variants. A thorough characterization of vaccine protection and its duration in time is needed to inform vaccination policies and enhance public trust. Methods We matched three national databases with exhaustive information on screening, vaccination and hospitalizations in France over the year 2021. We performed a two-step analysis to estimate vaccine effectiveness against severe forms of Covid-19 in people aged 50 years or over, combining: (i) a test-negative case–control design to assess vaccine effectiveness against symptomatic infections; and (ii) a survival analysis to assess the additional protection against severe outcomes (hospitalizations and inpatient deaths) in infected individuals. Results We found a high vaccine effectiveness in people aged 50 years or more, reaching 82% against symptomatic infections and 94% against severe outcomes, after a full vaccination scheme. Vaccine effectiveness against symptomatic infections strongly decreased over time, dropping to 53% after six months, but remained high against severe forms (90% after six months). The booster dose allowed restoring high protection levels. Vaccine protection and its evolution in time, showed little difference against the variants that circulated prior to December 2021 in France, including the Delta variant. Conclusion Though vaccine immunity decreases over time, vaccination remains crucial to provide individual protection against severe diseases. This decline can be reversed by the injection of a booster dose.