Hybrid, infection- and vaccination-induced protection against laboratory- confirmed SARS-CoV-2 infection in a European multi-centre prospective cohort of healthcare workers, 2021–2024

Healthcare workers (HCWs) face high occupational exposure to SARS-CoV-2 and are a priority group for vaccination. Both natural infection and vaccination—individually or combined as hybrid immunity—confer protection against SARS-CoV-2 infection. This study aimed to evaluate the protection conferred by hybrid, infection-induced, and vaccine-induced immunity against laboratory-confirmed SARS-CoV-2 infections in HCWs during the circulation of three pandemic and one post-pandemic Omicron sublineages.We conducted a prospective cohort study of HCWs from 18 hospitals across nine European countries. Participants underwent RT-PCR testing at enrolment and during weekly or fortnightly follow-ups. The study period was divided based on dominant Omicron sublineage circulation: BA.1/2 (Dec 16, 2021–Jun 1, 2022), BA.4/5/BQ.1 (Jun 2–Dec 31, 2022), BA.2/XBB (Jan 1–May 2, 2023), and post-pandemic XBB.1.5/BA.2.86 (Sep 1, 2023–May 21, 2024). We classified participants in four groups: hybrid immunity (prior infection and recent vaccination < 6 months), infection-induced immunity (prior infection, no recent vaccination), vaccine-induced immunity (recent vaccination, no prior infection), and a reference group (no prior infection, no recent vaccination). Adjusted hazard ratios (aHRs) for infection were calculated using Cox regression, adjusting for hospital, age, sex, any chronic condition, and patient-facing roles.A total of 3 133 HCWs were included: 2 572 (82%) female, 1 734 (55%) aged 40–59, and 563 (29%) with ≥ 1 chronic condition. Hybrid immunity showed significant protection during BA.1/2 (aHR = 0.37, 95%CI 0.21–0.63), BA.4/5/BQ.1 (aHR = 0.36, 95%CI 0.22–0.58), and XBB.1.5/BA.2.86 (aHR = 0.53, 95%CI 0.37–0.74) periods. Infection-induced immunity was protective across all periods, most during BA.1/2 (aHR = 0.26, 95%CI 0.12–0.53), and least during BA.2/XBB (aHR = 0.66, 95%CI 0.36–1.22). Vaccine-induced immunity alone offered limited protection during BA.1/2 (aHR = 0.72, 95%CI 0.49–1.06) and BA.4/5/BQ.1 (aHR = 0.77, 95%CI 0.50–1.19), with wide confidence intervals suggesting low statistical significance.In conclusion, hybrid and infection-induced immunity groups were more protected against infection caused by earlier emerging Omicron sub-lineages circulation and more protected compared to vaccination alone, which had no significant protective effect. These findings highlight the need for adaptive public health strategies, including timely vaccine updates and improved understanding of prior SARS-CoV-2 infection role, to inform COVID-19 vaccination policies for HCWs in the post-pandemic era.