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Background and objectives Because of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using samples from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2. Methods This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry. Results BCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS‐CoV‐2. Conclusions The immunomodulatory signature of BCG’s off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19.

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