Highlights d Human BCG vaccination induces a persistent innate immune training of CD14 + monocytes d BCG vaccination imprints a persistent transcriptomic myeloid bias on human HSPCs d Hepatic nuclear factors are regulators of BCG-induced trained immunity in HSPCs d BCG induces persistent epigenetic changes in peripheral CD14 + monocytes

Highlights d BCG vaccination of humans induces long-term immunophenotypic changes in neutrophils d BCG increases antimicrobial activity of neutrophils against unrelated pathogens d BCG-induced functional changes associate with modifications in histone methylation d Trained immunity may be a therapeutic target in neutrophilmediated diseases

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BACKGROUND. Induction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases. METHODS.We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis-and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity. RESULTS.While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination. CONCLUSION.The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.