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Randomized Controlled Trial
. 2018 Jan 10;23(1):89-100.e5.
doi: 10.1016/j.chom.2017.12.010.

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

Rob J W Arts  1 , Simone J C F M Moorlag  1 , Boris Novakovic  2 , Yang Li  3 , Shuang-Yin Wang  1 , Marije Oosting  1 , Vinod Kumar  3 , Ramnik J Xavier  4 , Cisca Wijmenga  3 , Leo A B Joosten  1 , Chantal B E M Reusken  5 , Christine S Benn  6 , Peter Aaby  6 , Marion P Koopmans  5 , Hendrik G Stunnenberg  2 , Reinout van Crevel  1 , Mihai G Netea  7
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Free article
Randomized Controlled Trial

BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

Rob J W Arts et al. Cell Host Microbe. .
Free article

Abstract

The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.

Keywords: BCG; IL-1; epigenetics; innate immune memory; monocytes; non-specific effects of vaccines; trained immunity; yellow fever vaccine.

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