BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity

Arts, R.J.W., Simone Moorlag, S.J.C.F.M., Novakovic, B., Stunnenberg, H.G., van Crevel, R., Netea, M.G.

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 randomised, placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprogramming 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 viraemia was highly correlated with the upregulation of IL-1b, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNg response. The importance of IL-1b 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-1b as a mediator of trained immunity responses.

Cell Host & Microbe 2018; 23: 89-100.