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.

结核疫苗卡介苗（BCG）对非相关感染具有异源有益作用。这些作用的基础尚未在人类中探索。在一项随机的安慰剂对照人类挑战研究中，我们发现BCG疫苗接种可诱导单核细胞在全基因组范围内的表观遗传重编程，并能防止由减毒的黄热病病毒疫苗株引起的实验性感染。表观遗传重编程伴随着功能变化，表明训练有素的免疫力。病毒血症的减少与IL-1β的上调高度相关，IL-1β是一种异源细胞因子，与诱导免疫力有关，但与特异性IFNγ反应无关。通过遗传，表观遗传学和免疫学研究证实了IL-1β在诱导训练性免疫中的重要性。在体内，然后进行功能性重编程和针对非相关病毒感染的保护作用，其中IL-1β作为受过训练的免疫反应的介体起着关键作用。