Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity

BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed gamma BCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with gamma BCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition receptors and histone methylation markers were assessed. The in vivo effects of gamma BCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. gamma BCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects were less strong than those induced by live BCG. gamma BCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that gamma BCG induces long-term training of innate immunity in vitro. In vivo, gamma BCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited.