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

J Leukoc Biol. 2015 Dec;98(6):995-1001. doi: 10.1189/jlb.4MA0215-059R. Epub 2015 Jun 16.


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 γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG 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 γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG 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. γBCG 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 γBCG induces long-term training of innate immunity in vitro. In vivo, γBCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited.

Keywords: heterologous immunity; nonspecific vaccination effects; trained immunity.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects*
  • Adult
  • Cytokines / immunology
  • Female
  • Gamma Rays*
  • Humans
  • Immunity, Innate / drug effects*
  • Male
  • Mycobacterium bovis / immunology*
  • Nod2 Signaling Adaptor Protein / immunology
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Time Factors
  • Up-Regulation / drug effects


  • Cytokines
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein