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Gamma-irradiated BCG vaccine (γBCG) is an inactivated (killed) whole-cell biologic vaccine developed by Radboud University Medical Center (Universitair Medisch Centrum Sint Radboud) in Nijmegen, Netherlands. It was designed as a safer alternative to the live attenuated Bacille Calmette-Guérin (BCG) vaccine for immunomodulation, particularly to treat sepsis-induced immunoparalysis, where live vaccines pose a risk of disseminated infection in immunocompromised patients. The vaccine acts by activating innate immune pattern recognition receptors, specifically Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), which triggers epigenetic reprogramming of monocytes via histone H3 lysine 4 trimethylation (H3K4me3). This process induces 'trained immunity'—an enhanced, non-specific innate immune memory response. In clinical studies (such as NCT02259608 and NCT02085590), γBCG demonstrated minimal in vivo effects on innate cytokine production but successfully induced heterologous Th1/Th17 adaptive immune responses.
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