Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes

Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off- target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.

Automated summary

This study shows that BCG vaccination leads to long-lasting epigenetic remodeling in circulating monocytes, a phenomenon that explains the off-target protection against viral infections. The findings highlight the importance of trained immunity in the beneficial effects of BCG vaccine.