Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens

Neonatal BCG vaccination is associated with a reduction in all-cause mortality. This study reports altered cytokine responses to heterologous pathogens and TLR ligands in BCG-vaccinated neonates compared to non-BCG-vaccinated controls, consistent with modulation of innate immunity. Abstract Background BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved. Methods Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. Results BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Conclusions Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality.