Bacillus Calmette-Guérin (BCG) vaccine reprograms human neonatal metabolism <i>in vivo</i> and <i>in vitro</i>

Abstract Immunization has significantly reduced infectious morbidity and mortality, but vaccine optimization and development is limited by incomplete understanding of how early life vaccines engage the distinct infant immune system to induce protection. We used plasma metabolomics to gain immunometabolic insight into the effects of Bacille Calmette-Guérin (BCG) which prevents disseminated TB and induces heterologous immunity to unrelated pathogens. For in vivo studies, low-birth weight newborns in Guinea-Bissau received a neonatal dose of Bacille Calmette-Guérin (early BCG) at birth or a catch-up after blood collection at four weeks post-birth (delayed BCG). For in vitro studies, human neonatal cord blood samples were stimulated for 18 hours with either vehicle (saline) or BCG. In vivo and in vitro plasma samples were profiled for global untargeted metabolomics and complex lipid panel lipidomics. BCG-induced perturbation of neonatal metabolic pathways was observed in vivo and confirmed in vitro. Lipid biomarkers of early BCG-induced response identified increased free fatty acids (FFA), and decreased lysoPC (LPC), lysoPE (LPE), monoacylglycerol (MAG), phosphatidylcholine (PC), phosphoethanolamine (PE) and triacylglycerol (TAG). BCG identified decrease on plasma levels of LPC, LPE, PC and MAG in vitro. Nucleotide purine and pyrimidine pathways are perturbed both in vivo and in vitro. Neonatal BCG vaccination alters the early life metabolism, in particular lipids implicated in immune response. This suggests that BCG-induced alterations in lipid pathways may contribute to its protective effect. Further studies may identify biomarkers of vaccine immunogenicity to inform development and optimization of early life vaccines.