Vaccine-induced Immunometabolic Reprogramming in Neonates from The Gambia and Papua New Guinea 2260646

Abstract Introduction Neonatal immunization reprograms metabolism to support immune activation, yet early-life systemic responses across populations remain poorly defined. Understanding these shifts is key for precision newborn vaccine design. Methods Peripheral blood plasma was collected at birth (day of life [DoL] 0, pre-vaccination) and DoL7 from infants in The Gambia (GAM, n = 230; 426 samples) and Papua New Guinea (PNG, n = 50; 65 samples) within the Expanded Program on Immunization Consortium. Infants received BCG, HBV, BCG+HBV, or delayed control. Untargeted LC—MS/MS metabolomics was performed, and antibody titers were measured at DoL30 and DoL128. Results Generalized Additive Mixed Models (gamm4) of longitudinal WGCNA modules showed that within 48h after birth in GAM, vaccination induced distinct metabolic signatures in four modules: Mod1 (PC/Plasmalogens), Mod4 (Acylcarnitines), Mod7 (Met/Cys/SAM/Taurine), and Mod17 (PC), representing lipid, energy, and amino acid/sulfur metabolism. By 200h, vaccine-specific effects in Mod1, Mod7, and Mod17 subsided as metabolic trajectories converged between vaccinated and unvaccinated infants, indicating transient early shifts. In GAM, Lipid Fatty Acid Dicarboxylate metabolites differed between vaccine arms, being downregulated with HBV but not BCG. In PNG, vaccination led to broad reductions in plasma metabolites by DoL7, especially amino acids and lipids, whereas GAM infants showed no comparable reduction. Cohort-specific divergence was seen in tryptophan metabolism and lysophospholipids (LPLs), which decreased in PNG but not in GAM; anthranilate rose ∼15% with BCG in GAM (p = 0.037) but fell ∼40% in PNG (p = 0.0029). Conclusion Neonatal vaccination induces robust yet transient systemic metabolic shifts with both conserved and population-specific features. We are developing an Immuno-Metabolic Response Score (IMRS) using sparse regression and logistic modeling to identify metabolite signatures predictive of antibody responses, with ongoing validation in neonatal immune assays. Funding Source NIH NIAID U19AI118608 UO1 & ADP NIAID contracts↑ Boston Children’s Hospital Award to Precision Vaccines↑ Program (PVP) Topic Categories Vaccines and Immunotherapy (VAC)