Identification of metabolic signatures of immune response following mRNA and inactivated vaccines against COVID-19: a systematic review

Background Metabolomic profiling offers insights into immune responses, yet a synthesis of systemic metabolic changes after COVID-19 vaccination is lacking. This review aims to characterize vaccination-induced metabolomic alterations and identify correlative biomarkers of responsiveness. Methods Following PRISMA 2020 guidelines (PROSPERO 1181037), four databases (PubMed, Embase, Scopus, Web of Science) were searched for studies using LC-MS, GC-MS, or NMR to analyse venous blood after COVID-19 vaccination. Inclusion criteria focused on original human studies. Risk of bias was assessed using ROBINS-I and RoB 2. Results Ten studies (n 1,200) evaluating mRNA and inactivated vaccines were included. Vaccination consistently altered amino acid pathways, specifically glutamine, phenylalanine, and tryptophan. Early activation of the kynurenine pathway (1–2 days post-dose) emerged as a predictor of stronger antibody responses. Inactivated vaccines triggered a “Warburg-like” metabolic switch, characterized by increased glycolysis and reduced TCA intermediates. Lipidomic changes were prominent; high baseline ceramides predicted low response, while sphingomyelins and short-chain fatty acids associated with positive immunity. Most studies showed a moderate risk of bias due to post-hoc grouping and confounding factors. Conclusions COVID-19 vaccination induces reproducible changes in amino acid, energy, and lipid metabolism. Kynurenine activity, baseline amino acids, and sphingolipid signatures are potential predictors of vaccine efficacy, supporting personalized immunization strategies.