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.