Impact of mRNA COVID-19 Vaccination on Immunometabolic Profiles in Patients with Lymphoid Malignancies 2260057

Abstract Introduction Metabolomics provides a comprehensive view of small molecules that reflect immune and physiological states. Understanding metabolic responses to vaccination reveals mechanisms of immune activation and variability. Patients with lymphoid malignancies (LM) often exhibit impaired vaccine responses, yet the metabolic basis remains unclear. This study uniquely investigates vaccine-induced metabolic remodeling in this immunocompromised population compared with healthy controls (HC). Methods A prospective cohort of 41 LM patients and 27 HC was analyzed. Plasma samples were collected before and after mRNA COVID-19 vaccination. Anti-Spike IgG levels were quantified using a single-molecule array (Simoa) assay, and untargeted metabolomics was performed using ultra-performance liquid chromatography mass spectrometry, identifying 1,492 metabolites. Multivariate clustering, pathway enrichment, and generalized additive mixed models assessed metabolic changes and responder-specific trajectories. Results Healthy controls showed a robust increase in anti-Spike antibody levels, while LM participants had lower and more heterogeneous responses. Distinct metabolic clustering was observed between LM and HC, and within LM between responders and non-responders. Enrichment analyses revealed remodeling of Amino Acid, Lipid and Energy pathways across vaccine doses. Responders showed activation of tryptophan, lysine, and fatty acid oxidation consistent with immunometabolic engagement, while non-responders showed dysregulation in acylcarnitine and lysophospholipid metabolism, suggesting altered lipid remodeling and mitochondrial function. Conclusion This study represents a unique metabolomic investigation of mRNA COVID-19 vaccination in patients with lymphoid malignancies, revealing immune activation in responders and metabolic dysregulation in non-responders. Findings highlight metabolomics as a precision tool for identifying vaccine responsiveness biomarkers and understanding immune regulation in immunocompromised hosts. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)