Vaccination elicits systemic immune responses that extend beyond antibody and lymphocyte activation, engaging coordinated metabolic and lipid pathways that modulate immune function. Nevertheless, how systemic molecular responses differ across COVID-19 vaccine platforms, including closely related mRNA platforms, remains poorly understood. Here, we performed integrated plasma proteomic, lipidomic, and metabolomic profiling of 53 SARS-CoV-2-naïve adults vaccinated with Pfizer-BioNTech, Moderna, or AstraZeneca COVID-19 vaccines. Samples were analysed across multiple timepoints using differential analysis and DIABLO-based multi-omics integration. Our findings reveal distinct platform-associated multi-omic molecular signatures not captured by unsupervised analyses alone. Pfizer-BioNTech vaccination was associated with widespread increases in immunoglobulin and complement associated proteins, together with broad decreases in lipid abundance and bidirectional metabolite changes. In contrast, the Moderna vaccination was associated with predominantly increased lipid abundance and bidirectional metabolite changes, with minimal univariate proteomic changes. AstraZeneca induced subtler yet coherent cross-omic shifts, detectable only through integrative modelling approaches. Despite these platform-associated differences, Pfizer and Moderna shared concordant changes in a subset of metabolites, including amino-acid and TCA-cycle-associated features, within divergent lipidomic contexts. These findings demonstrate that even closely related mRNA vaccine platforms are associated with distinct systemic molecular response patterns. This study establishes integration of multi-omics (as opposed to separate single-omic analyses) as a powerful framework for characterising vaccine-associated molecular responses, identifying candidate platform-specific molecular markers, and providing candidates for future molecular stratification studies.
