Author Identifier (ORCID)
Abstract
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.
Keywords
COVID-19 vaccination, multi-omics, proteomics, lipidomics, metabolomics, Pfizer-BioNTech, Moderna, AstraZeneca
Document Type
Journal Article
Date of Publication
2026
Article Number
1815543
Volume
17
Publisher
Frontiers
School
School of Medical and Health Sciences
Funding Information
The author(s) declared that financial support was received for this work and/or its publication. This study was co-funded by the CSIRO and the U.S. Food and Drug Administration, Office of the Chief Scientist, Medical Countermeasures Initiative, under FDA contract 75F40121C00144.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Content Type
Full object
First Page
1
Last Page
19
Recommended Citation
Klein, A. H., Beale, D. J., Nguyen, T. V., Liu, J. W., Jansen Van Vuren, P., Singanallur N. B., Lee C., Boomer A. C., Juno J. A., Kent S. J., Wheatley A. K., Au G. G., Vasan SS, Wilson L., & McAuley, A. J. (2026). Multi-omics integration reveals vaccine-specific molecular signatures and temporal dynamics of COVID-19 immune responses. Frontiers in Immunology, 17, Article 1815543. https://doi.org/10.3389/fimmu.2026.1815543