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As in other areas of drug development, mathematical modeling is a pivotal tool to support and expedite the mRNA vaccine development process. This study introduces a Quantitative Systems Pharmacology (QSP) model that captures key immune responses following mRNA vaccine administration, encompassing both tissue\u2010level and molecular\u2010level events. The model mechanistically describes the biological processes from the uptake of mRNA by antigen\u2010presenting cells at the injection site to the subsequent release of antibodies into the bloodstream. This two\u2010layer model represents a first attempt to link the molecular mechanisms leading to antigen expression with the immune response, paving the way for the future integration of specific vaccine attributes, such as mRNA sequence features and nanotechnology\u2010based delivery systems. Calibrated specifically for the BNT162b2 SARS\u2010CoV\u20102 vaccine, the model has undergone successful validation across various dosing regimens and administration schedules. The results underscore the model's effectiveness in optimizing dosing strategies and highlighting critical differences in immune responses, particularly among low\u2010responder groups such as the elderly. Furthermore, the model's adaptability has been demonstrated through its calibration for other mRNA vaccines, such as the Moderna mRNA\u20101273 vaccine, emphasizing its versatility and broad applicability in mRNA vaccine research and development.<\/jats:p>","DOI":"10.1002\/psp4.70041","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:45:32Z","timestamp":1748306732000},"page":"1213-1224","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Multiscale Quantitative Systems Pharmacology Model for the Development and Optimization of <scp>mRNA<\/scp> Vaccines"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2315-4808","authenticated-orcid":false,"given":"Lorenzo","family":"Dasti","sequence":"first","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology (CIBIO) University of Trento  Trento 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