A multiscale quantitative systems pharmacology model for the development and optimization of mRNA vaccines

The unprecedented effort to cope with the COVID‐19 pandemic has unlocked the potential of mRNA vaccines as a powerful technology, set to become increasingly pervasive in the years to come. 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‐level and molecular‐level events. The model mechanistically describes the biological processes from the uptake of mRNA by antigen‐presenting cells at the injection site to the subsequent release of antibodies into the bloodstream. This two‐layer 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‐based delivery systems. Calibrated specifically for the BNT162b2 SARS‐CoV‐2 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‐responder 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‐1273 vaccine, emphasizing its versatility and broad applicability in mRNA vaccine research and development.