Understanding the Pharmacology of COVID-19 mRNA Vaccines: Playing Dice with the Spike?

Coronavirus disease-19 (COVID-19) mRNA vaccines are the mainstays of mass vaccination campaigns in most Western countries. However, the emergency conditions in which their development took place made it impossible to fully characterize their effects and mechanism of action. Here, we summarize and discuss available evidence indicating that COVID-19 mRNA vaccines better reflect pharmaceutical drugs than conventional vaccines, as they do not contain antigens but an active SARS-CoV-2 S protein mRNA, representing at the same time an active principle and a prodrug, which upon intracellular translation results in the endogenous production of the SARS-CoV-2 S protein. Both vaccine-derived SARS-CoV-2 S protein mRNA and the resulting S protein exhibit a complex pharmacology and undergo systemic disposition. Defining COVID-19 mRNA vaccines as pharmaceutical drugs has straightforward implications for their pharmacodynamic, pharmacokinetic, clinical and post-marketing safety assessment. Only an accurate characterization of COVID-19 mRNA vaccines as pharmaceutical drugs will guarantee a safe, rational and individualized use of these products.