Multisystem Endothelial Inflammation: A Key Driver of Adverse Events Following mRNA-Containing COVID-19 Vaccines

mRNA-LNP-based COVID-19 vaccines, namely Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax, were successfully deployed to help control the SARS-CoV-2 pandemic, and their updated formulations continue to be recommended, albeit only for high-risk populations. One widely discussed aspect of these vaccines is their uniquely broad spectrum and increased incidence of adverse events (AEs), collectively referred to as post-vaccination syndrome (PVS). Although the reported PVS rate is low, the high number of administered doses among healthy individuals has resulted in a substantial number of reported vaccine-related injuries. A prominent manifestation of PVS is multisystem inflammation, hypothesized to result from the systemic transfection of organ cells with genetic instructions for a toxin, the spike protein, delivered with lipid nanoparticles (LNPs). In this narrative review, we focus on endothelial cells in the microcirculatory networks of various organs as primary sites of transfection with mRNA-LNP and consequent PVS. We outline the anatomical variations in the microcirculation contributing to the individual variability of symptoms and examine the molecular and cellular responses to vaccine nanoparticle exposure at the endothelial cell level with a focus on the pathways of a sustained cascade of toxic and autoimmune processes. A deeper understanding of the mechanisms underlying mRNA-LNP-induced AEs and PVS at the organ and cellular levels is critical for improving the safety of future vaccines and other therapeutic applications of this groundbreaking technology.