Microcirculatory Inflammation: A Key Driver of Adverse Reactions to mRNA-Containing COVID-19 Vaccines

The mRNA-based COVID-19 vaccines, 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 for protecting high-risk populations. One widely discussed aspect of these vaccines is their uniquely broad spectrum and in-creased incidence of adverse events (AEs), collectively referred to as post-vaccination syn-drome (PVS). Although PVS is rare, 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 systemic transfection of organ cells with genetic instructions for a toxin, the spike protein (SP)-, delivered via pro-inflammatory lipid nanoparticles (LNPs). In this review, we focus on endothelial cells in the dense microcirculatory networks of various organs as primary sites of transfection and PVS. We outline the anatomical variations of the microcirculation contributing to the individual variability of symptoms and examine the molecular and cellu-lar 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 under-standing of the mechanisms underlying mRNA-LNP-induced PVS and AEs at the cellular level is critical for improving the safety of future vaccines and other therapeutic applica-tions of this groundbreaking technology.