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

Abstract

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.

The Blind Spot in COVID-19 Vaccination Policies: Under-Reported Adverse Events

“…As one might expect, discrepancies in the nature of post-vaccination AEs may reflect, in addition to batchto-batch variations, a differential tissue/organ distribution of the vaccine formulation upon injection, whereas differences in the intensity of the symptoms may relate to the unknown, but presumably high level of spike protein produced by the cells, which are forced to express, against their nature, a biologically active but synthetic viral protein. Indeed, in a woman with mRNA-1273 COVID-19 vaccine-induced thrombocytopenia, plasma spike (S) protein level 10 days after vaccination was 10 ng/ml (Appelbaum et al, 2022), nearly 100 times higher than those reported by Ogata and colleagues in vaccinated subjects with no apparent adverse effects (Ogata et al, 2022), pointing to excessive vaccine-induced production of spike protein possibly causing AEs (Cosentino & Marino, 2022a, 2022b. The uncertainty surrounding the dose of the active product administered, which may be highly variable, and its biodistribution is deemed to be sufficient to justify a conscientious objection to mRNA technology (Provost et al, 2022).…”

Lyophilization process optimization and molecular dynamics simulation of mRNA-LNPs for SARS-CoV-2 vaccine

“…The emergence of SARS-CoV-2 prompted a global effort to develop protective vaccines. mRNA is an attractive form of the vaccine due to the exibility in antigen design and development and production [47][48][49][50][51] . However, effective mRNA vaccines require e cient delivery to cells and high antigen expression levels to induce robust immune responses and long-lasting protective immunity [52] .…”

Safety of COVID-19 Vaccines in Patients with Autoimmune Diseases, in Patients with Cardiac Issues, and in the Healthy Population

“…This evidence raises the question as to whether it is correct to consider any adverse events of the COVID-19 vaccination exclusively within 14–21 days after inoculation, given that the inoculated products persist for longer. Cosentino M. et al discuss that mRNA vaccines must be considered to be pharmaceuticals, and their pharmacokinetics should be studied in greater detail [ 124 ]. Both mRNA and Spike have been found in the breast milk of vaccinated women, which demonstrates that these products travel into the body and can be excreted with biological fluids [ 125 ].…”