Potential health risks of mRNA-based vaccine therapy: A hypothesis

Abstract

Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.

Keywords: Autoimmunity; Autoinflammation; DNA damage; Endogenous transposable elements; Genomic integration; IFN; LINE-1; TREX-1; mRNA vaccine; nms-mRNA.

Fig. 1

Schematic representation of our proposed hypothesis. Following intracellular delivery of the vaccine (1), vaccine nms-mRNA is released from the lipid-nanoparticles into the cytosol (2) and accumulated in the cytosol (3), which may unsilence TE expression (4), leading to the activation of foreign RNA and cytosolic DNA sensors, such as RLRs, RIG-I, MDA-5 and TREX1, and enhancing the expression of proinflammatory cytokines and type-I IFN (5). TE activity can lead to DNA damage via insertional mutagenesis and genomic instability, and enhancing the expression of pro-inflammatory cytokines and type-I IFN (6). Inflammasome activation may also have a regulatory role in preventing cGAS-STING mediated type-I IFN production, thus establishing a chronic regulatory circuit wherein type-I IFNs inhibit the inflammasome and the activated inflammasome also inhibits type I-IFN production (not shown in the figure).