Since December 2020, the global COVID-19 pandemic has been met with a ray of hope in the form of massive vaccination campaigns. Two mRNA vaccines, BNT162b2 and mRNA-1273, formulated with a novel technology, have been rapidly developed and widely administered to combat the spread of the disease.
These vaccines, produced by Pfizer/BioNTech and Moderna, respectively, encode the spike (S) protein of the SARS-CoV-2 virus, with modifications made to improve their pharmacological properties. However, concerns have been raised regarding the potential effects of mRNA vaccines on skeletal muscle cells and their possible epigenetic implications.
This article aims to explore the nucleotide sequence complementarity between the BNT162b2 mRNA vaccine, the original SARS-CoV-2 S gene sequence, and the entire human genome, including coding and noncoding RNA genes.
mRNA Vaccines and Mechanism of Action
The mRNA vaccines, BNT162b2 and mRNA-1273, utilize a groundbreaking technology that involves delivering modified mRNA molecules into the deltoid muscle through injection. These mRNA molecules act as templates for the synthesis of S proteins, triggering an immune response and subsequent immunization.
It is believed that cells producing S proteins transfer antigens to dendritic cells or function as antigen-presenting cells (APCs), which then process the S protein, present epitopes to lymphocytes, and initiate an immune response. However, the liposomes used to administer mRNA vaccines are not cell-specific in vivo, potentially leading to fusion with the plasma membrane of muscle fibers rather than efficient delivery to professional APCs.
Skeletal Muscle Damage and COVID-19 Vaccination
Recent reports have suggested the possibility of skeletal muscle damage following COVID-19 vaccination. While the administration of an inactivated viral vaccine against SARS-CoV-2 did not show adverse effects in patients with autoimmune inflammatory myopathies, this may be attributed to concurrent immunosuppression and prevention of pro-inflammatory pathways.
Understanding the effects of mRNA vaccines on skeletal muscle cells is crucial to assess their safety and potential adverse outcomes.
Epigenetic Crosstalk and Complementation
Foreign mRNA molecules introduced into the cytosol can interact with host cell noncoding RNAs (ncRNAs) and initiate a complex crosstalk, which may have significant implications for human health. Previous computational analyses have revealed sequence homology between RNA genes of SARS-CoV-2 and numerous human ncRNA transcripts.
These interactions and signaling pathways are known to play critical roles in various diseases, including neurological disorders, cardiovascular diseases, cancer, and autoimmunity. It is plausible that mRNA vaccines encoding the SARS-CoV-2 S protein could engage in epigenetic crosstalk with human genes and transcripts, potentially influencing cellular processes and contributing to disease development.
In Silico Analysis and Findings
To investigate the existence of nucleotide sequence complementarity between the BNT162b2 mRNA vaccine and the human genome, including both coding and ncRNA genes, an in silico analysis was conducted. By comparing the vaccine’s nucleotide sequence with the entirety of the human genome, potential complementarity and interaction sites were identified.
These findings were also compared with those obtained from analyzing the original SARS-CoV-2 S gene sequence. The results of this study shed light on the potential molecular interactions between the mRNA vaccines and the human genome, emphasizing the need for further research and understanding of their implications.
As the global vaccination efforts against COVID-19 continue, it is essential to thoroughly investigate the safety and potential long-term effects of mRNA vaccines. This article has highlighted concerns regarding the nucleotide sequence complementarity between the BNT162b2 mRNA vaccine, the SARS-CoV-2 S gene sequence, and the human genome.
The epigenetic crosstalk between foreign mRNA and host cell ncRNAs introduces complex interactions that may have health implications. In silico analysis serves as a starting point for further research and provides insight into potential molecular interactions.
Continued exploration in this field will contribute to a comprehensive understanding of mRNA vaccines and their impact on human health, guiding future vaccine development and safety assessments.
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Nucleotide sequence complementarity refers to the ability of two nucleic acid strands to form base pairs according to Watson-Crick rules. Complementarity can occur between different regions of the same strand (intramolecular), between two different strands (intermolecular), or between a strand and a complementary sequence in another molecule (intermolecular). Complementarity can have functional consequences, such as affecting the stability, folding, and interactions of nucleic acids. For example, complementarity can mediate the formation of secondary structures, such as hairpins, loops, and stem-loops, which can regulate gene expression, splicing, translation, and degradation. Complementarity can also facilitate the binding of nucleic acids to proteins, such as transcription factors, ribosomes, and enzymes, which can modulate their activity and specificity.
The mRNA COVID-19 vaccines contain synthetic mRNA molecules that encode the full-length or a modified version of the SARS-CoV-2 spike protein. The spike protein is responsible for binding to the host cell receptor, angiotensin-converting enzyme 2 (ACE2), and mediating viral entry. The vaccine mRNA molecules are encapsulated in lipid nanoparticles (LNPs) that protect them from degradation and enhance their delivery into host cells. Once inside the cells, the vaccine mRNA molecules are released from the LNPs and enter the cytoplasm, where they are translated into spike protein by ribosomes. The spike protein is then presented on the cell surface or secreted into the extracellular space, where it stimulates an immune response against SARS-CoV-2.
The vaccine mRNA molecules are designed to mimic natural mRNA molecules in terms of structure and function. However, they also contain some modifications that aim to improve their stability, expression, and immunogenicity. For example, the vaccine mRNA molecules contain modified nucleosides, such as pseudouridine and 1-methylpseudouridine, that reduce their recognition by innate immune sensors and increase their translation efficiency. The vaccine mRNA molecules also contain optimized 5′ and 3′ untranslated regions (UTRs) that enhance their stability and translation initiation. Moreover, the vaccine mRNA molecules contain polyadenylated tails that facilitate their export from the nucleus and their interaction with ribosomes.
The vaccine mRNA molecules are expected to be degraded rapidly by cellular enzymes after translation. However, there is a possibility that some of them may escape degradation and enter the nucleus, where they may interact with the host genome. This could happen through various mechanisms, such as passive diffusion, active transport, or endocytosis. Alternatively, some of the vaccine mRNA molecules may be reverse transcribed into complementary DNA (cDNA) by cellular or viral reverse transcriptases in the cytoplasm or in extracellular vesicles, and then integrated into the host genome by cellular or viral integrases. These scenarios could result in nucleotide sequence complementarity between the vaccine mRNA and the host genome.
Nucleotide sequence complementarity between the vaccine mRNA and the host genome could have potential implications for epigenetic crosstalk. Epigenetic crosstalk refers to the communication between different genomic regions or molecules that affects their epigenetic state and function. Epigenetic crosstalk can occur through various mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, non-coding RNA interference and long-range chromatin interactions. Epigenetic crosstalk can influence gene expression, chromatin structure, genomic stability and cellular differentiation.
reference link: https://www.sciencedirect.com/science/article/abs/pii/S0264410X23008198