Differences in Vaccine and SARS-CoV-2 Replication Derived mRNA: Implications for Cell Biology and Future Disease

Abstract

Codon optimization describes the process used to increase protein production by use of alternative but synonymous codon changes. In SARS-CoV-2 mRNA vaccines codon optimizations can result in differential secondary conformations that inevitably affect a protein’s function with significant consequences to the cell. Importantly, when codon optimization increases the GC content of synthetic mRNAs, there can be an inevitable enrichment of G-quartets which potentially form G-quadruplex structures. The emerging G-quadruplexes are favorable binding sites of RNA binding proteins like helicases that inevitably affect epigenetic reprogramming of the cell by altering transcription, translation and replication. In this study, we performed a RNAfold analysis to investigate alterations in secondary structures of mRNAs in SARS-CoV-2 vaccines due to codon optimization. We show a significant increase in the GC content of mRNAs in vaccines as compared to native SARS-CoV-2 RNA sequences encoding the spike protein. As the GC enrichment leads to more G-quadruplex structure formations, these may contribute to potential pathological processes initiated by SARS-CoV-2 molecular vaccination.

Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs

“…Recently, members of our team investigated possible alterations in secondary structure of mRNAs in SARS-CoV-2 vaccines due to codon optimization of synthetic mRNA transcripts ( McKernan et al, 2021 ). This study has shown that there is a significant enrichment of GC content in mRNAs in vaccines (53% in BNT162b2 and 61% in Moderna mRNA-1273) as compared to the native SARS-CoV-2 mRNA (36%).…”

“…This study has shown that there is a significant enrichment of GC content in mRNAs in vaccines (53% in BNT162b2 and 61% in Moderna mRNA-1273) as compared to the native SARS-CoV-2 mRNA (36%). The enriched GC content of mRNAs is the result of codon optimization performed during the development of the mRNAs used in SARS-CoV-2 vaccines, apparently without determining the effect on secondary structures, particularly the Guanine quadruplex (G quadruplex) formation ( McKernan et al, 2021 ).…”

SARS-CoV-2 Spike Protein in the Pathogenesis of Prion-like Diseases

“…In addition, it has become apparent that the human prion protein's mRNA contains multiple G4-forming motifs, and it has been hypothesized that G4s may play a critical role in causing the prion protein to assume its misfolded state [93]. The original nucleotide sequence in the virus version of spike protein mRNA only has the potential to form four G4 motifs, whereas the Pfizer version has the potential to produce nine, and the Moderna version can form 19 [94]. The author of a paper published in 2014, aptly titled, "G-quadruplexes within prion mRNA: the missing link in prion disease?"…”

Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, exosomes and microRNAs

“…Recently, members of our team investigated possible alterations in secondary structure of mRNAs in SARS-CoV-2 vaccines due to codon optimization of synthetic mRNA transcripts [71]. This study has shown that there is a significant enrichment of GC content in mRNAs in vaccines (53% in Pfizer BNT 162b2 and 61% in Moderna mRNA-1273) as compared to the native SARS-CoV-2 mRNA (36%).…”

“…This study has shown that there is a significant enrichment of GC content in mRNAs in vaccines (53% in Pfizer BNT 162b2 and 61% in Moderna mRNA-1273) as compared to the native SARS-CoV-2 mRNA (36%). The enriched GC content of mRNAs is the result of codon optimization performed during the development of the mRNAs used in SARS-CoV-2 vaccines, apparently without determining the effect on secondary structures, particularly the G quadruplex formation [71].…”