Are There Hidden Genes in DNA/RNA Vaccines?
Beaudoin, Christopher A
Blundell, Tom L
Frontiers Media SA
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Beaudoin, C. A., Bartas, M., Volná, A., Pečinka, P., & Blundell, T. L. (2022). Are There Hidden Genes in DNA/RNA Vaccines?. Front Immunol, 13 https://doi.org/10.3389/fimmu.2022.801915
Due to the fast global spreading of the Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2), prevention and treatment options are direly needed in order to control infection-related morbidity, mortality, and economic losses. Although drug and inactivated and attenuated virus vaccine development can require significant amounts of time and resources, DNA and RNA vaccines offer a quick, simple, and cheap treatment alternative, even when produced on a large scale. The spike protein, which has been shown as the most antigenic SARS-CoV-2 protein, has been widely selected as the target of choice for DNA/RNA vaccines. Vaccination campaigns have reported high vaccination rates and protection, but numerous unintended effects, ranging from muscle pain to death, have led to concerns about the safety of RNA/DNA vaccines. In parallel to these studies, several open reading frames (ORFs) have been found to be overlapping SARS-CoV-2 accessory genes, two of which, ORF2b and ORF-Sh, overlap the spike protein sequence. Thus, the presence of these, and potentially other ORFs on SARS-CoV-2 DNA/RNA vaccines, could lead to the translation of undesired proteins during vaccination. Herein, we discuss the translation of overlapping genes in connection with DNA/RNA vaccines. Two mRNA vaccine spike protein sequences, which have been made publicly-available, were compared to the wild-type sequence in order to uncover possible differences in putative overlapping ORFs. Notably, the Moderna mRNA-1273 vaccine sequence is predicted to contain no frameshifted ORFs on the positive sense strand, which highlights the utility of codon optimization in DNA/RNA vaccine design to remove undesired overlapping ORFs. Since little information is available on ORF2b or ORF-Sh, we use structural bioinformatics techniques to investigate the structure-function relationship of these proteins. The presence of putative ORFs on DNA/RNA vaccine candidates implies that overlapping genes may contribute to the translation of smaller peptides, potentially leading to unintended clinical outcomes, and that the protein-coding potential of DNA/RNA vaccines should be rigorously examined prior to administration.
Immunology, SARS-CoV-2, spike protein, DNA vaccine, RNA vaccine, ORF2b, ORF-Sh, codon optimization
Wellcome Trust (200814/Z/16/Z)
External DOI: https://doi.org/10.3389/fimmu.2022.801915
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334314