Are There Hidden Genes in DNA/RNA Vaccines?
🦠 🧬 💉, Beaudoin et al., Frontiers in Immunology, 2022.02
Beaudoin et al., Frontiers in Immunology, 2022.02
“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.”
Figure 1 | Structural characterization of ORF2b and ORF-Sh. Full-length ORF2b (cyan) aligned with one protomer of the HMPV P oligomerization domain (green) fixed in a bilayer membrane (gray) is depicted (A). ORF-Sh (cyan) aligned to the mouse early growth response protein 1 (EGR1) (PDB: 1p47) (green), which is a homolog of transcriptional repressor CTCF, bound to DNA (grey) is shown (B). Basic residues in the ORF-Sh protein are shown as dark blue sticks (B).