2. Modifications in the Vaccine mRNA Sequence
The technology behind the mRNA vaccines is complex and sophisticated, and much about it is new and poorly evaluated for safety [14]. The mRNA in the vaccines is very different from the mRNA sequence that the virus uses to encode the spike protein. A significant modification was to replace all of the uridines in the sequence with methylpseudouridines. This allows the mRNA to resist enzymatic breakdown. It has been shown that methylpseudouridine modifications support more than ten times as much protein as unmodified mRNAs, in part by preventing repression of translation initiation [15,16].
Other ingredients include polyethylene glycol and a synthetic cationic lipid, which facilitates escape from the lysosome into the cytoplasm and initiation of protein synthesis. The actual sequence itself is also modified, through a process called “codon optimization,” which involves substituting redundant codons that translate more efficiently than the codons the virus used for each amino acid. A codon replacement that actually changes the peptide sequence is also introduced, replacing two adjacent amino acids with a double proline sequence that disrupts the refolding step to facilitate membrane entry following binding to the ACE2 receptor. Finally, the mRNA molecule is “humanized” by inserting 5’ and 3’ untranslated regions (UTRs) ) on its two ends, sequences borrowed from long-lasting human mRNAs, and adding a long poly-A tail to further promote resistance to breakdown [14]. The spike protein shares regions of high molecular similarity with many important human proteins, and molecular mimicry may lead to autoimmune disease, especially because the vaccine induces a very strong antibody response [17].
It appears that the developers were very successful in assuring rapid synthesis of the spike protein sustained over a long period of time. Most mRNA molecules are eliminated within a few hours of their synthesis, whereas spike protein mRNA has been found in the draining lymph nodes of the arm muscle two months after vaccination, and this durability was associated with post-vaccine symptoms similar to the symptomatic profile of long COVID [18]. Fertig et al. have found mRNA circulating for at least two weeks after vaccination [19].