In phase I testing, Kremsner and his colleagues evaluated doses ranging from 2 to 20 micrograms of mRNA per injection. At the higher dose levels, the vaccine caused too many side effects, with trial participants frequently complaining of problems such as severe headaches, fatigue, chills and injection-site pain.
Some researchers wonder why the vaccine couldn’t be administered at higher doses without inducing side effects.
He and others think that the problem might lie in the mRNA sequence.
Modified RNA
All three mRNA vaccines encode a form of the coronavirus spike protein, which helps virus particles to penetrate human cells. But the Moderna and Pfizer–BioNTech vaccines use modified RNA, incorporating an mRNA nucleotide called pseudouridine — which is similar to uridine but contains a natural modification — in place of uridine itself. This is thought to circumvent the body’s inflammatory reactions to foreign mRNA. CureVac’s vaccine uses normal uridine and relies on altering the sequence of RNA letters in a way that does not affect the protein it codes for, but helps the vaccine to evade immune detection.
There are a few other possible explanations for CureVac’s tolerability problems. Structural differences in the non-coding regions of the CureVac sequence could play a part. Alternatively, the higher storage temperature of CureVac’s jab might have accelerated the breakdown of mRNA in the vial, yielding pieces of genetic code that would raise immune hackles.