Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design

Jacob Kames; David Dillon Holcomb; Ofer Kimchi; Michael DiCuccio; Nobuko Hamasaki-Katagiri; Tony Wang; Anton A Komar; Aikaterini Alexaki; Chava Kimchi-Sarfaty

Currently most published attempts of viral attenuation through codon pair deoptimization do not discuss the strategy for selecting which genes to deoptimize. Although codon pair deoptimization has been proven successful for viral attenuation [2, 32, 33] , the mechanism is not clear. In addition, it is reasonable to assume that for every successful published deoptimization attempt, there may be several unsuccessful and therefore unpublished ones. Similarly, there have been successful attempts to generate attenuated viruses through codon deoptimization [34] [35] [36] [37] . Understanding the mechanism that leads to viral attenuation requires a thorough characterization of the viral sequence and of the consequences of sequence changes. There are several factors that may contribute to the efficacy of deoptimization strategies. In changing the codon pair usage, the dinucleotide frequency and the GC content are altered; mRNA secondary structure and translational kinetics are also perturbed. Further, the CpG content is changing, leading potentially to altered immunogenicity. It is likely that codon pair (or codon) deoptimization leads to reduced expression, either due to changes in transcription, mRNA stability, or translation efficiency [38] . Alternatively, it is possible that deoptimization may lead to perturbed cotranslational folding [39] , resulting in altered protein conformation. In the case of the S protein, this may lead to decreased binding affinity for the ACE2 protein, thus affecting viral fitness.