Optimization and Deoptimization of Codons in SARS‐CoV‐2 and Related Implications for Vaccine Development

Abstract

The spread of coronavirus disease 2019 (COVID‐19), caused by severe respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has progressed into a global pandemic. To date, thousands of genetic variants have been identified among SARS‐CoV‐2 isolates collected from patients. Sequence analysis reveals that the codon adaptation index (CAI) values of viral sequences have decreased over time but with occasional fluctuations. Through evolution modeling, it is found that this phenomenon may result from the virus's mutation preference during transmission. Using dual‐luciferase assays, it is further discovered that the deoptimization of codons in the viral sequence may weaken protein expression during virus evolution, indicating that codon usage may play an important role in virus fitness. Finally, given the importance of codon usage in protein expression and particularly for mRNA vaccines, it is designed several codon‐optimized Omicron BA.2.12.1, BA.4/5, and XBB.1.5 spike mRNA vaccine candidates and experimentally validated their high levels of expression. This study highlights the importance of codon usage in virus evolution and provides guidelines for codon optimization in mRNA and DNA vaccine development.

Genetic Diversity of Grapevine Virus A in Three Australian Vineyards Using Amplicon High Throughput Sequencing (Amplicon-HTS)

“…Although synonymous substitutions conventionally are thought to have no direct impact on protein structure or function, studies have demonstrated their role in changing virus fitness by altering the secondary structure of RNAs and modifying codon usage bias during replication [ 76 , 77 , 78 ]. These alterations may lead to a reduction in translation and replication efficiency, resulting in decreased infectivity during transmission and weakened protein expression during virus evolution [ 77 , 78 , 79 ]. The intricate interplay between synonymous and nonsynonymous mutations in the GVA population under natural selection pressure and their implications for pathogenicity and the evolution of GVA merits further exploration.…”

Codon-optimization in gene therapy: promises, prospects and challenges

“…Codon optimization has played an important role in the development of RNA-based COVID-19 vaccines. Current research efforts are focused on further advancing the field of codon optimization for COVID-19 vaccines to address new strains of the coronavirus ( Wu et al, 2023 ). Unfortunately, it was not possible to provide here the specific metrics used for codon optimization in the above-mentioned studies for commercial product development.…”