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

Xinkai Wu1, Ke-Jia Shan1, Fuwen Zan2

  • 1State Key Laboratory of Protein and Plant Gene Research, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, 100871, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 2, 2023
PubMed

Insights

Codon usage in severe respiratory syndrome coronavirus 2 (SARS-CoV-2) evolved to reduce protein expression, impacting virus fitness. Optimizing codons for spike mRNA vaccines (Omicron variants) enhanced expression, aiding vaccine development.

Area of Science:

  • Virology
  • Molecular Biology
  • Vaccine Development

Background:

  • Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2.
  • Thousands of SARS-CoV-2 genetic variants identified globally.
  • Viral sequence analysis shows decreasing codon adaptation index (CAI) over time.

Purpose of the Study:

  • Investigate the role of codon usage in SARS-CoV-2 evolution and fitness.
  • Determine the impact of codon deoptimization on viral protein expression.
  • Develop and validate codon-optimized mRNA vaccine candidates against Omicron variants.

Main Methods:

  • Sequence analysis to calculate codon adaptation index (CAI).
  • Evolution modeling to understand mutation preferences.
  • Dual-luciferase assays to measure protein expression.
  • Design and experimental validation of mRNA vaccine candidates.

Main Results:

  • SARS-CoV-2 CAI values decreased over time, linked to mutation preference.
  • Codon deoptimization was found to weaken viral protein expression.
  • Codon-optimized Omicron BA.2.12.1, BA.4/5, and XBB.1.5 spike mRNA vaccines showed high expression.

Conclusions:

  • Codon usage significantly influences SARS-CoV-2 evolution and fitness.
  • Codon optimization is crucial for enhancing protein expression in mRNA vaccines.
  • This study provides a framework for developing effective mRNA and DNA vaccines.
Keywords:
SARS-CoV-2codon optimizationcodon usage biasspike proteinsynonymous mutationsvaccine design

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