Refining the Balance of Attenuation and Immunogenicity of Respiratory Syncytial Virus by Targeted Codon Deoptimization of Virulence Genes

• Type of Material: Article
• Authors: Jia Meng, Emory University; Sujin Lee, Emory University; Anne L. Hotard, Emory University; Martin Moore, Emory University
• Language: English
• Date: 2014-09-01
• Publisher: American Society for Microbiology: mBio
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Meng et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.01704-14
• Title of Journal or Parent Work: mBio
• ISSN: 2150-7511
• Volume: 5
• Issue: 5
• Start Page: e01704
• End Page: e01714
• Grant/Funding Information: This work was supported by NIH grants 1R01AI087798 and 1U19AI095227 and by Emory University and Children’s Healthcare of Atlanta funds.
• Keywords: INTERFERON REGULATORY FACTOR-3; Microbiology; Life Sciences & Biomedicine; EXPRESSION; TEMPERATURE; USAGE; NONSTRUCTURAL PROTEINS NS1; NF-KAPPA-B; CHIMPANZEES; VACCINE DEVELOPMENT; EPITHELIAL-CELLS; Science & Technology; GROWTH
• Research Categories: Health Sciences, Immunology; Health Sciences, Public Health; Health Sciences, General

Abstract

IMPORTANCE: Respiratory syncytial virus (RSV) is the leading cause of infant viral death in the United States and worldwide, and no vaccine is available. Live-attenuated RSV vaccines are the most studied in children but have suffered from genetic instability and low immunogenicity. In order to address both obstacles, we selectively changed the codon usage of the RSV nonstructural (NS) virulence genes NS1 and NS2 to the least-used codons in the human genome (deoptimization). Compared to parental RSV, the codon-deoptimized NS1/NS2 RSV was attenuated in vitro and in mice but induced higher levels of neutralizing antibodies and equivalent protection against challenge. We identified a new attenuating module that retains immunogenicity and is genetically stable, achieved through specific targeting of nonessential virulence genes by codon usage deoptimization.