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

Jia Meng; Sujin Lee; Anne L. Hotard; Martin Moore

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Author Notes:

Address correspondence to Martin L. Moore, Email: mlmoor2@emory.edu

We thank Edward Walsh for monoclonal antibody to RSV N protein and Michael Teng for antisera to RSV NS1 and NS2 proteins. We thank Ursula Buchholz and Karl-Klaus Conzelmann for BSR-T7/5 cells.

M.L.M. and Emory University are entitled to licensing fees derived from various agreements Emory has entered into related to products used in the research described in this paper. This study could affect his personal financial status. The terms of this agreement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

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Research Funding:

This work was supported by NIH grants 1R01AI087798 and 1U19AI095227 and by Emory University and Children’s Healthcare of Atlanta funds.

Keywords:

Science & Technology
Life Sciences & Biomedicine
Microbiology
NONSTRUCTURAL PROTEINS NS1
NF-KAPPA-B
INTERFERON REGULATORY FACTOR-3
EPITHELIAL-CELLS
VACCINE DEVELOPMENT
USAGE
TEMPERATURE
CHIMPANZEES
EXPRESSION
GROWTH

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

Jia Meng, Emory University

Sujin Lee, Emory University

Anne L. Hotard, Emory University

Martin Moore, Emory University

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Journal Title:

mBio

Volume:

Volume 5, Number 5

Publisher:

American Society for Microbiology: mBio | 2014-09-01, Pages e01704-e01714

Type of Work:

Article | Final Publisher PDF

Permanent URL:

https://pid.emory.edu/ark:/25593/mr3qb

Publisher DOI:

http://doi.org/10.1128/mBio.01704-14

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.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License ( http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits making multiple copies, distribution, public display, and publicly performance, distribution of derivative works, provided the original work is properly cited. This license requires copyright and license notices be kept intact, derivative works be licensed under the same terms or compatible terms as the original work, credit be given to copyright holder and/or author. This license prohibits exercising rights for commercial purposes.

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

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