A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation

Christopher C. Stobart, Christina A. Rostad, Zunlong Ke, Rebecca S. Dillard, Cheri M. Hampton, Joshua D. Strauss, Hong Yi, Anne L. Hotard, Jia Meng, Raymond J. Pickles, Kaori Sakamoto, Sujin Lee, Michael G. Currier, Syed M. Moin, Barney S. Graham, Marina S. Boukhvalova, Brian E. Gilbert, Jorge C. G. Blanco, Pedro A. Piedra, Elizabeth R. Wright () and Martin L. Moore ()
Additional contact information
Christopher C. Stobart: Emory University School of Medicine
Christina A. Rostad: Emory University School of Medicine
Zunlong Ke: School of Biology, Georgia Institute of Technology
Rebecca S. Dillard: Emory University School of Medicine
Cheri M. Hampton: Emory University School of Medicine
Joshua D. Strauss: Emory University School of Medicine
Hong Yi: Robert P Apkarian Integrated Electron Microscopy Core, Emory University
Anne L. Hotard: Emory University School of Medicine
Jia Meng: Emory University School of Medicine
Raymond J. Pickles: University of North Carolina
Kaori Sakamoto: College of Veterinary Medicine, University of Georgia
Sujin Lee: Emory University School of Medicine
Michael G. Currier: Emory University School of Medicine
Syed M. Moin: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Barney S. Graham: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Marina S. Boukhvalova: Sigmovir Biosystems Inc.
Brian E. Gilbert: Baylor College of Medicine
Jorge C. G. Blanco: Sigmovir Biosystems Inc.
Pedro A. Piedra: Baylor College of Medicine
Elizabeth R. Wright: Emory University School of Medicine
Martin L. Moore: Emory University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization and there remains no pediatric vaccine. RSV live-attenuated vaccines (LAVs) have a history of safe testing in infants; however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we seek to engineer an RSV LAV with enhanced immunogenicity. Genetic mapping identifies strain line 19 fusion (F) protein residues that correlate with pre-fusion antigen maintenance by ELISA and thermal stability of infectivity in live RSV. We generate a LAV candidate named OE4 which expresses line 19F and is attenuated by codon-deoptimization of non-structural (NS1 and NS2) genes, deletion of the small hydrophobic (SH) gene, codon-deoptimization of the attachment (G) gene and ablation of the secreted form of G. OE4 (RSV-A2-dNS1-dNS2-ΔSH-dGm-Gsnull-line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats.

Date: 2016
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DOI: 10.1038/ncomms13916

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