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

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...

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Autores principales: Stobart, Christopher C., Rostad, Christina A., Ke, Zunlong, Dillard, Rebecca S., Hampton, Cheri M., Strauss, Joshua D., Yi, Hong, Hotard, Anne L., Meng, Jia, Pickles, Raymond J., Sakamoto, Kaori, Lee, Sujin, Currier, Michael G., Moin, Syed M., Graham, Barney S., Boukhvalova, Marina S., Gilbert, Brian E., Blanco, Jorge C. G., Piedra, Pedro A., Wright, Elizabeth R., Moore, Martin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187593/
https://www.ncbi.nlm.nih.gov/pubmed/28000669
http://dx.doi.org/10.1038/ncomms13916
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author Stobart, Christopher C.
Rostad, Christina A.
Ke, Zunlong
Dillard, Rebecca S.
Hampton, Cheri M.
Strauss, Joshua D.
Yi, Hong
Hotard, Anne L.
Meng, Jia
Pickles, Raymond J.
Sakamoto, Kaori
Lee, Sujin
Currier, Michael G.
Moin, Syed M.
Graham, Barney S.
Boukhvalova, Marina S.
Gilbert, Brian E.
Blanco, Jorge C. G.
Piedra, Pedro A.
Wright, Elizabeth R.
Moore, Martin L.
author_facet Stobart, Christopher C.
Rostad, Christina A.
Ke, Zunlong
Dillard, Rebecca S.
Hampton, Cheri M.
Strauss, Joshua D.
Yi, Hong
Hotard, Anne L.
Meng, Jia
Pickles, Raymond J.
Sakamoto, Kaori
Lee, Sujin
Currier, Michael G.
Moin, Syed M.
Graham, Barney S.
Boukhvalova, Marina S.
Gilbert, Brian E.
Blanco, Jorge C. G.
Piedra, Pedro A.
Wright, Elizabeth R.
Moore, Martin L.
author_sort Stobart, Christopher C.
collection PubMed
description 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-dG(m)-Gs(null)-line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats.
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spelling pubmed-51875932017-01-03 A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation Stobart, Christopher C. Rostad, Christina A. Ke, Zunlong Dillard, Rebecca S. Hampton, Cheri M. Strauss, Joshua D. Yi, Hong Hotard, Anne L. Meng, Jia Pickles, Raymond J. Sakamoto, Kaori Lee, Sujin Currier, Michael G. Moin, Syed M. Graham, Barney S. Boukhvalova, Marina S. Gilbert, Brian E. Blanco, Jorge C. G. Piedra, Pedro A. Wright, Elizabeth R. Moore, Martin L. Nat Commun Article 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-dG(m)-Gs(null)-line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats. Nature Publishing Group 2016-12-21 /pmc/articles/PMC5187593/ /pubmed/28000669 http://dx.doi.org/10.1038/ncomms13916 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Stobart, Christopher C.
Rostad, Christina A.
Ke, Zunlong
Dillard, Rebecca S.
Hampton, Cheri M.
Strauss, Joshua D.
Yi, Hong
Hotard, Anne L.
Meng, Jia
Pickles, Raymond J.
Sakamoto, Kaori
Lee, Sujin
Currier, Michael G.
Moin, Syed M.
Graham, Barney S.
Boukhvalova, Marina S.
Gilbert, Brian E.
Blanco, Jorge C. G.
Piedra, Pedro A.
Wright, Elizabeth R.
Moore, Martin L.
A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
title A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
title_full A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
title_fullStr A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
title_full_unstemmed A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
title_short A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
title_sort live rsv vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187593/
https://www.ncbi.nlm.nih.gov/pubmed/28000669
http://dx.doi.org/10.1038/ncomms13916
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