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

Author

Listed:
  • Christopher C. Stobart

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta
    Present address: Department of Biological Sciences, Butler University, Indianapolis, Indiana 46208, USA)

  • Christina A. Rostad

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

  • Zunlong Ke

    (School of Biology, Georgia Institute of Technology)

  • Rebecca S. Dillard

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

  • Cheri M. Hampton

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

  • Joshua D. Strauss

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

  • Hong Yi

    (Robert P Apkarian Integrated Electron Microscopy Core, Emory University)

  • Anne L. Hotard

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta
    Present address: Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia 30329, USA)

  • Jia Meng

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta
    Present address: Alios BioPharma, Inc., South San Francisco, California 94080, USA)

  • Raymond J. Pickles

    (University of North Carolina)

  • Kaori Sakamoto

    (College of Veterinary Medicine, University of Georgia)

  • Sujin Lee

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

  • Michael G. Currier

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

  • 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
    Baylor College of Medicine)

  • Elizabeth R. Wright

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta
    Robert P Apkarian Integrated Electron Microscopy Core, Emory University)

  • Martin L. Moore

    (Emory University School of Medicine
    Children’s Healthcare of Atlanta)

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.

Suggested Citation

  • 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 & Suji, 2016. "A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13916
    DOI: 10.1038/ncomms13916
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    Cited by:

    1. Sonal V. Gidwani & Devarshi Brahmbhatt & Aaron Zomback & Mamie Bassie & Jennifer Martinez & Jian Zhuang & John Schulze & Jason S. McLellan & Roberto Mariani & Peter Alff & Daniela Frasca & Bonnie B. B, 2024. "Engineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Bryan S. Sibert & Joseph Y. Kim & Jie E. Yang & Zunlong Ke & Christopher C. Stobart & Martin L. Moore & Elizabeth R. Wright, 2024. "Assembly of respiratory syncytial virus matrix protein lattice and its coordination with fusion glycoprotein trimers," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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