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A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism

Author

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  • Anders Krarup

    (Janssen Infectious Diseases and Vaccines)

  • Daphné Truan

    (Janssen Infectious Diseases and Vaccines)

  • Polina Furmanova-Hollenstein

    (Janssen Infectious Diseases and Vaccines)

  • Lies Bogaert

    (Janssen Infectious Diseases and Vaccines)

  • Pascale Bouchier

    (Janssen Infectious Diseases and Vaccines)

  • Ilona J. M. Bisschop

    (Janssen Infectious Diseases and Vaccines)

  • Myra N. Widjojoatmodjo

    (Janssen Infectious Diseases and Vaccines)

  • Roland Zahn

    (Janssen Infectious Diseases and Vaccines)

  • Hanneke Schuitemaker

    (Janssen Infectious Diseases and Vaccines)

  • Jason S. McLellan

    (Geisel School of Medicine at Dartmouth)

  • Johannes P. M. Langedijk

    (Janssen Infectious Diseases and Vaccines)

Abstract

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain.

Suggested Citation

  • Anders Krarup & Daphné Truan & Polina Furmanova-Hollenstein & Lies Bogaert & Pascale Bouchier & Ilona J. M. Bisschop & Myra N. Widjojoatmodjo & Roland Zahn & Hanneke Schuitemaker & Jason S. McLellan &, 2015. "A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9143
    DOI: 10.1038/ncomms9143
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    Cited by:

    1. Nicole V. Johnson & Revina C. Scherpenzeel & Mark J. G. Bakkers & Ajit R. Ramamohan & Daan Overveld & Lam Le & Johannes P. M. Langedijk & Joost A. Kolkman & Jason S. McLellan, 2024. "Structural basis for potent neutralization of human respirovirus type 3 by protective single-domain camelid antibodies," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. 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.
    3. Karen J. Gonzalez & Jiachen Huang & Miria F. Criado & Avik Banerjee & Stephen M. Tompkins & Jarrod J. Mousa & Eva-Maria Strauch, 2024. "A general computational design strategy for stabilizing viral class I fusion proteins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Momei Zhou & Benjamin Vollmer & Emily Machala & Muyuan Chen & Kay Grünewald & Ann M. Arvin & Wah Chiu & Stefan L. Oliver, 2023. "Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Ching-Lin Hsieh & Scott A. Rush & Concepcion Palomo & Chia-Wei Chou & Whitney Pickens & Vicente Más & Jason S. McLellan, 2022. "Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    6. Ruipeng Lei & Timothy J. C. Tan & Andrea Hernandez Garcia & Yiquan Wang & Meghan Diefenbacher & Chuyun Teo & Gopika Gopan & Zahra Tavakoli Dargani & Qi Wen Teo & Claire S. Graham & Christopher B. Broo, 2022. "Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Mark J. G. Bakkers & Tina Ritschel & Machteld Tiemessen & Jacobus Dijkman & Angelo A. Zuffianò & Xiaodi Yu & Daan Overveld & Lam Le & Richard Voorzaat & Marlies M. Haaren & Martijn Man & Sem Tamara & , 2024. "Efficacious human metapneumovirus vaccine based on AI-guided engineering of a closed prefusion trimer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Johannes P. M. Langedijk & Freek Cox & Nicole V. Johnson & Daan Overveld & Lam Le & Ward Hoogen & Richard Voorzaat & Roland Zahn & Leslie Fits & Jarek Juraszek & Jason S. McLellan & Mark J. G. Bakkers, 2024. "Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Kwinten Sliepen & Laura Radić & Joan Capella-Pujol & Yasunori Watanabe & Ian Zon & Ana Chumbe & Wen-Hsin Lee & Marlon Gast & Jelle Koopsen & Sylvie Koekkoek & Iván Moral-Sánchez & Philip J. M. Brouwer, 2022. "Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Xiao Xiao & Arthur Fridman & Lu Zhang & Pavlo Pristatsky & Eberhard Durr & Michael Minnier & Aimin Tang & Kara S. Cox & Zhiyun Wen & Renee Moore & Dongrui Tian & Jennifer D. Galli & Scott Cosmi & Mich, 2022. "Profiling of hMPV F-specific antibodies isolated from human memory B cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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