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A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

Author

Listed:
  • Jimin Lee

    (University of Washington)

  • Cameron Stewart

    (University of Washington)

  • Alexandra Schäfer

    (University of North Carolina)

  • Elizabeth M. Leaf

    (University of Washington
    University of Washington)

  • Young-Jun Park

    (University of Washington
    Howard Hughes Medical Institute)

  • Daniel Asarnow

    (University of Washington)

  • John M. Powers

    (University of North Carolina)

  • Catherine Treichel

    (University of Washington
    University of Washington)

  • Kaitlin R. Sprouse

    (University of Washington
    Howard Hughes Medical Institute)

  • Davide Corti

    (a subsidiary of Vir Biotechnology)

  • Ralph Baric

    (University of North Carolina)

  • Neil P. King

    (University of Washington
    University of Washington)

  • David Veesler

    (University of Washington
    Howard Hughes Medical Institute)

Abstract

Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S2 subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S2 trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S2 subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2 trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.

Suggested Citation

  • Jimin Lee & Cameron Stewart & Alexandra Schäfer & Elizabeth M. Leaf & Young-Jun Park & Daniel Asarnow & John M. Powers & Catherine Treichel & Kaitlin R. Sprouse & Davide Corti & Ralph Baric & Neil P. , 2024. "A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49656-5
    DOI: 10.1038/s41467-024-49656-5
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    References listed on IDEAS

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    1. Alexandra C. Walls & M. Alejandra Tortorici & Berend-Jan Bosch & Brandon Frenz & Peter J. M. Rottier & Frank DiMaio & Félix A. Rey & David Veesler, 2016. "Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer," Nature, Nature, vol. 531(7592), pages 114-117, March.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Chunyan Wang & Rien Haperen & Javier Gutiérrez-Álvarez & Wentao Li & Nisreen M. A. Okba & Irina Albulescu & Ivy Widjaja & Brenda Dieren & Raul Fernandez-Delgado & Isabel Sola & Daniel L. Hurdiss & Ola, 2021. "A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Kizzmekia S. Corbett & Darin K. Edwards & Sarah R. Leist & Olubukola M. Abiona & Seyhan Boyoglu-Barnum & Rebecca A. Gillespie & Sunny Himansu & Alexandra Schäfer & Cynthia T. Ziwawo & Anthony T. DiPia, 2020. "SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness," Nature, Nature, vol. 586(7830), pages 567-571, October.
    5. Yunlong Cao & Fanchong Jian & Jing Wang & Yuanling Yu & Weiliang Song & Ayijiang Yisimayi & Jing Wang & Ran An & Xiaosu Chen & Na Zhang & Yao Wang & Peng Wang & Lijuan Zhao & Haiyan Sun & Lingling Yu , 2023. "Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution," Nature, Nature, vol. 614(7948), pages 521-529, February.
    6. Jing-Hui Tian & Nita Patel & Robert Haupt & Haixia Zhou & Stuart Weston & Holly Hammond & James Logue & Alyse D. Portnoff & James Norton & Mimi Guebre-Xabier & Bin Zhou & Kelsey Jacobson & Sonia Macie, 2021. "SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    7. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    8. Yuan Yuan & Duanfang Cao & Yanfang Zhang & Jun Ma & Jianxun Qi & Qihui Wang & Guangwen Lu & Ying Wu & Jinghua Yan & Yi Shi & Xinzheng Zhang & George F. Gao, 2017. "Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    9. Amin Addetia & Luca Piccoli & James Brett Case & Young-Jun Park & Martina Beltramello & Barbara Guarino & Ha Dang & Guilherme Dias de Melo & Dora Pinto & Kaitlin Sprouse & Suzanne M. Scheaffer & Jessi, 2023. "Neutralization, effector function and immune imprinting of Omicron variants," Nature, Nature, vol. 621(7979), pages 592-601, September.
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