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Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge

Author

Listed:
  • Ching-Lin Hsieh

    (The University of Texas at Austin)

  • Sarah R. Leist

    (University of North Carolina at Chapel Hill)

  • Emily Happy Miller

    (Albert Einstein College of Medicine
    Department of Medicine-Infectious Diseases, Albert Einstein College of Medicine)

  • Ling Zhou

    (The University of Texas at Austin)

  • John M. Powers

    (University of North Carolina at Chapel Hill)

  • Alexandra L. Tse

    (Albert Einstein College of Medicine)

  • Albert Wang

    (Albert Einstein College of Medicine)

  • Ande West

    (University of North Carolina at Chapel Hill)

  • Mark R. Zweigart

    (University of North Carolina at Chapel Hill)

  • Jonathan C. Schisler

    (The University of North Carolina at Chapel Hill)

  • Rohit K. Jangra

    (Albert Einstein College of Medicine
    Louisiana State University Health Sciences Center-Shreveport)

  • Kartik Chandran

    (Albert Einstein College of Medicine)

  • Ralph S. Baric

    (University of North Carolina at Chapel Hill)

  • Jason S. McLellan

    (The University of Texas at Austin)

Abstract

Ever-evolving SARS-CoV-2 variants of concern (VOCs) have diminished the effectiveness of therapeutic antibodies and vaccines. Developing a coronavirus vaccine that offers a greater breadth of protection against current and future VOCs would eliminate the need to reformulate COVID-19 vaccines. Here, we rationally engineer the sequence-conserved S2 subunit of the SARS-CoV-2 spike protein and characterize the resulting S2-only antigens. Structural studies demonstrate that the introduction of interprotomer disulfide bonds can lock S2 in prefusion trimers, although the apex samples a continuum of conformations between open and closed states. Immunization with prefusion-stabilized S2 constructs elicits broadly neutralizing responses against several sarbecoviruses and protects female BALB/c mice from mouse-adapted SARS-CoV-2 lethal challenge and partially protects female BALB/c mice from mouse-adapted SARS-CoV lethal challenge. These engineering and immunogenicity results should inform the development of next-generation pan-coronavirus therapeutics and vaccines.

Suggested Citation

  • Ching-Lin Hsieh & Sarah R. Leist & Emily Happy Miller & Ling Zhou & John M. Powers & Alexandra L. Tse & Albert Wang & Ande West & Mark R. Zweigart & Jonathan C. Schisler & Rohit K. Jangra & Kartik Cha, 2024. "Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45404-x
    DOI: 10.1038/s41467-024-45404-x
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    1. Aleksandar Antanasijevic & Leigh M. Sewall & Christopher A. Cottrell & Diane G. Carnathan & Luis E. Jimenez & Julia T. Ngo & Jennifer B. Silverman & Bettina Groschel & Erik Georgeson & Jinal Bhiman & , 2021. "Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. 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.
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    Cited by:

    1. Xandra Nuqui & Lorenzo Casalino & Ling Zhou & Mohamed Shehata & Albert Wang & Alexandra L. Tse & Anupam A. Ojha & Fiona L. Kearns & Mia A. Rosenfeld & Emily Happy Miller & Cory M. Acreman & Surl-Hee A, 2024. "Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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