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Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens

Author

Listed:
  • Xandra Nuqui

    (University of California San Diego)

  • Lorenzo Casalino

    (University of California San Diego)

  • Ling Zhou

    (The University of Texas at Austin)

  • Mohamed Shehata

    (University of California San Diego)

  • Albert Wang

    (Albert Einstein College of Medicine)

  • Alexandra L. Tse

    (Albert Einstein College of Medicine)

  • Anupam A. Ojha

    (University of California San Diego)

  • Fiona L. Kearns

    (University of California San Diego)

  • Mia A. Rosenfeld

    (University of California San Diego
    National Institutes of Health)

  • Emily Happy Miller

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Cory M. Acreman

    (The University of Texas at Austin)

  • Surl-Hee Ahn

    (University of California Davis)

  • Kartik Chandran

    (Albert Einstein College of Medicine)

  • Jason S. McLellan

    (The University of Texas at Austin)

  • Rommie E. Amaro

    (University of California San Diego
    University of California San Diego)

Abstract

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2’s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50976-9
    DOI: 10.1038/s41467-024-50976-9
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    as
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