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

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 Chandran, Ralph S. Baric and Jason S. McLellan ()
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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
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45404-x

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