Stabilized coronavirus spike stem elicits a broadly protective antibody
Ching-Lin Hsieh,
Anne P. Werner,
Sarah R. Leist,
Laura J. Stevens,
Ester Falconer,
Jory A. Goldsmith,
Chia-Wei Chou,
Olubukola M. Abiona,
Ande West,
Kathryn Westendorf,
Krithika Muthuraman,
Ethan J. Fritch,
Kenneth H. Dinnon, III,
Alexandra Schäfer,
Mark R. Denison,
James D. Chappell,
Ralph S. Baric,
Barney S. Graham,
Kizzmekia S. Corbett,
Jason S. McLellan
Affiliations
Ching-Lin Hsieh
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
Anne P. Werner
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Sarah R. Leist
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Laura J. Stevens
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Ester Falconer
AbCellera Biologics Inc., Vancouver, BC V5Y 0A1, Canada
Jory A. Goldsmith
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
Chia-Wei Chou
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
Olubukola M. Abiona
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Ande West
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Kathryn Westendorf
AbCellera Biologics Inc., Vancouver, BC V5Y 0A1, Canada
Krithika Muthuraman
AbCellera Biologics Inc., Vancouver, BC V5Y 0A1, Canada
Ethan J. Fritch
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Kenneth H. Dinnon, III
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Alexandra Schäfer
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Mark R. Denison
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
James D. Chappell
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Ralph S. Baric
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Barney S. Graham
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Kizzmekia S. Corbett
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Jason S. McLellan
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; Corresponding author
Summary: Current coronavirus (CoV) vaccines primarily target immunodominant epitopes in the S1 subunit, which are poorly conserved and susceptible to escape mutations, thus threatening vaccine efficacy. Here, we use structure-guided protein engineering to remove the S1 subunit from the Middle East respiratory syndrome (MERS)-CoV spike (S) glycoprotein and develop stabilized stem (SS) antigens. Vaccination with MERS SS elicits cross-reactive β-CoV antibody responses and protects mice against lethal MERS-CoV challenge. High-throughput screening of antibody-secreting cells from MERS SS-immunized mice led to the discovery of a panel of cross-reactive monoclonal antibodies. Among them, antibody IgG22 binds with high affinity to both MERS-CoV and severe acute respiratory syndrome (SARS)-CoV-2 S proteins, and a combination of electron microscopy and crystal structures localizes the epitope to a conserved coiled-coil region in the S2 subunit. Passive transfer of IgG22 protects mice against both MERS-CoV and SARS-CoV-2 challenge. Collectively, these results provide a proof of principle for cross-reactive CoV antibodies and inform the development of pan-CoV vaccines and therapeutic antibodies.
