Engineered immunogens to elicit antibodies against conserved coronavirus epitopes

A. Brenda Kapingidza, Daniel J. Marston, Caitlin Harris, Daniel Wrapp, Kaitlyn Winters, Dieter Mielke, Lu Xiaozhi, Qi Yin, Andrew Foulger, Rob Parks, Maggie Barr, Amanda Newman, Alexandra Schäfer, Amanda Eaton, Justine Mae Flores, Austin Harner, Nicholas J. Catanzaro, Michael L. Mallory, Melissa D. Mattocks, Christopher Beverly, Brianna Rhodes, Katayoun Mansouri, Elizabeth Itallie, Pranay Vure, Brooke Dunn, Taylor Keyes, Sherry Stanfield-Oakley, Christopher W. Woods, Elizabeth A. Petzold, Emmanuel B. Walter, Kevin Wiehe, Robert J. Edwards, David C. Montefiori, Guido Ferrari, Ralph Baric, Derek W. Cain, Kevin O. Saunders, Barton F. Haynes and Mihai L. Azoitei ()
Additional contact information
A. Brenda Kapingidza: Duke University
Daniel J. Marston: Duke University
Caitlin Harris: Duke University
Daniel Wrapp: Duke University
Kaitlyn Winters: Duke University
Dieter Mielke: Duke University
Lu Xiaozhi: Duke University
Qi Yin: Duke University
Andrew Foulger: Duke University
Rob Parks: Duke University
Maggie Barr: Duke University
Amanda Newman: Duke University
Alexandra Schäfer: University of North Carolina at Chapel Hill
Amanda Eaton: Duke University
Justine Mae Flores: Duke University
Austin Harner: Duke University
Nicholas J. Catanzaro: University of North Carolina at Chapel Hill
Michael L. Mallory: University of North Carolina at Chapel Hill
Melissa D. Mattocks: University of North Carolina at Chapel Hill
Christopher Beverly: Duke University
Brianna Rhodes: Duke University
Katayoun Mansouri: Duke University
Elizabeth Itallie: Duke University
Pranay Vure: Duke University
Brooke Dunn: Duke University
Taylor Keyes: Duke University
Sherry Stanfield-Oakley: Duke University
Christopher W. Woods: Duke University
Elizabeth A. Petzold: Duke University Medical Center
Emmanuel B. Walter: Duke University
Kevin Wiehe: Duke University
Robert J. Edwards: Duke University
David C. Montefiori: Duke University
Guido Ferrari: Duke University
Ralph Baric: University of North Carolina at Chapel Hill
Derek W. Cain: Duke University
Kevin O. Saunders: Duke University
Barton F. Haynes: Duke University
Mihai L. Azoitei: Duke University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing residues 815-823 adjacent to the fusion peptide, are highly conserved across sarbecoviruses and are recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current and emergent viruses. Here we employ computational modeling to design scaffolded immunogens that display the spike 815-823 peptide and the stem helix epitopes without the distracting and immunodominant receptor binding domain. These engineered proteins bind with high affinity and specificity to the mature and germline versions of previously identified broadly protective human antibodies. Epitope scaffolds interact with both sera and isolated monoclonal antibodies with broadly reactivity from individuals with pre-existing SARS-CoV-2 immunity. When used as immunogens, epitope scaffolds elicit sera with broad betacoronavirus reactivity and protect as “boosts” against live virus challenge in mice, illustrating their potential as components of a future pancoronavirus vaccine.

Date: 2023
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DOI: 10.1038/s41467-023-43638-9

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