Kavli Affiliate: Robert J Edwards
| Authors: 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 Schaefer, Amanda Eaton, Justine Mae Flores, Austin Hamer, Nicholas J Cantazaro, Jr., Michael L Mallory, Melissa D Mattocks, Christopher Berverly, Brianna Rhodes, Katayoun Mansouri, Elizabeth Van Itallie, Pranay Vure, Brooke Manness, Taylor Keyes, Sherry Stanfield-Oakley, Christopher W Woods, Elizabeth A Petzold, Emmanuel B Walter, Kevin Wiehe, Robert J Edwards, David Montefiori, Guido Ferrari, Ralph Baric, Derek W Cain, Kevin O Saunders, Barton F Haynes and Mihai L Azoitei
| Summary:
Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which can readily mutate to escape acquired immunity. Other regions in the spike S2 subunit, such as the fusion peptide and the stem helix, are highly conserved across sarbecoviruses and recognized by broadly reactive antibodies, providing hope that targeting these epitopes by vaccination could offer protection against both current and emergent viruses. Here we employed computational modeling to design epitope scaffolds that display the fusion peptide and the stem helix epitopes. The engineered proteins bound both mature and germline versions of multiple broad and protective human antibodies with high affinity. Binding specificity was confirmed both biochemically and via high resolution crystal structures. Finally, the epitope scaffolds showed potent engagement of antibodies and memory B-cells from subjects previously exposed to SARS-CoV2, illustrating their potential to elicit antibodies against the fusion peptide and the stem helix by vaccination.