Design, structure and plasma binding of ancestral β-CoV scaffold antigens

David Hueting, Karen Schriever, Rui Sun, Stelios Vlachiotis, Fanglei Zuo, Likun Du, Helena Persson, Camilla Hofström, Mats Ohlin, Karin Walldén, Marcus Buggert, Lennart Hammarström, Harold Marcotte, Qiang Pan-Hammarström, Juni Andréll () and Per-Olof Syrén ()
Additional contact information
David Hueting: KTH Royal Institute of Technology
Karen Schriever: KTH Royal Institute of Technology
Rui Sun: Karolinska Institutet
Stelios Vlachiotis: Karolinska Institutet
Fanglei Zuo: Karolinska Institutet
Likun Du: Karolinska Institutet
Helena Persson: KTH Royal Institute of Technology
Camilla Hofström: KTH Royal Institute of Technology
Mats Ohlin: Science for Life Laboratory
Karin Walldén: Stockholm University
Marcus Buggert: Karolinska Institutet
Lennart Hammarström: Karolinska Institutet
Harold Marcotte: Karolinska Institutet
Qiang Pan-Hammarström: Karolinska Institutet
Juni Andréll: Stockholm University
Per-Olof Syrén: KTH Royal Institute of Technology

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

Abstract: Abstract We report the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interact with plasma of patients recovered from COVID-19 but do not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yield high resolution structures (2.6–2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. The structures reveal an intricate hydrogen-bonding network mediated by well-resolved loops, both within and across monomers, tethering the N-terminal domain and RBD together. We show that AnSA-5 can induce and boost a broad-spectrum immune response against the wild-type RBD as well as circulating variants of concern in an immune organoid model derived from tonsils. Finally, we highlight how AnSAs are potent scaffolds by replacing the ancestral RBD with the wild-type sequence, which restores ACE2 binding and increases the interaction with convalescent plasma.

Date: 2023
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DOI: 10.1038/s41467-023-42200-x

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