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

Hueting, David ; Schriever, Karen ; Sun, Rui ; Vlachiotis, Stelios ; Zuo, Fanglei ; Du, Likun ; Persson, Helena ; Hofström, Camilla ; Ohlin, Mats LU orcid and Walldén, Karin , et al. (2023) In Nature Communications 14(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
article number
6527
publisher
Nature Publishing Group
external identifiers
  • pmid:37845250
  • scopus:85174288771
ISSN
2041-1723
DOI
10.1038/s41467-023-42200-x
language
English
LU publication?
yes
id
611b562d-327f-4bab-b473-e797ded3a94d
date added to LUP
2024-01-11 15:39:09
date last changed
2025-05-10 23:02:51
@article{611b562d-327f-4bab-b473-e797ded3a94d,
  abstract     = {{<p>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.</p>}},
  author       = {{Hueting, David and Schriever, Karen and Sun, Rui and Vlachiotis, Stelios and Zuo, Fanglei and Du, Likun and Persson, Helena and Hofström, Camilla and Ohlin, Mats and Walldén, Karin and Buggert, Marcus and Hammarström, Lennart and Marcotte, Harold and Pan-Hammarström, Qiang and Andréll, Juni and Syrén, Per Olof}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Design, structure and plasma binding of ancestral β-CoV scaffold antigens}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-42200-x}},
  doi          = {{10.1038/s41467-023-42200-x}},
  volume       = {{14}},
  year         = {{2023}},
}