Targeting of conserved spike epitopes enables broad antibody neutralisation of diverse bat sarbecoviruses
6 affiliations
- 1Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom
- 2Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute, London, United Kingdom
- 3The Pirbright Institute, Woking, Surrey, United Kingdom
- 4Structural Biology Science Technology Platform, The Francis Crick Institute, London, United Kingdom
- 5MRC-University of Glasgow Centre for Virus Research, The University of Glasgow, Glasgow, United Kingdom
- 6Department of Infectious Disease, South Kensington Campus, Imperial College London, London, United Kingdom
Abstract
The continuing evolution of SARS-CoV-2 variants of concern, and the increasing spillover potential of sarbecoviruses into the human population presents an important and urgent need to discover cross-reactive monoclonal antibodies (mAbs) for future therapeutic use and identify conserved neutralising epitopes that can be used for rationale design of broadly protective sarbecovirus vaccines. Here we study the neutralising epitopes on WIV-1 Spike of three mAbs that confer broad sarbecovirus and SARS-CoV-2 variant neutralisation, including XEC, JN.1, and XFG. mAb V1WT_06 binds a highly conserved RBD site V epitope that is mediated by the heavy chain alone. V1WT_06 contact residues are highly conserved in circulating viruses suggesting that the epitope is evolutionarily and functionally constrained. mAbs V1WT_41 and VA14_26 bind overlapping RBD class 4 epitopes with differing angles of approach that impact on the degree of ACE2 competition. We show that neutralisation by these mAbs is maintained when virus entry is via Japanese horseshoe bat and Halcyon horseshoe bat ACE2s. These mAbs are ideal candidates for therapeutic antibody development and inform the rational design of pan-betacoronavirus vaccines.
The increasing spillover risk of sarbecoviruses into humans stresses the urgent need to identify cross-reactive antibodies with therapeutic potential. This study uncovers the mechanisms of broad sarbecovirus cross-reactivity of three human antibodies that can inform the rational design of therapeutic antibodies and pan-coronavirus vaccines.
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BibTeX
@article{upadhyay2026targeting,
title = {{Targeting of conserved spike epitopes enables broad antibody neutralisation of diverse bat sarbecoviruses}},
author = {Ayush Upadhyay and Jeffrey Seow and Yilmaz Alguel and Joseph Newman and Nazia Thakur and Abigail L. Hay and Jerry C. H. Tam and Andrea Nans and Richard J. Orton and Dalan Bailey and Peter Cherepanov and Katie J. Doores},
journal = {PLOS Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pbio.3003882},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003882},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting of conserved spike epitopes enables broad antibody neutralisation of diverse bat sarbecoviruses
AU - Ayush Upadhyay
AU - Jeffrey Seow
AU - Yilmaz Alguel
AU - Joseph Newman
AU - Nazia Thakur
AU - Abigail L. Hay
AU - Jerry C. H. Tam
AU - Andrea Nans
AU - Richard J. Orton
AU - Dalan Bailey
AU - Peter Cherepanov
AU - Katie J. Doores
PY - 2026
DA - 2026/10/01
JO - PLOS Biology
DO - 10.1371/journal.pbio.3003882
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003882
AB - The continuing evolution of SARS-CoV-2 variants of concern, and the increasing spillover potential of sarbecoviruses into the human population presents an important and urgent need to discover cross-reactive monoclonal antibodies (mAbs) for future therapeutic use and identify conserved neutralising epitopes that can be used for rationale design of broadly protective sarbecovirus vaccines. Here we study the neutralising epitopes on WIV-1 Spike of three mAbs that confer broad sarbecovirus and SARS-CoV-2 variant neutralisation, including XEC, JN.1, and XFG. mAb V1WT_06 binds a highly conserved RBD site V epitope that is mediated by the heavy chain alone. V1WT_06 contact residues are highly conserved in circulating viruses suggesting that the epitope is evolutionarily and functionally constrained. mAbs V1WT_41 and VA14_26 bind overlapping RBD class 4 epitopes with differing angles of approach that impact on the degree of ACE2 competition. We show that neutralisation by these mAbs is maintained when virus entry is via Japanese horseshoe bat and Halcyon horseshoe bat ACE2s. These mAbs are ideal candidates for therapeutic antibody development and inform the rational design of pan-betacoronavirus vaccines. The increasing spillover risk of sarbecoviruses into humans stresses the urgent need to identify cross-reactive antibodies with therapeutic potential. This study uncovers the mechanisms of broad sarbecovirus cross-reactivity of three human antibodies that can inform the rational design of therapeutic antibodies and pan-coronavirus vaccines.
SN - 1545-7885
ER -