One Thousand SARS-CoV-2 Antibody Structures Reveal Convergent Binding and Near-Universal Immune Escape

Feng, Z.; Sang, Z.; Xiang, Y.; Escalera, A.; Weshler, A.; Schneidman- Duhovny, D.; Garcia-Sastre, A.; Shi, Y.

doi:10.1101/2025.08.07.669152

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bioRxiv · 10.1101/2025.08.07.669152

One Thousand SARS-CoV-2 Antibody Structures Reveal Convergent Binding and Near-Universal Immune Escape

Feng, Z.·Sang, Z.·Xiang, Y.·Escalera, A.·Weshler, A.·Schneidman- Duhovny, D.·Garcia-Sastre, A.·Shi, Y.

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Abstract

Since the emergence of SARS-CoV-2, understanding how antibodies recognize and adapt to viral evolution has been central to vaccine and therapeutic developments. To date, over 1,100 SARS-CoV-2 antibody structures--16% of all known antibody-antigen complexes--have been resolved, marking the largest structural biology effort towards a single pathogen. Here, we present a comprehensive analysis of this landmark dataset to investigate the principles of antibody recognition and immune escape. Human immunoglobulins (IgGs) and camelid single-chain antibodies dominate the dataset, collectively mapping 99% of the receptor-binding domain surface. Despite remarkable sequence and conformational diversity, antibodies exhibit striking convergence in their paratope structures, revealing evolutionary constraints in epitope selection. Structural and functional analyses reveal near-universal immune escape of antibodies, including all clinical monoclonals, by advanced variants such as KP3.1.1. On average, over one-third of antibody epitope residues are mutated. These findings support pervasive immune escape, underscoring the need to effectively leverage multi-epitope targeting strategies to achieve durable immunity.

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Feng, Z., Sang, Z., Xiang, Y., Escalera, A., Weshler, A., Schneidman- Duhovny, D., Garcia-Sastre, A., Shi, Y.. 2025-08-08. One Thousand SARS-CoV-2 Antibody Structures Reveal Convergent Binding and Near-Universal Immune Escape. https://doi.org/10.1101/2025.08.07.669152

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