Orphan broadly RBD-binding antibodies annotate three remaining conserved RBD epitopes along SARS-CoV-2 evolution
The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein continues to evolve, facilitating antibody evasion. It remains unclear whether any conserved RBD epitopes persist across SARS-CoV-2 variants and whether vaccination and/or breakthrough infection (BTI) can elicit antibodies capable of targeting these conserved regions to counter future variants. Here, using a heterogeneous double-bait single B-cell sorting strategy, we identify a subset of antibodies with broad-spectrum RBD binding, including recognition of SARS-CoV-1 and emerging variants such as EG.5.1, BA.2.86, JN.1, and KP.2/3. These broadly binding antibodies (bbAbs) exhibit elevated levels of somatic hypermutation but are infrequently derived from clonally expanded B lymphocytes. Passive transfer of representative bbAbs reduces viral infection in a male hamster model. Structural analyses reveals that these bbAbs primarily target three distinct, highly conserved RBD epitopes, suggesting potential regions of future mutational pressure and highlighting the presence of conserved and immunogenic RBD conformations that may serve as a foundation for the development of broadly protective vaccines.
Authors
- Christian T. Mayer (ORCID: https://orcid.org/0000-0002-0256-9650)
- Yiming Long
- Jiaying He
- Yuanchen Liu (ORCID: https://orcid.org/0000-0002-7753-9886)
- Lei Sun (ORCID: https://orcid.org/0000-0001-8741-0202)
- Hin Chu (ORCID: https://orcid.org/0000-0003-2855-9837)
- Anqi Xia (ORCID: https://orcid.org/0000-0001-9638-3074)
- Minxiang Xie (ORCID: https://orcid.org/0000-0003-0108-9556)
- Thiago Y. Oliveira (ORCID: https://orcid.org/0000-0002-2654-0879)
- Shibo Jiang (ORCID: https://orcid.org/0000-0001-8283-7135)
- Jialu Shi
- Xiaoyu Zhao (ORCID: https://orcid.org/0000-0002-0347-9104)
- Lu Lu (ORCID: https://orcid.org/0000-0002-2255-0391)
- Fan Wu (ORCID: https://orcid.org/0000-0003-1039-3752)
- Yan Yan (ORCID: https://orcid.org/0000-0002-5752-1910)
- Pengfei Wang (ORCID: https://orcid.org/0000-0003-2454-7652)
- Qiao Wang (ORCID: https://orcid.org/0000-0001-6416-1733)
- Rong Xia (ORCID: https://orcid.org/0000-0002-2463-6340)
- Youhua Xie (ORCID: https://orcid.org/0000-0002-2416-7708)
- Zijun Wang (ORCID: https://orcid.org/0000-0002-2095-2151)
- Yunjiao Zhou
- Jiayan Li (ORCID: https://orcid.org/0009-0000-3436-0483)
- Wenjing Zai (ORCID: https://orcid.org/0000-0003-2550-331X)
- Yuzhen Zhu
- Yinong Qiu
- Siyuan Sun
- L. Liu (ORCID: https://orcid.org/0009-0000-0973-9272)
- Qingsong Zhang
- Qiyu Mao
Institutions
- National Institutes of Health (US)
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Jinshan Hospital of Fudan University (CN)
- Pudong Medical Center (CN)
- National Cancer Institute (US)
- HKU-Pasteur Research Pole (HK)
- Shanghai Sunshine Rehabilitation Center (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Center for Cancer Research (US)
- Huashan Hospital (CN)
- State Key Laboratory of Genetic Engineering
- Rockefeller University (US)
- University of Hong Kong (HK)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1038/s41467-025-65596-0
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- National Natural Science Foundation of China
- Fudan University
- National Key Research and Development Program of China
- Shanghai Medical College, Fudan University