Cell Reports (Jul 2025)
Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift
- Ge Song,
- Meng Yuan,
- Hejun Liu,
- Tazio Capozzola,
- Ryan N. Lin,
- Jonathan L. Torres,
- Wan-ting He,
- Rami Musharrafieh,
- Katharina Dueker,
- Panpan Zhou,
- Sean Callaghan,
- Nitesh Mishra,
- Peter Yong,
- Fabio Anzanello,
- Gabriel Avillion,
- Anh Lina Vo,
- Xuduo Li,
- Yuexiu Zhang,
- Muzamil Makhdoomi,
- Ziqi Feng,
- Xueyong Zhu,
- Linghang Peng,
- David Nemazee,
- Yana Safonova,
- Bryan Briney,
- Andrew B. Ward,
- Dennis R. Burton,
- Ian A. Wilson,
- Raiees Andrabi
Affiliations
- Ge Song
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Meng Yuan
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Hejun Liu
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Tazio Capozzola
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Ryan N. Lin
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Jonathan L. Torres
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Wan-ting He
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Rami Musharrafieh
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Katharina Dueker
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Panpan Zhou
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Sean Callaghan
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Nitesh Mishra
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Peter Yong
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Fabio Anzanello
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Gabriel Avillion
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Anh Lina Vo
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Xuduo Li
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Yuexiu Zhang
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Muzamil Makhdoomi
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Ziqi Feng
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Xueyong Zhu
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Linghang Peng
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- David Nemazee
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Yana Safonova
- Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA
- Bryan Briney
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
- Andrew B. Ward
- IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Dennis R. Burton
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA; Corresponding author
- Ian A. Wilson
- IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
- Raiees Andrabi
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
- DOI
- https://doi.org/10.1016/j.celrep.2025.115948
- Journal volume & issue
-
Vol. 44,
no. 7
p. 115948
Abstract
Summary: Developing broad coronavirus vaccines hinges on identifying and understanding the molecular basis of conserved spike epitopes targeted by broadly neutralizing antibodies (bnAbs). Building on our earlier work identifying sarbecovirus receptor-binding domain (RBD) group 1 and 2 bnAbs, we now show that several of these antibodies retain neutralizing activity against highly mutated SARS-CoV-2 variants, including BA.2.86 and JN.1. Structural studies reveal that group 1 bnAbs use recurrent germline-encoded heavy-chain complementarity-determining region 3 (CDRH3) features to interact with a conserved RBD region that overlaps with class 4 bnAb site. Group 2 bnAbs recognize a less well-defined “site V” on the RBD and destabilize spike trimer. Notably, site V remains largely unchanged across SARS-CoV-2 variants and is conserved among diverse sarbecoviruses, highlighting its potential as a broad vaccine target. Our findings underscore the need for targeted vaccine strategies to induce immunofocused B cell responses to escape resistant subdominant spike RBD bnAb epitopes.
Keywords
