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

doi:10.1016/j.celrep.2025.115948

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 FengXueyong Zhu, Linghang Peng, David Nemazee, Yana Safonova, Bryan Briney, Andrew B. Ward, Dennis R. Burton, Ian A. Wilson, Raiees Andrabi

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English (US)
Article number	115948
Journal	Cell Reports
Volume	44
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2025.115948
State	Published - Jul 22 2025

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2025.115948

Cite this

Song, G., Yuan, M., Liu, H., Capozzola, T., Lin, R. N., Torres, J. L., He, W. T., Musharrafieh, R., Dueker, K., Zhou, P., Callaghan, S., Mishra, N., Yong, P., Anzanello, F., Avillion, G., Vo, A. L., Li, X., Zhang, Y., Makhdoomi, M., ... Andrabi, R. (2025). Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift. Cell Reports, 44(7), Article 115948. https://doi.org/10.1016/j.celrep.2025.115948

@article{7feb0dec3a2a495cad5a98a25cc04ab2,

title = "Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift",

abstract = "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.",

author = "Ge Song and Meng Yuan and Hejun Liu and Tazio Capozzola and Lin, \{Ryan N.\} and Torres, \{Jonathan L.\} and He, \{Wan ting\} and Rami Musharrafieh and Katharina Dueker and Panpan Zhou and Sean Callaghan and Nitesh Mishra and Peter Yong and Fabio Anzanello and Gabriel Avillion and Vo, \{Anh Lina\} and Xuduo Li and Yuexiu Zhang and Muzamil Makhdoomi and Ziqi Feng and Xueyong Zhu and Linghang Peng and David Nemazee and Yana Safonova and Bryan Briney and Ward, \{Andrew B.\} and Burton, \{Dennis R.\} and Wilson, \{Ian A.\} and Raiees Andrabi",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = jul,

day = "22",

doi = "10.1016/j.celrep.2025.115948",

language = "English (US)",

volume = "44",

journal = "Cell Reports",

issn = "2639-1856",

publisher = "Cell Press",

number = "7",

}

Song, G, Yuan, M, Liu, H, Capozzola, T, Lin, RN, Torres, JL, He, WT, Musharrafieh, R, Dueker, K, Zhou, P, Callaghan, S, Mishra, N, Yong, P, Anzanello, F, Avillion, G, Vo, AL, Li, X, Zhang, Y, Makhdoomi, M, Feng, Z, Zhu, X, Peng, L, Nemazee, D, Safonova, Y, Briney, B, Ward, AB, Burton, DR, Wilson, IA & Andrabi, R 2025, 'Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift', Cell Reports, vol. 44, no. 7, 115948. https://doi.org/10.1016/j.celrep.2025.115948

TY - JOUR

T1 - Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift

AU - Song, Ge

AU - Yuan, Meng

AU - Liu, Hejun

AU - Capozzola, Tazio

AU - Lin, Ryan N.

AU - Torres, Jonathan L.

AU - He, Wan ting

AU - Musharrafieh, Rami

AU - Dueker, Katharina

AU - Zhou, Panpan

AU - Callaghan, Sean

AU - Mishra, Nitesh

AU - Yong, Peter

AU - Anzanello, Fabio

AU - Avillion, Gabriel

AU - Vo, Anh Lina

AU - Li, Xuduo

AU - Zhang, Yuexiu

AU - Makhdoomi, Muzamil

AU - Feng, Ziqi

AU - Zhu, Xueyong

AU - Peng, Linghang

AU - Nemazee, David

AU - Safonova, Yana

AU - Briney, Bryan

AU - Ward, Andrew B.

AU - Burton, Dennis R.

AU - Wilson, Ian A.

AU - Andrabi, Raiees

PY - 2025/7/22

Y1 - 2025/7/22

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105009694122

UR - https://www.scopus.com/inward/citedby.url?scp=105009694122&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2025.115948

DO - 10.1016/j.celrep.2025.115948

M3 - Article

C2 - 40627497

AN - SCOPUS:105009694122

SN - 2639-1856

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 115948

ER -

Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this