Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift
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.
Authors
- Xuduo Li
- Pan-Pan Zhou (ORCID: https://orcid.org/0000-0001-5740-4303)
- Yana Safonova (ORCID: https://orcid.org/0000-0002-9634-4216)
- Hejun Liu
- Wanting He (ORCID: https://orcid.org/0000-0003-4692-3516)
- Ian A. Wilson (ORCID: https://orcid.org/0000-0002-6469-2419)
- Yuexiu Zhang (ORCID: https://orcid.org/0000-0002-3948-1425)
- Katharina Dueker (ORCID: https://orcid.org/0000-0003-0426-468X)
- Gabriel Avillion (ORCID: https://orcid.org/0000-0002-6898-7783)
- Meng Yuan (ORCID: https://orcid.org/0000-0001-9754-4503)
- Nitesh Mishra (ORCID: https://orcid.org/0000-0002-5387-0486)
- Peter Yong (ORCID: https://orcid.org/0000-0002-4899-3270)
- Fabio Anzanello (ORCID: https://orcid.org/0000-0002-9891-6476)
- Dennis R. Burton (ORCID: https://orcid.org/0000-0001-6711-9864)
- Sean Callaghan (ORCID: https://orcid.org/0000-0003-2966-994X)
- Xueyong Zhu (ORCID: https://orcid.org/0000-0002-6021-3740)
- Ryan N. Lin (ORCID: https://orcid.org/0009-0006-4839-5875)
- Anh L. Vo (ORCID: https://orcid.org/0000-0002-1819-4531)
- Bryan Briney (ORCID: https://orcid.org/0000-0001-9535-2866)
- Jonathan L. Torres (ORCID: https://orcid.org/0000-0003-0137-8497)
- Linghang Peng (ORCID: https://orcid.org/0000-0002-3600-2134)
- Tazio Capozzola (ORCID: https://orcid.org/0000-0002-7269-588X)
- David Nemazee (ORCID: https://orcid.org/0000-0002-4769-6311)
- Ziqi Feng
- Muzamil Ashraf Makhdoomi
- Ge Song (ORCID: https://orcid.org/0009-0006-5116-7208)
Institutions
- Scripps Research Institute (US)
- Johns Hopkins University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115948
- Citations
- 9
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 12.57