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; 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:10.1101/2023.04.26.538488

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

bioRxiv [Preprint]. 2023 Apr 27:2023.04.26.538488. doi: 10.1101/2023.04.26.538488.

Authors

Ge Song^{1

2

3}, Meng Yuan⁴, Hejun Liu⁴, Tazio Capozzola^{1

2

3}, Ryan N Lin⁴, Jonathan L Torres⁴, Wan-Ting He^{1

2

3}, Rami Musharrafieh^{1

2

3}, Katharina Dueker^{1

2

3}, Panpan Zhou^{1

2

3}, Sean Callaghan^{1

2

3}, Nitesh Mishra^{1

2

3}, Peter Yong^{1

2

3}, Fabio Anzanello^{1

2

3}, Gabriel Avillion^{1

2

3}, Anh Lina Vo^{1

2

3}, Xuduo Li^{1

2

3}, Muzamil Makhdoomi¹, Ziqi Feng⁴, Xueyong Zhu⁴, Linghang Peng¹, David Nemazee¹, Yana Safonova⁵, Bryan Briney^{1

2

3}, Andrew B Ward^{1

2

3

4}, Dennis R Burton^{1

2

3

6}, Ian A Wilson^{2

3

4

7}, Raiees Andrabi^{1

2

3

8}

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
² IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
⁷ Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ Lead Contact.

Abstract

Developing broad coronavirus vaccines requires identifying and understanding the molecular basis of broadly neutralizing antibody (bnAb) spike sites. In our previous work, we identified sarbecovirus spike RBD group 1 and 2 bnAbs. We have now shown that many of these bnAbs can still neutralize highly mutated SARS-CoV-2 variants, including the XBB.1.5. Structural studies revealed that group 1 bnAbs use recurrent germline-encoded CDRH3 features to interact with a conserved RBD region that overlaps with class 4 bnAb site. Group 2 bnAbs recognize a less well-characterized "site V" on the RBD and destabilize spike trimer. The site V has remained largely unchanged in SARS-CoV-2 variants and is highly conserved across diverse sarbecoviruses, making it a promising target for broad coronavirus vaccine development. Our findings suggest that targeted vaccine strategies may be needed to induce effective B cell responses to escape resistant subdominant spike RBD bnAb sites.

Publication types

Preprint