tetano
Editor, Senior Moderator
Cell Rep
. 2025 Jul 7;44(7):115948.
doi: 10.1016/j.celrep.2025.115948. Online ahead of print. Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift
Ge Song[SUP] 1 [/SUP], Meng Yuan[SUP] 2 [/SUP], Hejun Liu[SUP] 2 [/SUP], Tazio Capozzola[SUP] 3 [/SUP], Ryan N Lin[SUP] 2 [/SUP], Jonathan L Torres[SUP] 2 [/SUP], Wan-Ting He[SUP] 1 [/SUP], Rami Musharrafieh[SUP] 1 [/SUP], Katharina Dueker[SUP] 1 [/SUP], Panpan Zhou[SUP] 1 [/SUP], Sean Callaghan[SUP] 1 [/SUP], Nitesh Mishra[SUP] 1 [/SUP], Peter Yong[SUP] 1 [/SUP], Fabio Anzanello[SUP] 1 [/SUP], Gabriel Avillion[SUP] 1 [/SUP], Anh Lina Vo[SUP] 3 [/SUP], Xuduo Li[SUP] 3 [/SUP], Yuexiu Zhang[SUP] 4 [/SUP], Muzamil Makhdoomi[SUP] 5 [/SUP], Ziqi Feng[SUP] 2 [/SUP], Xueyong Zhu[SUP] 2 [/SUP], Linghang Peng[SUP] 5 [/SUP], David Nemazee[SUP] 5 [/SUP], Yana Safonova[SUP] 6 [/SUP], Bryan Briney[SUP] 7 [/SUP], Andrew B Ward[SUP] 8 [/SUP], Dennis R Burton[SUP] 9 [/SUP], Ian A Wilson[SUP] 10 [/SUP], Raiees Andrabi[SUP] 11 [/SUP]
Affiliations
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: CP: Immunology; RBD; SARS-CoV-2; antibodies; broadly neutralizing antibodies; conserved RBD bnAb sites; coronaviruses; sarbecoviruses; site V; spike; vaccines.
. 2025 Jul 7;44(7):115948.
doi: 10.1016/j.celrep.2025.115948. Online ahead of print. Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift
Ge Song[SUP] 1 [/SUP], Meng Yuan[SUP] 2 [/SUP], Hejun Liu[SUP] 2 [/SUP], Tazio Capozzola[SUP] 3 [/SUP], Ryan N Lin[SUP] 2 [/SUP], Jonathan L Torres[SUP] 2 [/SUP], Wan-Ting He[SUP] 1 [/SUP], Rami Musharrafieh[SUP] 1 [/SUP], Katharina Dueker[SUP] 1 [/SUP], Panpan Zhou[SUP] 1 [/SUP], Sean Callaghan[SUP] 1 [/SUP], Nitesh Mishra[SUP] 1 [/SUP], Peter Yong[SUP] 1 [/SUP], Fabio Anzanello[SUP] 1 [/SUP], Gabriel Avillion[SUP] 1 [/SUP], Anh Lina Vo[SUP] 3 [/SUP], Xuduo Li[SUP] 3 [/SUP], Yuexiu Zhang[SUP] 4 [/SUP], Muzamil Makhdoomi[SUP] 5 [/SUP], Ziqi Feng[SUP] 2 [/SUP], Xueyong Zhu[SUP] 2 [/SUP], Linghang Peng[SUP] 5 [/SUP], David Nemazee[SUP] 5 [/SUP], Yana Safonova[SUP] 6 [/SUP], Bryan Briney[SUP] 7 [/SUP], Andrew B Ward[SUP] 8 [/SUP], Dennis R Burton[SUP] 9 [/SUP], Ian A Wilson[SUP] 10 [/SUP], Raiees Andrabi[SUP] 11 [/SUP]
Affiliations
- PMID: 40627497
- DOI: 10.1016/j.celrep.2025.115948
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: CP: Immunology; RBD; SARS-CoV-2; antibodies; broadly neutralizing antibodies; conserved RBD bnAb sites; coronaviruses; sarbecoviruses; site V; spike; vaccines.