tetano
Editor, Senior Moderator
Nature
. 2021 Jul 14.
doi: 10.1038/s41586-021-03807-6. Online ahead of print.
SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape
Tyler N Starr[SUP] #[/SUP][SUP] 1 [/SUP], Nadine Czudnochowski[SUP] #[/SUP][SUP] 2 [/SUP], Zhuoming Liu[SUP] #[/SUP][SUP] 3 [/SUP], Fabrizia Zatta[SUP] 4 [/SUP], Young-Jun Park[SUP] 5 [/SUP], Amin Addetia[SUP] 1 [/SUP], Dora Pinto[SUP] 4 [/SUP], Martina Beltramello[SUP] 4 [/SUP], Patrick Hernandez[SUP] 2 [/SUP], Allison J Greaney[SUP] 1 6 [/SUP], Roberta Marzi[SUP] 4 [/SUP], William G Glass[SUP] 7 [/SUP], Ivy Zhang[SUP] 7 8 [/SUP], Adam S Dingens[SUP] 1 [/SUP], John E Bowen[SUP] 5 [/SUP], M Alejandra Tortorici[SUP] 5 [/SUP], Alexandra C Walls[SUP] 5 [/SUP], Jason A Wojcechowskyj[SUP] 2 [/SUP], Anna De Marco[SUP] 4 [/SUP], Laura E Rosen[SUP] 2 [/SUP], Jiayi Zhou[SUP] 2 [/SUP], Martin Montiel-Ruiz[SUP] 2 [/SUP], Hannah Kaiser[SUP] 2 [/SUP], Josh Dillen[SUP] 2 [/SUP], Heather Tucker[SUP] 2 [/SUP], Jessica Bassi[SUP] 4 [/SUP], Chiara Silacci-Fregni[SUP] 4 [/SUP], Michael P Housley[SUP] 2 [/SUP], Julia di Iulio[SUP] 2 [/SUP], Gloria Lombardo[SUP] 4 [/SUP], Maria Agostini[SUP] 2 [/SUP], Nicole Sprugasci[SUP] 4 [/SUP], Katja Culap[SUP] 4 [/SUP], Stefano Jaconi[SUP] 4 [/SUP], Marcel Meury[SUP] 2 [/SUP], Exequiel Dellota[SUP] 2 [/SUP], Rana Abdelnabi[SUP] 9 [/SUP], Shi-Yan Caroline Foo[SUP] 9 [/SUP], Elisabetta Cameroni[SUP] 4 [/SUP], Spencer Stumpf[SUP] 3 [/SUP], Tristan I Croll[SUP] 10 [/SUP], Jay C Nix[SUP] 11 [/SUP], Colin Havenar-Daughton[SUP] 2 [/SUP], Luca Piccoli[SUP] 4 [/SUP], Fabio Benigni[SUP] 4 [/SUP], Johan Neyts[SUP] 9 [/SUP], Amalio Telenti[SUP] 2 [/SUP], Florian A Lempp[SUP] 2 [/SUP], Matteo S Pizzuto[SUP] 4 [/SUP], John D Chodera[SUP] 7 [/SUP], Christy M Hebner[SUP] 2 [/SUP], Herbert W Virgin[SUP] 2 12 13 [/SUP], Sean P J Whelan[SUP] 3 [/SUP], David Veesler[SUP] 5 [/SUP], Davide Corti[SUP] 14 [/SUP], Jesse D Bloom[SUP] 15 16 17 [/SUP], Gyorgy Snell[SUP] 18 [/SUP]
Affiliations
Abstract
An ideal anti-SARS-CoV-2 antibody would resist viral escape[SUP]1-3[/SUP], have activity against diverse SARS-related coronaviruses (sarbecoviruses)[SUP]4-7[/SUP], and be highly protective through viral neutralization[SUP]8-11[/SUP] and effector functions[SUP]12,13[/SUP]. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E12[SUP]8[/SUP]) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
. 2021 Jul 14.
doi: 10.1038/s41586-021-03807-6. Online ahead of print.
SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape
Tyler N Starr[SUP] #[/SUP][SUP] 1 [/SUP], Nadine Czudnochowski[SUP] #[/SUP][SUP] 2 [/SUP], Zhuoming Liu[SUP] #[/SUP][SUP] 3 [/SUP], Fabrizia Zatta[SUP] 4 [/SUP], Young-Jun Park[SUP] 5 [/SUP], Amin Addetia[SUP] 1 [/SUP], Dora Pinto[SUP] 4 [/SUP], Martina Beltramello[SUP] 4 [/SUP], Patrick Hernandez[SUP] 2 [/SUP], Allison J Greaney[SUP] 1 6 [/SUP], Roberta Marzi[SUP] 4 [/SUP], William G Glass[SUP] 7 [/SUP], Ivy Zhang[SUP] 7 8 [/SUP], Adam S Dingens[SUP] 1 [/SUP], John E Bowen[SUP] 5 [/SUP], M Alejandra Tortorici[SUP] 5 [/SUP], Alexandra C Walls[SUP] 5 [/SUP], Jason A Wojcechowskyj[SUP] 2 [/SUP], Anna De Marco[SUP] 4 [/SUP], Laura E Rosen[SUP] 2 [/SUP], Jiayi Zhou[SUP] 2 [/SUP], Martin Montiel-Ruiz[SUP] 2 [/SUP], Hannah Kaiser[SUP] 2 [/SUP], Josh Dillen[SUP] 2 [/SUP], Heather Tucker[SUP] 2 [/SUP], Jessica Bassi[SUP] 4 [/SUP], Chiara Silacci-Fregni[SUP] 4 [/SUP], Michael P Housley[SUP] 2 [/SUP], Julia di Iulio[SUP] 2 [/SUP], Gloria Lombardo[SUP] 4 [/SUP], Maria Agostini[SUP] 2 [/SUP], Nicole Sprugasci[SUP] 4 [/SUP], Katja Culap[SUP] 4 [/SUP], Stefano Jaconi[SUP] 4 [/SUP], Marcel Meury[SUP] 2 [/SUP], Exequiel Dellota[SUP] 2 [/SUP], Rana Abdelnabi[SUP] 9 [/SUP], Shi-Yan Caroline Foo[SUP] 9 [/SUP], Elisabetta Cameroni[SUP] 4 [/SUP], Spencer Stumpf[SUP] 3 [/SUP], Tristan I Croll[SUP] 10 [/SUP], Jay C Nix[SUP] 11 [/SUP], Colin Havenar-Daughton[SUP] 2 [/SUP], Luca Piccoli[SUP] 4 [/SUP], Fabio Benigni[SUP] 4 [/SUP], Johan Neyts[SUP] 9 [/SUP], Amalio Telenti[SUP] 2 [/SUP], Florian A Lempp[SUP] 2 [/SUP], Matteo S Pizzuto[SUP] 4 [/SUP], John D Chodera[SUP] 7 [/SUP], Christy M Hebner[SUP] 2 [/SUP], Herbert W Virgin[SUP] 2 12 13 [/SUP], Sean P J Whelan[SUP] 3 [/SUP], David Veesler[SUP] 5 [/SUP], Davide Corti[SUP] 14 [/SUP], Jesse D Bloom[SUP] 15 16 17 [/SUP], Gyorgy Snell[SUP] 18 [/SUP]
Affiliations
- PMID: 34261126
- DOI: 10.1038/s41586-021-03807-6
Abstract
An ideal anti-SARS-CoV-2 antibody would resist viral escape[SUP]1-3[/SUP], have activity against diverse SARS-related coronaviruses (sarbecoviruses)[SUP]4-7[/SUP], and be highly protective through viral neutralization[SUP]8-11[/SUP] and effector functions[SUP]12,13[/SUP]. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E12[SUP]8[/SUP]) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.