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SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

Author

Listed:
  • Tyler N. Starr

    (Basic Sciences Division, Fred Hutchinson Cancer Research Center)

  • Nadine Czudnochowski

    (Vir Biotechnology)

  • Zhuoming Liu

    (Washington University School of Medicine)

  • Fabrizia Zatta

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Young-Jun Park

    (University of Washington)

  • Amin Addetia

    (Basic Sciences Division, Fred Hutchinson Cancer Research Center)

  • Dora Pinto

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Martina Beltramello

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Patrick Hernandez

    (Vir Biotechnology)

  • Allison J. Greaney

    (Basic Sciences Division, Fred Hutchinson Cancer Research Center
    University of Washington)

  • Roberta Marzi

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • William G. Glass

    (Memorial Sloan Kettering Cancer Center)

  • Ivy Zhang

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences)

  • Adam S. Dingens

    (Basic Sciences Division, Fred Hutchinson Cancer Research Center)

  • John E. Bowen

    (University of Washington)

  • M. Alejandra Tortorici

    (University of Washington)

  • Alexandra C. Walls

    (University of Washington)

  • Jason A. Wojcechowskyj

    (Vir Biotechnology)

  • Anna Marco

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Laura E. Rosen

    (Vir Biotechnology)

  • Jiayi Zhou

    (Vir Biotechnology)

  • Martin Montiel-Ruiz

    (Vir Biotechnology)

  • Hannah Kaiser

    (Vir Biotechnology)

  • Josh R. Dillen

    (Vir Biotechnology)

  • Heather Tucker

    (Vir Biotechnology)

  • Jessica Bassi

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Chiara Silacci-Fregni

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Michael P. Housley

    (Vir Biotechnology)

  • Julia Iulio

    (Vir Biotechnology)

  • Gloria Lombardo

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Maria Agostini

    (Vir Biotechnology)

  • Nicole Sprugasci

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Katja Culap

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Stefano Jaconi

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Marcel Meury

    (Vir Biotechnology)

  • Exequiel Dellota Jr

    (Vir Biotechnology)

  • Rana Abdelnabi

    (KU Leuven)

  • Shi-Yan Caroline Foo

    (KU Leuven)

  • Elisabetta Cameroni

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Spencer Stumpf

    (Washington University School of Medicine)

  • Tristan I. Croll

    (University of Cambridge)

  • Jay C. Nix

    (Lawrence Berkeley National Laboratory)

  • Colin Havenar-Daughton

    (Vir Biotechnology)

  • Luca Piccoli

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Fabio Benigni

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Johan Neyts

    (KU Leuven)

  • Amalio Telenti

    (Vir Biotechnology)

  • Florian A. Lempp

    (Vir Biotechnology)

  • Matteo S. Pizzuto

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • John D. Chodera

    (Memorial Sloan Kettering Cancer Center)

  • Christy M. Hebner

    (Vir Biotechnology)

  • Herbert W. Virgin

    (Vir Biotechnology
    Washington University School of Medicine
    UT Southwestern Medical Center)

  • Sean P. J. Whelan

    (Washington University School of Medicine)

  • David Veesler

    (University of Washington)

  • Davide Corti

    (Humabs BioMed SA, a subsidiary of Vir Biotechnology)

  • Jesse D. Bloom

    (Basic Sciences Division, Fred Hutchinson Cancer Research Center
    University of Washington
    Howard Hughes Medical Institute)

  • Gyorgy Snell

    (Vir Biotechnology)

Abstract

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse sarbecoviruses4–7, and be highly protective through viral neutralization8–11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies 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 trade-off 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 cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) 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 that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.

Suggested Citation

  • Tyler N. Starr & Nadine Czudnochowski & Zhuoming Liu & Fabrizia Zatta & Young-Jun Park & Amin Addetia & Dora Pinto & Martina Beltramello & Patrick Hernandez & Allison J. Greaney & Roberta Marzi & Will, 2021. "SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape," Nature, Nature, vol. 597(7874), pages 97-102, September.
  • Handle: RePEc:nat:nature:v:597:y:2021:i:7874:d:10.1038_s41586-021-03807-6
    DOI: 10.1038/s41586-021-03807-6
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    Citations

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    Cited by:

    1. Romain Rouet & Jake Y. Henry & Matt D. Johansen & Meghna Sobti & Harikrishnan Balachandran & David B. Langley & Gregory J. Walker & Helen Lenthall & Jennifer Jackson & Stephanie Ubiparipovic & Ohan Ma, 2023. "Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Yin-Feng Kang & Cong Sun & Jing Sun & Chu Xie & Zhen Zhuang & Hui-Qin Xu & Zheng Liu & Yi-Hao Liu & Sui Peng & Run-Yu Yuan & Jin-Cun Zhao & Mu-Sheng Zeng, 2022. "Quadrivalent mosaic HexaPro-bearing nanoparticle vaccine protects against infection of SARS-CoV-2 variants," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Leire Campos-Mata & Benjamin Trinité & Andrea Modrego & Sonia Tejedor Vaquero & Edwards Pradenas & Anna Pons-Grífols & Natalia Rodrigo Melero & Diego Carlero & Silvia Marfil & César Santiago & Dàlia R, 2024. "A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Mingxi Li & Yifei Ren & Zhen Qin Aw & Bo Chen & Ziqing Yang & Yuqing Lei & Lin Cheng & Qingtai Liang & Junxian Hong & Yiling Yang & Jing Chen & Yi Hao Wong & Jing Wei & Sisi Shan & Senyan Zhang & Jiwa, 2022. "Broadly neutralizing and protective nanobodies against SARS-CoV-2 Omicron subvariants BA.1, BA.2, and BA.4/5 and diverse sarbecoviruses," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Yanqun Wang & An Yan & Deyong Song & Maoqin Duan & Chuangchuang Dong & Jiantao Chen & Zihe Jiang & Yuanzhu Gao & Muding Rao & Jianxia Feng & Zhaoyong Zhang & Ruxi Qi & Xiaomin Ma & Hong Liu & Beibei Y, 2024. "Identification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Susan K. Vester & Rolle Rahikainen & Irsyad N. A. Khairil Anuar & Rory A. Hills & Tiong Kit Tan & Mark Howarth, 2022. "SpySwitch enables pH- or heat-responsive capture and release for plug-and-display nanoassembly," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Daniel N. Streblow & Alec J. Hirsch & Jeffrey J. Stanton & Anne D. Lewis & Lois Colgin & Ann J. Hessell & Craig N. Kreklywich & Jessica L. Smith & William F. Sutton & David Chauvin & Jennifer Woo & Be, 2023. "Aerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Andrew C. Hunt & Bastian Vögeli & Ahmed O. Hassan & Laura Guerrero & Weston Kightlinger & Danielle J. Yoesep & Antje Krüger & Madison DeWinter & Michael S. Diamond & Ashty S. Karim & Michael C. Jewett, 2023. "A rapid cell-free expression and screening platform for antibody discovery," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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