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Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies

Frauke Muecksch, Yiska Weisblum, Christopher O. Barnes, Fabian Schmidt, Dennis Schaefer-Babajew, Julio C C Lorenzi, Andrew I Flyak, Andrew T DeLaitsch, Kathryn E Huey-Tubman, Shurong Hou, Celia A. Schiffer, Christian Gaebler, Zijun Wang, Justin Da Silva, Daniel Poston, Shlomo Finkin, Alice Cho, Melissa Cipolla, Thiago Y. Oliveira, Katrina G. Millard, Victor Ramos, Anna Gazumyan, Magdalena Rutkowska, Marina Caskey, Michel C. Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul D. Bieniasz
doi: https://doi.org/10.1101/2021.03.07.434227
Frauke Muecksch
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Yiska Weisblum
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Christopher O. Barnes
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
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Fabian Schmidt
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Dennis Schaefer-Babajew
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Julio C C Lorenzi
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Andrew I Flyak
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
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Andrew T DeLaitsch
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
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Kathryn E Huey-Tubman
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Shurong Hou
4Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Celia A. Schiffer
4Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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Christian Gaebler
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Zijun Wang
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Justin Da Silva
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Daniel Poston
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Shlomo Finkin
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Alice Cho
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Melissa Cipolla
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Thiago Y. Oliveira
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Katrina G. Millard
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Victor Ramos
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Anna Gazumyan
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Magdalena Rutkowska
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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Marina Caskey
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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Michel C. Nussenzweig
3Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
4Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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  • For correspondence: nussen@mail.rockefeller.edu bjorkman@caltech.edu thatziio@rockefeller.edu pbieniasz@rockefeller.edu
Pamela J. Bjorkman
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
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  • For correspondence: nussen@mail.rockefeller.edu bjorkman@caltech.edu thatziio@rockefeller.edu pbieniasz@rockefeller.edu
Theodora Hatziioannou
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
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  • For correspondence: nussen@mail.rockefeller.edu bjorkman@caltech.edu thatziio@rockefeller.edu pbieniasz@rockefeller.edu
Paul D. Bieniasz
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA.
4Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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  • For correspondence: nussen@mail.rockefeller.edu bjorkman@caltech.edu thatziio@rockefeller.edu pbieniasz@rockefeller.edu
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Summary

Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.

Competing Interest Statement

The Rockefeller University has filed provisional patent applications in connection with this work on which M.C.N. (US patent 63/021,387) and Y.W., F.S., T.H. and P.D.B. (US patent 63/036,124) are listed as inventors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 08, 2021.
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Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies
Frauke Muecksch, Yiska Weisblum, Christopher O. Barnes, Fabian Schmidt, Dennis Schaefer-Babajew, Julio C C Lorenzi, Andrew I Flyak, Andrew T DeLaitsch, Kathryn E Huey-Tubman, Shurong Hou, Celia A. Schiffer, Christian Gaebler, Zijun Wang, Justin Da Silva, Daniel Poston, Shlomo Finkin, Alice Cho, Melissa Cipolla, Thiago Y. Oliveira, Katrina G. Millard, Victor Ramos, Anna Gazumyan, Magdalena Rutkowska, Marina Caskey, Michel C. Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul D. Bieniasz
bioRxiv 2021.03.07.434227; doi: https://doi.org/10.1101/2021.03.07.434227
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Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies
Frauke Muecksch, Yiska Weisblum, Christopher O. Barnes, Fabian Schmidt, Dennis Schaefer-Babajew, Julio C C Lorenzi, Andrew I Flyak, Andrew T DeLaitsch, Kathryn E Huey-Tubman, Shurong Hou, Celia A. Schiffer, Christian Gaebler, Zijun Wang, Justin Da Silva, Daniel Poston, Shlomo Finkin, Alice Cho, Melissa Cipolla, Thiago Y. Oliveira, Katrina G. Millard, Victor Ramos, Anna Gazumyan, Magdalena Rutkowska, Marina Caskey, Michel C. Nussenzweig, Pamela J. Bjorkman, Theodora Hatziioannou, Paul D. Bieniasz
bioRxiv 2021.03.07.434227; doi: https://doi.org/10.1101/2021.03.07.434227

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