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Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2

Alexandra C. Walls, Brooke Fiala, Alexandra Schäfer, Samuel Wrenn, Minh N. Pham, Michael Murphy, Longping V. Tse, Laila Shehata, Megan A. O'Connor, Chengbo Chen, Mary Jane Navarro, Marcos C. Miranda, Deleah Pettie, Rashmi Ravichandran, John C. Kraft, Cassandra Ogohara, Anne Palser, Sara Chalk, E-Chiang Lee, Elizabeth Kepl, Cameron M. Chow, Claire Sydeman, Edgar A. Hodge, Brieann Brown, Jim T. Fuller, Kenneth H. Dinnon III, Lisa E. Gralinski, Sarah R. Leist, Kendra L. Gully, Thomas B. Lewis, Miklos Guttman, Helen Y. Chu, Kelly K. Lee, Deborah H. Fuller, Ralph S. Baric, Paul Kellam, Lauren Carter, View ORCID ProfileMarion Pepper, View ORCID ProfileTimothy P. Sheahan, David Veesler, View ORCID ProfileNeil P. King
doi: https://doi.org/10.1101/2020.08.11.247395
Alexandra C. Walls
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Brooke Fiala
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Alexandra Schäfer
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Samuel Wrenn
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Minh N. Pham
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Michael Murphy
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Longping V. Tse
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Laila Shehata
4Department of Immunology, University of Washington, Seattle, WA 98109, USA
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Megan A. O'Connor
5Department of Microbiology, University of Washington, Seattle, WA 98109, USA
6Washington National Primate Research Center, Seattle, WA 98121, USA
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Chengbo Chen
7Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
8Biological Physics Structure and Design Program, University of Washington, Seattle, WA 91895, USA
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Mary Jane Navarro
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Marcos C. Miranda
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Deleah Pettie
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Rashmi Ravichandran
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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John C. Kraft
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Cassandra Ogohara
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Anne Palser
9Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
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Sara Chalk
9Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
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E-Chiang Lee
9Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
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Elizabeth Kepl
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Cameron M. Chow
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Claire Sydeman
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Edgar A. Hodge
7Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
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Brieann Brown
5Department of Microbiology, University of Washington, Seattle, WA 98109, USA
6Washington National Primate Research Center, Seattle, WA 98121, USA
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Jim T. Fuller
5Department of Microbiology, University of Washington, Seattle, WA 98109, USA
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Kenneth H. Dinnon III
10Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Lisa E. Gralinski
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Sarah R. Leist
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Kendra L. Gully
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Thomas B. Lewis
5Department of Microbiology, University of Washington, Seattle, WA 98109, USA
6Washington National Primate Research Center, Seattle, WA 98121, USA
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Miklos Guttman
7Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
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Helen Y. Chu
11Department of Medicine, University of Washington, Seattle, WA 98109, USA
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Kelly K. Lee
7Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
8Biological Physics Structure and Design Program, University of Washington, Seattle, WA 91895, USA
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Deborah H. Fuller
5Department of Microbiology, University of Washington, Seattle, WA 98109, USA
6Washington National Primate Research Center, Seattle, WA 98121, USA
12Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA
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Ralph S. Baric
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
10Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Paul Kellam
9Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom
13Department of Infectious Disease, Imperial College London, United Kingdom
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Lauren Carter
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Marion Pepper
4Department of Immunology, University of Washington, Seattle, WA 98109, USA
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  • ORCID record for Marion Pepper
Timothy P. Sheahan
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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  • ORCID record for Timothy P. Sheahan
David Veesler
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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  • For correspondence: dveesler@uw.edu neil@ipd.uw.edu
Neil P. King
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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  • ORCID record for Neil P. King
  • For correspondence: dveesler@uw.edu neil@ipd.uw.edu
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SUMMARY

A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.

Competing Interest Statement

A.C.W, D.V., and N.P.K. are named as inventors on patent applications filed by the University of Washington based on the studies presented in this paper. N.P.K. is a co-founder, shareholder, and chair of the scientific advisory board of Icosavax, Inc. H.Y.C. is a consultant for Merck and Pfizer, and has received research funding from Sanofi-Pasteur, Roche-Genentech, Cepheid, and Ellume outside of the submitted work. P.K., A.P., and S.C. are employees and shareholders of Kymab Ltd. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The other authors declare no competing interests.

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-ND 4.0 International license.
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Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2
Alexandra C. Walls, Brooke Fiala, Alexandra Schäfer, Samuel Wrenn, Minh N. Pham, Michael Murphy, Longping V. Tse, Laila Shehata, Megan A. O'Connor, Chengbo Chen, Mary Jane Navarro, Marcos C. Miranda, Deleah Pettie, Rashmi Ravichandran, John C. Kraft, Cassandra Ogohara, Anne Palser, Sara Chalk, E-Chiang Lee, Elizabeth Kepl, Cameron M. Chow, Claire Sydeman, Edgar A. Hodge, Brieann Brown, Jim T. Fuller, Kenneth H. Dinnon III, Lisa E. Gralinski, Sarah R. Leist, Kendra L. Gully, Thomas B. Lewis, Miklos Guttman, Helen Y. Chu, Kelly K. Lee, Deborah H. Fuller, Ralph S. Baric, Paul Kellam, Lauren Carter, Marion Pepper, Timothy P. Sheahan, David Veesler, Neil P. King
bioRxiv 2020.08.11.247395; doi: https://doi.org/10.1101/2020.08.11.247395
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Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2
Alexandra C. Walls, Brooke Fiala, Alexandra Schäfer, Samuel Wrenn, Minh N. Pham, Michael Murphy, Longping V. Tse, Laila Shehata, Megan A. O'Connor, Chengbo Chen, Mary Jane Navarro, Marcos C. Miranda, Deleah Pettie, Rashmi Ravichandran, John C. Kraft, Cassandra Ogohara, Anne Palser, Sara Chalk, E-Chiang Lee, Elizabeth Kepl, Cameron M. Chow, Claire Sydeman, Edgar A. Hodge, Brieann Brown, Jim T. Fuller, Kenneth H. Dinnon III, Lisa E. Gralinski, Sarah R. Leist, Kendra L. Gully, Thomas B. Lewis, Miklos Guttman, Helen Y. Chu, Kelly K. Lee, Deborah H. Fuller, Ralph S. Baric, Paul Kellam, Lauren Carter, Marion Pepper, Timothy P. Sheahan, David Veesler, Neil P. King
bioRxiv 2020.08.11.247395; doi: https://doi.org/10.1101/2020.08.11.247395

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