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Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

Seyhan Boyoglu-Barnum, Daniel Ellis, Rebecca A. Gillespie, Geoffrey B. Hutchinson, Young-Jun Park, Syed M. Moin, Oliver Acton, Rashmi Ravichandran, Mike Murphy, Deleah Pettie, Nick Matheson, Lauren Carter, Adrian Creanga, Michael J. Watson, Sally Kephart, John R. Vaile, George Ueda, Michelle C. Crank, Lance Stewart, Kelly K. Lee, Miklos Guttman, David Baker, John R. Mascola, David Veesler, Barney S. Graham, Neil P. King, View ORCID ProfileMasaru Kanekiyo
doi: https://doi.org/10.1101/2020.05.30.125179
Seyhan Boyoglu-Barnum
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Daniel Ellis
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
4Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, United States
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Rebecca A. Gillespie
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Geoffrey B. Hutchinson
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Young-Jun Park
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Syed M. Moin
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Oliver Acton
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Rashmi Ravichandran
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Mike Murphy
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Deleah Pettie
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Nick Matheson
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Lauren Carter
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Adrian Creanga
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Michael J. Watson
5Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
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Sally Kephart
5Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
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John R. Vaile
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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George Ueda
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Michelle C. Crank
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Lance Stewart
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Kelly K. Lee
5Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
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Miklos Guttman
5Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
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David Baker
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
6Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, United States
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John R. Mascola
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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David Veesler
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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Barney S. Graham
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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  • For correspondence: bgraham@nih.gov neil@ipd.uw.edu kanekiyom@nih.gov
Neil P. King
2Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
3Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
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  • For correspondence: bgraham@nih.gov neil@ipd.uw.edu kanekiyom@nih.gov
Masaru Kanekiyo
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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  • ORCID record for Masaru Kanekiyo
  • For correspondence: bgraham@nih.gov neil@ipd.uw.edu kanekiyom@nih.gov
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Abstract

Influenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in a highly immunogenic array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited hemagglutination inhibition and neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to commercial QIV in mice, ferrets, and nonhuman primates. The nanoparticle immunogens—but not QIV—simultaneously induced broadly protective antibody responses to heterologous viruses, including H5N1 and H7N9, by targeting the subdominant yet conserved HA stem. Unlike previously reported influenza vaccine candidates, our nanoparticle immunogens can alter the intrinsic immunodominance hierarchy of HA to induce both potent receptor-blocking and broadly cross-reactive stem-directed antibody responses and are attractive candidates for a next-generation influenza vaccine that could replace current seasonal vaccines.

One Sentence Summary Nanoparticle immunogens displaying four seasonal influenza hemagglutinins elicit neutralizing antibodies directed at both the immunodominant head and the conserved stem and confer broad protective immunity.

Competing Interest Statement

S.B.B., D.E., R.A.G., B.S.G., N.P.K., and M.K. are listed as inventors on a patent application based on the studies presented in this paper.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted May 31, 2020.
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Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines
Seyhan Boyoglu-Barnum, Daniel Ellis, Rebecca A. Gillespie, Geoffrey B. Hutchinson, Young-Jun Park, Syed M. Moin, Oliver Acton, Rashmi Ravichandran, Mike Murphy, Deleah Pettie, Nick Matheson, Lauren Carter, Adrian Creanga, Michael J. Watson, Sally Kephart, John R. Vaile, George Ueda, Michelle C. Crank, Lance Stewart, Kelly K. Lee, Miklos Guttman, David Baker, John R. Mascola, David Veesler, Barney S. Graham, Neil P. King, Masaru Kanekiyo
bioRxiv 2020.05.30.125179; doi: https://doi.org/10.1101/2020.05.30.125179
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Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines
Seyhan Boyoglu-Barnum, Daniel Ellis, Rebecca A. Gillespie, Geoffrey B. Hutchinson, Young-Jun Park, Syed M. Moin, Oliver Acton, Rashmi Ravichandran, Mike Murphy, Deleah Pettie, Nick Matheson, Lauren Carter, Adrian Creanga, Michael J. Watson, Sally Kephart, John R. Vaile, George Ueda, Michelle C. Crank, Lance Stewart, Kelly K. Lee, Miklos Guttman, David Baker, John R. Mascola, David Veesler, Barney S. Graham, Neil P. King, Masaru Kanekiyo
bioRxiv 2020.05.30.125179; doi: https://doi.org/10.1101/2020.05.30.125179

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