Combinatorial immune refocusing within the influenza hemagglutinin RBD improves cross-neutralizing antibody responses

Annie Dosey; Daniel Ellis; Seyhan Boyoglu-Barnum; Hubza Syeda; Mason Saunders; Michael J. Watson; John C. Kraft; Minh N. Pham; Miklos Guttman; Kelly K. Lee; Masaru Kanekiyo; Neil P. King

Cell Reports (Dec 2023)

Combinatorial immune refocusing within the influenza hemagglutinin RBD improves cross-neutralizing antibody responses

Annie Dosey,
Daniel Ellis,
Seyhan Boyoglu-Barnum,
Hubza Syeda,
Mason Saunders,
Michael J. Watson,
John C. Kraft,
Minh N. Pham,
Miklos Guttman,
Kelly K. Lee,
Masaru Kanekiyo,
Neil P. King

Affiliations

Annie Dosey: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
Daniel Ellis: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
Seyhan Boyoglu-Barnum: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Hubza Syeda: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Mason Saunders: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Michael J. Watson: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
John C. Kraft: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
Minh N. Pham: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
Miklos Guttman: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Kelly K. Lee: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
Masaru Kanekiyo: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Neil P. King: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 12
p. 113553

Abstract

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Summary: The receptor-binding domain (RBD) of influenza virus hemagglutinin (HA) elicits potently neutralizing yet mostly strain-specific antibodies. Here, we evaluate the ability of several immunofocusing techniques to enhance the functional breadth of vaccine-elicited immune responses against the HA RBD. We present a series of “trihead” nanoparticle immunogens that display native-like closed trimeric RBDs from the HAs of several H1N1 influenza viruses. The series includes hyperglycosylated and hypervariable variants that incorporate natural and designed sequence diversity at key positions in the receptor-binding site periphery. Nanoparticle immunogens displaying triheads or hyperglycosylated triheads elicit higher hemagglutination inhibition (HAI) and neutralizing activity than the corresponding immunogens lacking either trimer-stabilizing mutations or hyperglycosylation. By contrast, mosaic nanoparticle display and antigen hypervariation do not significantly alter the magnitude or breadth of vaccine-elicited antibodies. Our results yield important insights into antibody responses against the RBD and the ability of several structure-based immunofocusing techniques to influence vaccine-elicited antibody responses.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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