Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses

Masaru Kanekiyo; M Gordon Joyce; Rebecca A Gillespie; John R Gallagher; Sarah F Andrews; Hadi M Yassine; Adam K Wheatley; Brian E Fisher; David R Ambrozak; Adrian Creanga; Kwanyee Leung; Eun Sung Yang; Seyhan Boyoglu-Barnum; Ivelin S Georgiev; Yaroslav Tsybovsky; Madhu S Prabhakaran; Hanne Andersen; Wing-Pui Kong; Ulrich Baxa; Kathryn L Zephir; Julie E Ledgerwood; Richard A Koup; Peter D Kwong; Audray K Harris; Adrian B McDermott; John R Mascola; Barney S Graham

doi:10.1038/s41590-018-0305-x

Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses

Nat Immunol. 2019 Mar;20(3):362-372. doi: 10.1038/s41590-018-0305-x. Epub 2019 Feb 11.

Authors

Masaru Kanekiyo¹, M Gordon Joyce^{2

3}, Rebecca A Gillespie², John R Gallagher⁴, Sarah F Andrews², Hadi M Yassine^{2

5}, Adam K Wheatley^{2

6}, Brian E Fisher², David R Ambrozak², Adrian Creanga², Kwanyee Leung², Eun Sung Yang², Seyhan Boyoglu-Barnum², Ivelin S Georgiev^{2

7}, Yaroslav Tsybovsky⁸, Madhu S Prabhakaran², Hanne Andersen⁹, Wing-Pui Kong², Ulrich Baxa^{8

10}, Kathryn L Zephir², Julie E Ledgerwood², Richard A Koup², Peter D Kwong², Audray K Harris⁴, Adrian B McDermott², John R Mascola², Barney S Graham¹¹

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. kanekiyom@nih.gov.
² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁴ Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Biomedical Research Center, Qatar University, Doha, Qatar.
⁶ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
⁷ Vanderbilt Vaccine Center and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Electron Microscope Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁹ Bioqual, Inc., Rockville, MD, USA.
¹⁰ Cryo-EM facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
¹¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. bgraham@nih.gov.

Abstract

The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable receptor-binding domain (RBD) of viral hemagglutinin displayed on a nanoparticle (np) able to elicit antibody responses that neutralize H1N1 influenza viruses spanning over 90 years. Co-display of RBDs from multiple strains across time, so that the adjacent RBDs are heterotypic, provides an avidity advantage to cross-reactive B cells. Immunization with the mosaic RBD-np elicited broader antibody responses than those induced by an admixture of nanoparticles encompassing the same set of RBDs as separate homotypic arrays. Furthermore, we identified a broadly neutralizing monoclonal antibody in a mouse immunized with mosaic RBD-np. The mosaic antigen array signifies a unique approach that subverts monotypic immunodominance and allows otherwise subdominant cross-reactive B cell responses to emerge.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / administration & dosage
Antibodies, Neutralizing / immunology
Antibodies, Viral / immunology
B-Lymphocytes / drug effects
B-Lymphocytes / immunology
B-Lymphocytes / virology
Cross Reactions / drug effects
Cross Reactions / immunology
Female
Hemagglutinin Glycoproteins, Influenza Virus / chemistry
Hemagglutinin Glycoproteins, Influenza Virus / immunology*
Humans
Immunization
Influenza A Virus, H1N1 Subtype / immunology*
Influenza A Virus, H1N1 Subtype / metabolism
Influenza A Virus, H1N1 Subtype / physiology
Influenza Vaccines / administration & dosage
Influenza Vaccines / chemistry
Influenza Vaccines / immunology*
Influenza, Human / immunology*
Influenza, Human / prevention & control
Influenza, Human / virology
Mice, Inbred BALB C
Nanoparticles / chemistry*
Orthomyxoviridae Infections / immunology*
Orthomyxoviridae Infections / prevention & control
Orthomyxoviridae Infections / virology

Substances

Antibodies, Neutralizing
Antibodies, Viral
Hemagglutinin Glycoproteins, Influenza Virus
Influenza Vaccines

Abstract

Publication types

MeSH terms

Substances

Grants and funding