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Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses.

ABSTRACT: The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccine efforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypic protection in animals; however, the protection does not extend to group 2 viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, we show that introducing the group 2 glycan at Asn38HA1 to a group 1 stem-nanoparticle (gN38 variant) based on A/New Caledonia/20/99 (H1N1) broadens antibody responses to cross-react with group 2 HAs. Immunoglobulins elicited by the gN38 variant provide complete protection against group 2 H7N9 virus infection, while the variant loses protection against a group 1 H5N1 virus. The N38HA1 glycan thus is pivotal in directing antibody responses by controlling access to group-determining stem epitopes. Precise targeting of stem-directed antibody responses to the site of vulnerability by glycan repositioning may be a step towards achieving cross-group influenza protection.

SUBMITTER: Boyoglu-Barnum S

PROVIDER: S-EPMC7005838 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses.

Boyoglu-Barnum Seyhan S Hutchinson Geoffrey B GB Boyington Jeffrey C JC Moin Syed M SM Gillespie Rebecca A RA Tsybovsky Yaroslav Y Stephens Tyler T Vaile John R JR Lederhofer Julia J Corbett Kizzmekia S KS Fisher Brian E BE Yassine Hadi M HM Andrews Sarah F SF Crank Michelle C MC McDermott Adrian B AB Mascola John R JR Graham Barney S BS Kanekiyo Masaru M

Nature communications 20200207 1

The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccine efforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypic protection in animals; however, the protection does not extend to group 2 viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, we show that introducing the group 2 glycan at Asn38<sub>HA1</sub> to a group 1 stem-nanoparticle (gN38 variant) based on A/New Caledonia/20/99 (H1N1) br ...[more]

PMID: 32034141

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Project description:Despite the availability of seasonal vaccines and antiviral medications, influenza virus continues to be a major health concern and pandemic threat due to the continually changing antigenic regions of the major surface glycoprotein, hemagglutinin (HA). One emerging strategy for the development of more efficacious seasonal and universal influenza vaccines is structure-guided design of nanoparticles that display conserved regions of HA, such as the stem. Using the H1 HA subtype to establish proof of concept, we found that tandem copies of an alpha-helical fragment from the conserved stem region (helix-A) can be displayed on the protruding spikes structures of a capsid scaffold. The stem region of HA on these designed chimeric nanoparticles is immunogenic and the nanoparticles are biochemically robust in that heat exposure did not destroy the particles and immunogenicity was retained. Furthermore, mice vaccinated with H1-nanoparticles were protected from lethal challenge with H1N1 influenza virus. By using a nanoparticle library approach with this helix-A nanoparticle design, we show that this vaccine nanoparticle construct design could be applicable to different influenza HA subtypes. Importantly, antibodies elicited by H1, H5, and H7 nanoparticles demonstrated homosubtypic and heterosubtypic cross-reactivity binding to different HA subtypes. Also, helix-A nanoparticle immunizations were used to isolate mouse monoclonal antibodies that demonstrated heterosubtypic cross-reactivity and provided protection to mice from viral challenge via passive-transfer. This tandem helix-A nanoparticle construct represents a novel design to display several hundred copies of non-trimeric conserved HA stem epitopes on vaccine nanoparticles. This design concept provides a new approach to universal influenza vaccine development strategies and opens opportunities for the development of nanoparticles with broad coverage over many antigenically diverse influenza HA subtypes.

Dataset Information

Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses.

Publications

Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses.

Similar Datasets

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