Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages

ABSTRACT Influenza vaccines targeting the highly conserved stem of the hemagglutinin (HA) surface glycoprotein have the potential to protect against pandemic and drifted seasonal influenza viruses not covered by current vaccines. While HA stem-based immunogens derived from group 1 influenza A viruse...

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Autores principales:	Kizzmekia S. Corbett, Syed M. Moin, Hadi M. Yassine, Alberto Cagigi, Masaru Kanekiyo, Seyhan Boyoglu-Barnum, Sky I. Myers, Yaroslav Tsybovsky, Adam K. Wheatley, Chaim A. Schramm, Rebecca A. Gillespie, Wei Shi, Lingshu Wang, Yi Zhang, Sarah F. Andrews, M. Gordon Joyce, Michelle C. Crank, Daniel C. Douek, Adrian B. McDermott, John R. Mascola, Barney S. Graham, Jeffrey C. Boyington
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	hemagglutinin influenza influenza vaccines nanoparticle protein engineering vaccine design Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cd997d727dab4f9a9bff7e2660bf416f
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spelling	oai:doaj.org-article:cd997d727dab4f9a9bff7e2660bf416f2021-11-15T15:55:14ZDesign of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages10.1128/mBio.02810-182150-7511https://doaj.org/article/cd997d727dab4f9a9bff7e2660bf416f2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02810-18https://doaj.org/toc/2150-7511ABSTRACT Influenza vaccines targeting the highly conserved stem of the hemagglutinin (HA) surface glycoprotein have the potential to protect against pandemic and drifted seasonal influenza viruses not covered by current vaccines. While HA stem-based immunogens derived from group 1 influenza A viruses have been shown to induce intragroup heterosubtypic protection, HA stem-specific antibody lineages originating from group 2 may be more likely to possess broad cross-group reactivity. We report the structure-guided development of mammalian-cell-expressed candidate vaccine immunogens based on influenza A virus group 2 H3 and H7 HA stem trimers displayed on self-assembling ferritin nanoparticles using an iterative, multipronged approach involving helix stabilization, loop optimization, disulfide bond addition, and side-chain repacking. These immunogens were thermostable, formed uniform and symmetric nanoparticles, were recognized by cross-group-reactive broadly neutralizing antibodies (bNAbs) with nanomolar affinity, and elicited protective, homosubtypic antibodies in mice. Importantly, several immunogens were able to activate B cells expressing inferred unmutated common ancestor (UCA) versions of cross-group-reactive human bNAbs from two multidonor classes, suggesting they could initiate elicitation of these bNAbs in humans. IMPORTANCE Current influenza vaccines are primarily strain specific, requiring annual updates, and offer minimal protection against drifted seasonal or pandemic strains. The highly conserved stem region of hemagglutinin (HA) of group 2 influenza A virus subtypes is a promising target for vaccine elicitation of broad cross-group protection against divergent strains. We used structure-guided protein engineering employing multiple protein stabilization methods simultaneously to develop group 2 HA stem-based candidate influenza A virus immunogens displayed as trimers on self-assembling nanoparticles. Characterization of antigenicity, thermostability, and particle formation confirmed structural integrity. Group 2 HA stem antigen designs were identified that, when displayed on ferritin nanoparticles, activated B cells expressing inferred unmutated common ancestor (UCA) versions of human antibody lineages associated with cross-group-reactive, broadly neutralizing antibodies (bNAbs). Immunization of mice led to protection against a lethal homosubtypic influenza virus challenge. These candidate vaccines are now being manufactured for clinical evaluation.Kizzmekia S. CorbettSyed M. MoinHadi M. YassineAlberto CagigiMasaru KanekiyoSeyhan Boyoglu-BarnumSky I. MyersYaroslav TsybovskyAdam K. WheatleyChaim A. SchrammRebecca A. GillespieWei ShiLingshu WangYi ZhangSarah F. AndrewsM. Gordon JoyceMichelle C. CrankDaniel C. DouekAdrian B. McDermottJohn R. MascolaBarney S. GrahamJeffrey C. BoyingtonAmerican Society for Microbiologyarticlehemagglutinininfluenzainfluenza vaccinesnanoparticleprotein engineeringvaccine designMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	hemagglutinin influenza influenza vaccines nanoparticle protein engineering vaccine design Microbiology QR1-502
spellingShingle	hemagglutinin influenza influenza vaccines nanoparticle protein engineering vaccine design Microbiology QR1-502 Kizzmekia S. Corbett Syed M. Moin Hadi M. Yassine Alberto Cagigi Masaru Kanekiyo Seyhan Boyoglu-Barnum Sky I. Myers Yaroslav Tsybovsky Adam K. Wheatley Chaim A. Schramm Rebecca A. Gillespie Wei Shi Lingshu Wang Yi Zhang Sarah F. Andrews M. Gordon Joyce Michelle C. Crank Daniel C. Douek Adrian B. McDermott John R. Mascola Barney S. Graham Jeffrey C. Boyington Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
description	ABSTRACT Influenza vaccines targeting the highly conserved stem of the hemagglutinin (HA) surface glycoprotein have the potential to protect against pandemic and drifted seasonal influenza viruses not covered by current vaccines. While HA stem-based immunogens derived from group 1 influenza A viruses have been shown to induce intragroup heterosubtypic protection, HA stem-specific antibody lineages originating from group 2 may be more likely to possess broad cross-group reactivity. We report the structure-guided development of mammalian-cell-expressed candidate vaccine immunogens based on influenza A virus group 2 H3 and H7 HA stem trimers displayed on self-assembling ferritin nanoparticles using an iterative, multipronged approach involving helix stabilization, loop optimization, disulfide bond addition, and side-chain repacking. These immunogens were thermostable, formed uniform and symmetric nanoparticles, were recognized by cross-group-reactive broadly neutralizing antibodies (bNAbs) with nanomolar affinity, and elicited protective, homosubtypic antibodies in mice. Importantly, several immunogens were able to activate B cells expressing inferred unmutated common ancestor (UCA) versions of cross-group-reactive human bNAbs from two multidonor classes, suggesting they could initiate elicitation of these bNAbs in humans. IMPORTANCE Current influenza vaccines are primarily strain specific, requiring annual updates, and offer minimal protection against drifted seasonal or pandemic strains. The highly conserved stem region of hemagglutinin (HA) of group 2 influenza A virus subtypes is a promising target for vaccine elicitation of broad cross-group protection against divergent strains. We used structure-guided protein engineering employing multiple protein stabilization methods simultaneously to develop group 2 HA stem-based candidate influenza A virus immunogens displayed as trimers on self-assembling nanoparticles. Characterization of antigenicity, thermostability, and particle formation confirmed structural integrity. Group 2 HA stem antigen designs were identified that, when displayed on ferritin nanoparticles, activated B cells expressing inferred unmutated common ancestor (UCA) versions of human antibody lineages associated with cross-group-reactive, broadly neutralizing antibodies (bNAbs). Immunization of mice led to protection against a lethal homosubtypic influenza virus challenge. These candidate vaccines are now being manufactured for clinical evaluation.
format	article
author	Kizzmekia S. Corbett Syed M. Moin Hadi M. Yassine Alberto Cagigi Masaru Kanekiyo Seyhan Boyoglu-Barnum Sky I. Myers Yaroslav Tsybovsky Adam K. Wheatley Chaim A. Schramm Rebecca A. Gillespie Wei Shi Lingshu Wang Yi Zhang Sarah F. Andrews M. Gordon Joyce Michelle C. Crank Daniel C. Douek Adrian B. McDermott John R. Mascola Barney S. Graham Jeffrey C. Boyington
author_facet	Kizzmekia S. Corbett Syed M. Moin Hadi M. Yassine Alberto Cagigi Masaru Kanekiyo Seyhan Boyoglu-Barnum Sky I. Myers Yaroslav Tsybovsky Adam K. Wheatley Chaim A. Schramm Rebecca A. Gillespie Wei Shi Lingshu Wang Yi Zhang Sarah F. Andrews M. Gordon Joyce Michelle C. Crank Daniel C. Douek Adrian B. McDermott John R. Mascola Barney S. Graham Jeffrey C. Boyington
author_sort	Kizzmekia S. Corbett
title	Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
title_short	Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
title_full	Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
title_fullStr	Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
title_full_unstemmed	Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
title_sort	design of nanoparticulate group 2 influenza virus hemagglutinin stem antigens that activate unmutated ancestor b cell receptors of broadly neutralizing antibody lineages
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/cd997d727dab4f9a9bff7e2660bf416f
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Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages

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