Show simple item record

AuthorCorbett, Kizzmekia S
AuthorMoin, Syed M
AuthorYassine, Hadi M
AuthorCagigi, Alberto
AuthorKanekiyo, Masaru
AuthorBoyoglu-Barnum, Seyhan
AuthorMyers, Sky I
AuthorTsybovsky, Yaroslav
AuthorWheatley, Adam K
AuthorSchramm, Chaim A
AuthorGillespie, Rebecca A
AuthorShi, Wei
AuthorWang, Lingshu
AuthorZhang, Yi
AuthorAndrews, Sarah F
AuthorJoyce, M Gordon
AuthorCrank, Michelle C
AuthorDouek, Daniel C
AuthorMcDermott, Adrian B
AuthorMascola, John R
AuthorGraham, Barney S
AuthorBoyington, Jeffrey C
Available date2019-03-06T05:02:08Z
Publication Date2019-02-26
Publication NamemBioen_US
Identifierhttp://dx.doi.org/10.1128/mBio.02810-18
CitationCorbett KS, Moin SM, Yassine HM, Cagigi A, Kanekiyo M, Boyoglu-Barnum S, Myers SI, Tsybovsky Y, Wheatley AK, Schramm CA, Gillespie RA, Shi W, Wang L, Zhang Y, Andrews SF, Joyce MG, Crank MC, Douek DC, McDermott AB, Mascola JR, Graham BS, Boyington JC. Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages. MBio. 2019 Feb 26;10(1). pii: e02810-18. doi: 10.1128/mBio.02810-18.
URIhttp://hdl.handle.net/10576/11374
AbstractInfluenza 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. 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.
Languageen
PublisherAmerican Society for Microbiology
Subjectferritin
Subjecthemagglutinin
Subjectinfluenza
Subjectinfluenza vaccines
Subjectnanoparticle
Subjectprotein engineering
Subjectvaccine design
TitleDesign of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages.
TypeArticle
Issue Number1
Volume Number10
dc.identifier.essn 2150-7511


Files in this item

Icon

This item appears in the following Collection(s)

Show simple item record