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

MBio
Kizzmekia S CorbettJeffrey C Boyington

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 mul...Continue Reading

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Citations

Oct 11, 2019·Annual Review of Medicine·Raffael Nachbagauer, Peter Palese
Dec 25, 2019·Cold Spring Harbor Perspectives in Medicine·Nicholas C Wu, Ian A Wilson
Oct 30, 2019·Annals of the New York Academy of Sciences·Jennifer CableRino Rappuoli
Sep 26, 2020·Viruses·Nicholas C Wu, Ian A Wilson
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Aug 11, 2021·Viruses·Yogesh B NarkhedeEva-Maria Strauch
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Dec 19, 2021·NPJ Vaccines·Timothy M Caradonna, Aaron G Schmidt
Jan 9, 2022·The AAPS Journal·Dylan A HendyKristy M Ainslie

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Datasets Mentioned

BETA
EPI397685
MH631451
MH997407
MH997405
MK291365
MK291366

Methods Mentioned

BETA
immunoprecipitation
enzyme-linked immunosorbent assay
electrophoresis
transfection
electron microscopy
ELISAs
differential scanning calorimetry
ELISA
flow cytometry
transgenic

Software Mentioned

DNAML
Geneious
GraphPad Prism
MEGA7
VP
UCSF Chimera
Relion
SPIDER
GenScript
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