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TitleEliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses.
Journal, issue, pagesImmunity, Vol. 57, Issue 5, Page 1141-1159.e11, Year 2024
Publish dateMay 14, 2024
AuthorsRashmi Ray / Faez Amokrane Nait Mohamed / Daniel P Maurer / Jiachen Huang / Berk A Alpay / Larance Ronsard / Zhenfei Xie / Julianna Han / Monica Fernandez-Quintero / Quynh Anh Phan / Rebecca L Ursin / Mya Vu / Kathrin H Kirsch / Thavaleak Prum / Victoria C Rosado / Thalia Bracamonte-Moreno / Vintus Okonkwo / Julia Bals / Caitlin McCarthy / Usha Nair / Masaru Kanekiyo / Andrew B Ward / Aaron G Schmidt / Facundo D Batista / Daniel Lingwood /
PubMed AbstractBroadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, ...Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.
External linksImmunity / PubMed:38670113 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 4.02 Å
Structure data

42528

8ut3

EMDB-42528, PDB-8ut3:
CryoEM structure of A/Perth/16/2009 H3 in complex with flu HA central stem VH1-18 antibody UCA6
Method: EM (single particle) / Resolution: 2.8 Å

42529

8ut4

EMDB-42529, PDB-8ut4:
CryoEM structure of A/Michigan/45/2015 H1 in complex with flu HA central stem VH1-18 antibody 09-1B12
Method: EM (single particle) / Resolution: 3.3 Å

42530

8ut5

EMDB-42530, PDB-8ut5:
CryoEM structure of A/Michigan/45/2015 H1 in complex with flu HA central stem VH1-18 antibody UCA6_N55T
Method: EM (single particle) / Resolution: 3.5 Å

42531

8ut6

EMDB-42531, PDB-8ut6:
CryoEM structure of A/Perth/16/2009 H3 in complex with polyclonal Fab from mice immunized with H3 stem nanoparticles-15 days post immunization
Method: EM (single particle) / Resolution: 2.8 Å

42532

8ut7

EMDB-42532, PDB-8ut7:
CryoEM structure of A/Perth/16/2009 H3 in complex with polyclonal Fab from mice immunized with H3 stem nanoparticles-28 days post immunization
Method: EM (single particle) / Resolution: 2.7 Å

42533

8ut8

EMDB-42533, PDB-8ut8:
CryoEM structure of A/Shanghai/1/2013 H7 in complex with polyclonal Fab from mice immunized with H7 stem nanoparticles-15 days post-immunization
Method: EM (single particle) / Resolution: 3.2 Å

42534

8ut9

EMDB-42534, PDB-8ut9:
CryoEM structure of A/Shanghai/1/2013 H7 in complex with polyclonal Fab from mice immunized with H7 stem nanoparticles-28 days post immunization
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-42535: CryoEM structure of A/Perth/16/2009 H3
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-42536: CryoEM map of A/Shanghai/1/2013 H7 HA
Method: EM (single particle) / Resolution: 3.1 Å

PDB-8uwa:
VH1-18 QxxV class antibody 09-1B12 bound to A/Perth/16/2009 H3N2 hemagglutinin
Method: X-RAY DIFFRACTION / Resolution: 4.02 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • influenza a virus
  • mus musculus (house mouse)
  • influenza a virus (a/perth/16/2009(h3n2))
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Flu Hemagglutinin / Central stem epitope / VH1-18 / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / cryoEMPEM / antibody / stem / influenza / hemagglutinin

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