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TitleVaccine design via antigen reorientation.
Journal, issue, pagesNat Chem Biol, Vol. 20, Issue 8, Page 1012-1021, Year 2024
Publish dateJan 15, 2024
AuthorsDuo Xu / Joshua J Carter / Chunfeng Li / Ashley Utz / Payton A B Weidenbacher / Shaogeng Tang / Mrinmoy Sanyal / Bali Pulendran / Christopher O Barnes / Peter S Kim /
PubMed AbstractA major challenge in creating universal influenza vaccines is to focus immune responses away from the immunodominant, variable head region of hemagglutinin (HA-head) and toward the evolutionarily ...A major challenge in creating universal influenza vaccines is to focus immune responses away from the immunodominant, variable head region of hemagglutinin (HA-head) and toward the evolutionarily conserved stem region (HA-stem). Here we introduce an approach to control antigen orientation via site-specific insertion of aspartate residues that facilitates antigen binding to alum. We demonstrate the generalizability of this approach with antigens from Ebola, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses and observe enhanced neutralizing antibody responses in all cases. We then reorient an H2 HA in an 'upside-down' configuration to increase the exposure and immunogenicity of HA-stem. The reoriented H2 HA (reoH2HA) on alum induced stem-directed antibodies that cross-react with both group 1 and group 2 influenza A subtypes. Electron microscopy polyclonal epitope mapping (EMPEM) revealed that reoH2HA (group 1) elicits cross-reactive antibodies targeting group 2 HA-stems. Our results highlight antigen reorientation as a generalizable approach for designing epitope-focused vaccines.
External linksNat Chem Biol / PubMed:38225471 / PubMed Central
MethodsEM (single particle)
Resolution15.1 - 24.7 Å
Structure data

EMDB-42044: H2HA A/Japan/305/1957 complexed with mouse polyclonal Fab - wk 12, reoriented immunogen
Method: EM (single particle) / Resolution: 24.7 Å

EMDB-42045: H2HA A/Japan/305/1957 complexed with mouse polyclonal Fab - wk 12, control immunogen
Method: EM (single particle) / Resolution: 24.45 Å

EMDB-42046: H7N9 A/Shanghai/2/2013 complexed with mouse polyclonal Fab - wk 12, control immunogen
Method: EM (single particle) / Resolution: 23.5 Å

EMDB-42048: H3N2 A/Victoria/3/1975 complexed with mouse polyclonal Fab - wk 7, control immunogen
Method: EM (single particle) / Resolution: 17.6 Å

EMDB-42052: H3N2 A/Victoria/3/1975 complexed with mouse polyclonal Fab - wk 7, reoH2HA immunogen
Method: EM (single particle) / Resolution: 19.4 Å

EMDB-42056: H7N9 A/Shanghai/2/2013 complexed with mouse polyclonal Fab - wk 7, reoriented immunogen
Method: EM (single particle) / Resolution: 22.5 Å

EMDB-42058: H7N9 A/Shanghai/2/2013 complexed with mouse polyclonal Fab - wk 7, control immunogen
Method: EM (single particle) / Resolution: 15.1 Å

EMDB-42059: H7N9 A/Shanghai/2/2013 complexed with mouse polyclonal Fab - wk 7, reoriented immunogen
Method: EM (single particle) / Resolution: 20.1 Å

Source
  • Influenza A virus (A/Japan/305/1957(H2N2))
  • Mus musculus (house mouse)
  • H7N9 subtype (virus)
  • Influenza A virus (A/Victoria/3/1975(H3N2))

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