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TitleInfluenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 21, Page e2200821119, Year 2022
Publish dateMay 24, 2022
AuthorsXueyong Zhu / Julianna Han / Weina Sun / Eduard Puente-Massaguer / Wenli Yu / Peter Palese / Florian Krammer / Andrew B Ward / Ian A Wilson /
PubMed AbstractInfluenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of ...Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
External linksProc Natl Acad Sci U S A / PubMed:35594401 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution4.56 - 20.0 Å
Structure data

EMDB-26928: Negative stain map of cH4/3
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26929: Negative stain half map of cH4/3 state 1
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26930: Negative stain map of cH4/3 state 3
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26931: Negative stain map of cH4/3 state 3
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26932: Negative stain map of cH4/3 state 4
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26933: Negative stain map of cH15/3
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26934: Negative stain map of cH15/3 state 1
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26935: Negative stain map of cH15/3 state 2
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26937: Negative stain map of cH15/3 state 3
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26938: Negative stain map of cH15/3 state 4
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-26939: Negative stain map of cH15/3 in complex with CR9114 Fab
Method: EM (single particle) / Resolution: 20.0 Å

PDB-7u8j:
Crystal structure of chimeric hemagglutinin cH4/3 in complex with broad protective antibody 31.a.83
Method: X-RAY DIFFRACTION / Resolution: 4.9 Å

PDB-7u8l:
Crystal structure of chimeric hemagglutinin cH15/3 in complex with broad protective antibody 31.a.83
Method: X-RAY DIFFRACTION / Resolution: 4.56 Å

PDB-7u8m:
Crystal structure of chimeric hemagglutinin cH15/3 in complex with broad protective antibodies 31.a.83 and FluA-20
Method: X-RAY DIFFRACTION / Resolution: 5.39 Å

Source
  • influenza a virus
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/Immune System / Universal vaccine design / chimeric influenza hemagglutinin / HA trimer interface and stem / VIRAL PROTEIN-Immune System complex

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