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TitleThe Pre-Existing Human Antibody Repertoire to Computationally Optimized Influenza H1 Hemagglutinin Vaccines.
Journal, issue, pagesJ Immunol, Vol. 209, Issue 1, Page 5-15, Year 2022
Publish dateJul 1, 2022
AuthorsKaito Nagashima / John V Dzimianski / Julianna Han / Nada Abbadi / Aaron D Gingerich / Fredejah Royer / Sara O'Rourke / Giuseppe A Sautto / Ted M Ross / Andrew B Ward / Rebecca M DuBois / Jarrod J Mousa /
PubMed AbstractComputationally optimized broadly reactive Ag (COBRA) hemagglutinin (HA) immunogens have previously been generated for several influenza subtypes to improve vaccine-elicited Ab breadth. As nearly all ...Computationally optimized broadly reactive Ag (COBRA) hemagglutinin (HA) immunogens have previously been generated for several influenza subtypes to improve vaccine-elicited Ab breadth. As nearly all individuals have pre-existing immunity to influenza viruses, influenza-specific memory B cells will likely be recalled upon COBRA HA vaccination. We determined the epitope specificity and repertoire characteristics of pre-existing human B cells to H1 COBRA HA Ags. Cross-reactivity between wild-type HA and H1 COBRA HA proteins P1, X6, and Y2 were observed for isolated mAbs. The mAbs bound five distinct epitopes on the pandemic A/California/04/2009 HA head and stem domains, and most mAbs had hemagglutination inhibition and neutralizing activity against 2009 pandemic H1 strains. Two head-directed mAbs, CA09-26 and CA09-45, had hemagglutination inhibition and neutralizing activity against a prepandemic H1 strain. One mAb, P1-05, targeted the stem region of H1 HA, but did not compete with a known stem-targeting H1 mAb. We determined that mAb P1-05 recognizes a recently discovered HA epitope, the anchor epitope, and we identified similar mAbs using B cell repertoire sequencing. In addition, the trimerization domain distance from HA was critical to recognition of this epitope by mAb P1-05, suggesting the importance of protein design for vaccine formulations. Overall, these data indicate that seasonally vaccinated individuals possess a population of functional H1 COBRA HA-reactive B cells that target head, central stalk, and anchor epitopes, and they demonstrate the importance of structure-based assessment of subunit protein vaccine candidates to ensure accessibility of optimal protein epitopes.
External linksJ Immunol / PubMed:35697384 / PubMed Central
MethodsEM (single particle)
Resolution11.0 Å
Structure data

EMDB-26586: Negative stain EM map of Y2 COBRA hemagglutinin in complex with monoclonal antibody P1-05
Method: EM (single particle) / Resolution: 11.0 Å

Source
  • Cricetulus griseus (Chinese hamster)

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