tetano
Editor, Senior Moderator
J Immunol
. 2022 Jun 13;ji2101171.
doi: 10.4049/jimmunol.2101171. Online ahead of print.
The Pre-Existing Human Antibody Repertoire to Computationally Optimized Influenza H1 Hemagglutinin Vaccines
Kaito Nagashima[SUP] 1 2 [/SUP], John V Dzimianski[SUP] 3 [/SUP], Julianna Han[SUP] 4 [/SUP], Nada Abbadi[SUP] 1 2 [/SUP], Aaron D Gingerich[SUP] 2 [/SUP], Fredejah Royer[SUP] 2 [/SUP], Sara O'Rourke[SUP] 3 [/SUP], Giuseppe A Sautto[SUP] 2 [/SUP], Ted M Ross[SUP] 1 2 [/SUP], Andrew B Ward[SUP] 4 [/SUP], Rebecca M DuBois[SUP] 3 [/SUP], Jarrod J Mousa[SUP] 5 2 6 [/SUP]
Affiliations
Abstract
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
. 2022 Jun 13;ji2101171.
doi: 10.4049/jimmunol.2101171. Online ahead of print.
The Pre-Existing Human Antibody Repertoire to Computationally Optimized Influenza H1 Hemagglutinin Vaccines
Kaito Nagashima[SUP] 1 2 [/SUP], John V Dzimianski[SUP] 3 [/SUP], Julianna Han[SUP] 4 [/SUP], Nada Abbadi[SUP] 1 2 [/SUP], Aaron D Gingerich[SUP] 2 [/SUP], Fredejah Royer[SUP] 2 [/SUP], Sara O'Rourke[SUP] 3 [/SUP], Giuseppe A Sautto[SUP] 2 [/SUP], Ted M Ross[SUP] 1 2 [/SUP], Andrew B Ward[SUP] 4 [/SUP], Rebecca M DuBois[SUP] 3 [/SUP], Jarrod J Mousa[SUP] 5 2 6 [/SUP]
Affiliations
- PMID: 35697384
- DOI: 10.4049/jimmunol.2101171
Abstract
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