{"doi":"10.4049/jimmunol.2101171","title":"The Pre-Existing Human Antibody Repertoire to Computationally Optimized Influenza H1 Hemagglutinin Vaccines","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.","journal":"The Journal of Immunology","year":2022,"id":262080,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9464,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":314574,"name":"John V. Dzimianski","orcid":"0000-0002-2447-146X","position":1,"is_corresponding":false},{"id":284389,"name":"Julianna Han","orcid":"0000-0002-3402-2609","position":2,"is_corresponding":false},{"id":831324,"name":"Nada Abbadi","orcid":"0000-0003-0755-5482","position":3,"is_corresponding":false},{"id":400641,"name":"Aaron D. Gingerich","orcid":"0000-0002-8139-611X","position":4,"is_corresponding":false},{"id":753150,"name":"Fredejah Royer","orcid":null,"position":5,"is_corresponding":false},{"id":316031,"name":"Sara M. O’Rourke","orcid":null,"position":6,"is_corresponding":false},{"id":299104,"name":"Giuseppe A. Sautto","orcid":"0000-0002-0273-2235","position":7,"is_corresponding":false},{"id":245069,"name":"Ted M. Ross","orcid":"0000-0003-1947-7469","position":8,"is_corresponding":false},{"id":230082,"name":"Andrew B. Ward","orcid":"0000-0001-7153-3769","position":9,"is_corresponding":false},{"id":314577,"name":"Rebecca M. DuBois","orcid":"0000-0003-4185-5673","position":10,"is_corresponding":false},{"id":296075,"name":"Jarrod J. Mousa","orcid":"0000-0003-4709-2478","position":11,"is_corresponding":false},{"id":695604,"name":"Kaito Nagashima","orcid":"0000-0002-7501-6651","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T00:26:20.717229Z","pmid":"35697384","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}