Site-specific serology unveils cross-reactive monoclonal antibodies targeting influenza A hemagglutinin epitopes

Paparoditis, Philipp C. G.; Fruehwirth, Alexander; Bevc, Kajetana; Low, Jun Siong; Jerak, Josipa; Terzaghi, Laura; Foglierini, Mathilde; Fernandez, Blanca; Jarrossay, David; Corti, Davide; Sallusto, Federica; Lanzavecchia, Antonio; Cassotta, Antonino

doi:10.1002/eji.202451045

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Cassotta_2024_Wiley_Eur J Immunol_Site-specific serology

Journal article

Site-specific serology unveils cross-reactive monoclonal antibodies targeting influenza A hemagglutinin epitopes

Paparoditis, Philipp C. G. ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Fruehwirth, Alexander Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Bevc, Kajetana ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Low, Jun Siong ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Jerak, Josipa ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Terzaghi, Laura Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Foglierini, Mathilde ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Fernandez, Blanca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Jarrossay, David ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Corti, Davide ORCID Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland
Sallusto, Federica ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute for Microbiology, ETH Zurich, Zurich, Switzerland
Lanzavecchia, Antonio ORCID Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland - National Institute of Molecular Genetics, Milano, Italy
Cassotta, Antonino ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland

2024

Published in:

European journal of immunology. - 2024, vol. 54, no. 10, p. 2451045

English Efficient identification of human monoclonal antibodies targeting specific antigenic sites is pivotal for advancing vaccines and immunotherapies against infectious diseases and cancer. Existing screening techniques, however, limit our ability to discover monoclonal antibodies with desired specificity. In this study, we introduce a novel method, blocking of binding (BoB) enzyme-linked immunoassay (ELISA), enabling the detection of high-avidity human antibodies directed to defined epitopes. Leveraging BoB-ELISA, we analyzed the antibody response to known epitopes of influenza A hemagglutinin (HA) in the serum of vaccinated donors. Our findings revealed that serum antibodies targeting head epitopes were immunodominant, whereas antibodies against the stem epitope, although subdominant, were highly prevalent. Extending our analysis across multiple HA strains, we examined the cross-reactive antibody response targeting the stem epitope. Importantly, employing BoB-ELISA we identified donors harboring potent heterosubtypic antibodies targeting the HA stem. B-cell clonal analysis of these donors revealed three novel, genealogically independent monoclonal antibodies with broad cross-reactivity to multiple HAs. In summary, we demonstrated that BoB-ELISA is a sensitive technique for measuring B-cell epitope immunogenicity, enabling the identification of novel monoclonal antibodies with implications for enhanced vaccine development and immunotherapies.

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