{"doi":"10.1101/430157","title":"Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Throughout the last decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g. respiratory syncytial virus (RSV), influenza, dengue and others) have resisted vaccine development efforts, largely due to the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B-cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the Palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses\n                  <jats:italic>in vivo</jats:italic>\n                  and reshape established antibody hierarchies.\n                </jats:p>","journal":null,"year":null,"id":602856,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1546294,"name":"M Galloux","orcid":null,"position":1,"is_corresponding":false},{"id":1546296,"name":"SS Vollers","orcid":null,"position":2,"is_corresponding":false},{"id":1546298,"name":"L Csepregi","orcid":null,"position":3,"is_corresponding":false},{"id":1546301,"name":"C Yang","orcid":"0000-0002-4591-5373","position":4,"is_corresponding":false},{"id":1546302,"name":"D Descamps","orcid":null,"position":5,"is_corresponding":false},{"id":27479,"name":"Jaume Bonet","orcid":"0000-0001-5210-4387","position":6,"is_corresponding":false},{"id":1546304,"name":"S Friedensohn","orcid":null,"position":7,"is_corresponding":false},{"id":583209,"name":"Pablo Gaínza","orcid":"0000-0001-9197-0982","position":8,"is_corresponding":false},{"id":1546305,"name":"P Corthésy","orcid":null,"position":9,"is_corresponding":false},{"id":1289705,"name":"M Chen","orcid":"0000-0002-9663-7414","position":10,"is_corresponding":false},{"id":1546306,"name":"S Rosset","orcid":null,"position":11,"is_corresponding":false},{"id":1546308,"name":"MA Rameix-Welti","orcid":null,"position":12,"is_corresponding":false},{"id":1546311,"name":"JF Eléouët","orcid":null,"position":13,"is_corresponding":false},{"id":1546313,"name":"ST Reddy","orcid":null,"position":14,"is_corresponding":false},{"id":1546314,"name":"BS Graham","orcid":null,"position":15,"is_corresponding":false},{"id":1546315,"name":"S Riffault","orcid":null,"position":16,"is_corresponding":false},{"id":1546316,"name":"BE Correia","orcid":null,"position":17,"is_corresponding":false},{"id":1205749,"name":"Fabian Sesterhenn","orcid":"0000-0001-8331-4344","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Throughout the last decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g. respiratory syncytial virus (RSV), influenza, dengue and others) have resisted vaccine development efforts, largely due to the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B-cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the Palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses\n                  <jats:italic>in vivo</jats:italic>\n                  and reshape established antibody hierarchies.\n                </jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21097893","pmcid":null,"openalex_id":"https://openalex.org/W2894308446","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"716058","title":"Computational Design of Novel Functional Proteins for Immunoengineering"},{"funder_name":"Swiss National Science Foundation","grant_id":"163139","title":"Development of an epitope-focused vaccine for Respiratory Syncytial Virus"}],"total_grants":2,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2021,"count":2},{"year":2024,"count":1}],"oa_status":"green","license":"cc-by-nc","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2018/11/22/430157.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2018/11/22/430157.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/430157","host_type":"publisher"},{"url":"https://doi.org/10.1101/430157","host_type":"repository"},{"url":"http://prodinra.inra.fr/ft/8CF915B6-2FF1-45B6-90E2-C0919056E7B5","host_type":"repository"},{"url":"http://hdl.handle.net/20.500.11850/331744","host_type":"repository"},{"url":"https://doi.org/10.3929/ethz-b-000331744","host_type":"repository"},{"url":"https://doi.org/10.1371/journal.pbio.3000164","host_type":""},{"url":"https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000164&type=printable","host_type":""},{"url":"https://dx.doi.org/10.3929/ethz-b-000331744","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/30789898","host_type":""},{"url":"http://dx.doi.org/10.1371/journal.pbio.3000164","host_type":""},{"url":"https://doaj.org/article/bea6dfa8a79f40869e4c2d0a5963a80d","host_type":""},{"url":"https://dx.doi.org/10.1371/journal.pbio.3000164","host_type":""},{"url":"https://dx.doi.org/10.1101/430157","host_type":""},{"url":"https://sonar.ch/global/documents/3235","host_type":""},{"url":"https://inserm.hal.science/inserm-02138858v1","host_type":""},{"url":"https://inserm.hal.science/inserm-02138858v1/document","host_type":""},{"url":"http://prodinra.inra.fr/record/471321","host_type":""},{"url":"http://dx.doi.org/10.1101/430157","host_type":""},{"url":"https://doi.org/https://doi.org/10.1371/journal.pbio.3000164","host_type":""}],"fields_of_study":["Respiratory viral infections research","Immune Cell Function and Interaction","Influenza Virus Research Studies","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":[],"keywords":["Immunogen","Subdominant","Epitope","Virology","Neutralization","Biology","Neutralizing antibody","Antibody","Dengue vaccine","Immunodominance","Epitope mapping","Dengue virus","Immunology","Monoclonal antibody","Virus","570","rsv antibody","[SDV.IMM] Life Sciences [q-bio]/Immunology","QH301-705.5","[SDV]Life Sciences [q-bio]","respiratory syncytial virus","Recombinant Fusion Proteins","Genetic Vectors","610","Gene Expression","Receptors, Antigen, B-Cell","hiv","dependent enhancement","Antibodies, Monoclonal, Humanized","Antibodies, Viral","Epitopes","Mice","Immunogenicity, Vaccine","616","Escherichia coli","Respiratory Syncytial Virus Vaccines","Animals","Biology (General)","Cloning, Molecular","Palivizumab","hemagglutinin-stem","Mice, Inbred BALB C","respiratory syncytial virus;fusion-glycoprotein vaccine;structural basis;dependent enhancement;hemagglutinin-stem;dengue virus;rsv antibody;hiv;infection;cells","structural basis","fusion-glycoprotein vaccine","Antibodies, Neutralizing","infection","Respiratory Syncytial Viruses","Structural Homology, Protein","[SDV.IMM]Life Sciences [q-bio]/Immunology","cells","Computer-Aided Design","Nanoparticles","Female","Immunization","Viral Fusion Proteins","Research Article"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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