Jing Jing Wang, Linda Schönborn, Theodore E Warkentin, Luisa Müller, Thomas Thiele, Lena Ulm, Uwe Völker, Sabine Ameling, Sören Franzenburg, Lars Kaderali, Ana Tzvetkova, Alex Colella, Tim Chataway, Chee Wee Tan, Bridie Armour, Alexander Troelnikov, Lucy Rutten, James McCluskey, Roland Zahn, Tom P Gordon, Andreas Greinacher
Background: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare prothrombotic complication that occurs after adenoviral vector-based vaccination against coronavirus disease 2019; in rare cases, it can also occur after natural adenovirus infection. VITT is mediated by platelet-activating antibodies against the highly cationic protein platelet factor 4 (PF4). The underlying inciting antigen trigger and immunopathogenesis remain unknown.
Methods: We used antibody proteomics to determine the amino acid sequences of anti-PF4 antibodies from 21 patients with VITT and sequenced the genes encoding the immunoglobulin light-chain hypervariable region from 100 patients with VITT. To identify an adenoviral trigger, we used the antigen-binding fingerprints of anti-PF4 and anti-adenovirus protein antibodies to identify a shared serum clonotype and subsequently used adenovirus protein peptides and recombinant anti-PF4 VITT antibodies to map the mimicking linear epitope.
Results: Genomic and proteomic profiling of VITT antibodies revealed a shared immunoglobulin light-chain allele, IGLV3-21*02 or *03, harboring a critical somatic hypermutation, K31E. Only antibodies purified against adenoviral core protein VII (pVII) contained anti-PF4 species matching the VITT fingerprint; antibodies against intact virions or other adenoviral proteins did not. Cross-reactive IgGs were mapped to a basic linear epitope on pVII. A pathogenic anti-PF4 VITT antibody, back-mutated to germline (K31), lost its prothrombotic activity in vitro and in vivo and preferentially bound pVII, a finding that directly supported the role of the hypermutation in the antigenic shift from adenovirus pVII to PF4.
Conclusions: The results of our study indicate that VITT occurs when, in persons with immunoglobulin light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation develops that affects antibodies that recognize a specific epitope on the adenoviral core protein pVII, which results in misdirection of antibody targeting toward PF4. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00025738; EU Post-Authorization Study Register number, EUPAS45098.).
{"title":"Adenoviral Inciting Antigen and Somatic Hypermutation in VITT.","authors":"Jing Jing Wang, Linda Schönborn, Theodore E Warkentin, Luisa Müller, Thomas Thiele, Lena Ulm, Uwe Völker, Sabine Ameling, Sören Franzenburg, Lars Kaderali, Ana Tzvetkova, Alex Colella, Tim Chataway, Chee Wee Tan, Bridie Armour, Alexander Troelnikov, Lucy Rutten, James McCluskey, Roland Zahn, Tom P Gordon, Andreas Greinacher","doi":"10.1056/NEJMoa2514824","DOIUrl":"https://doi.org/10.1056/NEJMoa2514824","url":null,"abstract":"<p><strong>Background: </strong>Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare prothrombotic complication that occurs after adenoviral vector-based vaccination against coronavirus disease 2019; in rare cases, it can also occur after natural adenovirus infection. VITT is mediated by platelet-activating antibodies against the highly cationic protein platelet factor 4 (PF4). The underlying inciting antigen trigger and immunopathogenesis remain unknown.</p><p><strong>Methods: </strong>We used antibody proteomics to determine the amino acid sequences of anti-PF4 antibodies from 21 patients with VITT and sequenced the genes encoding the immunoglobulin light-chain hypervariable region from 100 patients with VITT. To identify an adenoviral trigger, we used the antigen-binding fingerprints of anti-PF4 and anti-adenovirus protein antibodies to identify a shared serum clonotype and subsequently used adenovirus protein peptides and recombinant anti-PF4 VITT antibodies to map the mimicking linear epitope.</p><p><strong>Results: </strong>Genomic and proteomic profiling of VITT antibodies revealed a shared immunoglobulin light-chain allele, IGLV3-21*02 or *03, harboring a critical somatic hypermutation, K31E. Only antibodies purified against adenoviral core protein VII (pVII) contained anti-PF4 species matching the VITT fingerprint; antibodies against intact virions or other adenoviral proteins did not. Cross-reactive IgGs were mapped to a basic linear epitope on pVII. A pathogenic anti-PF4 VITT antibody, back-mutated to germline (K31), lost its prothrombotic activity in vitro and in vivo and preferentially bound pVII, a finding that directly supported the role of the hypermutation in the antigenic shift from adenovirus pVII to PF4.</p><p><strong>Conclusions: </strong>The results of our study indicate that VITT occurs when, in persons with immunoglobulin light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation develops that affects antibodies that recognize a specific epitope on the adenoviral core protein pVII, which results in misdirection of antibody targeting toward PF4. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00025738; EU Post-Authorization Study Register number, EUPAS45098.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"669-683"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Belzutifan for Advanced Pheochromocytoma or Paraganglioma. Reply.","authors":"Camilo Jimenez, Mikkel Andreassen, Alfredo Berruti","doi":"10.1056/NEJMc2518226","DOIUrl":"https://doi.org/10.1056/NEJMc2518226","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"728"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Thromboprophylaxis for Atrial Fibrillation in Patients with Drug-Eluting Stents.","authors":"Gregory Y H Lip, Lukasz Kuzma","doi":"10.1056/NEJMe2517711","DOIUrl":"https://doi.org/10.1056/NEJMe2517711","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"713-715"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mucormycosis is a rapidly progressive, invasive fungal infection that affects patients who are severely immunocompromised, as well as patients with diabetes and persons with immunocompetence who have major trauma. Mucormycosis manifests in several clinical forms, including sino-orbital, rhinocerebral, sinopulmonary, gastrointestinal, cutaneous, musculoskeletal, osteoarticular, and disseminated mucormycosis, as well as single-organ disease. Although mucormycosis is often lethal, early intervention reduces mortality. Successful treatment depends on early detection and staging of the disease, timely initiation of antifungal therapy, surgical resection of infected tissue, reversal of immunodeficiencies, and correction of metabolic abnormalities. Liposomal amphotericin B is the preferred agent for initial antifungal therapy, with oral triazoles as alternative agents. Research on rapid molecular diagnostic strategies, new antifungal agents, host-directed immune augmentation, antivirulence immune therapeutics, and risk-based stratification to inform management of disease may substantially improve outcomes in patients with this highly destructive mycosis.
{"title":"Mucormycosis.","authors":"Dimitrios P Kontoyiannis, Thomas J Walsh","doi":"10.1056/NEJMra2412565","DOIUrl":"https://doi.org/10.1056/NEJMra2412565","url":null,"abstract":"<p><p>Mucormycosis is a rapidly progressive, invasive fungal infection that affects patients who are severely immunocompromised, as well as patients with diabetes and persons with immunocompetence who have major trauma. Mucormycosis manifests in several clinical forms, including sino-orbital, rhinocerebral, sinopulmonary, gastrointestinal, cutaneous, musculoskeletal, osteoarticular, and disseminated mucormycosis, as well as single-organ disease. Although mucormycosis is often lethal, early intervention reduces mortality. Successful treatment depends on early detection and staging of the disease, timely initiation of antifungal therapy, surgical resection of infected tissue, reversal of immunodeficiencies, and correction of metabolic abnormalities. Liposomal amphotericin B is the preferred agent for initial antifungal therapy, with oral triazoles as alternative agents. Research on rapid molecular diagnostic strategies, new antifungal agents, host-directed immune augmentation, antivirulence immune therapeutics, and risk-based stratification to inform management of disease may substantially improve outcomes in patients with this highly destructive mycosis.</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"684-698"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potassium Levels and Risk of Ventricular Arrhythmias.","authors":"Rodolfo F Rivera, Maria T Sciarrone Alibrandi","doi":"10.1056/NEJMc2518640","DOIUrl":"https://doi.org/10.1056/NEJMc2518640","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"723-724"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potassium Levels and Risk of Ventricular Arrhythmias.","authors":"Maxime Ingwiller","doi":"10.1056/NEJMc2518640","DOIUrl":"https://doi.org/10.1056/NEJMc2518640","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"725"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potassium Levels and Risk of Ventricular Arrhythmias.","authors":"Yifang Yuan, Yida Tang, Yangfeng Wu","doi":"10.1056/NEJMc2518640","DOIUrl":"https://doi.org/10.1056/NEJMc2518640","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"725"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Belzutifan for Advanced Pheochromocytoma or Paraganglioma.","authors":"Hussam Alkaissi, Karel Pacak","doi":"10.1056/NEJMc2518226","DOIUrl":"https://doi.org/10.1056/NEJMc2518226","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"727"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potassium Levels and Risk of Ventricular Arrhythmias.","authors":"Gilberto F Hurtado-Torres","doi":"10.1056/NEJMc2518640","DOIUrl":"https://doi.org/10.1056/NEJMc2518640","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"394 7","pages":"724"},"PeriodicalIF":78.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Health Consequences of Immigration Enforcement in U.S. Communities.","authors":"Melissa Arguello Belli","doi":"10.1056/NEJMp2516715","DOIUrl":"https://doi.org/10.1056/NEJMp2516715","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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