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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,31]]},"abstract":"<jats:p>\n                    During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human V\n                    <jats:sub>H<\/jats:sub>\n                    1-2 and V\u03ba1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and\/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single V\n                    <jats:sub>H<\/jats:sub>\n                    1-2 rearranges to human D3-3 and J\n                    <jats:sub>H<\/jats:sub>\n                    6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4\/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human V\n                    <jats:sub>H<\/jats:sub>\n                    - and V\u03ba-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2537053123","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T19:01:03Z","timestamp":1774292463000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human V\n                    <sub>H<\/sub>\n                    1-2-rearranging mouse models"],"prefix":"10.1073","volume":"123","author":[{"given":"Himanshu","family":"Batra","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Department of Genetics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Luo","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Department of Genetics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin O.","family":"Saunders","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]},{"name":"Department of Surgery, Duke University","place":["Durham"]},{"name":"Department of Integrative Immunobiology, Duke University School of Medicine","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn S.","family":"Higgins","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Microbiology and Immunology, University of North Carolina at Chapel Hill","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-3507","authenticated-orcid":false,"given":"Fanchong","family":"Jian","sequence":"additional","affiliation":[{"name":"Biomedical Pioneering Innovation Center, Peking University","place":["Beijing, China"]},{"name":"Changping Laboratory","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston"]},{"name":"Department of Pediatrics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Golam","family":"Kibria","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston"]},{"name":"Department of Pediatrics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. M.","family":"Jonaid","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston"]},{"name":"Department of Pediatrics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingchen J.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Department of Genetics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Eaton","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]},{"name":"Department of Surgery, Duke University","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Cronin","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]},{"name":"Department of Medicine, Duke University School of Medicine","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Mallory","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Microbiology and Immunology, University of North Carolina at Chapel Hill","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Mattocks","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Microbiology and Immunology, University of North Carolina at Chapel Hill","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Parks","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]},{"name":"Department of Surgery, Duke University","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther M.","family":"Lee","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]},{"name":"Department of Integrative Immunobiology, Duke University School of Medicine","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam Yongxin","family":"Ye","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Department of Genetics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9402-4326","authenticated-orcid":false,"given":"Aimee Chapdelaine","family":"Williams","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Department of Genetics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geeyoun","family":"Jung","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]},{"name":"Department of Genetics, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katayoun","family":"Mansouri","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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Batra S. Luo Q. J. Zhou A. Y. Ye F. W. Alt Data \u201cHTGTS-Rep-seq for humanized antibodies that broadly neutralize Omicron sub-variants.\u201d ArrayExpress. https:\/\/www.ebi.ac.uk\/biostudies\/arrayexpress\/studies\/E-MTAB-16106. Deposited 12 November 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2537053123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T19:01:37Z","timestamp":1774292497000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2537053123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":69,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2026,3,31]]}},"alternative-id":["10.1073\/pnas.2537053123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2537053123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]},"assertion":[{"value":"2025-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2537053123"}}