{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:14:52Z","timestamp":1787494492568,"version":"build-2736575974"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T00:00:00Z","timestamp":1735776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"DHAC | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1157744"],"award-info":[{"award-number":["APP1157744"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"DHAC | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1113904"],"award-info":[{"award-number":["APP1113904"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Research Future Fund","award":["MRF2001739"],"award-info":[{"award-number":["MRF2001739"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:p>\n                    The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the \u201cup\u201d conformation of the SARS-CoV-2 spike trimer. Increasing antibody affinity into the low picomolar range endowed potent neutralization of VOCs and protection of hACE2 mice from viral challenge. Cryoelectron microscopy and crystal structures of two affinity-matured antibodies (4C12-B12 and 4G1-C2) in complex with RBD highlighted binding modes and epitopes distal from mutational hotspots commonly overserved in VOCs, providing direct structural insights into the observed mutational resistance. Moreover, we further demonstrate that antibodies targeting the class 6 epitope, rather than being an artifact of in vitro selection, are common in the IgG1\n                    <jats:sup>+<\/jats:sup>\n                    memory B cell repertoire of convalescent patients and can be induced in human antibody V-gene transgenic mice through immunization. Our results highlight the importance of very high (picomolar) affinity in the development of neutralizing antibodies and vaccines and suggest an affinity threshold in the provision of broad and long-lasting immunity against SARS-CoV-2.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2417544121","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T14:00:24Z","timestamp":1735826424000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies"],"prefix":"10.1073","volume":"122","author":[{"given":"Ohan","family":"Mazigi","sequence":"first","affiliation":[{"name":"Garvan Institute of Medical Research","place":["Sydney, Australia"]},{"name":"University of New South Wales Sydney, St. Vincent\u2019s Clinical School, Faculty of Medicine","place":["Sydney, 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L.","family":"Burnett","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research","place":["Sydney, Australia"]},{"name":"University of New South Wales Sydney, School of Biomedical Sciences, Faculty of Medicine","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7086-3467","authenticated-orcid":false,"given":"Meghna","family":"Sobti","sequence":"additional","affiliation":[{"name":"University of New South Wales Sydney, St. Vincent\u2019s Clinical School, Faculty of Medicine","place":["Sydney, Australia"]},{"name":"Victor Chang Cardiac Research Institute","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0044-1394","authenticated-orcid":false,"given":"Gregory J.","family":"Walker","sequence":"additional","affiliation":[{"name":"University of New South Wales Sydney, School of Biomedical Sciences, Faculty of 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J.","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Bioscience, Molecular Horizons, and Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins, University of Wollongong","place":["Wollongong, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-3346","authenticated-orcid":false,"given":"Sebastian R.","family":"Schulz","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Friedrich-Alexander University Erlangen-N\u00fcrnberg","place":["Erlangen-N\u00fcrnberg, Germany"]},{"name":"University Hospital Erlangen","place":["Erlangen-N\u00fcrnberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-7696","authenticated-orcid":false,"given":"Markus","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center\u2013Leibniz Institute for Primate Research","place":["G\u00f6ttingen, Germany"]},{"name":"Faculty of Biology and Psychology, Georg-August University G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6086-9136","authenticated-orcid":false,"given":"Stefan","family":"P\u00f6hlmann","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center\u2013Leibniz Institute for Primate Research","place":["G\u00f6ttingen, Germany"]},{"name":"Faculty of Biology and Psychology, Georg-August University G\u00f6ttingen","place":["G\u00f6ttingen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1475-9272","authenticated-orcid":false,"given":"Jeffrey","family":"Post","sequence":"additional","affiliation":[{"name":"Prince of Wales Hospital","place":["Sydney, Australia"]},{"name":"Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales Australia","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Martinello","sequence":"additional","affiliation":[{"name":"Kirby Institute, University of New South Wales Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0026-1457","authenticated-orcid":false,"given":"Golo","family":"Ahlenstiel","sequence":"additional","affiliation":[{"name":"Blacktown Mt. 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