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The S2 subunit of the viral spike (S) glycoprotein is highly conserved among sarbecoviruses, making it an attractive target for broadly protective countermeasures. To elucidate the S2 antigenic landscape, we employed yeast surface display to isolate S2-targeted antibodies from COVID-19 convalescent donors. Biophysical characterization revealed that these S2 apex-directed antibodies preferentially bind to open spike conformations and a stabilized S2 construct but not to the closed, trimeric prefusion spike. Cryo-electron microscopy structures defined a cryptic epitope encompassing the upper helix and fusion peptide proximal region on S2. This epitope is conserved among sarbecoviruses but remains largely occluded in the closed prefusion conformation of the spikes. As a result, the antibodies exhibited weak neutralization activity against SARS-CoV-2 pseudoviruses, failed to neutralize authentic viruses, and did not provide protection in a lethal mouse challenge model using a mouse-adapted SARS-CoV-2 strain. These findings highlight a non-neutralizing epitope on S2 capable of eliciting antibodies during SARS-CoV-2 infection in humans and provide valuable reagents for probing S2 conformational dynamics and optimizing S2-based vaccine antigens.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014391","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:36:34Z","timestamp":1785778594000},"page":"e1014391","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural and functional characterization of a conserved cryptic epitope on SARS-CoV-2 spike S2 subunit"],"prefix":"10.1371","volume":"22","author":[{"given":"Ling","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Lin","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah R.","family":"Leist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Happy Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Horton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie R.","family":"Shoemaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Gardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Powers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Boutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Mallory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor M.","family":"Mullins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole V.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L.","family":"Tse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamyab","family":"Javanmardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily E.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Schisler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Marqusee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kartik","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph S.","family":"Baric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy D.","family":"Gollihar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3991-542X","authenticated-orcid":true,"given":"Jason S.","family":"McLellan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ppat.1014391.ref001","unstructured":"WHO Coronavirus (COVID-19) Dashboard. https:\/\/covid19.who.int 2023 March 13."},{"key":"ppat.1014391.ref002","unstructured":"Centers for Disease Control and Prevention. 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