{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:50:28Z","timestamp":1792788628117,"version":"4.5.0"},"reference-count":64,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2021YFC2301300"],"award-info":[{"award-number":["2021YFC2301300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2020YFA0907100"],"award-info":[{"award-number":["2020YFA0907100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Excellent Young Scientist Program from NSFC","award":["82122031"],"award-info":[{"award-number":["82122031"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Protective vaccines are crucial for preventing and controlling coronavirus disease 2019 (COVID-19). Updated vaccines are needed to confront the continuously evolving and circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. These vaccines should be safe, effective, amenable to easily scalable production, and affordable. Previously, we developed receptor binding domain (RBD) dimer-based protein subunit vaccines (ZF2001 and updated vaccines) in mammalian cells. In this study, we explored a strategy for producing RBD-dimer immunogens in\n                    <jats:italic>Pichia pastoris<\/jats:italic>\n                    . We found that wild-type\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>pastoris<\/jats:italic>\n                    produced hyperglycosylated RBD-dimer protein containing four N-glycosylation sites in\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>pastoris<\/jats:italic>\n                    . Therefore, we engineered the wild type\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>pastoris<\/jats:italic>\n                    (GS strain) into GS\u0394OCH1pAO by deleting the\n                    <jats:italic>OCH1<\/jats:italic>\n                    gene (encoding \u03b1-1,6-mannosyltransferase enzyme) to decrease glycosylation, as well as by overexpressing the\n                    <jats:italic>HIS4<\/jats:italic>\n                    gene (encoding histidine dehydrogenase) to increase histidine synthesis for better growth. In addition, RBD-dimer protein was truncated to remove the R328\/F329 cleavage sites in\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>pastoris<\/jats:italic>\n                    . Several homogeneous RBD-dimer proteins were produced in the GS\u0394OCH1pAO strain, demonstrating the feasibility of using the\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>pastoris<\/jats:italic>\n                    expression system. We further resolved the cryo-EM structure of prototype-Beta RBD-dimer complexed with the neutralizing antibody CB6 to reveal the completely exposed immune epitopes of the RBDs. In a murine model, we demonstrated that the yeast-produced RBD-dimer induces robust and protective antibody responses, which is suitable for boosting immunization. This study developed the yeast system for producing SARS-CoV-2 RBD-dimer immunogens, providing a promising platform and pipeline for the future continuous updating and production of SARS-CoV-2 vaccines.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012487","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T13:23:08Z","timestamp":1725024188000},"page":"e1012487","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Protective RBD-dimer vaccines against SARS-CoV-2 and its variants produced in glycoengineered Pichia pastoris"],"prefix":"10.1371","volume":"20","author":[{"given":"Tongxin","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dedong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kefang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxun","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianpan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taicheng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9762-5001","authenticated-orcid":true,"given":"Kun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3869-615X","authenticated-orcid":true,"given":"George F.","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"issue":"3","key":"ppat.1012487.ref001","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.cell.2020.06.035","article-title":"A universal design of Betacoronavirus vaccines against COVID-19, MERS, and SARS","volume":"182","author":"L Dai","year":"2020","journal-title":"Cell"},{"issue":"10","key":"ppat.1012487.ref002","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1093\/intimm\/dxab061","article-title":"Humoral and cellular immunity and the safety of COVID-19 vaccines: a summary of data published by 21 May 2021","volume":"33","author":"K Xu","year":"2021","journal-title":"Int Immunol"},{"issue":"12","key":"ppat.1012487.ref003","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/intimm\/dxac031","article-title":"Immunogenicity, efficacy and safety of COVID-19 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