{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T13:11:08Z","timestamp":1770642668944,"version":"3.49.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172244"],"award-info":[{"award-number":["82172244"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Major outbreaks of severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), together with the continuous risk of zoonotic spillover of animal sarbecoviruses, underscore the urgent need for vaccines that confer broad protection across the sarbecovirus subgenus. Current immunogen selection strategies for pansarbecovirus vaccine development predominantly rely on phylogenetic or spike sequence conservation analyses, which often fail to accurately predict the breadth of cross-neutralization. To overcome this limitation, we systematically evaluated cross-neutralization profiles among 25 representative sarbecoviruses from clades 1 and 3 via guinea pig antisera individually raised against full-length spike proteins in pseudovirus neutralization assays while excluding clade 2 viruses lacking known receptor usage. Neutralization profiling revealed four distinct immunogenic clusters that diverged from traditional phylogenetic relationships. Antisera induced by the palm civet\u2013derived SARS-CoV-1 strain SZ1 broadly neutralized all clade 1a viruses, whereas full coverage of clade 1b viruses required at least two distinct immunogens. Remarkably, sera elicited by multiple clade 1 immunogens also neutralized clade 3 viruses despite no prior exposure to clade 3 antigens. Guided by these findings, we proposed a minimal trivalent immunogen combination\u2014SZ1, SARS-CoV-2, and PCoV-GX\u2014that elicited broad neutralization against both clade 1 and clade 3. This rational approach eliminates the need for additional clade 3\u2013specific antigens and provides a preclinical framework for developing next-generation pansarbecovirus vaccines.<\/jats:p>","DOI":"10.1038\/s41392-025-02565-5","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:02:11Z","timestamp":1770595331000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunogenic relationship mapping supports a minimal-set trivalent vaccine strategy for broad sarbecovirus protection"],"prefix":"10.1038","volume":"11","author":[{"given":"Yeqing","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3097-8156","authenticated-orcid":false,"given":"Ziqi","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunbo","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4246-8889","authenticated-orcid":false,"given":"Weijin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhui","family":"Nie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"2565_CR1","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1056\/NEJMoa030781","volume":"348","author":"TG Ksiazek","year":"2003","unstructured":"Ksiazek, T. G. et al. A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med. 348, 1953\u20131966 (2003).","journal-title":"N. Engl. J. Med."},{"key":"2565_CR2","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1126\/science.1085952","volume":"300","author":"PA Rota","year":"2003","unstructured":"Rota, P. A. et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300, 1394\u20131399 (2003).","journal-title":"Science"},{"key":"2565_CR3","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","volume":"579","author":"P Zhou","year":"2020","unstructured":"Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270\u2013273 (2020).","journal-title":"Nature"},{"key":"2565_CR4","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/s41586-020-2313-x","volume":"583","author":"KP Xiao","year":"2020","unstructured":"Xiao, K. P. et al. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature 583, 286\u2013289 (2020).","journal-title":"Nature"},{"key":"2565_CR5","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/s41586-022-04532-4","volume":"604","author":"S Temmam","year":"2022","unstructured":"Temmam, S. et al. Bat coronaviruses related to SARS-CoV-2 and infectious for human cells. Nature 604, 330\u2013336 (2022).","journal-title":"Nature"},{"key":"2565_CR6","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1038\/nm.3985","volume":"21","author":"VD Menachery","year":"2015","unstructured":"Menachery, V. D. et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat. Med. 21, 1508\u20131513 (2015).","journal-title":"Nat. Med."},{"key":"2565_CR7","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","volume":"17","author":"J Cui","year":"2019","unstructured":"Cui, J., Li, F. & Shi, Z. L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 17, 181\u2013192 (2019).","journal-title":"Nat. Rev. Microbiol."},{"key":"2565_CR8","doi-asserted-by":"publisher","first-page":"3048","DOI":"10.1073\/pnas.1517719113","volume":"113","author":"VD Menachery","year":"2016","unstructured":"Menachery, V. D. et al. SARS-like WIV1-CoV poised for human emergence. Proc. Natl. Acad. Sci. USA 113, 3048\u20133053 (2016).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2565_CR9","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/nature12711","volume":"503","author":"XY Ge","year":"2013","unstructured":"Ge, X. Y. et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 503, 535\u2013538 (2013).","journal-title":"Nature"},{"key":"2565_CR10","doi-asserted-by":"publisher","first-page":"5432","DOI":"10.1016\/j.cell.2021.09.015","volume":"184","author":"AC Walls","year":"2021","unstructured":"Walls, A. C. et al. Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines. Cell 184, 5432\u20135447 (2021).","journal-title":"Cell"},{"key":"2565_CR11","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq0839","volume":"377","author":"AA Cohen","year":"2022","unstructured":"Cohen, A. A. et al. Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models. Science 377, eabq0839 (2022).","journal-title":"Science"},{"key":"2565_CR12","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1126\/science.abi4506","volume":"373","author":"DR Martinez","year":"2021","unstructured":"Martinez, D. R. et al. Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice. Science 373, 991\u2013998 (2021).","journal-title":"Science"},{"key":"2565_CR13","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj0070","volume":"382","author":"SH Wilks","year":"2023","unstructured":"Wilks, S. H. et al. Mapping SARS-CoV-2 antigenic relationships and serological responses. Science 382, eadj0070 (2023).","journal-title":"Science"},{"key":"2565_CR14","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abq4450","volume":"7","author":"AZ Mykytyn","year":"2022","unstructured":"Mykytyn, A. Z. et al. Antigenic cartography of SARS-CoV-2 reveals that Omicron BA.1 and BA.2 are antigenically distinct. Sci. Immunol. 7, eabq4450 (2022).","journal-title":"Sci. Immunol."},{"key":"2565_CR15","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1016\/j.chom.2022.10.012","volume":"30","author":"W Wang","year":"2022","unstructured":"Wang, W. et al. Antigenic cartography of well-characterized human sera shows SARS-CoV-2 neutralization differences based on infection and vaccination history. Cell Host Microbe 30, 1745\u20131758.e1747 (2022).","journal-title":"Cell Host Microbe"},{"key":"2565_CR16","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41586-022-04464-z","volume":"603","author":"TN Starr","year":"2022","unstructured":"Starr, T. N. et al. ACE2 binding is an ancestral and evolvable trait of sarbecoviruses. Nature 603, 913\u2013918 (2022).","journal-title":"Nature"},{"key":"2565_CR17","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.vaccine.2015.11.062","volume":"34","author":"K Kardani","year":"2016","unstructured":"Kardani, K., Bolhassani, A. & Shahbazi, S. Prime-boost vaccine strategy against viral infections: mechanisms and benefits. Vaccine 34, 413\u2013423 (2016).","journal-title":"Vaccine"},{"key":"2565_CR18","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1136\/gutjnl-2022-327216","volume":"72","author":"R Burm","year":"2023","unstructured":"Burm, R. et al. Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections. Gut 72, 1186\u20131195 (2023).","journal-title":"Gut"},{"key":"2565_CR19","doi-asserted-by":"publisher","first-page":"e285","DOI":"10.1016\/S2352-3018(24)00036-5","volume":"11","author":"I Frank","year":"2024","unstructured":"Frank, I. et al. Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial. Lancet HIV 11, e285\u2013e299 (2024).","journal-title":"Lancet HIV"},{"key":"2565_CR20","doi-asserted-by":"publisher","first-page":"4769","DOI":"10.1172\/JCI128699","volume":"129","author":"NG Rouphael","year":"2019","unstructured":"Rouphael, N. G. et al. DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial. J. Clin. Investig. 129, 4769\u20134785 (2019).","journal-title":"J. Clin. Investig."},{"key":"2565_CR21","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/s41591-021-01660-8","volume":"28","author":"KV Houser","year":"2022","unstructured":"Houser, K. V. et al. Safety and immunogenicity of a ferritin nanoparticle H2 influenza vaccine in healthy adults: a phase 1 trial. Nat. Med. 28, 383\u2013391 (2022).","journal-title":"Nat. Med."},{"key":"2565_CR22","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2024.2447615","volume":"14","author":"YF Ma","year":"2025","unstructured":"Ma, Y. F. et al. Enhanced antibody response to the conformational non-RBD region via DNA prime-protein boost elicits broad cross-neutralization against SARS-CoV-2 variants. Emerg. Microbes. Infect. 14, 2447615 (2025).","journal-title":"Emerg. Microbes. Infect."},{"key":"2565_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-11600-y","volume":"15","author":"Y Yamamoto","year":"2025","unstructured":"Yamamoto, Y. et al. Synergistic activation of bat SARS-like coronaviruses spike protein by elastase and TMPRSS2. Sci. Rep. 15, 26469 (2025).","journal-title":"Sci. Rep."},{"key":"2565_CR24","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41421-021-00256-3","volume":"7","author":"JH Nie","year":"2021","unstructured":"Nie, J. H. et al. Functional comparison of SARS-CoV-2 with closely related pangolin and bat coronaviruses. Cell Discov 7, 21 (2021).","journal-title":"Cell Discov"},{"key":"2565_CR25","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/s41564-020-0688-y","volume":"5","author":"M Letko","year":"2020","unstructured":"Letko, M., Marzi, A. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol. 5, 562\u2013569 (2020).","journal-title":"Nat. Microbiol."},{"key":"2565_CR26","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","volume":"581","author":"J Shang","year":"2020","unstructured":"Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221\u2013224 (2020).","journal-title":"Nature"},{"key":"2565_CR27","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1126\/science.1087139","volume":"302","author":"Y Guan","year":"2003","unstructured":"Guan, Y. et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in Southern China. Science 302, 276\u2013278 (2003).","journal-title":"Science"},{"key":"2565_CR28","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1126\/science.abb9983","volume":"369","author":"Y Watanabe","year":"2020","unstructured":"Watanabe, Y. et al. Site-specific glycan analysis of the SARS-CoV-2 spike. Science 369, 330\u2013333 (2020).","journal-title":"Science"},{"key":"2565_CR29","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1126\/science.abb2507","volume":"367","author":"D Wrapp","year":"2020","unstructured":"Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260\u20131263 (2020).","journal-title":"Science"},{"key":"2565_CR30","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh1766","volume":"373","author":"LS Wang","year":"2021","unstructured":"Wang, L. S. et al. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants. Science 373, eabh1766 (2021).","journal-title":"Science"},{"key":"2565_CR31","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1126\/science.abj3321","volume":"373","author":"D Pinto","year":"2021","unstructured":"Pinto, D. et al. Broad betacoronavirus neutralization by a stem helix-specific human antibody. Science 373, 1109\u20131115 (2021).","journal-title":"Science"},{"key":"2565_CR32","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1126\/science.abq3773","volume":"377","author":"C Dacon","year":"2022","unstructured":"Dacon, C. et al. Broadly neutralizing antibodies target the coronavirus fusion peptide. Science 377, 728\u2013735 (2022).","journal-title":"Science"},{"key":"2565_CR33","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1080\/22221751.2021.2014284","volume":"11","author":"Y Zhang","year":"2022","unstructured":"Zhang, Y. et al. A second functional furin site in the SARS-CoV-2 spike protein. Emerg. Microbes. Infect. 11, 182\u2013194 (2022).","journal-title":"Emerg. Microbes. Infect."},{"key":"2565_CR34","doi-asserted-by":"publisher","first-page":"3699","DOI":"10.1038\/s41596-020-0394-5","volume":"15","author":"JH Nie","year":"2020","unstructured":"Nie, J. H. et al. Quantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus-based assay. Nat. Protoc. 15, 3699\u20133715 (2020).","journal-title":"Nat. Protoc."},{"key":"2565_CR35","doi-asserted-by":"publisher","first-page":"e1009701","DOI":"10.1371\/journal.ppat.1009701","volume":"17","author":"M Rosati","year":"2021","unstructured":"Rosati, M. et al. Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques. PLoS Pathog 17, e1009701 (2021).","journal-title":"PLoS Pathog"},{"key":"2565_CR36","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1586\/14760584.2015.990890","volume":"14","author":"KE Broderick","year":"2015","unstructured":"Broderick, K. E. & Humeau, L. M. Electroporation-enhanced delivery of nucleic acid vaccines. Expert Rev. Vaccines 14, 195\u2013204 (2015).","journal-title":"Expert Rev. Vaccines"},{"key":"2565_CR37","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1016\/j.cell.2020.07.012","volume":"182","author":"QQ Li","year":"2020","unstructured":"Li, Q. Q. et al. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell 182, 1284\u20131294 (2020).","journal-title":"Cell"}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02565-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02565-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02565-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:02:11Z","timestamp":1770595331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02565-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2565"],"URL":"https:\/\/doi.org\/10.1038\/s41392-025-02565-5","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]},"assertion":[{"value":"21 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"48"}}