{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T21:17:31Z","timestamp":1768339051197,"version":"3.49.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"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>The immune imprinting against SARS-CoV-2 subvariants that dynamically evolves through sequential vaccination and infection has been rarely studied. Using antigenic cartography and neutralizing antibody (NAb) profiling, we demonstrate that prototype-targeting vaccination followed by Delta\/early Omicron breakthrough infections maintained dominant wild-type (WT)-focused immunity. However, XBB.1.5-adapted vaccination after BA.5 outbreaks shifted immune imprinting toward XBB.1.9.1, altering the antigenic landscape. NAb analysis revealed progressive WT-specific immunity enhancement through three-dose vaccination followed by BA.5 breakthrough infection (GMT: I-I\u2009=\u200935, I-I-I\u2009=\u200972, I-I-I-B5\u2009=\u2009807), followed by sharp decline after XBB reinfection (GMT: I-I-I-B5-XBB\u2009=\u2009231), confirming XBB\u2019s antigenic divergence. To investigate the relationship between population immune dynamics and XBB infection risk following the BA.5\/BF.7 wave, we analyzed the immune status of XBB breakthrough-infected and uninfected individuals from May to June 2023 (5\u20137 months post-wave). Utilizing an infection model calibrated to NAb titers against XBB.1.9.1, we estimated the 50% protective NAb titer against XBB infection to be 1:12.6. Retrospective analysis revealed that 80.3% of the population fell below this threshold in mid-2023, aligning with subsequent XBB resurgence. However, only 33.8% exhibited sub-protective JN.1 titers (&lt;12.6) by August 2024, explaining the absence of JN.1-driven endemicity. This longitudinal study maps the immune imprint transitions from WT dominance to XBB adaptation, providing critical insights into vaccine strategy optimization and emerging variant risk assessment. The work highlights how iterative immune exposures reshape population protection landscapes against evolving coronaviruses.<\/jats:p>","DOI":"10.1038\/s41392-025-02484-5","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:56:13Z","timestamp":1763038573000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immune imprinting toward SARS-CoV-2 XBB: implications for vaccine strategy and variant risk assessment"],"prefix":"10.1038","volume":"10","author":[{"given":"Xiaoyun","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guichang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5040-3201","authenticated-orcid":false,"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaying","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-5589","authenticated-orcid":false,"given":"Nanshan","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuxiang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongfang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"2484_CR1","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2023.2225638","volume":"12","author":"S Liu","year":"2023","unstructured":"Liu, S. et al. Sera from breakthrough infections with SARS-CoV-2 BA.5 or BF.7 showed lower neutralization activity against XBB.1.5 and CH.1.1. Emerg. Microbes Infect. 12, 2225638 (2023).","journal-title":"Emerg. Microbes Infect."},{"key":"2484_CR2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29417","volume":"96","author":"X Yang","year":"2024","unstructured":"Yang, X. et al. Immune escape of BA.2.86 is comparable to XBB subvariants from the plasma of BA.5- and BA.5-XBB-convalescent subpopulations. J. Med. Virol. 96, e29417 (2024).","journal-title":"J. Med. Virol."},{"key":"2484_CR3","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1136\/bmj.p1900","volume":"382","author":"O Dyer","year":"2023","unstructured":"Dyer, O. Covid-19: infections climb globally as EG.5 variant gains ground. BMJ 382, 1900 (2023).","journal-title":"BMJ"},{"key":"2484_CR4","unstructured":"3 Things to Know About JN.1, the New Coronavirus Strain (Yale Medicine, 2024), available from: https:\/\/www.yalemedicine.org\/news\/jn1-coronavirus-variant-covid."},{"key":"2484_CR5","doi-asserted-by":"publisher","first-page":"14001","DOI":"10.1073\/pnas.96.24.14001","volume":"96","author":"DJ Smith","year":"1999","unstructured":"Smith, D. J., Forrest, S., Ackley, D. H. & Perelson, A. S. Variable efficacy of repeated annual influenza vaccination. Proc. Natl. Acad. Sci. USA 96, 14001\u201314006 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2484_CR6","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.vaccine.2011.10.051","volume":"30","author":"Z Cai","year":"2012","unstructured":"Cai, Z., Zhang, T. & Wan, X. F. Antigenic distance measurements for seasonal influenza vaccine selection. Vaccine 30, 448\u2013453 (2012).","journal-title":"Vaccine"},{"key":"2484_CR7","doi-asserted-by":"publisher","first-page":"2273155","DOI":"10.1080\/21645515.2023.2273155","volume":"19","author":"T Zhao","year":"2023","unstructured":"Zhao, T., Huang, X. & Shu, Y. Comparing the immune response and protective effect of COVID-19 vaccine under different vaccination strategies. Hum. Vaccin. Immunother. 19, 2273155 (2023).","journal-title":"Hum. Vaccin. Immunother."},{"key":"2484_CR8","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/s41591-021-01656-4","volume":"28","author":"SA Valkenburg","year":"2022","unstructured":"Valkenburg, S. A. & Poon, L. L. M. Exploring the landscape of immune responses to influenza infection and vaccination. Nat. Med. 28, 239\u2013240 (2022).","journal-title":"Nat. Med."},{"key":"2484_CR9","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.vaccine.2021.12.006","volume":"40","author":"D Goldblatt","year":"2022","unstructured":"Goldblatt, D. et al. Towards a population-based threshold of protection for COVID-19 vaccines. Vaccine 40, 306\u2013315 (2022).","journal-title":"Vaccine"},{"key":"2484_CR10","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1093\/infdis\/162.5.1036","volume":"162","author":"RT Chen","year":"1990","unstructured":"Chen, R. T. et al. Measles antibody: reevaluation of protective titers. J. Infect. Dis. 162, 1036\u20131042 (1990).","journal-title":"J. Infect. Dis."},{"key":"2484_CR11","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1084\/jem.129.6.1307","volume":"129","author":"I Goldschneider","year":"1969","unstructured":"Goldschneider, I., Gotschlich, E. C. & Artenstein, M. S. Human immunity to the meningococcus. I. The role of humoral antibodies. J. Exp. Med. 129, 1307\u20131326 (1969).","journal-title":"J. Exp. Med."},{"key":"2484_CR12","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-10-18","volume":"10","author":"L Coudeville","year":"2010","unstructured":"Coudeville, L. et al. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a Bayesian random-effects model. BMC Med. Res. Methodol. 10, 18 (2010).","journal-title":"BMC Med. Res. Methodol."},{"key":"2484_CR13","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.vaccine.2012.11.037","volume":"31","author":"V Gilca","year":"2013","unstructured":"Gilca, V. et al. Antibody persistence and the effect of a booster dose given 5, 10 or 15 years after vaccinating preadolescents with a recombinant hepatitis B vaccine. Vaccine 31, 448\u2013451 (2013).","journal-title":"Vaccine"},{"key":"2484_CR14","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1038\/s41586-024-08315-x","volume":"637","author":"F Jian","year":"2025","unstructured":"Jian, F. et al. Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1. Nature 637, 921\u2013929 (2025).","journal-title":"Nature"},{"key":"2484_CR15","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/j.chom.2023.07.004","volume":"31","author":"YF Hu","year":"2023","unstructured":"Hu, Y. F. et al. Rational design of a booster vaccine against COVID-19 based on antigenic distance. Cell Host Microbe 31, 1301\u20131316 e1308 (2023).","journal-title":"Cell Host Microbe"},{"key":"2484_CR16","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/s41421-022-00501-3","volume":"8","author":"J Wang","year":"2022","unstructured":"Wang, J. et al. SARS-CoV-2 vaccination-infection pattern imprints and diversifies T cell differentiation and neutralizing response against Omicron subvariants. Cell Discov. 8, 136 (2022).","journal-title":"Cell Discov."},{"key":"2484_CR17","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/s41586-023-06753-7","volume":"625","author":"A Yisimayi","year":"2024","unstructured":"Yisimayi, A. et al. Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting. Nature 625, 148\u2013156 (2024).","journal-title":"Nature"},{"key":"2484_CR18","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.rce.2021.05.003","volume":"222","author":"J Reina","year":"2022","unstructured":"Reina, J. Possible effect of the \u201coriginal antigenic sin\u201d in vaccination against new variants of SARS-CoV-2. Rev. Clin. Esp. 222, 91\u201392 (2022).","journal-title":"Rev. Clin. Esp."},{"key":"2484_CR19","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/s41579-022-00708-x","volume":"20","author":"E Simon-Loriere","year":"2022","unstructured":"Simon-Loriere, E. & Schwartz, O. Towards SARS-CoV-2 serotypes? Nat. Rev. Microbiol. 20, 187\u2013188 (2022).","journal-title":"Nat. Rev. Microbiol."},{"key":"2484_CR20","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.1016\/j.scib.2023.09.048","volume":"68","author":"S Hu","year":"2023","unstructured":"Hu, S. et al. Classification of five SARS-CoV-2 serotypes based on RBD antigenicities. Sci. Bull. 68, 3003\u20133012 (2023).","journal-title":"Sci. Bull."},{"key":"2484_CR21","doi-asserted-by":"publisher","first-page":"381","DOI":"10.3201\/eid2902.221422","volume":"29","author":"DS Khoury","year":"2023","unstructured":"Khoury, D. S. et al. Correlates of protection, thresholds of protection, and immunobridging among Persons with SARS-CoV-2 infection. Emerg. Infect. Dis. 29, 381\u2013388 (2023).","journal-title":"Emerg. Infect. Dis."},{"key":"2484_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101174","volume":"41","author":"EH Lau","year":"2021","unstructured":"Lau, E. H. et al. Long-term persistence of SARS-CoV-2 neutralizing antibody responses after infection and estimates of the duration of protection. EClinicalMedicine 41, 101174 (2021).","journal-title":"EClinicalMedicine"},{"key":"2484_CR23","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2025.2459140","volume":"14","author":"P Wei","year":"2025","unstructured":"Wei, P. et al. In vivo determination of protective antibody thresholds for SARS-CoV-2 variants using mouse models. Emerg. Microbes Infect. 14, 2459140 (2025).","journal-title":"Emerg. Microbes Infect."},{"key":"2484_CR24","doi-asserted-by":"publisher","first-page":"2738","DOI":"10.1021\/acsnano.0c08379","volume":"15","author":"YF Kang","year":"2021","unstructured":"Kang, Y. F. et al. Rapid development of SARS-CoV-2 spike protein receptor-binding domain self-assembled nanoparticle vaccine candidates. ACS Nano 15, 2738\u20132752 (2021).","journal-title":"ACS Nano"}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02484-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02484-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02484-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:55:01Z","timestamp":1765806901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02484-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,13]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2484"],"URL":"https:\/\/doi.org\/10.1038\/s41392-025-02484-5","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,13]]},"assertion":[{"value":"22 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2025","order":6,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":7,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this article was revised:The corresponding author\u2019s affiliations have been rearranged to reflect the correct priority.","order":8,"name":"change_details","label":"Change Details","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":"372"}}