{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:55:13Z","timestamp":1787500513185,"version":"build-2736575974"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"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":["npj Vaccines"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Here we report on the development and comprehensive evaluations of an mRNA vaccine for chronic hepatitis B (CHB) treatment. In two different HBV carrier mouse models generated by viral vector-mediated HBV transfection (pAAV-HBV1.2 and rAAV8-HBV1.3), this vaccine demonstrates sufficient and persistent virological suppression, and robust immunogenicity in terms of induction of strong innate immune activation, high-level virus-specific antibodies, memory B cells and T cells. mRNA platform therefore holds prospects for therapeutic vaccine development to combat CHB.<\/jats:p>","DOI":"10.1038\/s41541-024-00813-3","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T02:02:42Z","timestamp":1706925762000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A therapeutic hepatitis B mRNA vaccine with strong immunogenicity and persistent virological suppression"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-8329","authenticated-orcid":false,"given":"Huajun","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyu","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narh Philip","family":"Amor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzhen","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiesen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenguang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuju","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-1397","authenticated-orcid":false,"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5662-1576","authenticated-orcid":false,"given":"Ang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-9470","authenticated-orcid":false,"given":"Yong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"813_CR1","unstructured":"World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections (WHO, 2021)."},{"key":"813_CR2","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/liv.13291","volume":"37","author":"G Grossi","year":"2017","unstructured":"Grossi, G., Vigano, M., Loglio, A. & Lampertico, P. Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs). Liver Int 37, 45\u201351 (2017).","journal-title":"Liver Int"},{"key":"813_CR3","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.cld.2016.06.002","volume":"20","author":"MA Konerman","year":"2016","unstructured":"Konerman, M. A. & Lok, A. S. Interferon Treatment for Hepatitis B. Clin. Liver Dis. 20, 645\u2013665 (2016).","journal-title":"Clin. Liver Dis."},{"key":"813_CR4","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1128\/JVI.01537-06","volume":"81","author":"J Wang","year":"2007","unstructured":"Wang, J., Gujar, S. A., Cova, L. & Michalak, T. I. Bicistronic woodchuck hepatitis virus core and gamma interferon DNA vaccine can protect from hepatitis but does not elicit sterilizing antiviral immunity. J. Virol. 81, 903\u2013916 (2007).","journal-title":"J. Virol."},{"key":"813_CR5","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1136\/gutjnl-2014-308041","volume":"64","author":"P Martin","year":"2015","unstructured":"Martin, P. et al. TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice. Gut 64, 1961\u20131971 (2015).","journal-title":"Gut"},{"key":"813_CR6","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/S1473-3099(20)30780-5","volume":"21","author":"T Vesikari","year":"2021","unstructured":"Vesikari, T. et al. Immunogenicity and safety of a tri-antigenic versus a mono-antigenic hepatitis B vaccine in adults (PROTECT): a randomised, double-blind, phase 3 trial. Lancet Infect. Dis. 21, 1271\u20131281 (2021).","journal-title":"Lancet Infect. Dis."},{"key":"813_CR7","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/s41590-022-01163-9","volume":"23","author":"C Li","year":"2022","unstructured":"Li, C. et al. Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine. Nat. Immunol. 23, 543\u2013555 (2022).","journal-title":"Nat. Immunol."},{"key":"813_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39376-7","volume":"14","author":"IT Lee","year":"2023","unstructured":"Lee, I. T. et al. Safety and immunogenicity of a phase 1\/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis. Nat. Commun. 14, 3631 (2023).","journal-title":"Nat. Commun."},{"key":"813_CR9","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/s41586-023-06063-y","volume":"618","author":"LA Rojas","year":"2023","unstructured":"Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144\u2013150 (2023).","journal-title":"Nature"},{"key":"813_CR10","doi-asserted-by":"crossref","unstructured":"mRNA Vaccine Slows Melanoma Recurrence. Cancer Discov 13, 1278 (2023).","DOI":"10.1158\/2159-8290.CD-NB2023-0028"},{"key":"813_CR11","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1080\/21645515.2020.1829899","volume":"17","author":"AO Aliprantis","year":"2021","unstructured":"Aliprantis, A. O. et al. A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults. Hum. Vaccin Immunother. 17, 1248\u20131261 (2021).","journal-title":"Hum. Vaccin Immunother."},{"key":"813_CR12","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/s41586-023-06127-z","volume":"621","author":"H Zhang","year":"2023","unstructured":"Zhang, H. et al. Algorithm for optimized mRNA design improves stability and immunogenicity. Nature 621, 396\u2013403 (2023).","journal-title":"Nature"},{"key":"813_CR13","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41392-021-00634-z","volume":"6","author":"R Yang","year":"2021","unstructured":"Yang, R. et al. A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduct. Target Ther. 6, 213 (2021).","journal-title":"Signal Transduct. Target Ther."},{"key":"813_CR14","doi-asserted-by":"publisher","first-page":"17862","DOI":"10.1073\/pnas.0608578103","volume":"103","author":"LR Huang","year":"2006","unstructured":"Huang, L. R., Wu, H. L., Chen, P. J. & Chen, D. S. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proc. Natl Acad. Sci. USA 103, 17862\u201317867 (2006).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"813_CR15","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1136\/gutjnl-2014-308964","volume":"65","author":"TY Zhang","year":"2016","unstructured":"Zhang, T. Y. et al. Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen. Gut 65, 658\u2013671 (2016).","journal-title":"Gut"},{"key":"813_CR16","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.jhep.2022.12.014","volume":"78","author":"L Wang","year":"2023","unstructured":"Wang, L. et al. Discovery of a first-in-class orally available HBV cccDNA inhibitor. J. Hepatol. 78, 742\u2013753 (2023).","journal-title":"J. Hepatol."},{"key":"813_CR17","doi-asserted-by":"publisher","first-page":"7345","DOI":"10.7150\/thno.37173","volume":"9","author":"G Yang","year":"2019","unstructured":"Yang, G. et al. HAT1 signaling confers to assembly and epigenetic regulation of HBV cccDNA minichromosome. Theranostics 9, 7345\u20137358 (2019).","journal-title":"Theranostics"},{"key":"813_CR18","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1053\/j.gastro.2020.01.032","volume":"158","author":"T Michler","year":"2020","unstructured":"Michler, T. et al. Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-Titer Hepatitis B Virus Carrier Mice. Gastroenterology 158, 1762\u20131775.e1769 (2020).","journal-title":"Gastroenterology"},{"key":"813_CR19","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1053\/j.gastro.2015.09.026","volume":"150","author":"Y Xia","year":"2016","unstructured":"Xia, Y. et al. Interferon-gamma and Tumor Necrosis Factor-alpha Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis. Gastroenterology 150, 194\u2013205 (2016).","journal-title":"Gastroenterology"},{"key":"813_CR20","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1136\/gutjnl-2017-315588","volume":"68","author":"HJ Zhao","year":"2019","unstructured":"Zhao, H. J. et al. Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8+ effector memory T cells. Gut 68, 2032\u20132043 (2019).","journal-title":"Gut"},{"key":"813_CR21","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/cmi.2013.43","volume":"11","author":"D Yang","year":"2014","unstructured":"Yang, D. et al. A mouse model for HBV immunotolerance and immunotherapy. Cell Mol. Immunol. 11, 71\u201378 (2014).","journal-title":"Cell Mol. Immunol."},{"key":"813_CR22","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1038\/s41423-022-00939-1","volume":"19","author":"H Zhao","year":"2022","unstructured":"Zhao, H. et al. Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction. Cell Mol. Immunol. 19, 1347\u20131360 (2022).","journal-title":"Cell Mol. Immunol."},{"key":"813_CR23","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1136\/gutjnl-2022-327059","volume":"72","author":"CY Meng","year":"2023","unstructured":"Meng, C. Y. et al. Engineered anti-PDL1 with IFNalpha targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance. Gut 72, 1544\u20131554 (2023).","journal-title":"Gut"},{"key":"813_CR24","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/s41565-020-0648-y","volume":"15","author":"W Wang","year":"2020","unstructured":"Wang, W. et al. Dual-targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic hepatitis B. Nat. Nanotechnol. 15, 406\u2013416 (2020).","journal-title":"Nat. Nanotechnol."},{"key":"813_CR25","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1016\/j.jhep.2014.07.005","volume":"61","author":"B Bengsch","year":"2014","unstructured":"Bengsch, B., Martin, B. & Thimme, R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J. Hepatol. 61, 1212\u20131219 (2014).","journal-title":"J. Hepatol."},{"key":"813_CR26","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/978-1-4939-1050-2_3","volume":"1180","author":"AT Feldman","year":"2014","unstructured":"Feldman, A. T. & Wolfe, D. Tissue processing and hematoxylin and eosin staining. Methods Mol. Biol. 1180, 31\u201343 (2014).","journal-title":"Methods Mol. Biol."}],"container-title":["npj Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41541-024-00813-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41541-024-00813-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41541-024-00813-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T05:05:38Z","timestamp":1707195938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41541-024-00813-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,3]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["813"],"URL":"https:\/\/doi.org\/10.1038\/s41541-024-00813-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.11.18.517095","asserted-by":"object"}]},"ISSN":["2059-0105"],"issn-type":[{"value":"2059-0105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,3]]},"assertion":[{"value":"23 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"J.H. is a full-time employee at Firestone Biotechnologies, Shanghai. The LinearDesign Algorithm was patented and owned by Baidu USA. China Pharmaceutical University and Shandong University have filed a provisional patent for the HBV mRNA vaccine listing H.Z., A.L., L.H., J.Z., Y.Y. as inventors. Other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22"}}