{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T16:34:59Z","timestamp":1792859699554,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFC2305700"],"award-info":[{"award-number":["2022YFC2305700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shandong Provincial Natural Science Foundation for Excellent Youth Scholars","award":["ZR2023YQ066"],"award-info":[{"award-number":["ZR2023YQ066"]}]},{"name":"Shandong Provincial Natural Science Foundation for Excellent Youth Scholars","award":["ZR2022YQ75"],"award-info":[{"award-number":["ZR2022YQ75"]}]},{"name":"Taishan Youth Scholar Fund of Shandong Province","award":["tsqn202312058"],"award-info":[{"award-number":["tsqn202312058"]}]},{"name":"Youth Student Fundamental Research Funds of Shandong University","award":["SDUQM2554"],"award-info":[{"award-number":["SDUQM2554"]}]},{"name":"Innovation and Entrepreneurship Training Program","award":["S202410422269"],"award-info":[{"award-number":["S202410422269"]}]},{"DOI":"10.13039\/501100012152","name":"National Postdoctoral Program for Innovative Talents","doi-asserted-by":"crossref","award":["BX20190192"],"award-info":[{"award-number":["BX20190192"]}],"id":[{"id":"10.13039\/501100012152","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2020M672064"],"award-info":[{"award-number":["2020M672064"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science Foundation for Young Scientists of China","award":["82001687"],"award-info":[{"award-number":["82001687"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Vaccines"],"abstract":"<jats:p>Chronic hepatitis B virus (HBV) infection remains a major global health challenge, substantially contributing to liver-related morbidity and mortality. Background\/Objectives: Developing therapeutic strategies that overcome immune tolerance and achieve functional cures is an urgent priority. Methods: In this study, we report a therapeutic vaccine comprising hepatitis B surface antigen (HBsAg) formulated with the dual adjuvant system CpG 1018S and QS-21. The immunogenicity and therapeutic efficacy of this vaccine were systematically evaluated in an rAAV8-HBV1.3-established chronic HBV mouse model. Results: The vaccine elicited a robust Th1-skewed immune response, characterized by elevated anti-HBs IgG2b titers and an increased IgG2b\/IgG1 ratio. Notably, immunized mice showed markedly reduced circulating HBsAg levels. Mechanistically, the CpG 1018S and QS-21 adjuvant system enhanced dendritic cell activation, maturation, and antigen presentation, expanded HBV-specific CD4+ and CD8+ T cell populations, and attenuated the expression of the exhaustion markers TIM-3 and TIGIT. Additionally, immunized mice exhibited restored T cell polyfunctionality, with an increased secretion of effector cytokines, including TNF-\u03b1 and IL-21. These responses collectively contributed to the reversal of T cell exhaustion and breakdown of immune tolerance, facilitating sustained viral suppression. Conclusions: Our findings demonstrate that the CpG 1018S\/QS-21-adjuvanted vaccine induces potent humoral and cellular immunity against chronic HBV infection and represents a promising candidate for clinical chronic HBV (CHB) treatment.<\/jats:p>","DOI":"10.3390\/vaccines13101014","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T10:49:34Z","timestamp":1759142974000},"page":"1014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A CpG 1018S\/QS-21-Adjuvanted HBsAg Therapeutic Vaccine as a Novel Strategy Against HBV"],"prefix":"10.3390","volume":"13","author":[{"given":"Zixuan","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Weng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhao","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirong","family":"Bi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuju","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-8329","authenticated-orcid":false,"given":"Huajun","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2101-2612","authenticated-orcid":false,"given":"Cunbao","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deping","family":"Meng","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan 250014, China"},{"name":"School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1001\/jama.2018.3795","article-title":"Chronic Hepatitis B Infection: A Review","volume":"319","author":"Tang","year":"2018","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41577-021-00549-4","article-title":"Immunobiology and pathogenesis of hepatitis B virus infection","volume":"22","author":"Iannacone","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18035","DOI":"10.1038\/nrdp.2018.35","article-title":"Hepatitis B virus infection","volume":"4","author":"Yuen","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tu, T., Budzinska, M.A., Shackel, N.A., and Urban, S. (2017). HBV DNA Integration: Molecular Mechanisms and Clinical Implications. Viruses, 9.","DOI":"10.3390\/v9040075"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.tim.2018.01.009","article-title":"Hepatitis B Virus","volume":"26","author":"Shih","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/s41573-019-0037-0","article-title":"Therapeutic strategies for hepatitis B virus infection: Towards a cure","volume":"18","author":"Fanning","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00046-19","DOI":"10.1128\/CMR.00046-19","article-title":"Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy","volume":"33","author":"Nguyen","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1136\/gutjnl-2015-309809","article-title":"HBV cccDNA: Viral persistence reservoir and key obstacle for a cure of chronic hepatitis B","volume":"64","author":"Nassal","year":"2015","journal-title":"Gut"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.coviro.2021.10.002","article-title":"Immunotherapy and therapeutic vaccines for chronic HBV infection","volume":"51","author":"Thimme","year":"2021","journal-title":"Curr. Opin. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1080\/21645515.2019.1651141","article-title":"Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: A phase 1b placebo-controlled trial","volume":"16","author":"Zoulim","year":"2020","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Khanam, A., Chua, J.V., and Kottilil, S. (2021). Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115497"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.virusres.2017.12.007","article-title":"Current concepts on immunopathogenesis of hepatitis B virus infection","volume":"245","author":"Peeridogaheh","year":"2018","journal-title":"Virus Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.3748\/wjg.v25.i27.3527","article-title":"Immune suppression in chronic hepatitis B infection associated liver disease: A review","volume":"25","author":"Li","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41541-022-00541-6","article-title":"Elucidation of the role of nucleolin as a cell surface receptor for nucleic acid-based adjuvants","volume":"7","author":"Kitagawa","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-0716-0872-2_4","article-title":"CpG Oligonucleotides as Vaccine Adjuvants","volume":"2197","author":"Kayraklioglu","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/14760584.2016.1213632","article-title":"Adjuvant system AS01: Helping to overcome the challenges of modern vaccines","volume":"16","author":"Didierlaurent","year":"2017","journal-title":"Expert. Rev. Vaccines"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"152905","DOI":"10.1016\/j.phymed.2019.152905","article-title":"Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review","volume":"60","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1080\/14760584.2021.1908133","article-title":"CpG-Adjuvanted Hepatitis B Vaccine (HEPLISAV-B(R)) Update","volume":"20","author":"Lee","year":"2021","journal-title":"Expert. Rev. Vaccines"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.coi.2019.02.009","article-title":"Understanding the immunology of Shingrix, a recombinant glycoprotein E adjuvanted herpes zoster vaccine","volume":"59","author":"Heineman","year":"2019","journal-title":"Curr. Opin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Luan, N., Cao, H., Wang, Y., Lin, K., and Liu, C. (2022). Ionizable Lipid Nanoparticles Enhanced the Synergistic Adjuvant Effect of CpG ODNs and QS21 in a Varicella Zoster Virus Glycoprotein E Subunit Vaccine. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14050973"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cao, H., Zhang, X., Cheng, J., Li, Y., Luan, N., Hu, J., Liang, B., Zhang, H., Gao, D., and Lei, Z. (2025). A QS21 + CpG-Adjuvanted Trivalent HSV-2 Vaccine and Trivalent HSV-2 mRNA Vaccine Induce a Strong Immune Response, Protect Against HSV-2 Infection, and Cross-Protect Against HSV-1 Infection in Mice. Vaccines, 13.","DOI":"10.3390\/vaccines13050497"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154","DOI":"10.7150\/ijbs.62424","article-title":"CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV","volume":"18","author":"Zhao","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/hep.26654","article-title":"Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection","volume":"59","author":"Lv","year":"2014","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e01741-17","DOI":"10.1128\/AAC.01741-17","article-title":"Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells","volume":"62","author":"Aillot","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1136\/gutjnl-2017-315588","article-title":"Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8(+) effector memory T cells","volume":"68","author":"Zhao","year":"2019","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.2147\/IJN.S317113","article-title":"Chitosan Nanovaccines as Efficient Carrier Adjuvant System for IL-12 with Enhanced Protection Against HBV","volume":"16","author":"Zhao","year":"2021","journal-title":"Int. J. Nanomed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1694","DOI":"10.1038\/cddis.2015.42","article-title":"T-cell exhaustion in chronic hepatitis B infection: Current knowledge and clinical significance","volume":"6","author":"Ye","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zheng, J.R., Wang, Z.L., and Feng, B. (2022). Hepatitis B functional cure and immune response. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1075916"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101612","DOI":"10.1016\/j.jcmgh.2025.101612","article-title":"Targeting Ferroptosis Restores the Antiviral Activity of CD8(+) T Cells During Chronic Hepatitis B Virus Infection","volume":"19","author":"Li","year":"2025","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1189\/jlb.68.4.455","article-title":"The immunobiology and clinical potential of immunostimulatory CpG oligodeoxynucleotides","volume":"68","author":"Weiner","year":"2000","journal-title":"J. Leukoc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"515","DOI":"10.2147\/IJN.S114477","article-title":"CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies","volume":"12","author":"Hanagata","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cancel, J.C., Crozat, K., Dalod, M., and Mattiuz, R. (2019). Are Conventional Type 1 Dendritic Cells Critical for Protective Antitumor Immunity and How?. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00009"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1126\/science.1164206","article-title":"Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity","volume":"322","author":"Hildner","year":"2008","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.cell.2019.02.005","article-title":"Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4(+) T Cell Immunity","volume":"177","author":"Binnewies","year":"2019","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1126\/science.1136080","article-title":"Differential antigen processing by dendritic cell subsets in vivo","volume":"315","author":"Dudziak","year":"2007","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101302","DOI":"10.1016\/j.smim.2019.101302","article-title":"Tim-3: A co-receptor with diverse roles in T cell exhaustion and tolerance","volume":"42","author":"Tang","year":"2019","journal-title":"Semin. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4409","DOI":"10.4049\/jimmunol.180.7.4409","article-title":"Lack of TIM-3 immunoregulation in multiple sclerosis","volume":"180","author":"Yang","year":"2008","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1016\/j.ymthe.2017.06.023","article-title":"A TIM-3 Oligonucleotide Aptamer Enhances T Cell Functions and Potentiates Tumor Immunity in Mice","volume":"25","author":"Gefen","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kosinska, A.D., Zhang, E., Johrden, L., Liu, J., Seiz, P.L., Zhang, X., Ma, Z., Kemper, T., Fiedler, M., and Glebe, D. (2013). Combination of DNA prime--adenovirus boost immunization with entecavir elicits sustained control of chronic hepatitis B in the woodchuck model. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003391"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.jhep.2016.05.016","article-title":"Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B","volume":"65","author":"Lok","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1053\/j.gastro.2019.03.044","article-title":"Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients with Chronic Hepatitis","volume":"157","author":"Boni","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.jhep.2019.06.028","article-title":"Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study","volume":"71","author":"Gane","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1084\/jem.20071949","article-title":"Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection","volume":"205","author":"Ha","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1080\/21645515.2016.1154247","article-title":"Comparative preclinical evaluation of AS01 versus other Adjuvant Systems in a candidate herpes zoster glycoprotein E subunit vaccine","volume":"12","author":"Fochesato","year":"2016","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-1-4939-6445-1_2","article-title":"Development of the CpG Adjuvant 1018: A Case Study","volume":"1494","author":"Campbell","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1177\/1060028020962050","article-title":"Heplisav-B: A Hepatitis B Vaccine with a Novel Adjuvant","volume":"55","author":"Champion","year":"2021","journal-title":"Ann. Pharmacother."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/10\/1014\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T04:30:01Z","timestamp":1759293001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/10\/1014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["vaccines13101014"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13101014","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]}}}