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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Therapeutic vaccination for chronic hepatitis B aims to restore HBV-specific T-cell immunity and contribute to a functional cure. We systematically compared the immune profiles and antiviral efficacy of four vaccine modalities: recombinant HBsAg (rHBsAg), antigen\u2013antibody immune complex (IC), a DNA vaccine encoding HBsAg (DNA-HBsAg), and an HBsAg-Fc fusion DNA vaccine (DNA-HBsAg-Fc). In na\u00efve mice, the rHBsAg vaccine predominantly induced anti-HBs IgG responses, whereas the IC vaccine elicited strong anti-HBs IgG and detectable CD4+ T-cell responses. In contrast, DNA vaccines preferentially induced HBsAg-specific CD8+ T-cell immunity, which was further enhanced by fusion to the Fc fragment of human IgG1. In the pre-immunization\/AAV-HBV model, high anti-HBs titers in rHBsAg and IC groups were associated with rapid clearance of circulating HBsAg but not with comparable reductions in HBcAg+ hepatocytes, whereas stronger HBsAg-specific CD8+ T-cell responses in the DNA vaccine groups were associated with greater reductions in HBcAg+ hepatocytes. However, in the therapeutic AAV-HBV model, all vaccine monotherapies showed limited and non-sustained antiviral efficacy, with only transient reductions in serum HBsAg and limited reductions in HBcAg+ hepatocytes. These findings highlight the distinct immune profiles of different vaccine platforms and an association between stronger HBsAg-specific CD8+ T-cell responses and reduced intrahepatic HBcAg expression, while underscoring the limited efficacy of vaccine monotherapy in the AAV-HBV model.<\/jats:p>","DOI":"10.3390\/ijms27198499","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:03:26Z","timestamp":1790172206000},"page":"8499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Profiles Elicited by Different HBV Vaccine Modalities and Their Associations with Serological and Intrahepatic Viral Outcomes"],"prefix":"10.3390","volume":"27","author":[{"given":"Huiying","family":"Xiao","sequence":"first","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Jinhang","family":"He","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China"},{"name":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Lili","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Songmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Molecular Biology, Experimental Teaching Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-5219","authenticated-orcid":false,"given":"Chao","family":"Qiu","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China"},{"name":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China"},{"name":"Minhang Hospital, Fudan University, Shanghai 201199, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-9184","authenticated-orcid":false,"given":"Xuanyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2024). 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