HEPLISAV-B Breaks Immune Tolerance and Induces HBV Control via CD4 T Cell-Dependent Mechanisms in a Chronic Hepatitis B Mouse Model.
1/5 보강
[BACKGROUND] Chronic hepatitis B virus (HBV) infection (CHB) affects nearly 300 million individuals globally and remains incurable with current antiviral therapies, which suppress viral replication bu
APA
Ahodantin J, Wu J, et al. (2026). HEPLISAV-B Breaks Immune Tolerance and Induces HBV Control via CD4 T Cell-Dependent Mechanisms in a Chronic Hepatitis B Mouse Model.. bioRxiv : the preprint server for biology. https://doi.org/10.64898/2026.03.13.711721
MLA
Ahodantin J, et al.. "HEPLISAV-B Breaks Immune Tolerance and Induces HBV Control via CD4 T Cell-Dependent Mechanisms in a Chronic Hepatitis B Mouse Model.." bioRxiv : the preprint server for biology, 2026.
PMID
41889877
Abstract
[BACKGROUND] Chronic hepatitis B virus (HBV) infection (CHB) affects nearly 300 million individuals globally and remains incurable with current antiviral therapies, which suppress viral replication but rarely achieve functional cure defined by sustained loss of hepatitis B surface antigen (HBsAg). CHB is characterized by profound virus-induced immune tolerance that limits the efficacy of conventional therapeutic vaccination strategies.
[OBJECTIVE] To evaluate the therapeutic efficacy and immunological mechanisms of HEPLISAV-B, a CpG-1018-adjuvanted HBsAg vaccine, in breaking immune tolerance and inducing functional cure-like responses in a murine model of CHB.
[DESIGN] Using the adeno-associated virus-HBV (AAV-HBV) mouse model, mice with high levels of persistent HBV viremia were vaccinated with two doses of HEPLISAV-B. Virological outcomes in the blood and liver, immune responses and mechanisms were assessed.
[RESULTS] HEPLISAV-B induced rapid and durable HBsAg clearance, markedly reduced circulating and intrahepatic HBV DNA and RNA, and suppressed viral replication without hepatocellular injury. Vaccination elicited robust, sustained anti-HBs IgG1 and IgA responses, enhanced HBsAg-specific T and B cell immunity, reduced CD4 regulatory T cells, and decreased PD-1 expression on CD4 T cells. Therapeutic efficacy was strictly dependent on CD4 T cells and the CD40/CD40L signaling pathway, but independent of CD8 T cells, indicating a CD4-driven, non-cytolytic antiviral mechanism critical for HEPLISAV-B induced HBV control.
[CONCLUSION] HEPLISAV-B effectively breaks HBV-induced immune tolerance and restores coordinated antiviral immunity through a CD4 T cell-/CD40L-dependent pathway. The findings support its potential as a therapeutic vaccine in CHB patients.
[KEY MESSAGES] Chronic HBV infection is marked by profound virus-induced immune tolerance, current antiviral therapies and vaccines fail to reliably induce HBsAg loss or restore effective antiviral immunity, highlighting the need for immune-based therapeutic strategies. This study demonstrates that the clinically approved vaccine HEPLISAV-B can break HBV immune tolerance in a chronic HBV mouse model, inducing durable HBsAg clearance and anti-HBs immunity, non-cytolytic depletion of intrahepatic HBV DNA, through a mechanism strictly dependent on CD4 T cells and CD40/CD40L signaling. These findings defined a CD4 T cell-CD40L/CD40 axis that is critical in CHB functional cure, and support testing HEPLISAV-B as a therapeutic vaccine in CHB patients.
[OBJECTIVE] To evaluate the therapeutic efficacy and immunological mechanisms of HEPLISAV-B, a CpG-1018-adjuvanted HBsAg vaccine, in breaking immune tolerance and inducing functional cure-like responses in a murine model of CHB.
[DESIGN] Using the adeno-associated virus-HBV (AAV-HBV) mouse model, mice with high levels of persistent HBV viremia were vaccinated with two doses of HEPLISAV-B. Virological outcomes in the blood and liver, immune responses and mechanisms were assessed.
[RESULTS] HEPLISAV-B induced rapid and durable HBsAg clearance, markedly reduced circulating and intrahepatic HBV DNA and RNA, and suppressed viral replication without hepatocellular injury. Vaccination elicited robust, sustained anti-HBs IgG1 and IgA responses, enhanced HBsAg-specific T and B cell immunity, reduced CD4 regulatory T cells, and decreased PD-1 expression on CD4 T cells. Therapeutic efficacy was strictly dependent on CD4 T cells and the CD40/CD40L signaling pathway, but independent of CD8 T cells, indicating a CD4-driven, non-cytolytic antiviral mechanism critical for HEPLISAV-B induced HBV control.
[CONCLUSION] HEPLISAV-B effectively breaks HBV-induced immune tolerance and restores coordinated antiviral immunity through a CD4 T cell-/CD40L-dependent pathway. The findings support its potential as a therapeutic vaccine in CHB patients.
[KEY MESSAGES] Chronic HBV infection is marked by profound virus-induced immune tolerance, current antiviral therapies and vaccines fail to reliably induce HBsAg loss or restore effective antiviral immunity, highlighting the need for immune-based therapeutic strategies. This study demonstrates that the clinically approved vaccine HEPLISAV-B can break HBV immune tolerance in a chronic HBV mouse model, inducing durable HBsAg clearance and anti-HBs immunity, non-cytolytic depletion of intrahepatic HBV DNA, through a mechanism strictly dependent on CD4 T cells and CD40/CD40L signaling. These findings defined a CD4 T cell-CD40L/CD40 axis that is critical in CHB functional cure, and support testing HEPLISAV-B as a therapeutic vaccine in CHB patients.