Abstract
During the natural course of chronic hepatitis B virus (HBV) infection, the hepatitis B e antigen (HBeAg) is typically lost, while the direct transmission of HBeAg-negative HBV may result in fulminant hepatitis B. While the induction of HBV-specific immune responses by therapeutic vaccination is a promising, novel treatment option for chronic hepatitis B, it remains unclear whether a loss of HBeAg may influence its efficacy or tolerability. We therefore generated an adeno-associated virus (AAV)-vector that carries a 1.3-fold overlength HBV genome with a typical stop-codon mutation in the pre-core region and initiates the replication of HBeAg(−) HBV in mouse livers. Infection of C57BL/6 mice established persistent HBeAg(−) HBV-replication without any detectable anti-HBV immunity or liver damage. HBV-carrier mice were immunized with TherVacB, a therapeutic hepatitis B vaccine that uses a particulate HBV S and a core protein for prime vaccination, and a modified vaccinia Ankara (MVA) for boost vaccination. The TherVacB immunization of HBeAg(+) and HBeAg(−) HBV carrier mice resulted in the effective induction of HBV-specific antibodies and the loss of HBsAg but only mild liver damage. Intrahepatic, HBV-specific CD8 T cells induced in HBeAg(−) mice expressed more IFNγ but showed similar cytolytic activity. This indicates that the loss of HBeAg improves the performance of therapeutic vaccination by enhancing non-cytolytic effector functions.
Highlights
To establish a mouse model that allows for the persistent replication or hepatitis B virus (HBV) that lacks the expression of hepatitis B e antigen (HBeAg), we first generated associated virus (AAV)-HBV vector encoding for a wild-type
As the modified vaccinia Ankara (MVA) vaccination aims to expand the effector T cell responses, we investigated whether HBV core-specific T cells were induced by TherVacB in mice replicating HBeAg(−)
As the MVA vaccination aims to expand the effector T cell responses, we investigated whether HBV core-specific T cells were induced by TherVacB in mice replicating HBeAg() HBV, compared to those replicating WT HBV one week after MVA boost
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Chronic HBV infection is the leading cause of liver cirrhosis and hepatocellular carcinoma (HCC), resulting in 880.000 deaths annually [1]. Recent reports estimate that approximately 3.5% of the world population suffers from chronic hepatitis B (CHB) [1]. Spontaneous resolution of the infection occurs only in less than 1% of these individuals [2]
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