Kosinska Anna D, Festag Julia, Mück-Häusl Martin, Festag Marvin M, Asen Theresa, Protzer Ulrike
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, D-81675 Munich, Germany.
German Center for Infection Research (DZIF), Munich Partner Site, D-81675 Munich, Germany.
Vaccines (Basel). 2021 Jul 31;9(8):841. doi: 10.3390/vaccines9080841.
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 , 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 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.
在慢性乙型肝炎病毒（HBV）感染的自然病程中，乙肝e抗原（HBeAg）通常会消失，而HBeAg阴性HBV的直接传播可能导致暴发性乙型肝炎。虽然通过治疗性疫苗接种诱导HBV特异性免疫反应是一种有前景的慢性乙型肝炎新治疗选择，但HBeAg的缺失是否会影响其疗效或耐受性仍不清楚。因此，我们构建了一种腺相关病毒（AAV）载体，其携带一个1.3倍超长HBV基因组，在前核心区有典型的终止密码子突变，并在小鼠肝脏中启动HBeAg（-）HBV的复制。C57BL/6小鼠感染后建立了持续性HBeAg（-）HBV复制，且未检测到任何抗HBV免疫或肝损伤。用一种治疗性乙型肝炎疫苗对HBV携带小鼠进行免疫，该疫苗使用颗粒状HBV S和核心蛋白进行初次接种，并用改良痘苗病毒安卡拉（MVA）进行加强接种。对HBeAg（+）和HBeAg（-）HBV携带小鼠进行免疫接种可有效诱导HBV特异性抗体并使HBsAg消失，但仅导致轻度肝损伤。在肝内，HBeAg（-）小鼠中诱导的HBV特异性CD8 T细胞表达更多的IFNγ，但细胞溶解活性相似。这表明HBeAg的缺失通过增强非细胞溶解效应功能改善了治疗性疫苗接种的效果。
