Abstract
Therapeutic vaccination against chronic hepatitis B must overcome high viral antigen load and local regulatory mechanisms that promote immune-tolerance in the liver and curtail hepatitis B virus (HBV)-specific CD8 T cell immunity. Here, we report that therapeutic heterologous HBcore-protein-prime/Modified-Vaccinia-Virus-Ankara (MVA-HBcore) boost vaccination followed by CpG-application augmented vaccine-induced HBcAg-specific CD8 T cell-function in the liver. In HBV-transgenic as well as AAV-HBV-transduced mice with persistent high-level HBV-replication, the combination of therapeutic vaccination with subsequent CpG-application was synergistic to generate more potent HBV-specific CD8 T cell immunity that improved control of hepatocytes replicating HBV.
Highlights
Chronic hepatitis B affects more than 250 million persons worldwide[1], and results from insufficient immune control of hepatitis B virus (HBV) infection[2,3], for which no curative direct anti-viral pharmacological treatment is available[4]
We report that therapeutic heterologous protein-prime/modified vaccinia virus Ankara (MVA)-vector-boost vaccination against hepatitis B synergizes with CpG-application to enhance numbers and functionality of HBcAg-specific CD8 T-cells in presence of high HBV-antigen levels in two preclinical models of persistent HBV infection, i.e. the AAV-HBV model and HBV-transgenic mice
Cytokines released from T cells like IFNγ/TNF control HBV-antigen expression through degradation of the HBV persistence form in infected hepatocytes[20,21]
Summary
Chronic hepatitis B affects more than 250 million persons worldwide[1], and results from insufficient immune control of hepatitis B virus (HBV) infection[2,3], for which no curative direct anti-viral pharmacological treatment is available[4]. We recently developed a therapeutic heterologous prime-boost vaccination protocol based on a prime with particulate HBV antigen followed by boost-vaccination with a recombinant modified vaccinia virus Ankara (MVA) expressing HBV-antigens[10], which compared to other currently employed therapeutic vaccination strategies induces strong antiviral immunity[7]. This therapeutic prime-boost vaccine elicits both, anti-HBs seroconversion and strong HBcAg-specific CD8 T cell immunity[10]. Inflammatory monocytes, that accumulate in the liver upon CpG injection, introduce an immunogenic microenvironment
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