Chronic hepatitis B virus (HBV) infections cause more than 800,000 deaths per year and currently approved treatments do not cure the disease. Because a hallmark of acute infection resolution is the presence of functional CD8+ T cells to the virus, activation of the immune system with therapeutic vaccines represents a potential approach for treating chronic hepatitis B. In this study, we evaluated the immunogenicity and efficacy of two attenuated vesiculovirus-based platforms expressing HBV Core antigen, the highly attenuated vesicular stomatitis virus (VSV) N4CT1 and a unique vaccine platform [virus-like vesicles (VLV)] that is based on a Semliki Forest virus replicon expressing the VSV glycoprotein. We found that heterologous prime-boost immunization with VLV and N4CT1 induced Core-specific CD8+ T cell responses in naïve mice. When immunized mice were later challenged with AAV-HBV, functional Core-specific CD8+ T cells were present in the liver, and mice were protected from establishment of persistent infection. In contrast, when mice with pre-established persistent HBV replication received prime-boost immunization, functional Core-specific CD8+ T cells were found in the spleen but not in the liver. These results highlight the importance of investigating the therapeutic value of different HBV antigens alone and in combination using preclinical animal models, and understanding the correlation between anti-HBV efficacy in these models with human infection.,Copyright © 2019 Elsevier B.V. All rights reserved.