ABSTRACT
Infection with hepatitis B virus (HBV) can initiate chronic hepatitis and liver inujry, eventually progressing to liver fibrosis or cancer and causing more than 600,000 deaths each year worldwide. Current treatments for chronic hepatitis B, relying on nucleoside antivirals and interferon, are inadequate and leave unmet need for immunotherapeutic approaches. This report describes virus-like vesicles (VLV), a form of self-amplifying RNA replicons, which express multiple HBV antigens (polymerase, core, and middle surface) from a single vector (HBV-VLV). The HBV-VLV induce HBV-specific T cell responses to all three HBV antigens. Immunization of naïve mice with the multiantigen HBV-VLV renders them resistant to acute challenge with HBV delivered by adeno-associated virus (AAV). Using a chronic model of HBV infection by AAV delivery of HBV, immunotherapeutic potential of the multiantigen HBV-VLV is demonstrated, as 40% of the HBV-VLV-treated mice showed a decline of the serum HBV surface antigen below detection limit and marked reduction in liver HBV RNA. These results warrant clinical evaluation of multiantigen HBV-VLV for immunotherapy of chronic hepatitis B.
IMPORTANCE More than 240 million people worldwide are chronically infected with hepatitis B virus. Current therapies are not sufficiently effective and often beyond the reach in the developing world. We describe a virus-like vesicle-based immunotherapeutic vaccine that expresses three major antigens of hepatitis B virus as a self-amplifying RNA replicon. By incorporating the three antigens in a single vaccine, we ensure broad T cell responses. We demonstrate that immunization with this vaccine protects mice from hepatitis B virus in a model of acute challenge. Importantly, treatment with this vaccine shows 40% efficacy in a mouse model of chronic hepatitis B. Thus, this study paves the way for evaluation of the multi-antigen virus-like vesicles as a tool for immunotherapy of chronic hepatitis B.