A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8⁺ T cell and antiviral responses

In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8⁺ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8⁺ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8⁺ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8⁺ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8⁺ T cell frequencies in spleen and liver.