Hepatitis B virus polymerase-specific T cell epitopes shift in a mouse model of chronic infection

Background: Chronic hepatitis B virus (HBV) infection (CHB) is a significant public health problem that could benefit from treatment with immunomodulators. Here we describe a set of therapeutic HBV vaccines that target the internal viral proteins. Methods: Vaccines are delivered by chimpanzee adenovirus vectors (AdC) of serotype 6 (AdC6) and 7 (AdC7) used in prime only or prime-boost regimens. The HBV antigens are fused into an early T cell checkpoint inhibitor, herpes simplex virus (HSV) glycoprotein D (gD), which enhances and broadens vaccine-induced cluster of differentiation (CD8)⁺ T cell responses. Results: Our results show that the vaccines are immunogenic in mice. They induce potent CD8⁺ T cell responses that recognize multiple epitopes. CD8⁺ T cell responses increase after a boost, although the breadth remains similar. In mice, which carry high sustained loads of HBV particles due to a hepatic infection with an adeno-associated virus (AAV)8 vector expressing the 1.3HBV genome, CD8⁺ T cell responses to the vaccines are attenuated with a marked shift in the CD8⁺ T cells’ epitope recognition profile. Conclusions: Our data show that in different stains of mice including those that carry a human major histocompatibility complex (MHC) class I antigen HBV vaccines adjuvanted with a checkpoint inhibitor induce potent and broad HBV-specific CD8⁺ T cell responses and lower but still detectable CD4⁺ T cell responses. CD8⁺ T cell responses are reduced and their epitope specificity changes in mice that are chronically exposed to HBV antigens. Implications for the design of therapeutic HBV vaccines are discussed.