Preclinical evaluation of therapeutic vaccines for chronic hepatitis B that stimulate antiviral activities of T cells and NKT cells

Background & Aims Liver diseases resulting from chronic hepatitis B virus (HBV) infection are a significant cause of morbidity and mortality. Vaccines that elicit T cell responses capable of controlling the virus represent a treatment strategy with potential for long-term effects. Here, we evaluated vaccines that induce the activity of type I natural killer T (NKT) cells to limit viral replication and license stimulation of conventional antiviral T cells. Methods Vaccines were prepared by conjugating peptide epitopes to an NKT cell agonist to promote co-delivery to antigen-presenting cells, encouraging NKT cell licensing and stimulation of T cells. Activity of the conjugate vaccines was assessed in transgenic mice expressing the complete HBV genome, administered intravenously to maximise access to NKT cell-rich tissues. Results The vaccines induced only limited antiviral activity in unmanipulated transgenic hosts, likely attributable to NKT cell activation as T cell tolerance to viral antigens is strong. However, in a model of chronic hepatitis B involving transfer of naïve HBV core antigen (HBcAg)-specific CD8+ T cells into the transgenic mice, which typically results in specific T cell dysfunction without virus control, vaccines containing the targeted HBcAg epitope induced prolonged antiviral activity due to qualitatively improved T cell stimulation. In a step towards a clinical product, vaccines were prepared using synthetic long peptides (SLPs) covering clusters of known HLA-binding epitopes and shown to be immunogenic in HLA transgenic mice. Predictions based on HLA distribution suggest a product containing three selected SLP-based vaccines could give >90 % worldwide coverage, with an average of 3.38 epitopes targeted per individual. Conclusions The novel vaccines described show promise for further clinical development as a treatment for chronic hepatitis B.