Article
Author: Burn, Olivia K ; Hermans, Ian F. ; Iannacone, Matteo ; Ravà, Micol ; Compton, Benjamin J ; Mooney, Anna H ; Gulab, Shivali A. ; Heath, William R. ; Sette, Alessandro ; Giustini, Leonardo ; Tang, Chingwen ; Guidotti, Luca G. ; Chisari, Francis V. ; Mooney, Anna H. ; Fumagalli, Valeria ; Di Lucia, Pietro ; Painter, Gavin F. ; Farrand, Kathryn J. ; Farrand, Kathryn J ; Guidotti, Luca G ; Burn, Olivia K. ; Draper, Sarah L. ; Chisari, Francis V ; Anderson, Regan J ; Hermans, Ian F ; Yuan, Weiming ; Heath, William R ; Godfrey, Dale I ; Anderson, Regan J. ; Gulab, Shivali A ; Compton, Benjamin J. ; Draper, Sarah L ; Godfrey, Dale I. ; Painter, Gavin F ; Bono, Elisa ; Sidney, John
Background & AimsLiver diseases resulting from chronic 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.MethodsVaccines 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.ResultsThe 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 naive 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 because of qualitatively improved T-cell stimulation. In a step towards a clinical product, vaccines were prepared using synthetic long peptides 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.ConclusionsThe novel vaccines described show promise for further clinical development as a treatment for chronic hepatitis B.Impact and ImplicationsAlthough there are effective prophylactic vaccines for HBV infection, it is estimated that 350-400 million people worldwide have chronic hepatitis B, putting these individuals at significant risk of life-threatening liver diseases. Therapeutic vaccination aimed at activating or boosting HBV-specific T-cell responses holds potential as a strategy for treating chronic infection, but has so far met with limited success. Here, we show that a glycolipid-peptide conjugate vaccine designed to coordinate activity of type I NKT cells alongside conventional antiviral T cells has antiviral activity in a mouse model of chronic infection. It is anticipated that a product based on a combination of three such conjugates, each prepared using long peptides covering clusters of known HLA-binding epitopes, could be developed further as a treatment for chronic hepatitis B with broad global HLA coverage.
