Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand

Hepatitis B virus (HBV) remains a major cause of morbidity and mortality worldwide. Treatments that can induce functional cure in patients chronically infected with this hepatotropic, non-cytopathic virus are desperately needed. Attempts to use therapeutic vaccines to expand the weak antiviral T-cell response and induce sustained immunity have been unsuccessful. However, exciting progress has been made in defining the molecular defects that must be overcome to harness T-cell immunity. A large arsenal of immunotherapeutic agents and direct-acting antivirals targeting multiple steps of the viral lifecycle is emerging. In this Review, we discuss how to translate the new insights into T-cell manipulation, combined with better understanding of patient heterogeneity, into optimisation of therapeutic vaccines against HBV. We review the opportunities and risks involved in boosting endogenous T-cell responses using combinations of next generation therapeutic vaccines and immunotherapy agents.