Therapeutic vaccination for chronic hepatitis B: why most vaccines failed and what may work

Over 30 years of therapeutic vaccine development have yet to deliver a functional cure for chronic HBV infection. Despite promising preclinical data, most therapeutic vaccine preparations have largely failed to restore HBV-specific B and T cell immunity in a clinically meaningful way. Only a recent trial combining siRNA Elebsiran and PEG-IFN-α reported a remarkable ∼50% HBsAg loss rate in chronic HBV patients who responded to a therapeutic vaccine based on PreS1/S2/S recombinant protein (BRII-179) administered prior to the trial. Here we dissect the immunological basis for this differential clinical outcome, and chart a path toward the next generation of effective therapeutic HBV vaccines.