Immunogenic Effects of Woodchuck Hepatitis Virus Surface Antigen Vaccine in Combination with Antiviral Therapy: Breaking of Humoral and Cellular Immune Tolerance in Chronic Woodchuck Hepatitis Virus Infection

Objective: A rational treatment strategy for chronic hepatitis B virus (HBV) infection might involve the modulation of immunity after the reduction of viremia and antigenemia. This strategy was tested in woodchucks chronically infected with the woodchuck hepatitis virus (WHV) by combining antiviral treatment with 1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)-uracil (L-FMAU) and therapeutic vaccination with WHV surface antigen (WHsAg). Methods: Chronic WHV carriers were treated with L-FMAU or placebo for 32 weeks. Half the woodchucks in each group then received four injections of a conventional WHsAg vaccine during the next 16 weeks. Results: Vaccination alone elicited low-level antibody to WHsAg (anti-WHs) in most carriers but did not affect serum WHV DNA, WHsAg or liver enzyme responses. Carriers treated first with L-FMAU to reduce WHV DNA and WHsAg and then vaccinated developed similar low-level anti-WHs and normalized liver enzymes. Following vaccinations, WHsAg-specific cell-mediated immunity (CMI) was demonstrated in both groups, but was significantly enhanced in carriers treated with L-FMAU, and was broadened to include WHV core antigen (WHcAg) and selected peptide epitopes of WHcAg and WHsAg. Anti-WHs and associated CMI to WHcAg and WHsAg were observed after drug discontinuation in half of the carriers that received L-FMAU alone. Conclusions: Vaccination with WHsAg following treatment with L-FMAU disrupted virus-specific humoral and cell-mediated immune tolerance in chronic WHV infection and enhanced the immune response profiles beyond those seen with monotherapies alone. The combination therapy resulted in immune response profiles that resembled those observed during resolution of WHV infection. The results in woodchucks demonstrate the feasibility of using such a combination therapy for the control of chronic HBV infection in humans.