Recently described advancements in the characterization and monitoring of the woodchuck immune system during the WHV infection, made this animal model particularly useful for development of the immunomodulatory approaches in chronic hepatitis B. The natural occurrence of chronic WHV infection in woodchucks, that is closely related to HBV infection in humans, allows to evaluate the potentially new therapeutic strategies directly in chronic WHV carriers. Up to date, several studies of diverse therapeutic vaccinations have been carried out in woodchucks ( Table 2) . The pioneer investigations based on therapeutic vaccines based on WHV core [96] or surface antigens in combination with a helper peptide FIS [120] , or with potent Th1 adjuvants like monophosphoryl lipid A [121] did not lead to satisfactory results. Those experiments proved that vaccinations could induce specific B-and/or T cell responses in chronic WHV carriers. However, this alone was not sufficient to achieve the control of virus replication. It is assumed that high level viremia, during the chronic hepatitis B, can inhibit the therapeutic effect of the vaccination. Treatment of chronic HBV patients with lamivudine could transiently restore HBV-specific T cell immune response [55, 56] . Therefore, reduction of viral load by the nucleos(t)ide analogues pretreatment might support the efficacy of immunization to enhance the virus-specific immune responses. This hypothesis was tested in three experimental trials of the combination therapies in chronic WHV carriers.