Protection against woodchuck hepatitis virus (WHV) infection by gene gun coimmunization with WHV core and interleukin-12

Woodchuck hepatitis virus (WHV) and hepatitis S virus (HBV) are closely sim ilar with respect to genomic organization, host antiviral responses, and pa thobiology of the infection. T-cell immunity against viral nucleocapsid (HB cAg or WHcAg) has been shown to play a critical role in viral clearance and protection against infection. Here we show that vaccination of healthy woo dchucks by gene gun bombardment with a plasmid coding for WHcAg (pCw) stimu lates proliferation of WHcAg-specific T cells but that these cells do not p roduce significant levels of gamma interferon (IFN-gamma) upon antigen stim ulation. In addition, animals vaccinated with pCw alone were not protected against WHV inoculation. In order to induce a Th1 cytokine response, anothe r group of woodchucks was immunized with pCw together with another plasmid coding for woodchuck interleukin-12 (IL-12). These animals exhibited WHcAg- specific T-cell proliferation with high IFN-gamma production and were prote cted against challenge with WHV, showing no viremia or low-level transient viremia after WHV inoculation. In conclusion, gene gun immunization with WH V core generates a non-Th1 type of response which does not protect against experimental infection. However, steering the immune response to a Th1 cyto kine profile by IL-12 coadministration achieves protective immunity. These data demonstrate a crucial role of Th1 responses in the control of hepadnav irus replication and suggest new approaches to inducing protection against HBV infection.