Characterizing the potential of DEC-205-mediated antigen delivery to dendritic cells as a tool to induce adaptive immunity against hepatitis C virus infection

HCV infection represents a serious worldwide public healthcare problem. Despite extensive investigations no effective vaccine does yet exist. DCs play a pivotal role in mediating immunity to pathogens and represent an exceptionally attractive target for vaccination. Therefore, the aim of this thesis was to test different in vivo DC targeting strategies with respect to their applicability for inducing antiviral immunity in the liver and thus to provide the basis for the development of a DC-based HCV vaccine. In the first part of this thesis two distinct in vivo DC targeting strategies, utilizing either the endocytosis receptor DEC-205 or the TLR2/6 heterodimer, were compared using the model antigen OVA. For this, mice were immunized with aDEC-205/OVA or the TLR2/6 agonist BPPcysMPEG, which was either separately delivered with the entire protein antigen or directly linked to the immunodominant MHC-I and MHC-II peptide epitopes (BPPcysOVAMPEG). Immunization with aDEC-205/OVA was found to be exceptionally potent in inducing Th1 cells and CTLs, which were capable of efficiently clearing virus-infected hepatocytes, whereas immunization with OVA and BPPcysMPEG resulted in a Th2 dominated CD4+ T cell response and failed to induce CTLs capable of killing virus-infected liver cells. In contrast, vaccination with BPPcysOVAMPEG was as efficient as aDEC-205/OVA treatment in inducing antiviral immunity in the liver. However, since vaccination against only a limited number of antigenic determinants is of great disadvantage with respect to the highly mutating virus HCV, targeting DEC-205 on DCs in vivo was identified to be superior to the TLR2/6. In the second part of the thesis, the analyses were extended towards the design of DEC-205-based HCV vaccine. First immunization trials in mice with both aDEC-205/NS3 and aDEC-205/Core were found to induce HCV-specific immune responses, thus providing a promising starting point for the future development of a DEC-205-based HCV vaccine.