Vaccine Development Strategies for Crimean-Congo Hemorrhagic Fever Virus and its Tick Vector

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne bunyavirus with an extensive geographic range and complex ecology. Ticks within the Hyalomma genera are the primary vector and reservoir of the virus and maintain the virus through a cryptic tick-vertebrate-tick cycle in nature. However, infection of humans with CCHFV can result in the severe disease known as Crimean-Congo hemorrhagic fever (CCHF). As humans are the only species that display clinical signs of disease from infection with CCHFV, vaccine development has focused on preventing human disease. Despite extensive research, no vaccine candidates have advanced to clinical trials. This dissertation aimed to utilize different vaccine platform technologies to target unique points in the CCHFV transmission cycle as new strategies for vaccine development for CCHFV. Vaccine candidates were developed against ticks for the preferred hosts of immature and adult H. marginatum ticks, and against the virus for prevention of human CCHF. The two anti-tick vaccine candidates utilized viral-vectored vaccine technology encoding the concealed tick antigen Subolesin or a chimeric Subolesin and rabies virus glycoprotein antigen. Neither vaccine candidate induced stronger humoral immunity than the conventional approach of purified protein in adjuvant. These studies showed that the vaccine type, specific viral vector used and the generation of a chimeric Subolesin antigen are key considerations for developing future anti-tick vaccines. For prevention of human CCHF, a candidate multi-epitope antigen for CCHFV was developed using bioinformatics and a plasmid-based DNA vaccine was evaluated in vitro and in vivo. Although the multi-epitope antigen was not immunogenic, these studies provide information about predicted immunogenic regions of the CCHFV glycoprotein precursor that should be evaluated for inclusion in rational vaccine development. Overall, this dissertation has evaluated three different vaccine development strategies, and provides information for future tick and CCHFV vaccine development research.