Identification of GP38 and NP antibodies and their protective mechanisms against CCHFV

Summary/Abstract Crimean-Congo hemorrhagic fever virus (CCHFV) is a ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. Fatality rates typically associated with CCHFV can be up to 40%. CCHFV has rapidly spread across large sections of Europe, Asia, and Africa. Recently, CCHFV and its tick reservoir have illustrated their continued ability to spread into previously naive regions. At the same time, U.S. citizen traffic has increased substantially to regions endemic with CCHFV, specifically South-Central Asia and the Black Sea Region. As a result, there is a substantial risk for transmission of CCHFV and/or its tick vector to the United States. CCHFV is not the only nairovirus that threatens the public. Other nairoviruses to include Nairobi Sheep Disease and Erve viruses as well as newly discovered members in Songling and Yezo viruses can cause human disease of varying severity and economic distress. There is no vaccine or prophylactic currently available for treatment of CCHF or any other nairovirus related disease. Recently studies have identified that including a 38 KD non-structural glycoprotein protein of CCHFV (GP38) as a vaccine antigen can confer a level of protection against CCHFV challenge. Also, targeting of CCHFV GP38 using non-neutralizing monoclonal antibodies (mAb) have been shown as a viable route to protective post-exposure broad-spectrum (mAb) strategies that show more potential than their neutralizing counterparts. Beyond GP38, examination of protection conferred by fast acting CCHFV viral replicon particles has revealed that non-neutralizing humoral responses to CCHFV nairovirus nucleoprotein (NP) are an important contributor to protection against these viruses. This proposal will reveal the protective attributes of non-neutralizing mAbs targeting these two viral proteins, opening the door to new routes of vaccine and therapeutic intervention for CCHFV and other related bunyaviruses. These insights will then be used to isolate from CCHFV survivors mAb candidates for further pre-clinical and clinical testing that are highly efficacious with broadly cross protective characteristics.