Background Crimean-Congo hemorrhagic fever (CCHF) is the most widely spread viral hemorrhagic disease, found in Europe, Asia, and Africa. The disease symptoms start and progress rapidly and can lead to bruising and bleeding, with high fatality rates of up to 50% in hospitalized patients. Currently there are no approved vaccines or therapeutics available, and treatment is supportive. The CCHFV glycoprotein is made up of two major structural glycoproteins, GC and GN, which are required for the virus attachment and entry. An additional protein, GP38, is a secreted byproduct derived from a glycoproptein precursor of GN and whose role remains unknown. Recently, the non-neutralizing mouse mAb 13G8 (anti-GP38) has shown 60-90% protection prophylactically or post-challenge in a mouse model when challenged with various CCHFV strains. This is noteworthy because neutralizing mouse mAbs to GC have not shown consistent protection in mouse models. Because most of the work has been on mice up till now, we decided to isolate and study mAbs from human survivors of CCHF. Methods The antibody response to GC and GP38 were measured in CCHF patients from Turkey ∼ 6 months after infection, and one high titer sample was selected for mAb isolation. For this purpose, a combined proteomics/genomics approach was performed; plasma Abs were isolated using sequential affinity chromatography, peptides subjected to Mass spectrometry, and then matched to single cell VDJ sequence libraries constructed from PBMCs. mAbs were tested for binding and neutralization, and one candidate used for in-vivo evaluation with Ifnar1- mice (lacking IFN) challenged with CCHF virus. Results 11 anti-GP38 and 8 anti-Gc antibodies were isolated. All anti-Gc (and none of the GP38) mAbs exhibited neutralization. Anti-GP38 antibodies were segregated into 6 epitope groups based on competition assays (including 3 not described before). CC5-17, the human mAb sharing the same epitope as 13G8, showed 50% protection two separate experiments in Ifnar1- mice (when given 30 minutes prior to challenge, or 1 and 4 days after challenge). Conclusion The non-neutralizing gp38 antibodies have proven to afford protection before or after exposure to CCHFV. Human mAbs have the potential for protection and/or prevention of CCHF. Disclosures All Authors: No reported disclosures.
