The pathogenesis of genetically diverse strains of Crimean-Congo hemorrhagic fever virus in the cynomolgus macaque model

Abstract

Purpose: Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus with a wide geographical distribution, which includes Africa, the Balkans, the Middle East, Russia and western Asia. As a result of its wide dissemination, there is a considerable amount of genetic diversity amongst different CCHFV strains. Infection with CCHFV can cause a severe, often fatal, human disease characterized by fever and hemorrhage. No licensed vaccines or therapeutics currently exist to treat infection with CCHFV. The development of a non-human primate (NHP) model that recapitulates human disease would significantly benefit development efforts for medical countermeasures to CCHFV. In a recent study by another group, cynomolgus macaques were infected intravenously with a European isolate of CCHFV and the animals experienced a severe, sometimes lethal, disease state. We expanded upon this initial study using the same intravenous NHP model to compare disease progression with the previous European isolate versus another contemporary isolate of central Asian origin. Methods & Materials: Two groups of cynomolgus macaques were infected intravenously with either the European isolate (Kosova Hoti) or the Asian isolate (Afg09-2990). Animals were then monitored with real-time temperature telemetry and regularly assessed across a range of clincial criteria. Serological collection was performed on a daily basis during acute phase, and a range of viremic, hematological, blood chemistry, and immunological assays were performed. Results: While we achieved a robust disease state for both challenge groups, our CCHFV disease model was not as severe as the initial study reported by Haddock, et al. Interestingly, despite its higher initial viremic load, Afg09-2990 appeared to resolve more quickly than Kosova Hoti with regard to both fever and clinical score criteria. Aside from this, both virus strains caused largely analogous disease states, which reflected many symptoms seen in human disease. Conclusion: In this comparative study, we found that European and Asian CCHFV strains caused very similar disease profiles in cynomolgus macaques. This strongly suggests that future medical countermeasures can be tested in this NHP model for multiple CCHFV strains. In addition, the differences we observed in the severity of our disease model relative to that previously reported suggests that further model optimization may be desirable.