Characterization of the Interferon αβ receptor knockout mouse model of Crimean-Congo hemorrhagic fever (CCHF) and assessment of Adenovirus based CCHF virus vaccine efficacy and correlates of protection

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Zivcec, Marko
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Oxford Journals
Crimean-Congo hemorrhagic fever (CCHF) is an inflammatory disease caused by the tick-borne pathogen CCHF virus (CCHFV). CCHFV is widely distributed with a endemic area including central and western Asia, the Middle East, southeastern Europe and the African continent, and can be transmitted to humans directly by tick bite or by contact with body fluids of infected animals or people. Most animals, while susceptible to CCHFV infection, do not display disease signs following infection, therefore, the development of CCHF disease models has been severely hampered. The lack of disease models has resulted in a lack of characterization of disease progression and lack of evaluated clinical countermeasures. The aims of this study were to further characterize a recently reported small animal model, the interferon alpha/beta receptor knockout (IFNAR-/-) mouse model of CCHF and to utilize this model to evaluate the protective efficacy of Adenovirus (Ad) vaccines as well as mechanisms of protection. To achieve the goals of the study hematological, coagulation, virological, pathological and cytokine/chemokine parameters of IFNAR-/- mice were assessed chronologically following CCHFV challenge. Vaccines were developed by construction of Ad expressing CCHFV nucleocapsid protein (Ad-NP) and glycoproteins (complete glycoprotein precursor Ad-GPC, and mature glycoproteins Ad-GN and Ad-GC). IFNAR-/- mice were then evaluated for adaptive immune responses following Ad vaccination and then challenged with a lethal dose of CCHFV and monitored for survival. To determine the roles of humoral and cell mediated adaptive immune responses in protection against CCHFV, experiments using adoptive transfers of Ad vaccinated IFNAR-/- mice to naïve IFNAR-/- mice and depletion of B- and/or T-cells were undertaken. The results demonstrate that IFNAR-/- mice develop an inflammatory, lethal disease following CCHFV challenge that resembles human CCHF; Ad-NP and Ad-NP/Ad-GPC vaccinated IFNAR-/- mice are protected from CCHFV iii challenge; and that humoral responses are essential for protection from CCHFV while T-cell responses are dispensable, at least in this vaccine platform, in this animal model. These studies provide the basis for more detailed work in vivo and suggest which mechanisms of protection may be important for subsequent advances in CCHFV vaccinology.
Microbiology, Virology, Vaccine, Immunology
Zivcec, M., et al., Lethal Crimean-Congo Hemorrhagic Fever Virus Infection in Interferon alpha/beta Receptor Knockout Mice Is Associated With High Viral Loads, Proinflammatory Responses, and Coagulopathy. J Infect Dis, 2013 Jun 15;207(12):1909-21