Immunization of Knock-Out α/β Interferon Receptor Mice against High Lethal Dose of Crimean-Congo Hemorrhagic Fever Virus with a Cell Culture Based Vaccine

Abstract

Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne zoonotic disease. The disease has been reported in many countries of Africa, Asia, the Middle East, and in Eurasia. During the past decade, new foci of CCHF have emerged in the Balkan Peninsula, southwest Russia, the Middle East, western China, India, Africa, and Turkey. CCHF virus produces severe hemorrhagic manifestations in humans with fatality rates up to 30%. Vaccine development efforts have been significantly hampered by a lack of animal models and therefore, no protective vaccine has been achieved. Lately, IFN α/β receptor deficient (IFNAR−/−) mice have been established as a novel small animal model of CCHF virus infection. In the present study, we found that IFNAR−/− mice highly susceptible to CCHF virus Turkey-Kelkit06 strain. Immunization with the cell culture based vaccine elicited a significant level of protection against high dose challenge (1,000 PPFU) with a homologous CCHF virus in IFNAR−/− mice.

Development of vaccines against Crimean-Congo haemorrhagic fever virus

“…In an attempt to avoid the regulatory complications of a mouse brain derived vaccine, a purified, formalin inactivated preparation of CCHFV derived from cell culture was published in 2015 [97]. Vaccination required the use of alum adjuvant and although the data showed that this vaccine was able to induce neutralising antibodies, no studies of T cell immunity were performed.…”

“…Additionally, the challenge route used in vaccine assessment studies should mimic natural infection by tick bite. Several CCHFV studies use the intraperitoneal route of challenge [97] which is not a normal route and may potentially alter the course of disease progression.…”

The Development of a Novel Diagnostic Assay That Utilizes a Pseudotyped Vesicular Stomatitis Virus for the Detection of Neutralizing Activity against Crimean-Congo Hemorrhagic Fever Virus

“…Its relative ease of use will also support high throughput, lending itself to studies on the role of neutralizing antibodies in protecting from further CCHFV in survivors, for example. In this context, it will be an invaluable new tool in studying specific antibody responses induced by the many novel CCHFV vaccine candidates currently undergoing research and development (5,24,25). It is known that CCHFV infects various wild and domestic animals, such as cattle, sheep, goats, buffalo, hares, squirrels, mice, rats, and hedgehogs (26)(27)(28)(29).…”

“…The case-fatality rate is high (nearly 30%; 1,3,4), yet there are currently no established countermeasures for the treatment or prevention of CCHF. Although there is no robust evidence to suggest that the antibody response is the seat of protection against CCHFV, the use of an effective vaccine to develop neutralizing antibodies is a possible preventive strategy (5,6). In this context, measurement of neutralizing antibody activity in the blood of infected individuals could be a useful indicator of the efficacy, duration, and cross-reactivity between the vaccine and alternative strains of CCHFV.…”

Crimean-Congo Hemorrhagic Fever

“…Despite insufficient neutralizing antibody titers in mice immunized with DNA plasmids developed against virus capsid and envelope proteins, Th1 response was reported to be important in protection [99] . A vaccine developed in Turkey against the Turkey-Kelkit-06 CCHFV strain resulted in measurable levels of neutralizing antibody in the serum of infected mice after a second vaccination [100] . In another study, a vaccine expressing CCHFV glycoproteins was shown to improve cellular and humoral immunity in mice, but did not prevent death [101,102] .…”