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A DNA-based vaccine protects against Crimean-Congo haemorrhagic fever virus disease in a Cynomolgus macaque model.

ABSTRACT: There is currently no specific prophylaxis or vaccine against Crimean-Congo haemorrhagic fever virus (CCHFV). Crimean-Congo haemorrhagic fever (CCHF) is a severe febrile illness transmitted by Hyalomma ticks in endemic areas, handling of infected livestock or care of infected patients. We report here the successful protection against CCHFV-mediated disease in a non-human primate disease model. Cynomolgus macaques were vaccinated with a DNA-based vaccine using in vivo electroporation-assisted delivery. The vaccine contained two plasmids encoding the glycoprotein precursor (GPC) and the nucleoprotein (NP) of CCHFV. Animals received three vaccinations and we recorded potent antibody and T cell responses after vaccination. While all sham-vaccinated animals developed viraemia, high tissue viral loads and CCHF-induced disease, the NP + GPC vaccinated animals were significantly protected. In conclusion, this is evidence of a vaccine that can protect against CCHFV-induced disease in a non-human primate model. This supports clinical development of the vaccine to protect groups at risk for contracting the infection.

SUBMITTER: Hawman DW

PROVIDER: S-EPMC7854975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A cynomolgus macaque model for Crimean-Congo haemorrhagic fever.

Project description:Crimean-Congo haemorrhagic fever (CCHF) is the most medically significant tick-borne disease, being widespread in the Middle East, Asia, Africa and parts of Europe 1 . Increasing case numbers, westerly movement and broadly ranging case fatality rates substantiate the concern of CCHF as a public health threat. Ixodid ticks of the genus Hyalomma are the vector for CCHF virus (CCHFV), an arbovirus in the genus Orthonairovirus of the family Nairoviridae. CCHFV naturally infects numerous wild and domestic animals via tick bite without causing obvious disease2,3. Severe disease occurs only in humans and transmission usually happens through tick bite or contact with infected animals or humans. The only CCHF disease model is a subset of immunocompromised mice4-6. Here, we show that following CCHFV infection, cynomolgus macaques exhibited hallmark signs of human CCHF with remarkably similar viral dissemination, organ pathology and disease progression. Histopathology showed infection of hepatocytes, endothelial cells and monocytes and fatal outcome seemed associated with endothelial dysfunction manifesting in a clinical shock syndrome with coagulopathy. This non-human primate model will be an invaluable asset for CCHFV countermeasures development.

| S-EPMC6717652 | biostudies-literature

Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever.

Project description:Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne bunyavirus, can cause a life-threatening hemorrhagic syndrome in humans but not in its animal host. The virus is widely distributed throughout southeastern Europe, the Middle East, Africa, and Asia. Disease management has proven difficult and there are no broadly licensed vaccines or therapeutics. Recombinant vesicular stomatitis viruses (rVSV) expressing foreign glycoproteins (GP) have shown promise as experimental vaccines for several viral hemorrhagic fevers. Here, we developed and assessed a replication competent rVSV vector expressing the CCHFV glycoprotein precursor (GPC), which encodes CCHFV structural glycoproteins. This construct drives strong expression of CCHFV-GP, in vitro. Using these vectors, we vaccinated STAT-1 knock-out mice, an animal model for CCHFV. The vector was tolerated and 100% efficacious against challenge from a clinical strain of CCHFV. Anti-CCHFV-GP IgG and neutralizing antibody titers were observed in surviving animals. This study demonstrates that a rVSV expressing only the CCHFV-GP has the potential to serve as a replication competent vaccine platform against CCHF infections.

| S-EPMC6533279 | biostudies-literature

A novel vaccine against Crimean-Congo Haemorrhagic Fever protects 100% of animals against lethal challenge in a mouse model.

Project description:Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. Between 15-70% of reported cases are fatal. There is no approved vaccine available, and preclinical protection in vivo by an experimental vaccine has not been demonstrated previously. In the present study, the attenuated poxvirus vector, Modified Vaccinia virus Ankara, was used to develop a recombinant candidate vaccine expressing the CCHF virus glycoproteins. Cellular and humoral immunogenicity was confirmed in two mouse strains, including type I interferon receptor knockout mice, which are susceptible to CCHF disease. This vaccine protected all recipient animals from lethal disease in a challenge model adapted to represent infection via a tick bite. Histopathology and viral load analysis of protected animals confirmed that they had been exposed to challenge virus, even though they did not exhibit clinical signs. This is the first demonstration of efficacy of a CCHF vaccine.

| S-EPMC3951450 | biostudies-literature

Adenoviral vectored vaccination protects against Crimean-Congo Haemorrhagic Fever disease in a lethal challenge model.

Project description:BackgroundThe tick-borne bunyavirus, Crimean-Congo Haemorrhagic Fever virus (CCHFV), can cause severe febrile illness in humans and has a wide geographic range that continues to expand due to tick migration. Currently, there are no licensed vaccines against CCHFV for widespread usage.MethodsIn this study, we describe the preclinical assessment of a chimpanzee adenoviral vectored vaccine (ChAdOx2 CCHF) which encodes the glycoprotein precursor (GPC) from CCHFV.FindingsWe demonstrate here that vaccination with ChAdOx2 CCHF induces both a humoral and cellular immune response in mice and 100% protection in a lethal CCHF challenge model. Delivery of the adenoviral vaccine in a heterologous vaccine regimen with a Modified Vaccinia Ankara vaccine (MVA CCHF) induces the highest levels of CCHFV-specific cell-mediated and antibody responses in mice. Histopathological examination and viral load analysis of the tissues of ChAdOx2 CCHF immunised mice reveals an absence of both microscopic changes and viral antigen associated with CCHF infection, further demonstrating protection against disease.InterpretationThere is the continued need for an effective vaccine against CCHFV to protect humans from lethal haemorrhagic disease. Our findings support further development of the ChAd platform expressing the CCHFV GPC to seek an effective vaccine against CCHFV.FundingThis research was supported by funding from the Biotechnology and Biological Sciences Research Council (UKRI-BBSRC) [BB/R019991/1 and BB/T008784/1].

| S-EPMC10025009 | biostudies-literature

Accelerated DNA vaccine regimen provides protection against Crimean-Congo hemorrhagic fever virus challenge in a macaque model.

Project description:Crimean-Congo hemorrhagic fever virus (CCHFV) is widely distributed throughout Africa, the Middle East, Southern Asia, and Southern and Eastern Europe. Spread by Hyalomma ticks or by contact with infected animals, CCHF begins non-specifically but can rapidly progress to severe, sometimes fatal, disease. Due to the non-specific early symptoms and often unrecognized infections, patients often present to healthcare systems exhibiting later stages of disease, when treatment is limited to supportive care. Consequently, simple vaccines are critically needed to protect populations at risk of CCHFV infection. Currently, there are no widely approved vaccines for CCHFV. We have previously reported significant efficacy of a three-dose DNA-based vaccination regimen for CCHFV in cynomolgus macaques (Macaca fasicularis). Here, we show that in cynomolgus macaques, plasmid-expressed CCHFV nucleoprotein (NP) and glycoprotein precursor (GPC) antigens elicit primarily humoral and cellular immunity, respectively. We found that a two-dose vaccination regimen with plasmids expressing the NP and GPC provides significant protection against CCHFV infection. Studies investigating vaccinations with either antigen alone showed that plasmid-expressed NPs could also confer protection. Cumulatively, our data show that this vaccine confers robust protection against CCHFV and suggest that both humoral and cellular immunity contribute to optimal vaccine-mediated protection.

| S-EPMC9931546 | biostudies-literature

A global compendium of human Crimean-Congo haemorrhagic fever virus occurrence.

Project description:In order to map global disease risk, a geographic database of human Crimean-Congo haemorrhagic fever virus (CCHFV) occurrence was produced by surveying peer-reviewed literature and case reports, as well as informal online sources. Here we present this database, comprising occurrence data linked to geographic point or polygon locations dating from 1953 to 2013. We fully describe all data collection, geo-positioning, database management and quality-control procedures. This is the most comprehensive database of confirmed CCHF occurrence in humans to-date, containing 1,721 geo-positioned occurrences in total.

| S-EPMC4409013 | biostudies-literature

Humoral or Cellular Immunity Induced by RNA Vaccine Protects IFNAR-/- Mice against Crimean-Congo Hemorrhagic Fever Virus Infection

Project description:Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is on the World Health Organizations list over emerging pathogens and prioritized diseases. With global distribution, high fatality rate and no approved treatment or vaccine, CCHF constitute a treat against the global health. In the current study we show full protection of mice against lethal CCHFV infection due to mRNA-LNP vaccination. IFNAR-/- mice received two immunizations with either mRNA-LNP encoding for the CCHFV nucleoprotein, glycoproteins or a combination of both. While unvaccinated mice showed clear signs of severe disease, vaccinated mice was significantly protected. Vaccine induced immune responses due to vaccination was evaluated both in IFNAR-/- and immunocompetent mice and a strong humoral and cellular immune response was observed in both mouse models with high titers of neutralizing antibodies and primed T-cells. In addition, we conducted a proteomic analysis on liver samples from vaccinated and unvaccinated mice after CCHFV infection to determine the effect of vaccination on the protein profile. Similar to what has been observed in humans due to vaccination, there was an effect on metabolic pathways. In conclusion, this study shows very promising results regarding development of a vaccine against CCHFV.

2021-11-15 | PXD023300 | Pride

Host response transcriptomic analysis of Crimean-Congo hemorrhagic fever pathogenesis in the cynomolgus macaque model

Project description:A NanoString targeted gene panel was used to elucidate the transcriptomic changes occurring in non-human primate whole blood during Crimean Congo Hemorrhagic Fever Virus infection.

2021-09-23 | GSE169698 | GEO

Host response transcriptomic analysis of Crimean-Congo hemorrhagic fever pathogenesis in the cynomolgus macaque model.

Project description:Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne RNA virus prevalent in Asia, Europe, and Africa, and can cause a hemorrhagic disease (CCHF) in humans with mortality rates as high as 60%. A general lack of both effective medical countermeasures and a comprehensive understanding of disease pathogenesis is partly driven by an historical lack of viable CCHF animal models. Recently, a cynomolgous macaque model of CCHF disease was developed. Here, we document the targeted transcriptomic response of non-human primates (NHP) to two different CCHFV strains; Afghan09-2990 and Kosova Hoti that both yielded a mild CCHF disease state. We utilized a targeted gene panel to elucidate the transcriptomic changes occurring in NHP whole blood during CCHFV infection; a first for any primate species. We show numerous upregulated genes starting at 1 day post-challenge through 14 days post-challenge. Early gene changes fell predominantly in the interferon stimulated gene family with later gene changes coinciding with an adaptive immune response to the virus. There are subtle differences between viral strains, namely duration of the differentially expressed gene response and biological pathways enriched. After recovery, NHPs showed no lasting transcriptomic changes at the end of sample collection.

| S-EPMC8494817 | biostudies-literature

History and classification of Aigai virus (formerly Crimean-Congo haemorrhagic fever virus genotype VI).

Project description:Crimean-Congo haemorrhagic fever virus (CCHFV) is the medically most important member of the rapidly expanding bunyaviral family Nairoviridae. Traditionally, CCHFV isolates have been assigned to six distinct genotypes. Here, the International Committee on Taxonomy of Viruses (ICTV) Nairoviridae Study Group outlines the reasons for the recent decision to re-classify genogroup VI (aka Europe-2 or AP-92-like) as a distinct virus, Aigai virus (AIGV).

| S-EPMC10026732 | biostudies-literature

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