scholarly journals Immunogenicity of a DNA-Based Sindbis Replicon Expressing Crimean–Congo Hemorrhagic Fever Virus Nucleoprotein

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1491
Author(s):  
Thomas Tipih ◽  
Mark Heise ◽  
Felicity Jane Burt
Keyword(s):  
Immune Response ◽  
Sindbis Virus ◽  
Cytokine Production ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Virus Vector ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

Crimean–Congo hemorrhagic fever virus (CCHFV) infrequently causes hemorrhagic fever in humans with a case fatality rate of 30%. Currently, there is neither an internationally approved antiviral drug nor a vaccine against the virus. A replicon based on the Sindbis virus vector encoding the complete open reading frame of a CCHFV nucleoprotein from a South African isolate was prepared and investigated as a possible candidate vaccine. The transcription of CCHFV RNA and recombinant protein production by the replicon were characterized in transfected baby hamster kidney cells. A replicon encoding CCHFV nucleoprotein inserted in plasmid DNA, pSinCCHF-52S, directed transcription of CCHFV RNA in the transfected cells. NIH-III heterozygous mice immunized with pSinCCHF-52S generated CCHFV IgG specific antibodies with notably higher levels of IgG2a compared to IgG1. Splenocytes from mice immunized with pSinCCHF-52S secreted IFN-γ and IL-2, low levels of IL-6 or IL-10, and no IL-4. No specific cytokine production was registered in splenocytes of mock-immunized mice (p < 0.05). Thus, our study demonstrated the expression of CCHFV nucleoprotein by a Sindbis virus vector and its immunogenicity in mice. The spectrum of cytokine production and antibody profile indicated predominantly Th1-type of an anti-CCHFV immune response. Further studies in CCHFV-susceptible animals are necessary to determine whether the induced immune response is protective.

Crimean-Congo hemorrhagic fever virus delays activation of the innate immune response

2008 ◽  
Vol 80 (8) ◽  
pp. 1397-1404 ◽  
Author(s):  
Ida Andersson ◽  
Helen Karlberg ◽  
Mehrdad Mousavi-Jazi ◽  
Luis Martínez-Sobrido ◽  
Friedemann Weber ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Hemorrhagic Fever ◽  
Innate Immune ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

scholarly journals Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Jorma Hinkula ◽  
Stéphanie Devignot ◽  
Sara Åkerström ◽  
Helen Karlberg ◽  
Eva Wattrang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Vaccine Candidates ◽  
Th1 Response ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR−/−) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is responsible for hemorrhagic diseases in humans, with a high mortality rate. There is no FDA-approved vaccine, and there are still gaps in our knowledge of the immune responses to infection. The recently developed mouse models mimic human CCHF disease and are useful to study the immunogenicity and the protection by vaccine candidates. Our study shows that mice vaccinated with a specific DNA vaccine were fully protected. Importantly, we show that neutralizing antibodies are not sufficient for protection against CCHFV challenge but that an extra Th1-specific cellular response is required. Moreover, we describe the identification of five conserved B-cell epitopes, of which only one was previously known, that could be of great importance for the development of diagnostics tools and the improvement of vaccine candidates.

scholarly journals Worldwide epidemiology of Crimean-Congo Hemorrhagic Fever Virus in humans, ticks and other animal species, a systematic review and meta-analysis

2021 ◽  
Vol 15 (4) ◽  
pp. e0009299
Author(s):  
Jean Thierry Ebogo Belobo ◽  
Sebastien Kenmoe ◽  
Cyprien Kengne-Nde ◽  
Cynthia Paola Demeni Emoh ◽  
Arnol Bowo-Ngandji ◽  
...  
Keyword(s):  
Systematic Review ◽  
Low Income ◽  
Animal Species ◽  
Meta Analysis ◽  
Random Effect ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

There are uncertainties about the global epidemiological data of infections due to Crimean-Congo hemorrhagic fever virus (CCHFV). We estimated the global case fatality rate (CFR) of CCHFV infections and the prevalence of CCHFV in humans, ticks and other animal species. We also explored the socio-demographic and clinical factors that influence these parameters. In this systematic review with meta–analyses we searched publications from database inception to 03rd February 2020 in Pubmed, Scopus, and Global Index Medicus. Studies included in this review provided cross-sectional data on the CFR and/or prevalence of one or more targets used for the detection of CCHFV. Two independent investigators selected studies to be included. Data extraction and risk of bias assessment were conducted independently by all authors. Data collected were analysed using a random effect meta-analysis. In all, 2345 records were found and a total of 312 articles (802 prevalence and/or CFR data) that met the inclusion criteria were retained. The overall CFR was 11.7% (95% CI = 9.1–14.5), 8.0% (95% CI = 1.0–18.9), and 4.7% (95% CI = 0.0–37.6) in humans with acute, recent, and past CCHFV infections respectively. The overall CCHFV acute infections prevalence was 22.5% (95% CI = 15.7–30.1) in humans, 2.1% (95% CI = 1.3–2.9) in ticks, and 4.5% (95% CI = 1.9–7.9) in other animal species. The overall CCHFV recent infections seroprevalence was 11.6% (95% CI = 7.9–16.4) in humans and 0.4% (95% CI = 0.0–2.9) in other animal species. The overall CCHFV past infections seroprevalence was 4.3% (95% CI = 3.3–5.4) in humans and 12.0% (95% CI = 9.9–14.3) in other animal species. CFR was higher in low-income countries, countries in the WHO African, South-East Asia and Eastern Mediterranean regions, in adult and ambulatory patients. CCHFV detection rate in humans were higher in CCHFV suspected cases, healthcare workers, adult and hospitalized patients, ticks of the genus Ornithodoros and Amblyomma and in animals of the orders Perissodactyla and Bucerotiformes. This review highlights a significant disease burden due to CCHFV with a strong disparity according to country income levels, geographic regions, various human categories and tick and other animal species. Preventive measures in the light of these findings are expected.

scholarly journals Crimean–Congo Hemorrhagic Fever Virus Past Infections Are Associated with Two Innate Immune Response Candidate Genes in Dromedaries

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Sara Lado ◽  
Jan Futas ◽  
Martin Plasil ◽  
Tom Loney ◽  
Pia Weidinger ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Linear Regression Analysis ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Immune Defense ◽  
Innate Immune ◽  
Fever Virus ◽  
Future Research ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

Dromedaries are an important livestock, used as beasts of burden and for meat and milk production. However, they can act as an intermediate source or vector for transmitting zoonotic viruses to humans, such as the Middle East respiratory syndrome coronavirus (MERS-CoV) or Crimean–Congo hemorrhagic fever virus (CCHFV). After several outbreaks of CCHFV in the Arabian Peninsula, recent studies have demonstrated that CCHFV is endemic in dromedaries and camel ticks in the United Arab Emirates (UAE). There is no apparent disease in dromedaries after the bite of infected ticks; in contrast, fever, myalgia, lymphadenopathy, and petechial hemorrhaging are common symptoms in humans, with a case fatality ratio of up to 40%. We used the in-solution hybridization capture of 100 annotated immune genes to genotype 121 dromedaries from the UAE tested for seropositivity to CCHFV. Through univariate linear regression analysis, we identified two candidate genes belonging to the innate immune system: FCAR and CLEC2B. These genes have important functions in the host defense against viral infections and in stimulating natural killer cells, respectively. This study opens doors for future research into immune defense mechanisms in an enzootic host against an important zoonotic disease.

Healthy individuals’ immune response to the Bulgarian Crimean-Congo hemorrhagic fever virus vaccine

Vaccine ◽  
2012 ◽  
Vol 30 (44) ◽  
pp. 6225-6229 ◽  
Author(s):  
Mehrdad Mousavi-Jazi ◽  
Helen Karlberg ◽  
Anna Papa ◽  
Iva Christova ◽  
Ali Mirazimi
Keyword(s):  
Immune Response ◽  
Virus Vaccine ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Healthy Individuals ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

scholarly journals Crimean-Congo Hemorrhagic Fever Virus (CCHFV): A Silent but Widespread Threat

2021 ◽  
Author(s):  
Paul A. Kuehnert ◽  
Christopher P. Stefan ◽  
Catherine V. Badger ◽  
Keersten M. Ricks
Keyword(s):  
One Health ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Virus Vector ◽  
Disease Spread ◽  
Fatality Rate ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
High Fatality Rate ◽  
Endemic Areas

Abstract Purpose of Review This review is aimed at highlighting recent research and articles on the complicated relationship between virus, vector, and host and how biosurveillance at each level informs disease spread and risk. Recent Findings While human cases of CCHFV and tick identification in non-endemic areas in 2019–2020 were reported to sites such as ProMed, there is a gap in recent published literature on these and broader CCHFV surveillance efforts from the late 2010s. Summary A review of the complex aspects of CCHFV maintenance in the environment coupled with high fatality rate and lack of vaccines and therapeutics warrants the need for a One-Health approach toward detection and increased biosurveillance programs for CCHFV.

scholarly journals Immunocompetent mouse model for Crimean-Congo hemorrhagic fever virus

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
David W Hawman ◽  
Kimberly Meade-White ◽  
Shanna Leventhal ◽  
Friederike Feldmann ◽  
Atsushi Okumura ◽  
...  
Keyword(s):  
Mouse Model ◽  
Severe Disease ◽  
Case Fatality ◽  
Febrile Illness ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Type I ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Viral Determinants

Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne febrile illness with wide geographic distribution. CCHF is caused by infection with the Crimean-Congo hemorrhagic fever virus (CCHFV) and case fatality rates can be as high as 30%. Despite causing severe disease in humans, our understanding of the host and viral determinants of CCHFV pathogenesis are limited. A major limitation in the investigation of CCHF has been the lack of suitable small animal models. Wild-type mice are resistant to clinical isolates of CCHFV and consequently, mice must be deficient in type I interferon responses to study the more severe aspects of CCHFV. We report here a mouse-adapted variant of CCHFV that recapitulates in adult, immunocompetent mice the severe CCHF observed in humans. This mouse-adapted variant of CCHFV significantly improves our ability to study host and viral determinants of CCHFV-induced disease in a highly tractable mouse model.

scholarly journals Crimean-Congo Hemorrhagic Fever Virus-Encoded Ovarian Tumor Protease Activity Is Dispensable for Virus RNA Polymerase Function

2009 ◽  
Vol 84 (1) ◽  
pp. 216-226 ◽  
Author(s):  
Éric Bergeron ◽  
César G. Albariño ◽  
Marina L. Khristova ◽  
Stuart T. Nichol
Keyword(s):  
Protease Activity ◽  
Ovarian Tumor ◽  
Antiviral Drug ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
L Protein ◽  
Hemorrhagic Fever Virus ◽  
Virus Rna ◽  
N Terminus

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus (genus Nairovirus, family Bunyaviridae) associated with high case fatality disease outbreaks in regions of Africa, Europe, and Asia. The CCHFV genome consists of three negative-strand RNA segments, S, M, and L. The unusually large virus L polymerase protein and the need for biosafety level 4 (BSL-4) containment conditions for work with infectious virus have hampered the study of CCHFV replication. The L protein has an ovarian tumor (OTU) protease domain located in the N terminus, which has led to speculation that the protein may be autoproteolytically cleaved to generate the active virus L polymerase and additional functions. We report the successful development of efficient CCHFV helper virus-independent S, M, and L segment minigenome systems for analysis of virus RNA and protein features involved in replication. The virus RNA segment S, M, and L untranslated regions were found to be similar in support of replication of the respective minigenomes. In addition, the OTU domain located in the N terminus of the expressed virus L protein was shown to be a functional protease. However, no evidence of L protein autoproteolytic processing was found, and the OTU protease activity was dispensable for virus RNA replication. Finally, physiologically relevant doses of ribavirin inhibited CCHFV minigenome replication. These results demonstrated the utility of the minigenome system for use in BSL-2 laboratory settings to analyze CCHFV biology and in antiviral drug discovery programs for this important public health and bioterrorism threat.

scholarly journals Immunocompetent Mouse Model for Crimean-Congo Hemorrhagic Fever Virus

2020 ◽  
Author(s):  
David W. Hawman ◽  
Kimberly Meade-White ◽  
Shanna Leventhal ◽  
Friederike Feldmann ◽  
Atsushi Okumura ◽  
...  
Keyword(s):  
Mouse Model ◽  
Severe Disease ◽  
Case Fatality ◽  
Febrile Illness ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Type I ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Viral Determinants

AbstractCrimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne febrile illness with wide geographic distribution. CCHF is caused by infection with the Crimean-Congo hemorrhagic fever virus (CCHFV) and case fatality rates can be as high as 30%. Despite causing severe disease in humans, our understanding of the host and viral determinants of CCHFV pathogenesis are limited. A major limitation in the investigation of CCHF has been the lack of suitable small animal models. Wild-type mice are resistant to clinical isolates of CCHFV and consequently, mice must be deficient in type I interferon responses to study the more severe aspects of CCHFV. We report here a mouse-adapted variant of CCHFV that recapitulates in adult, immunocompetent mice the severe CCHF observed in humans. This mouse-adapted variant of CCHFV significantly improves our ability to study host and viral determinants of CCHFV-induced disease in a highly tractable mouse model.

scholarly journals Nucleoside-modified mRNA vaccines protect IFNAR -/- mice against Crimean Congo hemorrhagic fever virus infection

2021 ◽  
Author(s):  
Sofia Appelberg ◽  
Lijo John ◽  
Norbert Pardi ◽  
Ákos Végvári ◽  
Sándor Bereczky ◽  
...  
Keyword(s):  
Immune Response ◽  
Global Health ◽  
Immune Responses ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Fatality Rate ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
High Fatality Rate ◽  
The World

Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is on the World Health Organizations’ list of prioritized diseases and pathogens. With global distribution, high fatality rate and no approved vaccine or effective treatment, CCHF constitutes a threat against global health. In the current study, we demonstrate that vaccination with nucleoside-modified mRNA-lipid nanoparticles (mRNA-LNP), encoding for the CCHFV nucleoprotein (N) or glycoproteins (GcGn) protect IFNAR -/- mice against lethal CCHFV infection. In addition, we found that both mRNA-LNP induced strong humoral and cellular immune responses in IFNAR -/- and immunocompetent mice and that neutralizing antibodies are not necessary for protection. When evaluating immune responses induced by immunization including CCHFV Gc and Gn antigens, we found the Gc protein to be more immunogenic compared to the Gn protein. Hepatic injury is prevalent in CCHF and contributes to the severity and mortality of the disease in humans. Thus, to understand the immune response in the liver after infection and the potential effect of the vaccine, we performed a proteomic analysis on liver samples from vaccinated and control mice after CCHFV infection. Similar to observations in humans, vaccination affected the metabolic pathways. In conclusion, this study shows that a CCHFV mRNA-LNP vaccine, based on viral nucleo- or glycoproteins, mediate protection against CCHFV induced disease. Consequently, genetic immunization is an attractive approach to prevent disease caused by CCHFV and we believe we have necessary evidence to bring this vaccine platform to the next step in the development of a vaccine against CCHFV infection. Importance Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic pathogen causing Crimean-Congo hemorrhagic fever (CCHF), a severe fever disease. CCHFV have a wide distribution and are endemic in several areas around the world. Cases of CCHF are also being reported in new areas, indicating an expansion of the disease, which is of high concern. Dispersion of the disease, high fatality rate and no approved vaccine makes CCHF a threat to global health. The development of a vaccine is thus of great importance. Here we show 100% protection against lethal CCHFV infection in mice immunized with mRNA-LNP encoding for different CCHFV proteins. The vaccination showed both robust humoral and cellular immunity. mRNA-LNP vaccines combine the ability to induce an effective immune response, the safety of a transient carrier and the flexibility of genetic vaccines. This and our results from the current study support the development of a mRNA-LNP based vaccine against CCHFV.

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