Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.

Crimean-Congo Hemorrhagic Fever Virus for Clinicians-Epidemiology, Clinical Manifestations, and Prevention.

Crimean-Congo hemorrhagic fever (CCHF) is a tickborne infection that can range from asymptomatic to fatal and has been described in >30 countries. Early identification and isolation of patients with suspected or confirmed CCHF and the use of appropriate prevention and control measures are essential for preventing human-to-human transmission. Here, we provide an overview of the epidemiology, clinical features, and prevention and control of CCHF. CCHF poses a continued public health threat given its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, and potential for severe and fatal illness, in addition to the limited medical countermeasures for prophylaxis and treatment. A high index of suspicion, comprehensive travel and epidemiologic history, and clinical evaluation are essential for prompt diagnosis. Infection control measures can be effective in reducing the risk for transmission but require correct and consistent application.

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

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.

In silico formulation of a next-generation multiepitope vaccine for use as a prophylactic candidate against Crimean-Congo hemorrhagic fever.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease transmitted to humans and livestock animals through the bite of infected ticks or close contact with infected persons' blood, organs, or other bodily fluids. The virus is responsible for severe viral hemorrhagic fever outbreaks, with a case fatality rate of up to 40%. Despite having the highest fatality rate of the virus, a suitable treatment option or vaccination has not been developed yet. Therefore, this study aimed to formulate a multiepitope vaccine against CCHF through computational vaccine design approaches. METHODS: The glycoprotein, nucleoprotein, and RNA-dependent RNA polymerase of CCHF were utilized to determine immunodominant T- and B-cell epitopes. Subsequently, an integrative computational vaccinology approach was used to formulate a multi-epitopes vaccine candidate against the virus. RESULTS: After rigorous assessment, a multiepitope vaccine was constructed, which was antigenic, immunogenic, and non-allergenic with desired physicochemical properties. Molecular dynamics (MD) simulations of the vaccine-receptor complex show strong stability of the vaccine candidates to the targeted immune receptor. Additionally, the immune simulation of the vaccine candidates found that the vaccine could trigger real-life-like immune responses upon administration to humans. CONCLUSIONS: Finally, we concluded that the formulated multiepitope vaccine candidates would provide excellent prophylactic properties against CCHF.

Nucleoside-Modified mRNA Vaccines Protect IFNAR-/- Mice against Crimean-Congo Hemorrhagic Fever Virus Infection.

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 with 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 has a wide distribution and is 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.

Crimean-Congo hemorrhagic fever: Immunopathogenesis and recent advances in the development of vaccines.

Crimean-Congo hemorrhagic fever is a serious vector-borne zoonotic viral infection which leads to severe illness and fatalities in people living in endemic regions and becoming infected sporadically. Hyalomma ticks are responsible for the transmission of the virus which belongs to the family Nairoviridae. This disease spreads through ticks bite, infected tissues, or blood of viremic animals, and from infected humans to others. Serological studies also indicate the presence of the virus in various domestic and wild animals to be a risk factor for the transmission of the disease. Crimean-Congo hemorrhagic fever virus elicits many immune responses during the infection including inflammatory, innate, and adaptive immune responses. The development of an effective vaccine could be a promising method for the control and prevention of disease in endemic areas. The purpose of this review is to highlight the importance of CCHF, its mode of transmission, the interaction of the virus with the hosts and ticks, immunopathogenesis, and advances in immunization.

Recent advances in treatment Crimean-Congo hemorrhagic fever virus: A concise overview.

The Crimean Congo Hemorrhagic Fever Virus (CCHFV) is widespread in Africa, Asia, and Europe, among other places. The disease was initially discovered in the Crimean cities of the Soviet Union and the Congo, and it was given the name Crimean Congo because it induces hemorrhagic fever. According to studies, when the virus enters the body, it settles in immune cells such as macrophages and dendritic cells, causing them to malfunction and secrete inflammatory cytokines such as TNF-alpha, IL1, and IL6, resulting in cytokine storms that induces shock via endothelial activation and vascular leakage, while on the other hand, clots and disseminated intravascular coagulation (DIC) formation causes massive defects in various organs such as the liver and kidneys, as well as fatal bleeding. Disease prevention and treatment are crucial since no other effective vaccination against the disease has yet been developed. Immunotherapy is utilized as a consequence. One of the most effective treatments, when combined with compensatory therapies such as blood and platelet replacement, water, electrolytes, Fresh Frozen Plasma (FFP) replacement, and other compensatory therapies, is one of the most effective treatments. Studies; show that immunotherapy using IVIG and neutralizing and non-neutralizing monoclonal antibodies; cytokine therapy, and anti-inflammatory therapy using corticosteroids are effective ways to treat the disease.

Health beliefs and behaviors of livestock industry workers regarding Crimean-Congo hemorrhagic fever in Northwest of Iran.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is an acute, feverous disease that is caused by tick bites or humans' direct contact with the blood and tissues of infected livestock and humans. The transmission of the disease is also possible via human-to-human contacts and nosocomial transmission is well described. The majority of patients suffering from this disease are slaughterhouse workers (including butchers), farmers, veterinarians and hospital staff. Thus, this study aimed to investigate the health behaviors of butchers regarding CCHF and study factors affecting such behaviors based on the health belief model. METHODS: This is a descriptive cross-sectional study conducted on 500 butchers in Ardabil Province in 2020 by a multistage sampling method. The participants of the study completed the researcher-made questionnaire of health belief model and health behaviors model relevant to CCHF. The collected data were then analyzed by descriptive statistical tests and linear regression analysis. RESULTS: The mean (SD) age of the participants was 44.4 (10.5) years, and 96% were males. Only 11.1% of the participants displayed acceptable disease-preventive behaviors. The validity and reliability of the developed questionnaire were confirmed. The results of the exploratory factor analysis showed that the constructs of the model explained 84% of the total variance. The results of the study revealed that among the variables of the health belief model, perceived susceptibility (p-value = 0.006, ß = 0.152) and perceived barriers (p-value = 0.023, ß = 0.14) were the strongest factors predicting disease-preventive behaviors regarding CCHF. CONCLUSION: The results of the study showed that the health belief model can predict preventive behaviors for CCHF. Therefore, designing and executing interventions based on the results of this study may encourage such preventive behaviors in butchers.

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of the most widespread tick-borne viral infection in humans. CCHFV encodes a secreted glycoprotein (GP38) of unknown function that is the target of a protective antibody. Here, we present the crystal structure of GP38 at a resolution of 2.5 Å, which revealed a novel fold primarily consisting of a 3-helix bundle and a ß-sandwich. Sequence alignment and homology modeling showed distant homology between GP38 and the ectodomain of Gn (a structural glycoprotein in CCHFV), suggestive of a gene duplication event. Analysis of convalescent-phase sera showed high titers of GP38 antibodies indicating immunogenicity in humans during natural CCHFV infection. The only protective antibody for CCHFV in an adult mouse model reported to date, 13G8, bound GP38 with subnanomolar affinity and protected against heterologous CCHFV challenge in a STAT1-knockout mouse model. Our data strongly suggest that GP38 should be evaluated as a vaccine antigen and that its structure provides a foundation to investigate functions of this protein in the viral life cycle.IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen that poses a high risk to public health. Due to the high morbidity and mortality rates associated with CCHFV infection, there is an urgent need to develop medical countermeasures for disease prevention and treatment. CCHFV GP38, a secreted glycoprotein of unknown function unique to the Nairoviridae family, was recently shown to be the target of a protective antibody against CCHFV. Here, we present the crystal structure of GP38, which revealed a novel fold with distant homology to another CCHFV glycoprotein that is suggestive of a gene duplication event. We also demonstrate that antibody 13G8 protects STAT1-knockout mice against heterologous CCHFV challenge using a clinical isolate from regions where CCHFV is endemic. Collectively, these data advance our understanding of GP38 structure and antigenicity and should facilitate future studies investigating its function.

Crimean Congo hemorrhagic fever serosurvey in humans for identifying high-risk populations and high-risk areas in the endemic state of Gujarat, India.

BACKGROUND: Crimean Congo Hemorrhagic Fever (CCHF) is a highly infectious zoonotic disease of humans transmitted by Hyalomma ticks. Earlier studies have shown CCHF seroprevalence in livestock throughout India, yet sporadic outbreaks have been recorded mostly from the Gujarat state of India since 2011. Occupational vulnerability to CCHF for animal handlers, veterinarians, abattoir workers, and healthcare workers has been documented. The current study was planned to determine the seroprevalence of CCHF with an intention to identify the high -risk population and high -risk areas from Gujarat state, India. METHODS: Based on the socio-clinical data, the human population of Gujarat was divided into eight categories viz. A: CCHF affected person/house/close contact, B: Neighborhood contacts, C: Animal handlers, D: General population, E: Farmers, F: Abattoir workers, G: Veterinarian, H: Healthcare workers. A total of 4978 human serum samples were collected from 33 districts of Gujarat during year 2015, 2016 and 2017. All the samples were screened for the presence of anti-CCHFV IgG using indigenously developed anti-CCHFV IgG ELISA. Univariate regression analysis was performed to recognize significant risk factors for CCHF seropositivity. RESULTS: Twenty-five serum samples were found to be positive with an overall CCHF human seropositivity of 0.5% (95% CI 0.30-0.74%). Gender predisposition to CCHF prevalence was observed in males (OR: 2.80; p-value: 0.020). The risk for seropositivity increased sevenfold when a person was in contact or neighbor with a CCHF case (OR 7.02; p-value: < 0.0001). No significant difference in seropositivity was observed within different age groups. Veterinarians, healthcare workers, and control group were found to be seronegative for CCHF. CONCLUSIONS: In-spite of CCHF sporadic outbreaks reported in Gujarat, the seropositivity for CCHF in the state was low as compared to other endemic countries. Males, close contacts and neighbors were identified as a high-risk population for CCHF infection. To recognize the high-risk area, tick screening and animal serosurvey would be a wiser choice. The study also suggests circulation and under diagnoses of CCHFV in the naïve regions of Gujarat.

Towards the first multi-epitope recombinant vaccine against Crimean-Congo hemorrhagic fever virus: A computer-aided vaccine design approach.

Crimean-Congo hemorrhagic fever (CCHF) is considered one of the major public health concerns with case fatality rates of up to 80%. Currently, there is no effective approved vaccine for CCHF. In this study, we used a computer-aided vaccine design approach to develop the first multi-epitope recombinant vaccine for CCHF. For this purpose, linear B-cell and T-cell binding epitopes from two structural glycoproteins of CCHF virus including Gc and Gn were predicted. The epitopes were further studied regarding their antigenicity, allergenicity, hydrophobicity, stability, toxicity and population coverage. A total number of seven epitopes including five T-cell and two B-cell epitopes were screened for the final vaccine construct. Final vaccine construct composed of 382 amino acid residues which were organized in four domains including linear B-cell, T-cell epitopes and cholera toxin B-subunit (CTxB) along with heat labile enterotoxin IIc B subunit (LT-IIc) as adjuvants. All the segments were joined using appropriate linkers. The physicochemical properties as well as the presence of IFN-γ inducing epitopes in the proposed vaccine, was also checked to determining the vaccine stability, solubility and its ability to induce cell-mediated immune responses. The 3D structure of proposed vaccine was subjected to the prediction of computational B-cell epitopes and molecular docking studies with MHC-I and II molecules. Furthermore, molecular dynamics stimulations were performed to study the vaccine-MHCs complexes stability during stimulation time. The results suggest that our proposed vaccine was stable, well soluble in water and potentially antigenic. Results also demonstrated that the vaccine can induce both humoral and cell-mediated immune responses and could serve as a promising anti-CCHF vaccine candidate.

Repellency effect of flumethrin pour-on formulation against vectors of Crimean-Congo haemorrhagic fever.

BACKGROUND: Ticks are able to transmit important diseases to humans, including Rocky Mountain spotted fever, Q fever, Crimean-Congo haemorrhagic fever, summer Russian encephalitis, and relapsing fever. AIMS: To determine the repellency effect of 1% flumethrin pour-on formulation against hard ticks. METHODS: The concentration of flumethrin pour-on formulation was 1 mg/10 kg body weight and was administered on the dorsal midline from the head to the base of the tail. The livestock included cows, goats, oxen and sheep in 2 villages in Ardabil Province, Islamic Republic of Iran. RESULTS: We studied 200 livestock comprising 5 age groups (< 2, 3-4, 5-6, 7-8 and >8 years). The main hard ticks identified were Hyalomma species (62.5%) and Rhipicephalus bursa (37.5%). In the treatment village, the maximum number of ticks per animal was 11.6 in oxen, 9.5 in sheep, 8.9 in goats and 8.6 in cattle. The repellency effect of flumethrin remained for 2 months. CONCLUSIONS: Flumethrin provided 2 months protection against hard ticks. Therefore, it could be used in the livestock industry. Control of ticks is important for prevention of disease transmission.

Crimean-Congo Hemorrhagic Fever (CCHF) in Pakistan: The "Bell" is Ringing Silently.

Pakistan is being hit by communicable and noncommunicable diseases over time. Among these, tickborne viral disease, Crimean-Congo hemorrhagic fever (CCHF) is one of the most fatal infections. Rapid climate change aroused by industrial, occupational, and agricultural activities to support ever-growing human population has been considered the single most causative basis for emergence or re-emergence of CCHF in Pakistan, where it has biannual peaks between the months of March-May and August-October. Many factors, including poor sanitation at farms, villages, and cities, unhygienic transportation and slaughter of animals at numerous sites within a city, inefficient tick-control programs, post-slaughter piles of animal remains other than meat, nomadic lifestyle, and lack of trained animal and human healthcare staff, are contributing to the spread of CCHF. Pakistan has confirmed cases of CCHF in almost every province: Sindh (Karachi), Punjab (Faisalabad, Multan, and Rawalpindi), Balochistan (Quetta) and Khyber Pakhtunkhwa (Peshawar). The root cause behind the spread of CCHF in Pakistan seems to be the absence of an effective disease surveillance system in the human as well as the animal populations. Most of the time, CCHF cases are not diagnosed, and if they are diagnosed they are not reported. If these cases are reported, there are not enough effective measures by the relevant provincial and district authorities. There is a need to educate the general public, farmers, and healthcare workers about the causes, transmission, and dangers of CCHF. An immediate plan for the implementation of a surveillance system, standard preventive measures, early detection, proper treatment, and timely response is urgently needed. Without such a plan, the accumulation of factors responsible for the sudden outbreak of CCHF may pose a serious threat to humans and animals in different geographical regions of the country.

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.

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.

Global research trends of World Health Organization's top eight emerging pathogens.

BACKGROUND: On December 8th, 2015, World Health Organization published a priority list of eight pathogens expected to cause severe outbreaks in the near future. To better understand global research trends and characteristics of publications on these emerging pathogens, we carried out this bibliometric study hoping to contribute to global awareness and preparedness toward this topic. METHOD: Scopus database was searched for the following pathogens/infectious diseases: Ebola, Marburg, Lassa, Rift valley, Crimean-Congo, Nipah, Middle Eastern Respiratory Syndrome (MERS), and Severe Respiratory Acute Syndrome (SARS). Retrieved articles were analyzed to obtain standard bibliometric indicators. RESULTS: A total of 8619 journal articles were retrieved. Authors from 154 different countries contributed to publishing these articles. Two peaks of publications, an early one for SARS and a late one for Ebola, were observed. Retrieved articles received a total of 221,606 citations with a mean ± standard deviation of 25.7 ± 65.4 citations per article and an h-index of 173. International collaboration was as high as 86.9%. The Centers for Disease Control and Prevention had the highest share (344; 5.0%) followed by the University of Hong Kong with 305 (4.5%). The top leading journal was Journal of Virology with 572 (6.6%) articles while Feldmann, Heinz R. was the most productive researcher with 197 (2.3%) articles. China ranked first on SARS, Turkey ranked first on Crimean-Congo fever, while the United States of America ranked first on the remaining six diseases. Of retrieved articles, 472 (5.5%) were on vaccine - related research with Ebola vaccine being most studied. CONCLUSION: Number of publications on studied pathogens showed sudden dramatic rise in the past two decades representing severe global outbreaks. Contribution of a large number of different countries and the relatively high h-index are indicative of how international collaboration can create common health agenda among distant different countries.

How to Tackle Natural Focal Infections: From Risk Assessment to Vaccination Strategies.

Natural focal diseases are caused by biological agents associated with specific landscapes. The natural focus of such diseases is defined as any natural ecosystem containing the pathogen's population as an essential component. In such context, the agent circulates independently on human presence, and humans may become accidentally infected through contact with vectors or reservoirs. Some viruses (i.e., tick-borne encephalitis and Congo-Crimean hemorrhagic fever virus) are paradigmatic examples of natural focal diseases. When environmental changes, increase of reservoir/vector populations, demographic pressure, and/or changes in human behavior occur, increased risk of exposure to the pathogen may lead to clusters of cases or even to larger outbreaks. Intervention is often not highly cost-effective, thus only a few examples of large-scale or even targeted vaccination campaigns are reported in the international literature. To develop intervention models, risk assessment through disease mapping is an essential component of the response against these neglected threats and key to the design of prevention strategies, especially when effective vaccines against the disease are available.

Vector prevalence and detection of Crimean-Congo haemorrhagic fever virus in Golestan Province, Iran.

BACKGROUND & OBJECTIVES: Crimean-Congo haemorrhagic fever virus (CCHFV) causes severe disease with fatality rate of 30%. The virus is transmitted to humans through the bite of an infected tick, direct contact with the products of infected livestock as well as nosocomially. The disease occurs sporadically throughout many of African, Asian and European countries. Different species of ticks serve either as vector or reservoir for CCHFV. This study was aimed to determine the prevalence of CCHFV in hard ticks (Ixodidae) in the Golestan Province of Iran. METHODS: A molecular survey was conducted on hard ticks (Ixodidae) isolated from six counties in Golestan Province, north of Iran during 2014-15. The ticks were identified using morphological characteristics and presence of CCHFV RNA was detected using RT-PCR. RESULTS: Data revealed the presence of CCHFV in 5.3% of the ticks selected for screening. The infected ticks belonged to Hyalomma dromedarii, Hy. anatolicum, Hy. marginatum and Rhipicephalus sanguineus species. INTERPRETATION & CONCLUSION: The study demonstrated that Hyalomma ticks are the main vectors of CCHFV in Golestan Province. Thus, preventive strategies such as using acaricides and repellents in order to avoid contact with Hyalomma ticks are proposed.

Biosafety standards for working with Crimean-Congo hemorrhagic fever virus.

In countries from which Crimean-Congo haemorrhagic fever (CCHF) is absent, the causative virus, CCHF virus (CCHFV), is classified as a hazard group 4 agent and handled in containment level (CL)-4. In contrast, most endemic countries out of necessity have had to perform diagnostic tests under biosafety level (BSL)-2 or -3 conditions. In particular, Turkey and several of the Balkan countries have safely processed more than 100 000 samples over many years in BSL-2 laboratories. It is therefore advocated that biosafety requirements for CCHF diagnostic procedures should be revised, to allow the tests required to be performed under enhanced BSL-2 conditions with appropriate biosafety laboratory equipment and personal protective equipment used according to standardized protocols in the countries affected. Downgrading of CCHFV research work from CL-4, BSL-4 to CL-3, BSL-3 should also be considered.

Identifying main drivers and testing control strategies for CCHFV spread.

Crimean Congo Haemorrhagic Fever (CCHF) is an emerging zoonotic disease. The causative agent is a virus (CCHFV), mainly transmitted by ticks of the species Hyalomma marginatum in Eastern Europe and Turkey. In order to test potential scenarios for the control of pathogen spread, the basic reproduction number (R0) for CCHF was calculated. This calculation was based on a population dynamics model and parameter values from the literature for pathogen transmission. The tick population dynamics model takes into account the major processes involved and gives estimates for tick survival from one stage to the other and number of feeding ticks. It also considers the influence of abiotic (meteorological variables) and biotic factors (host densities) on model outputs, which were compared with data collected in Central Anatolia (Turkey). R0 computation was thereafter used to test control strategies and especially the effect of acaricide treatment. Simulation results indicate that such treatments could have valuable effects provided that the acaricide is applied regularly throughout the spring and summer, and over several years. Furthermore, a sensitivity analysis to abiotic and biotic factors showed that, even though temperature has a strong impact on model outputs, host (mainly hare) densities also play a role. The kind of model we have developed provides insight into the ability of different strategies to prevent and control disease spread and has proved its relevance when associated with field trials.

Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF), caused by infection with CCHF virus (CCHFV), is viral hemorrhagic fever with high case fatality rate. CCHFV is classified to Family Bunyaviridae, Genus Nairovirus. CCHF is endemic to Africa, Eastern Europe, the Middle East, central Asia, and southern Asia. CCHFV is maintained in nature in several spe- cies of ticks (Hyalomma and Ixodes species) and mammals. Humans are infected with CCHFV by tick-bite or direct contact with viremic animals such as sheep. The CCHF-endemic re- gions are relatively economically disadvantaged areas, therefore CCHF is considered to be one of the neglected infectious diseases. The pathophysiology has not yet been clarified fully. It is necessary to clarify the pathophysiology of CCHF and to develop specific antiviral drug- based therapy and vaccines, which might be effective in confering protection against CCHFV infections in the near future, because CCHF outbreaks continue to occur in the endemic re- gions.