Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  There are some commercial ELISA tests available (antigen multiple species and Cow IgG) for use in animals.

  List of commercially available diagnostics (Diagnostics for Animals).

  In humans, several commercial ELISA kits (IgG and IgM), IFA’s and real time PCRs are available.

  There are numerous “In house” real time PCR and serological assays that have been published by dedicated CCHFV and/or bunyavirus research laboratories. Not validated commercially.

  GAPS :

  Antibody detection detects evidence of exposure (not necessarily current infection unless an IgM test is used).

  Although various commercial detection systems are commercially available for CCHF virus genomes as well as for the detection of IgG and IgM antibodies, there are still no reliable comparative data on their diagnostic sensitivity and specificity. This is mainly due to the lack of internationally recognized standards for CCHFV diagnostics, i.e. antibodies and virus containing inactivated samples.

  These missing standards should not only cover the usual laboratory strains but also the genetic variety of orthonairoviruses, so that it becomes evident to what extent both molecular and serological assays are suitable for all infections with representatives of this diverse group of viruses.

  Another gap is that no rapid tests are yet available as bed-side or pen-side tests with which suspected cases can be easily confirmed. The development of such assays has so far failed due to the comparatively low virus concentrations in body fluids and swab samples, meaning that negative results are of little diagnostic value.

  The development of high-affinity molecular antibodies against the nucleoprotein as well as against other immunogenic virus proteins would also be particularly important for these purposes as well as for the development of serological assays.

  Little information is available about how quickly antibody levels drop, nor whether the antibodies are protective.

  Development of novel bio-safe neutralization assays.

  Extent of cross-reactivities of suspected animal sera with other related viruses should be more investigated.

  Valid In house diagnostic reagents from research laboratories might be available under MTA agreements. Promote licensing for industrial manufacturing.

• Diagnostic kits validated by International, European or National Standards

  None.

  GAPS :

  Validation of diagnostic kits according to approved/accepted standards.

• Diagnostic method(s) described by International, European or National standards

  Available methodology (some methods recommended by WOAH).

  GAPS :

  Pan PCR methods (for detection of all geographical CCHFV clades).

• Commercial potential for diagnostic kits in Europe

  Yes for endemic and at risk regions/countries.

  GAPS :

  Commercial serological tests for humans and animals with increased sensitivity and specificity would be convenient.

• DIVA tests required and/or available

  Not available.

  GAPS :

  DIVA tests will be required as soon as any CCHFvaccine candidates are developed for animal (livestock) species.

• Vaccines availability

• Commercial vaccines availability (globally)

  No commercial vaccine is yet available for animals.For humans, a commercially available inactivated vaccine derived from mouse brain has been developed (BulBio-NCIP Ltd, strain V 42/81) and used in the former Soviet Union and Bulgaria (not FDA or EMA approved).

  GAPS :

  Development of a safe and effective vaccine for human use has a high priority (WHO blueprint R&D).Animal vaccine research to break the virus cycle in nature (anti -tick vector vaccine, ATV).Animal vaccine against CCHF and other more prevalent disease (polyvalent vaccine strategy).

• Marker vaccines available worldwide

  None.

  GAPS :

  Several vaccine platforms could provide marker features for vaccine improvement.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Few CCHF vaccines are in clinical phase I trials: MVA, ChAdOx and DNA based vaccines.All effective in preclinical models, inducing cellular and antibody responses.

  GAPS :

  Addressing optimal antigen combinations for stronger and durable immune responses.

• Commercial potential for vaccines in Europe

  Yes for humans.Possible for animal CCHF vaccines in endemic areas to control/limit the spread of the virus to humans.Yes for anti- tick vaccines.

  GAPS :

  Availability of valid animal models and safety facilities for testing.

• Regulatory and/or policy challenges to approval

  No major challenges in regulations foreseen.

• Commercial feasibility (e.g manufacturing)

  Only for current inactivated vaccines if granted approval from regulatory agencies (FDA or EMA).

  GAPS :

  Current inactivated vaccine needs more safety studies and improvement for FDA or EMA approval.

• Opportunity for barrier protection

  Several barriers for CCHFV spillover to humans identified at the ecological, epidemiological and biological levels.

  GAPS :

  More insights in the potential of a sustainable One Health approach to disease control.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None in animals as no evidence of clinical disease. The World Health Organization recommends ribavirin (RBV) as the anti-viral medication of choice for CCHF. However, there is no consensus on the role of specific antiviral therapy in the management of patients, with very limited evidence so far on its efficacy.

  GAPS :

  Development and or characterization of new antivirals should be prioritized. Continued debate on ribavirin efficacy.

• Future therapy

  Not applicable, not enough knowledge. Preclinical data on Favipiravir, alone or in combination with RBV. New antivirals and repurposed drugs proposed (Baloxavir, 2′-Deoxy-2′fluorocytidine, Tygecicline). Monoclonal antibodies (against NP, GPc and GP38) have some preclinical evidence.

  GAPS :

  Testing efficacy of novel monoclonal neutralizing antibodies as immunotherapeutic agents. Further data on RBV dosage and combination therapy of RBV and Favipiravir is required. Preclinical data is missing for 2′-Deoxy-2′fluorocytidine and clinical trials not yet performed for other treatments. Priority should be given to oral antivirals and mAbs.

• Commercial potential for pharmaceuticals in Europe

  Yes, for humans.With the relatively high number of cases each year in Turkiye and cases occurring in Spain, besides recent detection of infected ticks in some parts of France, the commercial potential of CCHF treatments should increase.

  GAPS :

  Explore the uses of anti-CCHFV drugs in animals Novel drug screening or repositioning. For use in animals in high prevalence areas.

• Regulatory and/or policy challenges to approval

  Not applicable or lack of regulations for applying novel anti-CCHFV pharmaceuticals in animals destined to human consumption.

  GAPS :

  Explore if the use of potential antiviral drugs in animals would be accepted.

• Commercial feasibility (e.g manufacturing)

  Yes for ribavirin and favipiravir.

  GAPS :

  Test if recombinant products expressing recombinant antibodies could be easily scalable.

• New developments for diagnostic tests

• Requirements for diagnostics development

  Diagnosis of suspected CCHF must be performed in specially equipped, bio-safety level 3 and 4 laboratories.In endemic countries diagnosis is made in BSL-3 facilities (BSL-2 in Turkiye), although virus culture is only performed at BSL-4 laboratories.

  GAPS :

  Provided the virus can be easily inactivated, it might be advisable to revise current biosafety requirements for CCHFV diagnosis. However, since consequences of eventual transmission are so bad, keeping some level of biosafety aspect around, even after inactivation, is recommended.Reassign or reconsider biosafety levels according on the type of work to be performed.

• Time to develop new or improved diagnostics

  Short, since currently there are good tools available for developing novel and biosafe diagnostics.

  GAPS :

  Developing more sensitive and biosafe diagnostic tools for CCHF virus.

• Cost of developing new or improved diagnostics and their validation

  Costly, and difficult in view of the need for biosafety requirements.

  GAPS :

  Establish a EU centralised supply of CCHF standards for validation of novel diagnostics.Design an EU reference laboratory for CCHF.

• Research requirements for new or improved diagnostics

  Approaches for diagnostic methods should be standardised and validated.Limited requirements for new diagnostics in animals.

  GAPS :

  Developing standards (serum and virus strain panels) for diagnostic validation.Establishing a European laboratory network with capacities to test performance of novel diagnostic developments.

• Technology to determine virus freedom in animals

  Monitoring the absolute number of virus genomic copies in tissues is now possible and affordable using technologies such as digital PCR.Virus isolation in cell culture in BSL-4 laboratory.Inoculation of samples in sensitive animal models (STAT-1KO; IFNARKO mice).

  GAPS :

  EU reference laboratory for CCHF.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  Animal models for CCHF infection are currently available but the biggest challenge is lack of good animal models. There is only one reliable animal model available (NHP), which put us in a difficult situation, as there are very few laboratories around the world who can do these experiments.A major hindrance in developing vaccines against CCHF virus is the wide genetic variation noted in different strains. Nucleic acid sequence analysis has demonstrated extensive genetic diversity, particularly between viruses from different geographic regions. However, genetic variation does not correlate with serotype variants, since currently, there is only one serotype for CCHFV.

  GAPS :

  There are needs to facilitate to get access to facility to perform the NHP experiments in most successful vaccine candidates (which are selected in mice models).More extensive preclinical trials to confirm whether/how genetic variation affects vaccine efficacy should be performed using currently available animal models.

• Time to develop new or improved vaccines

  2-6 years. The most successful and easy to produce are the genetic vaccines, such as mRNA and DNA vaccines with good preclinical data.

• Cost of developing new or improved vaccines and their validation

  10-30 million euro (ready to enter to Phase 3).

• Research requirements for new or improved vaccines

  Animal models to test efficacy of vaccine developments are available but located in very unique infrastructure in US and only one in Europe. Virus manipulation and growth needs to be performed in BSL4 laboratories.

  GAPS :

  Perform immunity/efficacy tests in enhanced BSL3Ag laboratories would facilitate more research towards vaccine development in animals.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  Currently available antiviral drugs of unknown efficacy.Antibodies, and novel antivirals such as favipiravir, other nucleoside analogs. Screening for antiviral compounds would be possible using surrogate, low pathogenic orthonairoviruses (i.e Hazara virus, AP92 Aigai strain etc).

  GAPS :

  Improved animal models. Testing with surrogate virus in adequate models would also speed up screening of novel compounds.A network for preclinical and clinical studies among endemic countries and academic institutions worldwide should speed-up development.

• Time to develop new or improved pharmaceuticals

  Unknown.

• Cost of developing new or improved pharmaceuticals and their validation

  Unknown but likely to be expensive.

• Research requirements for new or improved pharmaceuticals

  The development of novel prevention and therapeutic strategies for use in humans is important.Pharma companies with extensive antiviral drug portfolios look for high throughput systems.

  GAPS :

  More research on possible additional antiviral drug therapy.Plan randomised clinical trial to ascertain the benefits of ribavirin treatment in humans and combination with Favipiravir (phase Ib already started).Developing new treatment strategies (such as neutralizing Ab).More research on CCHFV pathogenesis to develop new therapeutic strategies. Use of large animal models.A high throughput drug screening system yet to be available in BSL-4 facilities.Establish a correlation between CCHFV GP pseudotyped viruses and drug efficacy (entry-inhibitors related) against CCHFV.

Disease details

• Description and characteristics

• Pathogen

  CCHF is a zoonotic viral disease that is asymptomatic in infected animals, but a serious threat to humans. The virus which causes CCHF is an arbovirus which is a member of the Orthonairoviridae family, in the Bunyavirales order.

  GAPS :

  The general knowledge of migration, epidemiology, re-assortment, recombination and pathogenesis of the virus is very limited.Knowledge about pathogenicity differences among strains is missing.

• Variability of the disease

  Based on geographical origin and phylogenetic analyses of the S gene segment, CCHFV has previously been classified into nine geographical clades – four in Africa, three in Europe, and two in Asia. CCHFV is transmitted by ticks from different genera (Hyalomma, Dermacentor, Rhipicephalus) and can infect several mammalian species (cattle, sheep, goats, hares, hedgehogs), causing disease only in man. The disease has a seasonal pattern, related to the increased activity of ticks, and peaks between spring and early autumn.

  GAPS :

  The knowledge on transmission from animal to human is limited (how long infected animals shed the virus, can domestic animals shed the virus in milk, infectious dose and so on).

• Stability of the agent/pathogen in the environment

  CCHFV is stable for up to 10 days in blood kept at 40°C (104°F).

• Species involved

• Animal infected/carrier/disease

  The CCHF virus may infect a wide range of domestic and wild animals but there is no evidence that the virus causes disease in animals. Many birds are resistant to infection, but ostriches are susceptible and may show a high prevalence of infection in endemic areas. CCHFV can be found in ostrich blood for 1 to 4 days and in visceral organs for up to five days after experimental infection.

  Experimental infection studies have been performed in a variety of wild and domestic animals. In small animals (hedgehog, hare, squirrel, mouse, rat) there are no clinical signs and short viremia depending of the route used (Intracranial, intrademal, intramuscular, intravenous, subcutaneous).

  Experimental infections have been performed in several livestock species, including ruminants (cattle, sheep) and equids (horses, donkeys). They develop a transient viremia and anti-CCHFV antibodies 1 week postinoculation.

  Additionally, maternal transfer of anti-CCHFV antibodies was demonstrated in sheep. Absence of clinical signs in the majority of animals tested, with the exception of sheep and horses where a mild fever was observed.

  GAPS :

  Prevalence needs to be measured in animals in endemic areas.Other livestock species to be experimentally tested for infectivity (i.e. suids, sheep, goats, poultry).

• Human infected/disease

  Up to date five members of the Orthonairovirus genus have been implicated as causes of human disease: the Dugbe. Kasokero Erve and Nairobi sheep disease viruses, and CCHFV, which is the most important human pathogen amongst them. Human beings are the only host of CCHFV in whom the disease manifestations are visible. Seroprevalence studies in endemic and non-endemic areas have been published.

  GAPS :

  Host and pathogen factors associated with severity and outcome of the disease have to be determined.

• Vector cyclical/non-cyclical

  Members of the orthonairovirus genus are transmitted by argasid or ixodid ticks. Once infected, the tick remains infected through its developmental stages. The mature tick may transmit the infection to large vertebrates, such as livestock.Population dynamics depends on climatic factors, ecologic changes and wildlife and human factors.Some studies on CCHFV molecular detection in ticks have been published.

  GAPS :

  The competence of other hard ticks genera for CCHFV replication should be studied.A standard programme should be planned to achieve knowledge of arthropod vector distribution and dynamics.Introduction of a standard programme to predict tick activities in European counties.Examination of vectors and reservoir hosts for the presence of CCHF virus by using standard, especially molecular diagnostic techniques.Areas of risk for the establishment of the vector, considering climatic and ecological conditions in Europe, need to be identified.Vector surveillance needs to be strengthened.Tick attachement time for efficient virus transmission to the host (animal/human).

• Reservoir (animal, environment)

  CCHF virus has been found in around 31 species of ticks in seven genera of the family Ixodidae (hard ticks) acting both as vector and reservoir for CCHFV. Ticks of the genus Hyalomma are particularly important to the ecology as they appear to be the most efficient and common vector for the virus. CCHFV has been isolated from a number of species including cattle, sheep, goats, hares, hedgehogs, dogs and mice. Antibodies have been reported in horses, donkeys, pigs, rhinoceroses, giraffes, buffalo and other mammalian species.The virus infection has been commonly demonstrated among smaller vertebrate wildlife such as hares and hedgehogs. They are believed to act as amplifying hosts and maintain the virus in nature and act as a source of the virus for the immature Hyalomma ticks which feed on them. In general adult ticks prefer cattle and immature ticks prefer scrub hares.

  GAPS :

  Tick competence studies in different species needs to be addressed to understand their role as virus reservoirs.

• Description of infection & disease in natural hosts

• Transmissibility

  Trans-ovarial, transstadial and venereal transmission have been demonstrated amongst some vector species, in particular the Hyalomma ticks. Many species of mammals can transmit CCHFV to ticks when they are viraemic.

  GAPS :

  Tick attachement time for efficient virus transmission to the host (animal/human).

• Pathogenic life cycle stages

  CCHFV usually circulates between asymptomatic animals and ticks in an enzootic cycle.

  GAPS :

  An understanding of the pathogenesis and cycle in animals would be of use. Especially the incubation time, length of the viraemic phase and the length of time after the initial infection and viraemic phase that infected animals would continue to be able to infect ticks. Once the viraemic phase is completed is there a low level of circulating virus in the blood which has the potential to infect feeding ticks or does the development of antibodies preclude any circulating virus?

• Signs/Morbidity

  There is no evidence that the virus causes disease in animals although a wide range of domestic and wild animals may become infected with CCHF virus. Sheep, goats and cattle develop high titers of virus in blood, but tend not to fall ill. Birds are generally resistant with the exception of ostriches.

  GAPS :

  Will the high titres developed reduce the levels of circulating virus resulting in the animals being less infectious to ticks?Why animals do not develop any sign of disease?

• Incubation period

  Mammals become viraemic and can transmit CCHFV in their blood and tissues. Domesticated ruminants including cattle, sheep and goats are viraemic for one week after experimental infection.

• Mortality

  None in animals: Large herbivores have the highest seroprevalence to CCHFV. Seroprevalence rates of 13–36% have been reported in some studies, while others suggest that more than 50% of adult livestock in endemic regions have antibodies. Animals carry CCHFV asymptomatically. Deaths occur only in newborn rodents.

  GAPS :

  Update seroprevalence studies in animals in European endemic and non-endemic regions.

• Shedding kinetic patterns

  Domestic ruminant animals, such as cattle, sheep and goats, are viraemic for around one week after becoming infected.

  GAPS :

  Studies to better understand and reveal the natural cycle of CCHF virus in animals, humans and vectors.Virus transmission between animals can occur in the absence of vector? Is there evidence for vertical virus transmission?

• Mechanism of pathogenicity

  Non-pathogenic in animals.

  GAPS :

  Research on CCHF pathogenesis and immune response in experimentally infected animals.

• Zoonotic potential

• Reported incidence in humans

  The disease occurs sporadically throughout much of Africa, Asia, and Europe and results in an approximately 30% fatality rate.

  GAPS :

  The exact incidence per endemic country is not known.

• Risk of occurence in humans, populations at risk, specific risk factors

  CCHFV poses a great threat to public health due to its high mortality rate in humans, its modes of transmission, and its large geographical distribution. Ticks are a major route for the transmission of the disease to humans either through bites or crushing an infected tick on the skin. Secondary cases are frequently seen due to human to human transmission via percutaneous or per mucosal exposure to blood and body fluids containing the virus. Others may acquire the virus from direct contact with blood or other infected tissues from livestock. Cases have occurred in those involved with the livestock industry, such as agricultural workers, slaughterhouse workers and veterinarians.

  GAPS :

  Models for predicting the risk of human CCHF cases should be developed and/or improved.

• Symptoms described in humans

  The incubation period in humans is 1-14 days depending on the route of transmission. Human infections begin with nonspecific febrile symptoms, but progress to a serious hemorrhagic syndrome with a high case fatality rate. After a short incubation period (1-14 days), the onset of symptoms is sudden, with fever, chills, myalgia (aching muscles), dizziness, neck pain and stiffness, backache, severe headache, sore eyes and photophobia and back and abdominal pains. There may be nausea, vomiting and sore throat early on, which may be accompanied by diarrhoea and generalised abdominal pain. Over the next few days, the patient may experience sharp mood swings, and may become confused and aggressive. After two to four days, the agitation may be replaced by sleepiness, depression and lassitude, and the abdominal pain may localize to the right upper quadrant, with detectable hepatomegaly (liver enlargement).

  Additional symptoms can include neuropsychiatric, and cardiovascular changes. In severe cases, hemorrhagic manifestations, ranging from petechiae to large areas of ecchymosis, develop.

  Few studies on immune response in CCHF have been published.

  GAPS :

  The knowledge is limited and further research on CCHF pathogenesis and immune response is necessary.

• Estimated level of under-reporting in humans

  Low due to the severity of the clinical signs. However, there are many mild and asymptomatic cases which remain undetected.

• Likelihood of spread in humans

  Although the causative virus is often transmitted by ticks, animal-to-human and human-to-human transmission also occurs. Fortunately, human illness occurs infrequently, although animal infection may be more common.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  None.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  No impact.

• Slaughter necessity according to EU rules or other regions

  Not necessary or required.

• Geographical distribution and spread

• Current occurence/distribution

  CCHF virus is distributed through large areas of Sub-Saharan Africa, South-Eastern Europe, Middle-East, Central Asia, India and North- West of China. It has been found in parts of Europe including southern regions of the former USSR (Crimea, Astrakhan, Rostov, Uzbekistan, Kazakhstan, Tajikistan), Turkey, Bulgaria, Greece (1 case), Albania and Kosovo province of the former Yugoslavia, Spain and France. The geographical distribution of the virus mirrors that of its principal tick vector Hyalomma spp. Presence of CCHFV genome detected in ticks from deers in southwest Spain. Recent human cases derived from tick bite and nosocomial infection appeared Spain in September 2016 as the first cases in Western Europe. In 2013 a case occurred in Spain (retrospectively diagnosed).

  GAPS :

  Further evaluation and classification of environmental conditions that can influence the spatiotemporal distribution and dynamics of CCHF.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Endemic in certain areas but with no disease in the animals.

• Speed of spatial spread during an outbreak

  Outbreaks in animals are not obvious due to the asymptomatic nature of the infection.

• Transboundary potential of the disease

  Potential for transboundary movement especially with the movement of potentially asymptomatic carriers which have the potential to infect ticks at their new destination.

  GAPS :

  Do long term asymptomatic carriers exist or is it only the incubating and viraemic animals which pose a problem?Do long term asymptomatic carriers exist or is it only the incubating and viraemic animals which pose a problem?

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  Animals become infected with CCHF from the bite of infected ticks.

• Occasional mode of transmission

  Direct contact with contaminated fluids (in humans).

• Conditions that favour spread

  Factors which impact on tick population.

• Detection and Immune response to infection

• Mechanism of host response

  Unclear.Some studies on immune response have been published. A cytokine storm is observed.

  GAPS :

  Today there is an animal model for developing vaccine and antivirals, however, still we need to identify an animal model for studying host response to infection.Further research is needed to study the immune response in animal models and in patients for evaluation of intervention and control strategies.

• Immunological basis of diagnosis

  Serological tests. Detection of IgM and IgG antibodies (ELISA, IFA). Commercial serological tests for humans and animals with increased sensitivity and specificity are needed.

  GAPS :

  A reliable BSL-2 neutralization assay is needed.

• Main means of prevention, detection and control

• Sanitary measures

  Persons living in endemic areas should use personal protective measures that include avoidance of areas where tick vectors are abundant and when they are active (Spring to Fall); regular examination of clothing and skin for ticks, and their removal; and use of repellents.Persons who work with livestock or other animals in the endemic areas can take practical measures to protect themselves. These include the use of repellents on the skin (e.g. DEET) and clothing (e.g. permethrin) and wearing gloves or other protective clothing to prevent skin contact with infected tissue or blood (1).

• Mechanical and biological control

  The tick vectors are numerous and widespread and tick control with acaricides (chemicals intended to kill ticks) is only a realistic option for well-managed livestock production facilities.

• Diagnostic tools

  In humans:

  CCHF can be diagnosed by isolating the virus from blood, plasma or tissues. Cell cultures can only detect high concentrations of the virus, and this technique is most useful during the first five days of illness. Animal inoculation into newborn mice is more sensitive than culture, and can detect the virus for a longer period. CCHFV is identified by indirect immunofluorescence or reverse transcription-polymerase chain reaction (RT-PCR) assays. Virus isolation must be carried out in maximum biocontainment laboratories (BSL-4).The use of real-time reverse transcription-polymerase chain reaction (RT-PCR), in clinical and tick samples has allowed for both rapid diagnosis of disease and molecular epidemiology studies. Whilst this technique is highly sensitive the genetic variability in CCHFV strains, means that single set of primers cannot detect all virus variants, and most RT-PCR assays are either designed to detect local variants or lack sensitivity. Viral antigens can be identified with enzyme-linked immunoassay (ELISA) or immunofluorescence, but this test is less sensitive than PCR.Tests detect CCHFV-specific IgM, or a rise in IgG titers in paired acute and convalescent sera. IgG and IgM can usually be found with indirect immunofluorescence or ELISA after 7-9 days of illness. Other serologic tests such as complement fixation and hemagglutination inhibition have been used but lacked sensitivity.

  In animals:

  Serology can identify animals that have been infected or exposed to CCHFV. An IgG ELISA can detect antibodies for the remainder of the animal’s life; other tests, including complement fixation and indirect fluorescent antibody, usually detect antibodies for shorter periods. Viraemia can be recognized by virus isolation and other techniques but these tests are not used diagnostically.

  GAPS :

  Limited commercial kits for serology in animals.

• Vaccines

  None.A mouse-brain derived vaccine is used in specific groups in Bulgaria (not FDA approved).Many preclinical reports on vaccine candidates have been published.

  GAPS :

  To date, several candidates available (tested in laboratory mice), and one in Non-human primates. A few of these vaccine candidates are in Phase I trials. the research program needs to further investigate these candidates.An FDA approved vaccine for humans is needed.

• Therapeutics

  Symptomatic treatment in humans. Controversial data on the use of ribavirin (WHO recommends the use of ribavirin). T-705 (favipiravir) was suggested.

  GAPS :

  Test novel drugs for CCHF control.

• Biosecurity measures effective as a preventive measure

  The CCHF virus is also a potential bioterrorist agent; it has been listed in the U.S. as a CDC/NIAID Category C priority pathogen.

• Border/trade/movement control sufficient for control

  Not applicable although acaricides can be used before movement.

• Prevention tools

  Control of ticks.

  Acaricides can be used on livestock and other domesticated animals to control ticks, particularly before slaughter or export. In humans in endemic regions, prevention depends on avoiding bites from infected ticks and contact with infected blood or tissues. Measures to avoid tick bites include tick repellents, environmental modification (brush removal, insecticides), avoidance of tick habitat and regular examination of clothing and skin for ticks. Protective clothing and gloves should be worn whenever skin or mucous membranes could be exposed to viremic animals, particularly when blood and tissues are handled. Unpasteurized milk should not be drunk. In meat, CCHFV is usually inactivated by post-slaughter acidification. It is also killed by cooking. Human outbreaks have occurred after exposure to infected ostriches during slaughter; these infections seem to be preventable by keeping the birds free of ticks for 14 days before slaughter. In some countries, ostriches are subjected to a 30-day pre-slaughter quarantine period at export facilities.

  GAPS :

  The shedding and presence of the virus in meat should be investigated. To date there is possibility to investigate these issues in research facilities with capacities to perform animal experimentation with large animals (bovines, ovines) in BSL-4 conditions.

• Surveillance

  Serosurveillance of animals.Seroprevalence studies in humans available.

  GAPS :

  The seroprevalence in wildlife is not sufficiently studied.

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  Little experience although there appears to be a gradual spread of the CCHF virus into other parts of Europe.

• Costs of above measures

  Unknown although apart from acaricide usage there are no specific measures available for control of animal carriers.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes.

• WOAH disease card available

  N.A.

• WOAH Terrestrial Animal Health Code

  N.A.

• WOAH Terrestrial Manual

  Direct links to the WOAH.

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  Can have a high mortality in individuals who become infected.

• Zoonosis: cost of treatment and control of the disease in humans

  Expensive, but limited control measures available.

• Direct impact (a) on production

  No impact on production.

• Direct impact (b) cost of private and public control measures

  No costs for animals.

• Indirect impact

  Limited impact at present although if the disease becomes a major problem could have an impact on tourism, however, the presence of CCHFV, in endemic areas have a big impact for farmers, which in turn may affect the production.

• Trade implications

• Impact on international trade/exports from the EU

  None at present, however, illegal trade has an impact for spreading of the virus.

• Impact on EU intra-community trade

  None at present. See above.

• Impact on national trade

  None at present.

• Links to climate

  Seasonal cycle linked to climate

  Not specifically linked but will depend on the influence of the climate on tick populations.

• Distribution of disease or vector linked to climate

  Based on the distribution of the vector.Population dynamics depends on climatic factors, ecologic changes and wildlife and human factors.

  GAPS :

  The role of environmental change, including climate change, needs further assessment.

• Outbreaks linked to extreme weather

  Yes ; dry summers leading to tick aggressiveness.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  Changes in climatic conditions could expand the range of the tick vectors, and increase the incidence of disease.

  GAPS :

  Tools to monitor and predict virus migration along with potential movement of the associate ticks as a result of climate change.

• Main perceived obstacles for effective prevention and control

  Widespread in nature, recycling of the virus between the small/ large mammals and the ticks. Limited measures available to break the cycle.

• Main perceived facilitators for effective prevention and control

  Methods to control the Hyalomma spp ticks

  • Ectoparasitic: acaricidal control
  • Develop genetically resistant animals
  • Control movement of infected animals
  • Anti-tick vaccines (ATVs)
  • Pheromone-based tick control
  • Integrated control of ticks

  It has been shown that where wild animals run with domestic animals (cattle) tick control on cattle will also reduce tick burden on the wild animals.Animal and human vaccines.

  GAPS :

  Information drawn from vector and animal surveillance is crucial for predicting human risk for CCHF infection but also for other tick-borne diseases.

  • The standardisation of protocols for tick collection from animals, their identification and screening for possible human pathogens would be helpful;
  • Diagnostic capacity would need to be developed accordingly;
  • Vaccine development for domestic animals.

  A better understanding of the epidemiology of CCHF in ticks, domestic livestock and wild animal populations, will support the identification of human risk factors for infection and the development of better diagnostics, antiviral drugs and vaccines for humans.Information on transmission capacity in other tick species like Riphicephalus.Stimulation of host cross-reactive immunity for controlling multiple tick species.

Global challenges

• Antimicrobial resistance (AMR)

• Mechanism of action

  N.A.

• Conditions that reduce need for antimicrobials

  N.A.

• Alternatives to antimicrobials

  N.A.

• Impact of AMR on disease control

  N.A.

• Established links with AMR in humans

  N.A.

• Digital health

• Precision technologies available/needed

  N.A.

• Data requirements

  N.A.

• Data availability

  N.A.

• Data standardisation

  N.A.

• Climate change

• Role of disease control for climate adaptation

  Unknown.

• Effect of disease (control) on resource use

  Unknown.

• Effect of disease (control) on emissions and pollution (greenhouse gases, phosphate, nitrate, …)

  Unknown.

• Preparedness

• Syndromic surveillance

  Not possible since animals do not present clinical signs.

  GAPS :

  Cryptic Species involved in the natural cycle?

• Diagnostic platforms

  Some available and reliable.

  GAPS :

  Why so high prevalence in ruminants?

• Mathematical modelling

  Several published models. Decreasing the tick survival time is an efficient method to control the disease.

  GAPS :

  Not all important variables are included in the studies.

• Intervention platforms

  Several available (nucleic acid, viral vectored) tested preclinically.Anti-tick vaccine strategies available.

  GAPS :

  Efficacy in large animals and better models of infectionBest vaccine strategies still need to be defined.

• Communication strategies

  Not known.

Main critical gaps

• Major gaps :

  • Few adequate facilities to handle live virus and perform animal experiments limits research on vaccine developments and treatment strategies for humans and animals.
  • Better understanding of the clinical aspects of the disease and the immune respons to the virus.
  • Future research on the virus-vector interaction, the CCHFV dynamics in reservoirs and vectors, the role of birds and wildlife.
  • Establishment of rapid and more sensative diagnostics.
  • More studies on the role of climate change in the distribution of ticks and the establishment of new CCHFV endemic areas.

Conclusion

• The knowledge on CCHF pathogenesis and immune response is limited. The research activities concerning CCHF disease have been restricted to very few institutes/laboratories, for several reasons:

  • The handling of the virus requires high containment laboratories (BSL-4)
  • Endemic countries do not have the facilities to conduct basic and/or applied research programs,
  • The lack of clinical specimens from patients, animals and ticks.

Sources of information

• Expert group composition

  Alejandro Brun, CISA-INIA-CSIC, Spain – [Leader]

  Ali Mirazimi, Karolinska Institute, Sweden

  Martin H. Groschup, Friedrich Loeffler Institute, Germany

  Gema Lorenzo, CISA-INIA-CSIC, Spain

  Octavio Arce, Hospital Militar de la Defensa Gomez-Ulla, Spain

• Date of submission by expert group

  May 2024

• References

  Kuhn JH et al. Journal of General Virology 2024; 105(4):001974 ; https://pubmed.ncbi.nlm.nih.gov/38687001/https://pubmed.ncbi.nlm.nih.gov/38687001/

  https://ictv.global/report/chapter/nairoviridae/nairoviridae/orthonairovirus;

  https://www.woah.org/fileadmin/Home/fr/Health_standards/tahm/3.01.05_CCHF.pdf;

  https://www.ecdc.europa.eu/sites/default/files/documents/crimean-congo-haemorrhagic-fever-spatial-distribution-december-2023.pdf

  Bhowmick, S et al. Epidemiologia 2022; 3(1), 116-134 ; https://www.mdpi.com/2673-3986/3/1/10

  Ahata, B and Akçapinar GB. Front Immunol 2023; 14: 1238882; Ahata, B and Akçapinar GB. Front Immunol 2023; 14: 1238882; https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1238882/full

  Kasaija, PD et al. Vaccines 2023; 11(1), 99;https://www.mdpi.com/2076-393X/11/1/99

  Sorvillo, PD et al. Trop. Med. Infect. Dis. 2020; 5(3), 113 ; https://www.mdpi.com/2414-6366/5/3/113

  Spengler, JR et al. Antiviral Research 2016; https://pubmed.ncbi.nlm.nih.gov/27713073/