Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  Only few antibody detection competitive ELISA kits are available in the market.Real-time RT-PCR detection assays (group specific) are commercially available from different companies.Real-time RT-PCR serotyping assays for the seven serotypes are available only in house.In-house RT-qPCR (Wernike et al. 2015) is also available, capable of identifying with good sensitivity Western and Eastern EHDV on field samples/virus isolates.

  List of commercial diagnostic kits (Diagnostics for Animals).

  GAPS :

  There is the need of more variety in the market. No tests detecting antigen are commercially available.No serotype specific ELISAs are available. Some in house serotype-specific real time RT-PCR are not able to detect some new strains (e.g., EHDV-8 from Tunisia). More sensitive and specific molecular assays are needed. Fully validated pen-side diagnostic tests could be helpful.

• Diagnostic kits validated by International, European or National Standards

  The competitive VP7 ELISA is one of the WOAH recommended test for prevalence of infection-surveillance and individual animal freedom from infection prior to movement, and is widely used amongst veterinary diagnostic laboratories, both for domestic and wild ruminant species.

  GAPS :

  No proficiency tests have been ever organised to harmonise European Union laboratories performance. It would also be advisable to include North African countries in future harmonisation studies.

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

  The WOAH Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2022 – Chapter 3.1.7 – Table 1 summarizes the diagnostic tests available for the diagnosis of EHD and their best-fitted purpose. The methods are also described in the chapter.

• Commercial potential for diagnostic kits in Europe

  Neither adequate number of serological commercial kits nor antigen detection tests are available in the market.Group specific real-time RT- PCR assays are commercially available but only in house serotype-specific RT-PCR are available. Their sensitivity depends on the different strains and need to be checked every time a new strain emerges.

  GAPS :

  Due to the presence of EHDV-8 in Europe and the need to test animal moving from restricted areas, there is a high commercial potential for EHD diagnostic kits.

• DIVA tests required and/or available

  No serological DIVA tests are currently available. In general, no vaccines are currently available in Europe.

  GAPS :

  Vaccines, DIVA vaccines and DIVA tests may be necessary in the near future.Need for of official recognition of a panel of EHDV reference strains.

• Vaccines availability

• Commercial vaccines availability (globally)

  No vaccine products are now available in Europe. The only available inactivated and live modified vaccines are in Japan. They are against the Ibaraki strain of EHDV serotype 2. Inactivated vaccine also includes bovine ephemeral fever virus. Autogenous inactivated vaccines produced from EHDV-1 or EHDV-2 isolates originating from ill or dead deer in affected herds are also available in North America. A vaccine containing BTV-17 and EHDV-1 and 2 is also available.

  GAPS :

  To develop and produce vaccines, drug companies need incentive conditions that only recently after the EHDV introduction in Europe are present.Join efforts from veterinary service institutions and private companies to develop, test and produce EHD vaccines should be recommended.

• Marker vaccines available worldwide

  No marker vaccines are available.

  Subunit vaccines, using individual expressed proteins, DNA vaccines, VLP, recombinant virus delivery systems all have potential to deliver effective protection. There is ongoing research in these areas. These approaches would all be amenable to DIVA assay development.Third generation vaccines also could be useful such as RNA vaccines.

  GAPS :

  The market soon will require efficacious and safe DIVA vaccines against EHDV-8, however vaccines capable of protecting from all serotypes or vaccine platforms that can easily be updated with emerging serotypes (such as RNA vaccines) will be more than welcome.

  No immunological products are now available; however, subunit vaccines are in commercial development in the USA. Efforts are required to produce and commercialise experimental vaccine candidates. There is a need to develop cross reactive vaccine reagents/ strategies. These approaches would all be amenable to DIVA assay development.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  The only available vaccines are those produced in US (for deer) and Japan. The Ibaraki live attenuated vaccine is efficacious, but care should be taken when using it to avoid foetal malformation and reassortment phenomena.There is very little known about cross-serotype protection.The autogenous vaccines can be useful, but they can only be used in the herd of origin and they are not tested for efficacy.

  GAPS :

  There is a need for efficacious and safe vaccines, in particular against EHDV-8, the current threat to Europe. Vaccines against all serotypes will be needed for future threats.

• Commercial potential for vaccines in Europe

  To date, the interest of pharmaceutical companies is minor.Currently, vaccines are required in areas where EHDV is circulating to protect animals and allow their safe movement from infected areas.

  GAPS :

  Following the introduction in Europe, the potential for vaccines is increasing due to reduce production losses and avoid movement restrictions from infected areas.

• Regulatory and/or policy challenges to approval

  No regulatory or policy challenges are required for approval.

  To allow authorisation of vaccines in a more streamlined way provided the seed vaccine meets the regulatory requirements. This is particularly important for the type- specific vaccines, as a new set of reagents/approval is needed for each type. A truly cross-reactive vaccine might avoid such problems.

  If a generic set of procedures and materials for vaccine production could be approved, then a change of only the seed virus/antigen might allow / lead to a more rapid approval for the recently alarming strain.

  The development of more appropriate/effective vaccine adjuvants/ carriers. The use of toll-like receptors to direct the immune response may lead to more effective immune responses to single-shot / non-replicating or virus-vectored vaccines.

  GAPS :

  Difficulties of licensing, producing and commercialising new generation vaccines.

• Commercial feasibility (e.g manufacturing)

  Following the EHDV-8 introduction of Europe, the commercial feasibility of the vaccine production is extremely valuable.

  GAPS :

  Only proposals and projects for vaccine development are available at the time, no commercial vaccines are in the market.

• Opportunity for barrier protection

  Low.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  Repellent could be used to protect animals from midge attacks. Symptomatic treatment and supportive care could be given to infected and sick animals. Cost-effectiveness should be evaluated, and the withdrawal period of drugs taken into consideration. Slaughtering of animals should also be considered on an ethical basis.

• Future therapy

  Not foreseeable at the moment.

  GAPS :

  Possibility of developing therapies targeting specific viral proteins/ functions, e.g. RNA silencing or specific inhibition of specific viral enzymes.

• Commercial potential for pharmaceuticals in Europe

  Commercial potential for developing specific therapies is very low.

• Regulatory and/or policy challenges to approval

  Not needed at present.

• Commercial feasibility (e.g manufacturing)

  Not needed at present.

• New developments for diagnostic tests

• Requirements for diagnostics development

  Knowledge of the antibody kinetic following infection as well as the duration of RNAemia. Duration of RNAemia and viraemia might be different according to different strains. RNAemia may last several months (4 months), viraemia several days or weeks. Understand field and optimal environment conditions for viral transmission. Knowing the genomic characteristic of the circulating strains.Knowledge on which (wild) species in Europe are susceptible to infection and what are the kinetics of the biological parameters of the infection (viraemia, RNAemia, Ab, cellular immunity).

  GAPS :

  DIVA tests will be helpful if DIVA vaccines are available in the future. Continuous upgrade of the PCR test could be necessary for newly circulating strains.

• Time to develop new or improved diagnostics

  The time necessary to develop a novel assay varies according to the technique, but if required it can be short.However, the process of evaluation and validation of the test, also considering the multiple serotypes and strains, could take a long time.

  GAPS :

  A joint effort of commercial companies and research laboratories in order to share resources and expertise and speed up the developing steps.

• Cost of developing new or improved diagnostics and their validation

  Medium to high depending on the test.

  GAPS :

  Public private partnership may be needed to share resources and reduce cost.

• Research requirements for new or improved diagnostics

  Studies on the viral genes and proteins of the virus. Studies on pathogenesis. Cross-serotype reactions. Widening of the sequence database.

• Technology to determine virus freedom in animals

  ELISA and PCR. Serotype-specific PCRs. Viral genome sequencing when results are inconclusive.

  GAPS :

  Need for official recognition of a panel of EHDV reference strains.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  An ideal vaccine should be safe, effective, inexpensive and lifelong.

  GAPS :

  Better knowledge on:

  • The virus biology and variability in different animal species and vectors.
    • Evaluate its capacity to persist in susceptible animals, or susceptible insect populations ;
    • comparative study of the pathogenesis of the virus in cattle vs deer ;
    • comparative study of the pathogenesis of the virus in various deer species.
  • The host immune response (cellular and humoral) involved in the protection.
    • in-depth studies of clinical signs of EHDV in cattle and deer in relation to humoral and cellular immunity and in relation to maternal antibody kinetics ;
    • serotype cross protection.
  • The function of viral genes and proteins.
    • detailed analyses of the genetic factors modulating the pathogenesis of the virus in cattle and deer.
  • Susceptibility of insect populations.
    • immune mechanisms in the insect vectors;
    • characterization of the potential vector of EHDV in Europe and Mediterranean basin;
    • identification and characterization of areas favourable to the presence and abundance of the vector.

• Time to develop new or improved vaccines

  Depending on the type of vaccine. For inactivated vaccines, it could be a couple of years. Most of the time however depends on the preparation of the dossier. For second or third generation vaccines the time could be longer.

• Cost of developing new or improved vaccines and their validation

  Unpredictable.

• Research requirements for new or improved vaccines

  Research is needed to develop vaccines that are safe and able to provide lifelong protection against all serotypes, both in the wild and domestic ruminant host.Subunit vaccines provide serotype specific protection but are not long-lived and may and/or may not provide some cross-serotype protection.Understanding antigen interference in a multi-serotype vaccine formulation is needed.Novel vaccine platforms could be explored (e.g., subunit, VLP, mRNA).Possibility of preparing a bivalent vaccine against BTV-EHDV (BTV-4 or BTV-8 and EHDV-8).

  GAPS :

  Better understanding of the molecular biology of the virus.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  Not applicable at the moment.

• Time to develop new or improved pharmaceuticals

  Not applicable at the moment.

• Cost of developing new or improved pharmaceuticals and their validation

  Not applicable at the moment.

• Research requirements for new or improved pharmaceuticals

  Not applicable at the moment.

Disease details

• Description and characteristics

• Pathogen

  EHD virus (EHDV) is a non-enveloped virus of the genus Orbivirus (family Sedoreoviridae), approximately 80 nm in diameter. Its genome consists of 10 dsRNA segments (from 1 to 10), encoding for 7 structural (VP1 to VP7) and 5 non-structural proteins (NS1 to NS5).VP2 is the outermost protein of the virion and is the major target of neutralizing antibodies. Its antigenic heterogeneity determines the serotype characteristics. Currently, 7 serotypes (1, 2 and 4 to 8) are officially recognized which exhibit partial (EHDV-6 and -8) or low level of cross-protection. Further two new serotypes form South Africa and Japan have been proposed but they are not officially recognised.VP7 is the core protein that is common to all serotypes and is used as group specific antigen in the immunoenzymatic assays for identifying infected animals. Antibodies to the related Bluetongue virus (BTV) can have some cross-reactivity with some serological assays.The virus is stable at –70°C and in blood, tissue suspension or washed blood cells held at 4°C. It is inactivated by ethanol and sodium hypochlorite solution.

  GAPS :

  • Increasing the knowledge of virus biology (cell binding, cell entry, replication, assembly and packaging, release).
  • Potential for the identification of novel serotypes/strains using the NGS technologies, as reported for the Bluetongue virus (BTV).
  • Identify virulence factors and the role of the different non-structural (NS) proteins.

• Variability of the disease

  EHD is an acute, infectious, non-contagious, sometimes fatal viral disease of some wild ungulates (North American white-tailed deer). In recent years, increasing reports of EHDV strains/serotypes that have been capable of infecting cattle causing severe disease and production losses were recorded. EHDV pathogenicity is extremely variable depending on the virus strains and infected hosts. Morbidity and mortality can be significant in the North American white-tailed deer and low in the other species. However, it is worth to note that an extensive outbreak caused by the Ibaraki strain of EHDV serotype 2 in Japan in the ‘50s caused the death of more than 50000 animals. Outbreaks of EHDV-6 and 7 also caused diseases and death in cattle in Northern African and Middle East countries as well as the recent EHDV-8 outbreaks reported in Tunisia, Italy and Spain. Israeli and Japanese EHDV-1 caused milder clinical signs compared to EHDV-6 and -7. EHDV was also found responsible for abortions in infected animals, and it was detected in cattle foetuses.

  Natural infection elicits both antibody and cell mediated response. The neutralising antibody response is able to protect animals from subsequent infections with homologous serotype. Cross-protection among serotypes is low (with the possible exception for serotypes 6 and 8).

  As a vector borne disease, EHDV spread and transmission depend on the presence of vectors.

  Reassortment between different serotypes/strains has been observed in the field, and may play an important role in virus evolution.

  EHDV-7 responsible for the Israeli 2020 outbreak probably originated from Australia. However, the last sequence publication on Australian EHDVs was many years ago. Chinese and Japanese recent circulating EHDV strains are not closely related to Israeli EHDV-7. Currently. it is not easy to trace back the identity of circulating EHDV strains, there is a need of more data related to circulating strains and their sequences.

  GAPS :

  • Investigate pathogenicity in the hosts.
  • Set up a genomic surveillance to define the existence and global distribution of different virus strains and topotypes, and determine strain-related variations in virulence and vector competence.
  • Explore the EHDV vector competence and infection in Culicoides spp., and its role in virus persistence and emergence.
  • Investigate the possible role of climate change on the future distribution of the disease.
  • Use of reverse genetics technologies to explore the genetic basis for biological characteristics (e.g. virulence or transmissibility, serotype, temperature dependence, vector competence, etc) of different virus strains.
  • Provide sequence data for multiple well-documented isolates of EHDV, to get information concerning their molecular epidemiology and the processes of virus evolution. These efforts will provide ‘reference’ sequences for each of the ten genome segments from specific EHDV lineages, topotypes and strains around the world, to identify genome segment reassortment events and strain movements in the field.
  • Precise the taxonomy and serotype classification.

• Stability of the agent/pathogen in the environment

  As a non-enveloped virus, the EHDV is very stable. It is stable for years when frozen at ≤70°C but can be inactivated at -20°C. It is stable for years in whole blood kept in a refrigerator.

  GAPS :

  Investigation of the overwintering mechanisms and possible re-emergence after one or more vector-free season.

• Species involved

• Animal infected/carrier/disease

  The disease affects both wild and domestic ruminants. Clinical disease is often observed in North American white-tailed deer in which morbidity and mortality can be significant. In cattle, subclinical infections seem to be the more frequent event, though clinical outbreaks have been recently reported for serotypes 1, 2, 6, 7 and 8. Clinical outbreaks in US cattle are rare and associated with drought conditions when animal are under stress conditions.Other cervids such as mule deer and pronghorn as well as camelids can also be affected. Similarly, sheep, goats and many other artiodactyls may be susceptible to EHDV infection although in general they don’t show clinical signs.Viable virus can be retrieved from an infected mammalian host up to approximately 2 months; the infection is life-long in the vectors. In studies carried out in US viraemia is cleared by 10 dpi. Viral RNA can be detected longer. Similar findings were observed during the Israeli EHDV outbreaks, where viraemia lasted few weeks only.

  GAPS :

  • Evaluate species-specific factors influencing the clinical outcome.
  • Investigate the potential role of wildlife species in the persistence of EHDV in the environment.
  • Investigate the potential role of the vertebrate host as a carrier for EHDV – overwintering mechanism.

• Human infected/disease

  No.

• Reservoir (animal, environment)

  Biological vectors are biting midges of the genus Culicoides. No vertical transmission has been reported so far. In temperate climate, infection and disease are then seasonal, occurring in the late summer and autumn while in tropical regions, it can occur all year around.

  GAPS :

  • Identify impact and competence of the different Culicoides species involved in the transmission of EHDV in the different ecological zones (episystems).
  • Investigate other possible transmission routes (via other biological vectors, by mechanical transmission involving other biting insect species, via an oral route such as ingestion of infected meat/placenta, horizontal transmission) including transplacental transmission of the virus, as demonstrated for some serotypes of BTV.

• Description of infection & disease in natural hosts

• Transmissibility

  EHD is a non-contagious disease. Transmission occurs through the bites of infected adult blood-feeding midge of the genus Culicoides. Transplacental transmission has been reported for the vaccine strain of the Ibaraki strain, the only live vaccine available so far and in tissues of aborted cattle foetuses and placenta (EHDV-6 and 7) during the Israeli EHDV outbreaks. Trade of EHDV infected and uncontrolled animals is probably occurring.

  GAPS :

  • Understand the processes and mechanisms that underly transmission of EHDV by arthropod vectors, including factors that promote, or act as barriers to transmission / vector competence with specific virus strains.
  • Full genome analyses and comparison of genetic variations between vector and non-vector populations / species of Culicoides, to determine the mechanisms involved in biological barriers to infection / transmission.
  • Define the thermal & vector requirements of EHDV in both the field and laboratory conditions, to predict incursion risk into the EU.
  • Investigate the effect of temperature on the extrinsic incubation period (EIP) in different species of Culicoides midges.
  • The genetic control of vector competence.
  • During outbreaks, investigate the proportion of spread by wind in relation to transmission by animal movement taking into account different regions of Europe and the world.
  • Investigate the potential role of ticks and other arthropod vectors in the transmission of EHDV.

• Pathogenic life cycle stages

  Vector gets the infection when feeding on a viraemic ruminant host. After the extrinsic incubation period, the infected Culicoides is able to transmit the virus to susceptible vertebrate host by biting it.

  GAPS :

  • Vector competence and ability of different species of Culicoides vectors to transmit different serotypes/strains of EHDV.
  • Investigate the infection dynamic of EHDV serotypes: incubation period, infection route, viraemia, immune response, virus excretion etc…
  • Verify/identify possible existence of an endemic life cycle.
  • Investigate the occurrence of reassortment phenomena in vertebrate hosts and Culicoides spp.

• Signs/Morbidity

  In cattle, most of the EHDV infections are in general subclinical. However, in the last decades, some strains have been able to cause severe diseases. In the white-tailed deer, infections can be severe.

  Acute EHD in cattle: fever, anorexia, reduced milk yield, reddening of the eyes, hyperaemia and crusting of the oral mucosa, drooling, oral and nasal erosions and crusting, cyanosis of the mucosae, blue tongue from lack of oxygenated blood, dyspnoea, reddening of the udder and teats, lameness, breaking of hooves caused by growth interruptions.Abortions have been reported in severely affected pregnant animals. Post-mortem examination: haemorrhages in the heart.

  Acute EHD in deer: fever, weakness, inappetence, excessive salivation, severe oedema of the head and neck, hyperaemia of the conjunctivae and mucous membranes of the oral cavity, coronitis, stomatitis, oral and nasal ulcers or erosions. Lesions are characterised by extensive oral ulceration and widespread haemorrhage and oedema.

  GAPS :

  • Understand why some strains are more virulent than others.
  • Assess the susceptibility of different deer species and wild ruminants to EHDV-8.

• Incubation period

  Incubation period is around 2-10 days. Infected animals are usually infectious to Culicoides for several weeks, deer up to 60 days, cattle from 1 to 8 weeks. Extrinsic incubation period in vectors is 10-14 days.

  GAPS :

  • Investigate for how long the EHDV, and in particular EHD-8 infected animals remain infectious to midges.
  • Explore sequels in recovered animals following mild infections.

• Mortality

  Up to 10% in cattle, up to 90% in white tailed deer. In other hosts, the infection appears to be asymptomatic.

  GAPS :

  Investigate the host resistance and susceptibility factors and EHDV virulence determining the clinical outcome of infection.

• Shedding kinetic patterns

  The duration of EHDV positivity by RT-PCR in the blood of infected deer and cattle is not well established, but, as for BTV, it is likely that RNAemia lasts longer than the period over which virus is still infectious.In deer experimentally infected with EHDV-2, virus RNA could be detected by RT-PCR in 2 days post-infection and all infected animals were viraemic starting from day 4 pi. In a few deer, it was possible to isolate EHDV for more than 50 days, but usually infectious virus could be no longer detected after 3 weeks from date of infection.In cattle, the viraemia may vary from 1 to six weeks depending on the strain/serotype.

  GAPS :

  • There are no comprehensive data on how long do deer and cattle remain infectious/viraemic.
  • Information on EHDV latent and infectious periods and period of detection by molecular methods under natural environmental and laboratory conditions for EHDV-8 and other serotypes/strains is absent.
  • Are there vertebrate host or virus genetic factors involved in the length of the infectious period?
  • Determination of genetic factors of different vector species involved into the viral transmission, which could have influence on the length of the infectious period or/and duration of transmission to susceptible host.

• Mechanism of pathogenicity

  Following the bite of an infectious midge, EHDV initially replicates in endothelial cells and skin-resident phagocytic cells, which then transport the virus in the draining lymph nodes.Then, through the blood stream (first viraemia), EHDV disseminates to other sites of replication, such as spleen, where it replicates in the endothelium of capillaries, followed by a second viremia.Replication in small vessels leads to cellular damage with increased permeability (oedema), diffuse haemorrhages, and necrosis.Replication of EHDV in target cells triggers the immune response, leading to the clearance of the virus in most of the cases.Due to the association of EHDV with red blood cells, where it is protected from antibodies, virions and antibodies can be present in the blood at the same time.

  GAPS :

  • Is there any particular molecular mechanisms related to pathogenicity and virulence?
  • Do the innate and/or acquired immune responses play a role in the pathogenesis of disease?
  • Does the saliva of Culicoides play a role in the pathogenesis of disease?

• Zoonotic potential

• Reported incidence in humans

  EHD is not a significant threat to human health.

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

  None – EHD does not affect humans, nor is there any risk of the disease being contracted or spread through meat or milk.

• Symptoms described in humans

  None.

• Likelihood of spread in humans

  None.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  The impact depends on various factors like breeds/species, immune status of the vertebrate host, strain/serotype, and eventually environmental factors. No vaccines are currently available.

  GAPS :

  Control of vectors and movement of viremic animals.

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

  EHDV is a major disease of white-tailed deer. In USA, the disease is widespread and can cause massive deer mortality. However, it is not thought to cause a significant long-term effect on deer populations. Other wild ungulates can be infected but they usually do not develop clinical signs.

  GAPS :

  • Investigate the pathogenesis of EHDV infection in different wildlife species to assess relative susceptibilities.
  • Understand the potential impact on endangered species by different EHDV strains in recently affected areas.

• Slaughter necessity according to EU rules or other regions

  Only on an ethical basis.

• Geographical distribution and spread

• Current occurence/distribution

  As a vector-borne viral disease, the distribution of EHDV depends on the presence and abundance of the vectors. The virus is present in numerous countries extending approximately between 45°N and 35°S although in some regions (North America) it may extend to 50^oN. Within most of these regions, vector transmission is limited to those periods of the year when adult Culicoides are active (e.g. Southern Europe, Africa, the Americas, Australia, the Middle East and some countries of southern Asia and Oceania).In some regions virus infection is often associated with mild clinical disease in the native cattle and deer populations. However, introduction of exotic strains may lead to more severe disease in these native breeds. The introduction of exotic cattle breeds may also lead to more severe disease caused by local strains of virus.In the United States, the distribution of vector usually limits infections to the southern and western states. In other countries, the distribution of the vectors similarly limits the distribution of the virus. However, information is not always up to date. Several countries do not report test results or no testing is performed, so the disease status or changes in status therefore remain unknown.EHDV-8 has recently been recorded in Tunisia, Italy and Spain in part matching the distribution of the known vector species Culicoides imicola.

  GAPS :

  • Disseminate information and share diagnostic tools regarding EHD.
  • Identification of suitable areas for EHDV circulation based on vector, host dependent factors and environmental factors (DLST, NLST, NDVI, EVI, precipitation, altitude….).
  • Understand and model the distribution, spread, persistence and risks represented by EHDV including viral, vector and host dependent factors, and the importance of environmental factors, such as temperature (day and night), humidity, geographic conditions, etc
  • Investigate the EHDV-8 vector competence of the North African, the Middle East and “European” species of Culicoides.
  • Investigate the possible role of climate change on the future distribution of the disease.

• Epizootic/endemic- if epidemic frequency of outbreaks

  It is difficult to assess the EHDV circulation, as most of the infections can be asymptomatic. EHDV is endemic in some states of US in the wild deer population. In many other countries, EHD is sporadic, with occasional reports of epidemic episodes.Transmission is seasonal in temperate climate (starting season usually is late summer-early autumn).The nature of future climate change in Europe is uncertain. Hotter summers are considered likely to lead to an increased likelihood of further incursions, spread and persistence of EHDV in Europe.

  GAPS :

  • Continuous monitoring and overview of global EHD situation.
  • Implement passive (and possibly active) surveillance in countries at risk of introduction/re-emergence.
  • Organise training and simulation exercises for field veterinarians.

• Speed of spatial spread during an outbreak

  The rate of the EHDV spread after introduction or re-emergence might depend on several factors related to the vector (abundance and level of competence), to the host (species, immune status, animal density), and to eco-climatic conditions (time of year, humidity, vegetation, etc..). Wind might play an important role dispersing infected Culicoides over considerable large distances across water (e.g. from Northern Africa to Sicily, Sardinia).

  GAPS :

  • Understand in vivo replication and transmission routes, and the significance of climate, providing input into predicting and modelling viral dissemination /risks.
  • Identify risks associated with EHD and develop epidemiological models for its spread & control.
  • Investigate the speed of spatial spread of EHD depending on the different transmission modes under varying meteorological and environmental conditions.
  • Assess the rates of spread through different Culicoides species taking into consideration host preference, efficiency of transmission etc.

• Transboundary potential of the disease

  With its introduction in Southern Europe, EHDV has recently demonstrated its capability to expand its geographic range and to cross borders. The wide distributions of vector species of Culicoides, their high mobility and their adaptability to various climatic conditions. Apart from possible spread by infected midges through the wind, it should not be forgotten that one of the most important way of EHDV spread is through the movement of viraemic animals.

  GAPS :

  Investigate the vector species capable of transmitting EHDV (EHDV-8) and their distribution in Europe and north African countries.

• Route of Transmission

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

  EHDV is transmitted to the vertebrate (ruminant) hosts via the bites of virus-infected haematophagous Culicoides midges that act as biological vectors of the virus. Vector midges play a crucial role to the natural epidemiology and spread of EHDV. Midges of certain species in the genus Culicoides become infected by feeding on viraemic animals (the vertebrate host). After a replication period of 7-14 days in the insect’s salivary glands (development time being dependent upon temperature), the virus can be transmitted to a new vertebrate host during feeding. Infected midges remain infective for lifetime.

  Infection of the midge is generally a relatively inefficient process, while less than ~10% of insects that ingest a viraemic blood meal may become infected, depending on the insect vector species. Conversely, transmission of virus from a fully infected insect to mammalian host is an extremely efficient process (possibly up to 100% efficient). This may help to explain the transmission of virus by wind borne insects over large distances. Vector midges can fly short distances of 1- 2 km, but they can be blown much farther by wind. Long distance spread of EHDV from infected areas to adjacent uninfected areas can occur via the wind-borne dissemination of virus-infected midges, especially over water reservoirs, as sea (from North Africa to Sicily and Sardinia).The movement of EHDV-infected animals can be responsible for translocation of EHDV, however, such occurrences are only important if the local vector population within the receiving region is either present or able to efficiently acquire and transmit the introduced virus.

  GAPS :

  • Verify the infection rate of EHDV competent vector species.
  • Determine the likelihood of introduction of EHDV into new regions.
  • Assess if Culicoides saliva, which contains multiple proteins including proteases, can modify the virus capsid, viral binding properties and infectivity, as for BTV.

• Occasional mode of transmission

  Transplacental and natural transmission has been reported after using Ibaraki life modified vaccine, and in Israeli cattle following natural infections with EHDV-6 and EHDV-7.

  GAPS :

  • Assess more information on transplacental transmission, is it limited to Ibaraki life modified virus vaccine as lab adapted vaccine strains or it may involve other strains/serotypes as observed in Israel?
  • Verify if venereal transmission from infected male ruminants to females and their offspring might occur and if so, assess its epidemiological role.
  • Assess whether oral transmission to ruminants (eating infected placenta, ingestion of virus-containing colostrum) and carnivores (eating infected meat) might occur.
  • Control possible contamination of biological products, notably those that utilize foetal bovine serum/life attenuated vaccines.
  • Check the possibility and the role of the anthropogenic infection in mediating the introduction of these viruses.

• Conditions that favour spread

  Presence and abundance of competent Culicoides spp. and high animal density in an area. High temperature and relative humidity, wind conditions that can blow the vector into new areas. Naive host populations; introduction of exotic EHDV strains.

  GAPS :

  See Section “Seasonal cycle linked to climate”.

• Detection and Immune response to infection

• Mechanism of host response

  The mechanism is complex and involves inflammation, humoral with neutralizing and non-neutralizing antibodies and cell-mediated immunity.Immunity (naturally acquired after infection or induced by vaccination) against one serotype generally does not cross protect against infection with another serotype. Duration of the immune protection is unknown but indirect field evidence suggests it may last for lifespan.The nature of the antiviral response in the insect vector is poorly characterised.

  GAPS :

  • Study the host immune responses in vaccinated animals.
  • Determination of duration of protection in vaccinated animals to challenge with recent homologous and heterologous EHDV strains.
  • Determination of immune evasion mechanisms as well as the role of different type of immune responses in the pathogenesis of disease.
  • Understand the immune responses to EHDV for planning vaccination strategies: including possible existence of viral neutralizing epitopes involved in type specific and cross-reactive immune reactions and protection.
  • Identify mechanisms by which viruses evade host innate and adaptive immune responses.
  • Understand the mechanism of prolonged viraemia.
  • Identify cell receptors in mammals and insects for all serotypes.
  • Assess the importance of cell-mediated immunity and the precise mechanisms for protective immunity.
  • Identify viral proteins / sites involved in a protective cell mediated response.
  • Investigate the activated signalling pathways during infection.
  • Investigate the nature of the innate barriers in the insects.
  • Verify whether some viruses are able to kill the vector (as shown for other arboviruses).
  • Assess whether infection induces acquired immune mechanisms in the vectors.

• Immunological basis of diagnosis

  Neutralizing antibodies against outer protein VP2 are serotype specific. For this reason, classical serological diagnostic methods as serum/virus neutralization tests are used for virus identification and detection of seroconverted animals after natural exposure or vaccination campaigns. Antibodies against the serogroup-specific VP7 are detected by the current commercial ELISAs. This assay is used for detecting animals that have been infected with EHDV.

  GAPS :

  Development of serotype-specific ELISAs.

• Main means of prevention, detection and control

• Sanitary measures

  Quarantine and serological surveillance; vector control; zoning.Testing and safe importation of live animals are the most important sanitary measure to avoid the introduction of EHDV in a free country.Prompt reporting of EHD outbreaks, presence of appropriate serological and entomological surveillance and monitoring programme are strongly recommended to control the disease and the spread of infection.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

• Mechanical and biological control

  The measures to control and eradicate the disease include vector control (use of insecticides in the animal premises and in the areas where these insects live, insect repellents onto animals, mosquitoes nets, etc.), restriction of movements of live ruminants from affected areas to non-infected regions where the vector is present.Restriction of movements is the most important control measure, since vaccines are currently not available.

  GAPS :

  Develop more effective insecticides with shorter withdrawal period.

• Prevention through breeding

  EHDV RNA was detected in the testes of naturally infected mule deer, and the virus was implicated as a cause of testicular degeneration. Because of the lack of information regarding EHDV presence in germplasm, the risk of introduction via this pathway cannot be excluded.

  GAPS :

  Studies to confirm or exclude the possible EHDV sexual transmission should be performed.

• Diagnostic tools

  Antibody detection: ELISAs, Virus Neutralisation. Antigen detection: Real time RT-PCR; serotype specific RT-PCR for all serotypes, virus isolation, NGS.

  GAPS :

  • Develop serotype specific ELISAs,
  • RT-PCR assays need to be tested/validated against a wider range of strains and updated as required.
  • Develop innovative diagnostic tools, including multiplex assays (able to identify different virus serotypes or vectors at the same time). Mixed samples, containing multiple serotypes, can be missed by current diagnostic methodologies/work- flows.

• Vaccines

  No vaccines are available in Europe.In Japan, both live and inactivated vaccines against the Ibaraki strain of EHDV serotype 2 are commercially available. The inactivated vaccine includes bovine ephemeral fever virus.Autogenous inactivated vaccines are used in affected herds by US deer farmers.

  GAPS :

  Development and supply of inactivated vaccines is an urgent need, at least against the serotype(s) at risk of introduction into a free area.

• Therapeutics

  No specific treatment is available other than supportive therapy.

  GAPS :

  Explore the possibility of developing antiviral drugs/medicines/medications.

• Biosecurity measures effective as a preventive measure

  EHD has been notifiable to the WOAH since 2008 and is listed as categories D+E in the EU Animal Health Law, Commission Implementing Regulation 2018/1882/EU. Control rules and measures to limit the EHDV spread in the EU, including the establishment of restriction areas and a ban on animals of the susceptible species leaving those areas.Control, monitoring, surveillance and restrictions on movements of susceptible species in relation to bluetongue should be adopted.Since EHD is non-contagious, it is not necessary or appropriate to isolate infected animals for disease control. However, animal introduction from infected areas should be banned or comply with international regulations.Measures to reduce the contact between hosts and vectors by using insect -repellent, housing of livestock during the times when the vector midges are most active, screening of access points (windows, doors) using fine mesh capable of excluding midges, or coarser mesh impregnated with a suitable insecticide such as a synthetic pyrethroid could be implemented.If possible, contact between wildlife and livestock should be avoided.

• Border/trade/movement control sufficient for control

  Prevent the introduction of EHDV into free areas through the restriction of animal movements.Testing of the animals before trade.

• Prevention tools

  None.

• Surveillance

  A surveillance program should be implemented to confirm that EHDV is not circulating in an area, to detect a new introduction and to identify infected areas. Susceptible hosts should be tested before moving. Entomological surveillance is mandatory for an effective control program. In areas where the disease is not present, seminars for a selected audience (veterinarians, farmers, etc) would be desirable.

  GAPS :

  • Develop more effective insecticides with shorter withdrawal period.
  • Development and supply of inactivated vaccines is an urgent need, at least against the serotype(s) at risk of introduction into a free area.

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

  A successful control requires the contemporaneous appliance of both vaccination of susceptible animal and restricting movement of viraemic animals between EHD-affected and EHD-free zones. As currently, if we exclude the vaccines against the Ibaraki strain (EHDV-2) for cattle in Japan and the autogenous vaccines for deer in US. Autogenous vaccines have contrasting reports of effectiveness. Subunit vaccines for US strains of EHDV are in development but currently no immunological product are available. Vector control has been the primary control method utilized.Eradication and control of EHD in infected regions has been very difficult. The presence of a wild host and vector transmission makes prevention, control, and eradication even more difficult.

  GAPS :

  Development and supply of inactivated vaccines is an urgent need, at least against the serotype(s) at risk of introduction into a free area.

• Costs of above measures

  Costs of the control measures and their effects have not been evaluated but based on the costs calculated for other similar diseases, it is likely they are very high.

  GAPS :

  Evaluate the cost and benefit of the application of surveillance programme and restriction measures due to EHD epidemic.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes.

• WOAH disease card available

  https://www.woah.org/app/uploads/2021/03/epizootic-heamorrhagic-disease.pdf

• WOAH Terrestrial Animal Health Code

  https://www.woah.org/fileadmin/Home/eng/Health_standards/tahc/current/chapitre_ehd.pdf

• WOAH Terrestrial Manual

  https://www.woah.org/fileadmin/Home/eng/Health_standards/tahm/3.01.07_EHD.pdf

• Socio-economic impact

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

  None.

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

  None.

• Direct impact (a) on production

  EHD infection can cause death, loss of productivity, loss of milk yield, abortion. The severity of the symptoms depends on many variables including virulence of the EHDV strain, immune status of the animal population etc.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

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

  Cost of application of control measures, testing, and impact on movement controls, reduced ability to export or to move within a country.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

• Indirect impact

  Indirect losses include lost revenue due to trade restrictions limiting access to higher value markets.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

• Trade implications

• Impact on international trade/exports from the EU

  Preventing the spread of disease through international trade is one of the primary objectives of the World Organisation for Animal Health. This is achieved by establishing international standards that facilitate trade while minimising the risk of introducing diseases such as EHD. Chapter 8.7 of the Terrestrial Animal Health Code outlines the requirements that should be met for a country or zone to be defined as free of EHDV and the sanitary measures that should be applied when importing live animals, semen and embryos into an EHDV-free country or zone. No studies for evaluating the costs have been carried out. However, it is not difficult to guess that ban or restriction measures on animal movement can have dramatic effects on the livestock sector of a country.The duration of EHDV viraemia in domestic ruminants has been a critical issue in international trade and placement of trade barriers. The WOAH currently recognizes a 60 day infective period.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

• Impact on EU intra-community trade

  As said before, control rules and measures to combat EHD in the EU have been included in the EU Animal Health Law, Commission Implementing Regulation 2018/1882/EU. No studies for evaluating the costs have been carried out. However, it is not difficult to guess that ban or restriction measures on animal movement can have dramatic effects on the livestock sector of a country.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

• Impact on national trade

  In case of presence of restriction zones for different EHDV serotypes or the contemporaneous presence of restriction and EHDV-free areas in a country, ban or restriction measures on animal movement can have dramatic effects on its livestock sector.

  GAPS :

  Develop safe and efficacious vaccines against specific EHDV strains or serotypes.

• Links to climate

• Seasonal cycle linked to climate

  In temperate zones, infection has a seasonal occurrence. Temperature and humidity could influence the Culicoides life cycle, their survival, and the extrinsic incubation period.

  GAPS :

  Culicoides life cycle, EHDV development in the midge and seasonal distribution of EHD outbreaks taking also into account environmental conditions, farm/animal density in different parts of Europe / the world.

• Distribution of disease or vector linked to climate

  The presence and abundance of competent vectors are associated with climate and environmental conditions and, consequently, occurrence of disease is also linked to the climate. Warmer seasons may also increase the breeding/multiplicity period of vector populations.

  GAPS :

  • Investigate whether temperature influence vector competency.
  • Understand the effects of the ongoing climate change on the distribution of the vectors.

• Outbreaks linked to extreme weather

  Warmer winters in Europe may enable the adult Culicoides midges to overwinter more frequently. Because of their capability to travel by wind for 100s of kilometres, increases in wind movements allows Culicoides to colonize new habitats and spread EHDV to areas distant from the original source.

  GAPS :

  See above.

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

  Vectorial capacity is significantly affected by environmental factors that might influence on dynamics and intensity of vector-vertebrate contact in time and space (e.g. seasonal vector population densities, biting rates, and feeding frequencies). Temperature also influences vector developmental rates and life history parameters, and may modify vector competence. Changes on any of these factors will potentially alter the distribution and spread of the disease. EHDV infection and transmission by vectors may then be enhanced by high temperature and vector survival rates. Increasing environmental temperature (climate change) will also lengthen the vector season.

  Temperature is an important factor in controlling the vector competence of Culicoides vectors for Orbiviruses. Orbiviral development in Culicoides midges is unable to occur at temperatures below about 10°C to 15°C depending on the Orbivirus species and strain. Furthermore, there needs to be a minimum amount of time at suitable temperatures (expressed as “day degrees or hour degrees”) for completion of the development cycle in the Culicoides vector before virus transmission can occur.

  GAPS :

  • Investigate the EHDV vector competence of different Culicoides species and verify the effect of temperature.
  • Investigate whether the replication of different virus strains is affected by changes in ambient temperature, and the molecular basis for such variations.

• Main perceived obstacles for effective prevention and control

  No vaccines are currently available except for a live vaccine against EHDV-2 in Japan and inactivated vaccines white tail deer in the US.No passive and/or active surveillance plans are implemented so far.

• Main perceived facilitators for effective prevention and control

  The strong similarity between EHDV and BTV on structure and biological features allows gathering most of the EHDV’s behaviour and development of effective prevention and control measures.A solid and consolidated international laboratory network with sharing of diagnostic reagents and assays may facilitate fast diagnosis and prevention of further viral spread.

Global challenges

• Antimicrobial resistance (AMR)

• Mechanism of action

  Not applicable.

• Conditions that reduce need for antimicrobials

  Not applicable.

• Alternatives to antimicrobials

  Not applicable.

• Impact of AMR on disease control

  Not applicable.

• Established links with AMR in humans

  Not applicable.

• Digital health

• Precision technologies available/needed

  At international and country level, public web sites are available for disseminating information and continuously updated data to have: the latest on National and European Regulations; the current and past epidemiological situations; updated maps on entomological and serological surveillance activities; the current epidemiological situations in the Mediterranean Basin; rules and regulations.

  GAPS :

  • National informative system recording outbreaks and surveillance activities should be implemented at least at National level.
  • National informative systems should be able to communicate to share information on the epidemiological situation present in each country.

• Data requirements

  Data related to outbreaks and surveillance activities.

• Data availability

  NA.

• Data standardisation

  NA.

• Climate change

• Role of disease control for climate adaptation

  None.

• Effect of disease (control) on resource use

  None.

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

  None.

• Preparedness

• Syndromic surveillance

  Not in place.

• Diagnostic platforms

  Not in place.

• Mathematical modelling

  Not in place.

• Intervention platforms

  Not in place.

• Communication strategies

  Not in place.

Main critical gaps

• • No vaccines against existing EHDV and in particular EHDV-8 are available.
  • As well, no DIVA vaccines with the possibility of using DIVA assays are currently in the market.
  • Data on the duration of viraemia and on the antibody response following infection with EHDV-8 and EHDV
  • Data on species of Culicoides capable of transmitting EHDV.
  • Epidemiological role of different species of domestic and wild ruminants in maintaining and spreading EHDV infection.
  • Serotype specific ELISA.
  • Effect of climate change on the distribution of the disease in the future.
  • Surveillance plans are not in place in risk areas of both European and Mediterranean countries.

Conclusion

• The risk that EHDV-8 spread in new territories of Europe causing severe economic losses in the livestock industry is quite high.Climate change and globalization will probably facilitate the spread of EHDV.Authorities should be prepared implementing early warning system to early detect and face the eventual EHDV incursions. It is not possible to contain the disease as vaccines are not available, so all control should be based on restriction measures. A joint public and private effort is necessary for vaccine development and commercialization.

Sources of information

• Expert group composition

  Giovanni Savini, IZSAM, Italy – [Leader].

  Alessio Lorusso, IZSAM, Italy.

  Stephan Zientara, ANSES, France.

  Emmanuel Breard, ANSES, France.

  William C. Wilson, USDA Agricultural Research Service, KS, US.

  Carrie Batten, PI, UK.

  Salah Hammami, ENMV, Tunisia.

  Soufien Sghaier, IRVT, Tunisia.

  Thameur Ben Hassine, CRDA, Nabeurl,Tunisia.

  Natalia Golender, KVI, Israel.

  Birgit Makoschey, MSD Animal Health / Intervet International BV, The Netherlands.

  Luigi Ruocco,Ministry of Health, Italy.

  Massimo Spedicato, IZSAM, Italy.

• Date of submission by expert group

  June 2023

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