Diseases

Bluetongue

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Control Tools

  • Diagnostics availability

  • Commercial diagnostic kits available worldwide

    Many different antibody detection ELISA kits are available commercially. These include competitive and double antigen ELISAs.

    Real-time RT-PCR detection assays (group specific) are available commercially from many companies.

    Real-time RT-PCR serotyping assays for European types 1, 2, 4, 6, 8, 9, 11, 16, 25 are also available commercially.

  • Commercial diagnostic kits available in Europe

    Many different antibody detection ELISA kits are available commercially. These include competitive and double antigen ELISAs.

    Real-time RT-PCR detection assays (group specific) are available commercially from many companies.

    Real-time RT-PCR serotyping assays for European types 1, 2, 4, 6, 8, 9, 11, 16, 25 are also available commercially.

    GAPS:

    • Real-time RT-PCR assays are needed for remaining serotypes. Although these are currently under development, further access to variants of each serotype (from around the world) and further validation are required.
    • Real-time and conventional RT-PCR assays have been developed for all 26 BTV types. However they require further evaluation and their commercial availability depends on demand.
    • These assays will potentially need updating as new isolates/variants are detected in the field.
    • Other diagnostic systems could potentially also be developed.
  • Diagnostic kits validated by International, European or National Standards

    Host: Agar-gel-immunodiffusion and competitive ELISA; virus neutralization test.

    Pathogen: virus isolation in embryonated chicken eggs and insect or mammalian cell cultures. Virus neutralisation test. Real-time and gel based RT-PCR for viral genome detection.

    GAPS: RT-PCR amplification and sequence analyses, followed by phylogenetic comparison to existing datasets, gives the most accurate identification of each virus strain and can identify reassortants strains, which may be biologically important. Although this technology may be unsuited to routine diagnosis it is used to provide important data on individual outbreak strains.

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

    Host: Agar-gel-immunodiffusion and competitive ELISA; virus neutralization test.

    Pathogen: virus isolation in embryonated chicken eggs and insect or mammalian cell cultures. Virus neutralisation test. Real-time and gel based RT-PCR for viral genome detection.

    GAPS: RT-PCR amplification and sequence analyses, followed by phylogenetic comparison to existing datasets, gives the most accurate identification of each virus strain and can identify reassortants strains, which may be biologically important. Although this technology may be unsuited to routine diagnosis it is used to provide important data on individual outbreak strains.

  • Commercial potential for diagnostic kits in Europe

    Test systems for antibody detection are commercially available. No antigen detection tests are commercially available.

    Bluetongue group specific real-time RT- PCR tests are commercially available. Type specific real-time RT- PCR tests are available for European types (1, 2, 4, 6, 8, 9, 11, 16 and 25). There is potential for the remaining types (under development).

    GAPS: Real-time RT-PCR assays are needed for remaining types. Although these are currently under development, further access to variants (topotypes) of each serotype (from around the world) and further validation are required.

  • DIVA tests required and/or available

    No serological DIVA tests are currently available but are needed for international trade in animals, and as an important part of control measures to detect infected animals when there is widespread vaccination.

    RT-PCR assays can be used in this way in combination with inactivated vaccines. In particular in surveillance programs and longitudinal studies, RT-PCR-diagnostics can be very beneficial. These assays have played a very important role in surveillance during recent vaccination campaigns with inactivated vaccines in Europe. A continued process for the development of more sensitive tests (with the possibility of pooling) and automation/robotizing makes this technique very reliable and competitive to ELISAs.

    The live virus vaccines generate NS proteins and the current inactivated vaccines also contain NS-proteins, so it may therefore be difficult or even impossible to develop reliable DIVA assays for either of these vaccine categories. Next generation vaccines (currently under development) will allow DIVA strategies / assays. In particular recently developed reverse genetics opens new possibilities.

    GAPS:

    • DIVA assay required, and need to be used in combination with DIVA vaccines, when available.
    • There is a need for serological as well as molecular DIVA assays
    • Currently RT-PCR assays can be used to identify animals that do not represent a transmission risk.
  • Opportunities for new developments

    GAPS:

    1. Further development of existing real-time assays, may be required to maintain effectiveness to detect new BTV isolates/variants. Further validation of RT-PCR assays is required for the serotype-specific real-time RT-PCR assays that are designed detect specifically the remaining BTV types.

    2. Initial studies indicate that chip based technologies to detect viral RNA, can be used to identify members of the BTV group and each serotype. However commercialisation will depend on cost and ease of use. This technology will need further development.

    3. It may be possible to develop a pen-side assay for BTV. Although in view of the relatively long term nature of BTV outbreaks this may be more important for differential diagnosis (e.g. compared to FMDV) than directly valuable as a tool against BTV.

    4. By expressing individual BTV VP2 proteins from different serotypes, and generating either polyclonal or monoclonal type-specific antibodies to them, it may be possible to develop ‘type-specific ELISA’ to detect antibodies to each BTV serotype. These may be useful to track movements of new types in areas that have previously been vaccinated against an existing serotype.

    5. Micro-arrays technology in order to identify circulating BTVs on a genome segment level.

  • Vaccines availability

  • Commercial vaccines availability (globally)

    Live vaccines:

    • Available and produced in India, Turkey, South Africa, North Africa, Russia and Europe. Modified virus vaccines are cheap, easy to produce. A single dose is usually effective in controlling clinical BTV outbreaks in areas of endemic disease and in the face of outbreaks.
    • Traditional attenuated vaccines bare the risk of transmission and reassortment (exchange of genetic segments), when used during the vector season and do not conform with the European Pharmacopeia.
    • Vaccines against almost all BTV serotypes are available. Multi-valent (up to penta) vaccines are available.
    • None of the attenuated vaccines have a European Marketing Authorisation. Some countries issue a ‘Temporary Authorisation for Use’ (TAU), which isn’t a license but a permission to use. TAU’s are valid for one year with possibility for renewal (see below).

    Inactivated vaccines: produced by a number of companies in Europe. Some contain partially purified and jnactivated virus.

    GAPS:

    • Live vaccines: License, Conformity with European Pharmacopeia. New serotypes do not have vaccines available. Cross reactivity of vaccines needs further development/study. Study on safety, production capacity in Europe and quality standards are needed.
    • Inactivated vaccines: European Commission long-term planning of management of antigen and vaccine stocks (see also vaccine bank). No subunit vaccines commercially available as yet. Needed: Incentives for producers to develop and produce ‘ahead’ of crisis. Vaccine producers need incentives to develop, test and produce vaccine for a non-existing market.
    • Subunit vaccines are not yet commercially available, but have been developed and concept proven experimentally.
    • Other possibilities based on the recently developed reverse genetics. Novel antigen delivery methods, e.g. recombinant virus carriers. DNA, better adjuvants.
  • Commercial vaccines authorised in Europe

    License: Five types of ‘licences’ are known:

    • Marketing Authorisation (MA): issued by the European Medicines Agency (EMEA). Validity: Europe, unlimited time.
    • European MA under exceptional circumstances: a MA under exceptional circumstances is a marketing authorisation with annual renewal, [Reg 2004/28 Art.39.7; Dir 2001/82 Art. 26.3.] Once commitments are fulfilled, a Full MA is granted. Validity: European Union
    • National MA: a country may issue a national MA (for example Switzerland in 2008 for a vaccine against BTV8). Validity: national.
    • Provisional MA (PMA): if a product is not ready to obtain a full MA, some countries issue a PMA. In general, a PMA is granted for 1 to 2 years, renewable. Validity: national.
    • Temporary Authorisation of Use (TAU): a TAU is not a marketing authorisation but the authorisation to use a non-registered product. Validity: nationally; one year. There are two special cases: Import License (Portugal) and field trial authorization of use (Germany).

    In 2009, 6 different methods were applied to ‘license’ vaccine or allow the use of the vaccine in the country. None of the companies producing inactivated vaccines has received a European Marketing authorisation by 2009.

    In 2009, two companies have received a marketing authorisation under exceptional circumstances for a vaccine against BTV8.

    However, inactivated sero specific vaccines produced by a number of companies in Europe. In 2009 vaccines against BTV serotype 1,2,4,8 and 9 are available and either licensed under TAU or MA under exceptional circumstances. By 2010 no subunit vaccine is commercially available / licensed. It is not expected that subunit vaccines will become commercially available.

    GAPS:

    • Registration process long, heavy and complex.
    • Clear guidelines/legislation by the European Commission are missing (No European wide standard): each country chooses the type of license it would like to issue even though preference should be given to a product holding a MA or MA under exceptional circumstances. Legal background not ready for:

    o Multi-strain license*

    o Rapid licensing process for vaccines used in emergency**

    o Impact of vaccination on international trade…(EU adjusted legislation several times)

    *There is now the possibility to create a multi-strain dossier. If a company launches a multi strain dossier additional serotypes can be added.

    ** No written standards/comparisons for Bluetongue so that the experience gained in bluetongue could shorten the process for other vector borne diseases. This gap analysis could used to identify parallels with other diseases

    • Vaccine market potential: Legislation for the use of vaccines varies by country; EU process: long and heavy. Funding for development

    o No existing EC legislation/Guidelines how to proceed with a ‘new’ or exotic serotype (vaccinate or not)

    o Currently separate authorisations are required for vaccines for each serotype. It may be possible to develop a generic authorisation that would apply to essentially similar vaccines but for different ‘types’ reducing the amount of data required prior to licensing.

  • Marker vaccines available worldwide

    None. Sub-unit 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. The recently developed reverse genetics opens new possibilities. These approaches would all be amenable to DIVA assay development.

    GAPS:

    • Need for efficacious and safe DIVA vaccine
    • Further work is needed to commercialise experimental vaccine candidates and to develop cross reactive vaccine reagents/ strategies. These approaches would all be amenable to DIVA assay development.
  • Marker vaccines authorised in Europe

    None.

  • Effectiveness of vaccines / Main shortcomings of current vaccines

    Live attenuated are effective and provide long lasting immunity with a single dose but animals vaccinated by live vaccines cannot be differentiated from infected animals. There is also potential for some live vaccine strains to cause disease, particularly in naive animals/populations. Transmission and reassortment of some live vaccine strains can/has also occurred in the field

    Inactivated or recombinant vaccines may need two injections to afford effective protection. The duration of immunity may also be shorter, requiring annual re-vaccination.

    No reliable DIVA assay is currently available for the inactivated BTV vaccines, and it may be difficult or even impossible to develop one.

    All of the current monovalent live or inactivated vaccines are type specific. Cross-protection can be generated by serial vaccination with multiple serotype vaccines.

    GAPS:

    • Ideally: one shot application for inactivated vaccine that gives a long-lasting protection from vireamia and clinical signs.
    • Work is needed to explore the nature of cross-serotype specific protection and epitopes, and cross topotype protection and the viral antigens involved. This may lead to development of truly cross-reactive vaccines, offering protection against multiple serotypes. These would be particularly welcome in areas where multiple types are circulating and causing disease. They could also be used in a wider eradication campaign.
  • Commercial potential for vaccines in Europe

    The commercial potential for future vaccines against BTV is low. Sales of inactivated vaccines against BTV decreased substantially in the European Market from 2008 to 2009 and will further decrease in 2010. Many countries decided to move from compulsory, government driven vaccination policy to voluntary, and private driven vaccination schedules.

    The future BTV vaccine market is decreasing even though the vaccine protects from clinical disease and helps to avoid losses due to trade barriers. The future BTV vaccine market is a highly unpredictable and thus poses a great risk for vaccine producers. Consequently, vaccine producer are reluctant to take risks to develop new vaccines for a ‘non-existing market’.

    If there is a move towards disease control or even eradication in endemic areas (such as India) there may be greater demand for truly effective and cross-reactive vaccines. Any future incursions into northern Europe could also increase the demand for relevant vaccines.

    Inactivated vaccines offer significant advantages over attenuated vaccines because absence of replicating virus eliminates concerns about viraemia, vector transmission and reversion to virulence.

    Recent recombinant DNA technology has provided novel approaches to developing safe vaccines. This technology offers substantial advantages both in terms of safety and the potential of developing a marker vaccine. The latter could be used as a prophylaxis in areas at risk, without endangering the “free” status of the region. An accompanying serological test would allow the distinction between vaccinated and infected animals. DNA recombinant technology involves the synthesis of immunogenic proteins and particles that elicit highly protective immune responses. Naked DNA vaccines may have a similar potential.

    Subunit vaccines are under development but not commercially available at the present time. With the highly unpredictable market and high development costs it is doubtful whether subunit vaccines against BTV will reach the market soon.

    GAPS: Inactivated vaccines & subunit vaccines:

    • European BTV strain bank where vaccine producer have quick access to strains with full description of all details (eg origin, organ, location) is needed
    • Antigen bank containing a minimum stock of antigens and serotypes for the future
    • Vaccination ring around Europe: Protect Europe by vaccinating North Africa, Israel and Greece => European Commission supports financially or by providing high quality BTV vaccine the vaccination programs in those countries, which pose a risk to Europe (known as entry doors
    • It may be difficult for companies to provide vaccines to cope with a fluctuating market and provide appropriate vaccine for arrival of new serotypes.
    • If vaccines with longer shelf life can be developed a central vaccine bank might be feasible.
    • Diva assays needed for next-generation sub-unit vaccines.
  • Regulatory and/or policy challenges to 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 current 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.

    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:

    • Registration process long, heavy and complex.
    • Clear guidelines/legislation by the European Commission are missing (No European wide standard): each country chooses the type of license it would like to issue even though preference should be given to a product holding a MA or MA under exceptional circumstances. Legal background not ready for:

    o Multi-strain license*

    o Rapid licensing process for vaccines used in emergency**

    o Impact of vaccination on international trade…(EU adjusted legislation several times)

    *There is now the possibility to create a multi-strain dossier. If a company launches a multi strain dossier additional serotypes can be added.

    ** No written standards/comparisons for Bluetongue so that the experience gained in bluetongue could shorten the process for other vector borne diseases. This gap analysis could used to identify parallels with other diseases

    • Vaccine market potential: Legislation for the use of vaccines varies by country; EU process: long and heavy. Funding for development

    o No existing EC legislation/Guidelines how to proceed with a ‘new’ or exotic serotype (vaccinate or not)

    o Currently separate authorisations are required for vaccines for each serotype. It may be possible to develop a generic authorisation that would apply to essentially similar vaccines but for different ‘types’ reducing the amount of data required prior to licensing.

    • Registration process and acceptance by registration bodies (EMEA) of multi-valent vaccines.
    • There is now the possibility to create a multi-strain dossier. If a company launches a multi strain dossier additional serotypes can be added. Studies of the target host immune system are needed in order to engineer more effective vaccine delivery mechanisms (cross-serotype / single shot).
  • Commercial feasibility (e.g manufacturing)

    High.

    GAPS: Commercial feasibility is in general high which does not necessarily mean that vaccine is available in a short time if there is no stock available (endemic and exotic strains), see also antigen/vaccine bank and market risks.

  • Opportunity for barrier protection

    Low.

  • Opportunity for new developments

    Multivalent vaccines with longer shelf life. Multivalent or cross-reactive vaccines with longer shelf life and associated DIVA assay. Development of single shot inactivated or sub-unit vaccines. Non-replicating vaccines that generate a longer lived immune response. GAPS: Registration process and acceptance by registration bodies (EMEA) of multi-valent vaccines. There is now the possibility to create a multi-strain dossier. If a company launches a multi strain dossier additional serotypes can be added.
  • Pharmaceutical availability

  • Current therapy (curative and preventive)

    None.

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

  • Future therapy

    None.

  • Commercial potential for pharmaceuticals in Europe

    None at present.

  • Regulatory and/or policy challenges to approval

    None.

  • Commercial feasibility (e.g manufacturing)

    Not applicable at present.

  • Opportunities for new developments

    A range of possibilites including husbandry modification, vector control, habitat alteration, adult vector insecticides, use of larvicides.

  • New developments for diagnostic tests

  • Requirements for diagnostics development

    Kinetics of antibody response. Kinetics of virus replication at the genome and protein level.

    GAPS: Better knowledge of antigenicity / cross reactivity of viral proteins between different strains / topotypes.

  • Time to develop new or improved diagnostics

    If required can be done fast, depends on priorities. The step that takes the time is a full evaluation/validation of the assay with a wide range of strains.

  • Cost of developing new or improved diagnostics and their validation

    If a company has to start from scratch in the development and validation of new or improved diagnostics it will take long time and the cost will be significant. Cooperation between diagnostic/research labs and commercial companies is absolutely necessary in order to pool resources, take advantage of relevant expertise, and reduce cost.

  • Research requirements for new or improved diagnostics

    Develop diagnostic reagents based on viral genes and proteins to specifically distinguish viral infection from vaccination. Cooperation and serious involvement of public and private labs with a combination of research and diagnostics is necessary.

    GAP: International sequence database.

  • Technology to determine virus freedom in animals

    Serology and PCR-diagnostics. Serotype-specific ELISAs and serotype-specific PCRs for all serotypes are useful to determine freedom for a respective serotype.

  • New developments for vaccines

  • Requirements for vaccines development / main characteristics for improved vaccines

    Safe, lifelong and broad protection.

    GAPS:

    • Better knowledge on the virus diversity and variability in different animal species and vectors.
    • Better knowledge on the function of viral genes and proteins.
    • Better knowledge on the virus biology and its capacity to persist in susceptible animals, or susceptible insect populations.
    • Better knowledge on the immune mechanisms (cellular and humoral) involved in protection.
    • Better knowledge on immune mechanisms in the insect vectors.
  • Time to develop new or improved vaccines

    5 years.

  • Cost of developing new or improved vaccines and their validation

    Expensive.

  • Research requirements for new or improved vaccines

    Further research is recommended in order to establish efficacy and safety of candidate vaccines in cattle, sheep and goats. With a high efficacy and safety, vaccination could be extended to all ruminant species in order to stop transmission of the virus.

    Further research is required in the development of vaccines that are safe and lifelong protective for livestock against all 26 BTV serotypes.

    GAPS:

    • Development of vaccines that protect against all BTV serotypes. This could be achieved through cross reactive vaccines, or serotype specific vaccines against all serotypes.
    • Development of inactivated (DIVA) vaccines for each of the 24 BTV serotype. This could potentially be achieved through cross reactive vaccines.
    • Development of recombinant / subunit (DIVA) vaccines against individual and multiple serotypes of BTV. Again the scope for cross-reactive vaccines needs to be explored
    • Develop novel subunit vaccines and associated DIVA assays.
    • Increase understanding of the immune responses to BTV to improve vaccination strategies: including identification of viral epitopes involved in type specific and cross-reactive immune protection;
    • Further understanding is needed of the significance of strain / topotype variation in the specificity, efficacy of neutralizing antibody and cell mediated responses.
    • More work is required in the development / evaluation of novel / appropriate antigen delivery platforms / adjuvants.
  • New developments for pharmaceuticals

  • Requirements for pharmaceuticals development

    None anticipated at present.

  • Time to develop new or improved pharmaceuticals

    Not applicable.

  • Cost of developing new or improved pharmaceuticals and their validation

    Not applicable.

  • Research requirements for new or improved pharmaceuticals

    None at present apart from new methods of vector control both in terms of killing vectors but also preventing vectors form attacking hosts.

Disease details

  • Description and characteristics

  • Pathogen

    Bluetongue virus (BTV) is the type species of the genus Orbivirus, family Reovirdae. The bluetongue virus particle is approximately 80 nm in diameter, is non-enveloped and is composed of three concentric protein layers, which enclose one copy each of the ten linear segments of double-stranded RNA that form the virus genome. The viral genome segments code for 7 structural proteins (VP1-VP7) and 3 non structural proteins (NS1-NS3). All bluetongue isolates share common antigenic determinants, the most immunodominant of which is the core surface protein VP7. Detection of antibodies to VP7 can be used for identification of BTV infected animals. The outer-most capsid protein, VP2, is variable and determines the identity of the specific serotype of the virus. Including the recent identification of two novel BTV types, a total of 26 serotypes have been identified worldwide.

    The highly conserved atomic structure of the BTV core has been resolved by x-ray crystallography. Although the structure of outer capsid proteins of a few serotypes has been explored by cryo-microscopy, no atomic structures are as yet available. Although the core proteins of BTV are highly conserved, they show sequence variations that reflect the geographic origins of the virus isolate, identifying at least two major ‘topotypes’ (east and west) along with a number of sub-groups.

    GAPS:

    • Identify and understand the mechanisms involved in cell binding and initiation of infection, genome replication, assembly and packaging, control of differential protein expression levels in mammalian and insect cells, release and transmission of BTV at the molecular, cellular and whole organism level.
    • Analyse virus structure and infection/replication mechanisms at the molecular level: including cell entry, replication and virus assembly, using biological assays and reverse genetics to explore the structure/ function/properties of individual proteins.
    • Determine the atomic structure, / function relationships and molecular organisation of the outer capsid layer and proteins of selected viruses from different BTV serotypes, and different topotypes, using x-ray crystallography, cryo-electron microscopy, reverse genetics, biochemical and immunological / immuno-staining studies. These analyses would provide a better understanding of the structural and epitope basis for variability and cross-reactivity between BTV serotypes, potentially providing a basis for the design of cross-reactive vaccines.
    • Some of the BTV genome segments contain alternative initiation sites for translation, as well as alternative open reading frames. The significance (if any) of the translation products from these ORFs has yet to be determined.
    • The recent identification of two new BTV serotypes using the latest generation of diagnostic assays and sequencing technologies/databases, suggests that there are still other serotypes / viruses yet to be discovered. The biological/disease significance of these new strains has not yet been fully explored. Furthermore, the remarkable genetic heterogeneity amongst field strains of BTV remains to be fully characterized, which is important as this genetic variation in turn translates into virus strains with different biological properties such as virulence and, perhaps, vector tropism.
  • Variability of the disease

    BTV has a wide pathogenic variability, which is partially virus strain dependent and partially host dependent. The neutralising antibody response generated during infection of the mammalian host is protective but it is BTV serotype specific. However an immune response is also generated against the more conserved (cross-reactive) core and non-structural proteins, which also appears to be at least partially protective against the clinical disease. This is likely to involve both antibody and cell-mediated responses. Consequently although susceptible hosts can be sequentially infected by multiple different BTV serotypes, they become progressively protected against the more severe aspects of the disease. Cross-reactions (usually low level or one way) may also occur with other orbiviruses especially Epizootic Haemorrhagic Disease virus (EHDV).

    Owing to the insect transmission, in temperate climates, the infection and disease is seasonal occurring in the late summer and autumn. Not all serotypes of BTV are present in each of the areas where it exists around the world.

    Different vector species also exist in different regions (episystems) around the world and variations may exist in the viruses present in a region that reflect adaptation to the vectors that are present.

    Several ‘western’ BTV strains (BTV-1, 6, 8, and 11) have been detected in northern Europe, suggesting that they can be transmitted effectively by Culicoides species present in the region. However, several additional BTV strains (eastern BTV-1, 9, 16 and western BTV-2 and 4) have persisted in Southern Europe without (so far) spreading to the north. This has provided a unique opportunity for these viruses to exchange genome segments, generating novel virus strains, some of which appear to have distinct biological characteristics

    GAPS:

    • BTV genome sequence analyses to define the existence and global distribution of different virus serotypes / lineages / topotypes; determine significance of strain variations and genome-segment-reassortment, in infection of the mammalian host, infection of different insect vectors, and transmission between them.
    • Investigate why viruses emerge and persist and what determines their transmissibility, changes in their distribution, and evolution.
    • The identity of neutralising epitopes on the outer capsid proteins (VP2 and VP5) of BTV has not been fully resolved for the different serotypes. These is evidence for at least some cross-reactive sites between types, identification of which could help to support the design and development of cross-reactive vaccines.
    • The nature of the mammalian cell-mediated immune response against BTV and its role in protection against homologous and heterologous strains / topotypes has not been fully explored.
    • Use of new reverse genetics technologies to explore the genetic basis for biological characteristics (e.g. virulence or transmissibility, serotype, temperature dependence etc) of different virus strains.
    • The immune response of adult Culicoides to BTV infection has not been explored, but may have an important role in persistence and transmission of different viruses by different insect species / populations.
    • Provide sequence data for multiple well documented isolates of BTV, to provide information concerning their molecular epidemiology and the processes of virus evolution. These studies will provide ‘reference’ sequences for each of the ten genome segments from specific BTV lineages, topotypes and strains around the world, to identify genome segment reassortment events and strain movements in the field.
  • Stability of the agent/pathogen in the environment

    The bluetongue virus (BTV) is very stable. It survives essentially forever when frozen, although the process of freezing and thawing will itself reduce the titre of virus by approximately 1 log10. It can survive for years in whole blood kept in a refrigerator. The virus survives as long as 60 days in the circulation after infection of a ruminant, and infection persists life-long in vector insects. The virus apparently survives freezing winters. However, the mechanism behind this survival or ‘over-wintering’ remains unknown although vertical transmission in the mammalian host has been demonstrated and may contribute although this is disputed. . It has been proposed that BTV “overwinters” in temperate areas through low level circulation of the virus in animals and vectors, including infected adult insects that survive for relatively long periods even in winter. There is also some evidence for detection of BTV RNA in Culicoides larvae collected in the field from outbreak sites in North America. This suggests that in some cases the virus may be transmitted vertically in the insect vector, However, attempts to recover infectious virus were unsuccessful and the epidemiological significance of these observations is uncertain.

    GAP: Understanding the over wintering mechanism(s) in the host, vector and/or environment including potential differences between species and distinguished ecological zones.

  • Species involved

  • Animal infected/carrier/disease

    Bluetongue virus infects many domesticated, zoo and wild ruminants including sheep, goats, cattle, South American camelids, buffalo, bison, deer, antelope, bighorn sheep and North American elk. Clinical disease is most often seen in sheep, occasionally in goats, but rarely in cattle. However, with BTV-8 in the EU, clinical disease in cattle was reported from several countries. Severe disease can also occur in some wild ruminants including white-tailed deer (Odocoileus virginianus), pronghorn (Antilocapra americana) and desert bighorn sheep (Ovis canadensis). Disease also has been described in an extensive variety of non-African ungulates in zoos in Europe, and in South American camelids present in the UK, France, Germany and USA. In Africa, some large carnivores have antibodies to bluetongue and fatal disease has been described in Eurasian lynx. In North America a contaminated vaccine resulted in abortions and deaths in pregnant dogs.

    GAPS:

    • The role of wildlife species in the persistence of BTV in the environment.
    • The role of carnivores including domestic dogs in the transmission of BTV.
    • Understanding the over-wintering mechanisms including more investigation on the potential role of reservoir and vertebrate host in carrying the virus.
    • The potential role of the vertebrate host as a carrier for BTV – overwintering mechanism.
  • Human infected/disease

    No.

  • Vector cyclical/non-cyclical

    Biological vectors are Culicoides species. BTV infection/recovery from tick species were also reported, although the epidemiological significance of these observations is uncertain.

    GAPS:

    • Identification and impact of the different Culicoides species involved in the transmission of BTV in the different ecological zones.
    • Understanding of BTV transmission by other routes (e.g. via other biological vectors, by mechanical transmission involving other biting insect species, via an oral route such as ingestion of infected meat/placenta).
  • Reservoir (animal, environment)

    Cattle are the main reservoir and amplification hosts. Sheep and possibly other ruminants are also a potential source of virus for transmission.

    GAP: Understanding the over-wintering mechanisms including more investigation on the potential role of reservoir and vertebrate host in carrying the virus.

  • Description of infection & disease in natural hosts

  • Transmissibility

    Insects: Transmission primarily by biting midges (adult females of certain Culicoides species). Non contagious disease, however, there is also evidence for oral infection / transmission, although this is uncommon and its epidemiological significance uncertain. Trans-placental transmission occurs with lab-adapted viruses (mostly live attenuated vaccine strains) and also some virulent field strains such as the current European BTV-8 strain.

    The proteases present in saliva from adult Culicoides can modify the outer capsid proteins of the virus, enhancing its infectivity for the vector insect and removing its hemagglutination activity. These changes and enzymes may therefore play a significant role in the infection processes in both the insect and mammalian host.

    GAPS:

    • Understand the processes and mechanisms which underlie transmission of BTV 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 barriers to infection / transmission.
    • Culicoides saliva contains a large number (undetermined) of individual proteins, including both enzymes (e.g. proteases) and inhibitors. The role of these proteins needs further investigation.
    • Define the thermal & vector requirements of BTV in both the field and laboratory, to predict incursion risk into the EU.
    • Investigate the effect of temperature on the extrinsic incubation period (EIP) in different species of Culicoides midges.
    • Mechanism of transplacental transmission: a) Determine the viral genetic factors involved in transplacental transmission. b) Determine why transplacental transmission occurs with some field strains (for example the northern European strain of BTV-8) but not others. c) Determine why transplacental transmission occurs in animals infected with laboratory adapted BTV strains far more readily than with field strains. d) Determine the molecular mechanisms controlling transplacental transmission. e) Determine whether viraemic newborns play a role in BTV spread/overwintering, and the importance of colostral antibodies in suppressing infection.
    • Investigate further a possible role for oral transmission, through infected colostrum or placenta, in the spread and over-wintering of BTV.
    • Determine the significance of short distance (local) spread as compared to long distance spread?
    • 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 BTV.
  • Pathogenic life cycle stages

    During its life cycle the virus infects arthropod and vertebrate hosts. The virus has an enzootic cycle and is transmitted from arthropod vector to competent reservoir host. Domain: Viral hosts belong to the Domain Eucarya.

    GAP: Vector competence and ability of different species of Culicoides vectors to transmit different serotypes / strains / topotypes of BTV.

  • Signs/Morbidity

    The vast majority of infections with bluetongue are clinically inapparent. In a percentage of infected sheep and occasionally other ruminants, more severe disease can occur. The severity of clinical signs depends on breed and immune status of the host, and is greater in naive animals / populations.

    • Acute form (sheep and some species of deer)
    • Transient fever (up to 42°C), depression
    • Inflammation, haemorrhages (particularly in the skin), ulceration, erosion and necrosis of the mucosae of the mouth, swollen and sometimes cyanotic tongue
    • Lameness due to coronitis or pododermatitis
    • Abortion of severely affected animals (often without virus-infection of the fetus)
    • Torticollis,
    • Conjunctivitis,
    • Severe pulmonary oedema, serous effusions and subcutaneous and intermuscular oedema
    • Complications of pneumonia
    • Emaciation
    • Either death within 8-10 days or long recovery with alopecia, sterility and growth delay.

    Can be teratogenic in cattle and sheep (depending on strain), and can lead to dummy calf syndrome. Early embryonic loss and decreased reproductive efficiency is a more frequently seen manifestation of the disease in cattle and can be devastating to their calf/milk production. Clinical signs in cattle also include hyperaemia and necrosis of the muzzle (“burnt muzzle”) and patchy dermatitis.

    GAPS:

    • Why are some strains of BTV more pathogenic than others?
    • What is the basis for the reduced severity of clinical signs in those animals that have previously been infected with heterologous serotypes. Is a cell-mediated or cross-reactive antibody response involved.
  • Incubation period

    In sheep, the incubation period is usually around 5 to 10 days although this may be dependent on the infectious dose of virus. Cattle can become viraemic starting at 3-4 days post-infection, but rarely develop clinical symptoms. Animals are usually infectious to the insect vector for several weeks.

    GAPS:

    • Does the incubation period in cattle and sheep vary according to the infectious dose of the virus?
    • Is the period of infection similar after natural infection (= bites by infected midges, via an oral route, or mechanical transmission) as compared to experimental infection.
    • How variable is the incubation period and infectious period in culicoides-infected animals in the field.
    • What is the maximum length of time that animals remain infectious to midges compared to persistence of viral RNA and virus (isolated in the lab)?
  • Mortality

    In sheep, the severity of disease varies with the breed of sheep, immune status, virus strain and environmental stresses. The morbidity rate can be as high as 100% in this species. The mortality rate is usually 0-30%, but can be up to 70% in highly susceptible sheep. Similar morbidity and mortality rates are seen occasionally in certain other species, including South American camelids, zoo and free ranging non-African ungulates, with a morbidity rate as high as 100% and a mortality rate of 80-90%.

    Most (but not all) infections in cattle, goats and North American elk are asymptomatic. In cattle, up to 5% of the animals infected with certain BTV serotypes (serotype 8 in particular) may become ill, but deaths are rare. In some animals, lameness and poor condition can persist for some time.

    GAPS:

    • Host and virulence factors determining the clinical outcome of infection.
    • Why are some strains of BTV more virulent than other in cattle and sheep?
    • Why are certain breeds of sheep resistant to BTV infection whereas other breeds are extremely susceptible?
    • Natural resistance - why are African ruminants in general more resistant than non-African ruminants.
    • It has been suggested that the introduction of novel exotic strains to endemic areas can result in more severe disease in native breeds (as observed in India). Is this due to differences in the virus topotype, resulting in a reduction in cross-reactive, non-neutralising antibody based or cell mediated cross-protection?
  • Shedding kinetic patterns

    Although virus may be detected in the blood of cattle and sheep by RT-PCR for several months, infected animals usually only transmit virus to a competent biting vector for a number of weeks (at most) after infection. The OIE states that the infectious period is up to 60 days post infection although most animals are infectious to vectors for a shorter period.

    GAPS:

    • Identification of the infectious period and period of detection by PCR under natural environmental conditions.
    • How long do sheep and cattle remain infectious and is the length of the infectious period dependent on the infectious dose?
    • Is there a correlation between Ct values in real-time RT-PCR assays that can be used to give a reliable indication of transmission risk (i.e. the presence of infectious virus) in the late stages of infection?
    • Are there host genetic factors involved in controlling the length of the infectious period?
    • Are there genetic factors of BTV involved in controlling the infectious period?
    • Are there genetic factors of the vector involved in controlling the infectious period of the host (does the species of infecting Culicoides influence the length of the infectious period).
    • The role of Culicoides saliva and the significance of the local hypersensitivity reaction, in the mechanism and kinetics of infection and dissemination in the mammalian host.
  • Mechanism of pathogenicity

    After infection via the saliva of a biting midge, BTV can infect and is transported by different cell types, including cellular components of the host’s immune system. The virus spreads to and multiplies in the regional lymph nodes and then disseminates to secondary organs of replication, followed by dissemination in the blood. This systemic multiplication and spread allows ample opportunity for humoral and cell-mediated immune responses to develop. As BTV is associated with the cellular fraction of the blood where it is protected from the effects of humoral antibody, extended viraemia may occur and virus and antibody may circulate in the system at the same time.

    GAPS:

    • What are the molecular mechanisms related to pathogenicity?
    • The role of innate and acquired immune responses in the pathogenesis of disease.
    • The role of Culicoides saliva in the pathogenesis of disease.
    • Sites of transient persistence of BTV in the vertebrate host.
  • Zoonotic potential

  • Reported incidence in humans

    Bluetongue is not a significant threat to human health. Only one suspect human case has ever been reported, but reasonable precautions should be taken while working with this virus.

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

    None - Bluetongue does not affect humans, nor is there any risk of the disease being contracted or spread through meat or milk. (EFSA)

  • Symptoms described in humans

    None.

  • Estimated level of under-reporting in humans

    None.

  • Likelihood of spread in humans

    None.

  • Impact on animal welfare and biodiversity

  • Both disease and prevention/control measures related

    Variable impact depending on species, immune status, the virulence, and genotype/topotype of the of the infecting virus strain.

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

    Possibly if susceptible. There is evidence for BTV specific antibodies in large carnivores in Africa. Eurasian Lynx fed with infected meat also became fatally infected with BTV-8. It is possible that the incidence of BTV could represent a significant threat of infection and even the survival of endangered predator species.

    Certain deer species (e.g. white tailed deer) can also be very susceptible to BTV infection showing very severe clinical signs, including significant fatalities.

    GAPS:

    • Investigate the pathogenesis of BTV infection in different wildlife species to assess relative susceptibilities.
    • Understand the potential impact on endangered species of the introduction of exotic strains / topotypes in endemic areas.
    • The efficacy of vaccination against BTV, has not been assessed in predator species, (e,g, in dogs)
  • Slaughter necessity according to EU rules or other regions

    Only for animals welfare reasons. BTV-8 caused severe clinical signs in sheep necessitating, for animal welfare reasons, slaughter.

  • Geographical distribution and spread

  • Current occurence/distribution

    The virus is present in a broad band of countries extending approximately between 40°N and 35°S although in some regions (e.g. China, North America, and more recently Europe) it may extend to 55oN. Bluetongue virus has been shown by serology and by virus isolation to be limited to regions where vector species of Culicoides are present and within these regions vector transmission is limited to those periods of the year when adult Culicoides are active (e.g. Africa, the Americas, Australia, the Middle East and some countries of southern Asia and Oceania).

    The virus is present in some regions with little associated clinical disease in the native ruminant populations. However introduction of exotic strains (topotypes) may lead to more severe disease in these native breeds. The introduction of exotic 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.

    Until recently bluetongue had only been recorded in southern regions of the EU including parts of Italy, Spain, France, Greece and Portugal, matching the distribution of the known vector species Culicoides imicola . However, since 1998 the bluetongue situation in the EU has changed considerably, with incursions of six new serotypes into southern Europe and serotypes 1, 6, 8 and 11 into northern Europe. In late summer 2006 several northern European countries reported the first ever outbreaks of bluetongue in the region, caused by BTV serotype 8 (BTV-8), including Holland, Belgium, Germany, Luxembourg and France. Further outbreaks were reported in 2007 and 2008. In 2007 northern Europe experienced a dramatic increase of new cases in the existing infected areas, and cases numbered into the many tens of thousands, as the disease spread steadily across most of Europe, including an incursion in the UK.

    Affected countries began vaccination programmes in 2008 when, as expected, disease re-emerged in many of them. Vaccination with inactivated vaccines has proved highly successful, dramatically reducing the number of BTV cases in the majority of northern and western European countries in 2008. The exception was France which reported over 23,000 cases of BTV-8 and over 3,500 cases of BTV1 in 2008. However the vaccination campaign had a dramatic effect in France during 2009, with a total of only three successful virus isolations. Compulsory and voluntary vaccination programmes have continues against BTV-1 and BTV-8 throughout 2009 and into 2010. These campaigns have been extremely successful with no cases of BTV-8 being reported throughout 2010 in Northern and Western Europe.

    GAPS:

    • To understand and model the distribution, spread, persistence and risks represented by BTV including viral, vector and host dependent factors, and the importance of environmental factors, such as temperature (day and night), humidity, geographic conditions, etc.
    • Identification of apparent associations between some genotypes of virus and some vector species has resulted in a concept of viral-vector ’episystems’.
    • A more complete understanding of these epidemiological aspects may further facilitate international trade in ruminants.
    • 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.
  • Epizootic/endemic- if epidemic frequency of outbreaks

    Capable of being endemic in southern Europe. Possibility of being epidemic across the whole of Europe as far north as Scandinavia. Transmission is seasonal and usually depends on the infection of the Culicoides vectors from the reservoir hosts such as cattle early in the season.

    GAPS:

    • Continuous monitoring and overview of global BT situation.
    • Investigate the competence of the northern European species of Culicoides midges.
    • The nature of future climate change in Europe is uncertain. Hotter summers are considered likely to lead to an increased likelihood of further BTV incursions in Northern Europe, and perhaps persistence of the virus.
  • Seasonality

    Seasonal cycle related to the movement life cycle and seasonal abundance of the adults of Culicoides vectors.

    GAP: Factors involved in vector survival throughout the winter period, and their re-emergence during the vector season (usually summer).

  • Speed of spatial spread during an outbreak

    Can be high depending on the infection rate in the Culicoides vectors and the time of the year. The wind borne spread of infected Culicoides can be rapid, and can lead to dispersal of the virus considerable distances across water (e.g. from Morocco to Iberia, or across the English Channel).

    Initial spread may involve small numbers of infected animals over large distances caused by movements of infected animals or vector insects (as seen in Europe during 2006), but spread in subsequent seasons (2007) involved very large numbers of animals across massive areas.

    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 BT and develop epidemiological models for its spread & control.
    • Investigate the speed of spatial spread of BT depending on the different transmission modes under varying meteorological and environmental conditions.
    • Rates of spread through different Culicoides species taking into consideration host preference, efficiency of transmission etc.
  • Transboundary potential of the disease

    Bluetongue virus has recently expanded its geographic range and is able to cross borders due to the wide distributions of vector species of Culicoides, their high mobility and their adaptability to various climatic conditions.

    Significantly, the route of transmission of BTV-6, 8 and 11 to northern Europe are all unknown. Although such events are rare, they are clearly of major epidemiological significance.

    GAPS:

    • Impact of global trade, animal movement, cultural habits and travel on disease spread in relation to long distance dispersal mechanism like wind spread.
    • Understanding of gradual and apparently limited expansion versus “long distance incursions”. Both are not always related to the involved Culicoides species. Why?
  • Seasonal cycle linked to climate

    In many parts of the world infection has a seasonal occurrence. Climate, particularly ambient temperature has an impact on the Culicoides life cycle and survival of the vector. It may also impact on the development of BTV in the vector.

    GAPS: Culicoides life cycle, BTV development in the midge and seasonal distribution of BT 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

    Distribution of the vector is linked to climate and environmental conditions and as a consequence occurrence of disease also linked to the vector. Warmer seasons may allow development of BTV in species of Culicoides which are not able to transmit the virus at lower temperatures.

    GAP: Modelling the potential effects of climate change on the distribution of culicoides vectors and BTV into the future.

  • Outbreaks linked to extreme weather

    Warmer winters in Europe may enable the adult Culicoides midges to overwinter more frequently. However, vector Culicoides can travel by wind for 100s of kilometres, thus increases in wind movements may enable colonization of new habitats by vectors and the rapid spread of BTV to areas remote from the source.

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

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

    Vector Culicoides breeding and survival is governed by ecological factors, such as rainfall, temperature, humidity and soil characteristics. BTV infection and transmission by vectors is enhanced by high temperature and by vector survival rates. Any impact of climate change on any of these factors will potentially alter the distribution and spread of the disease

    Increasing environmental temperature (climate change) will also extend the vector season.

    Vector competence of Culicoides vectors for Orbiviruses is partly controlled by temperature. Orbivirus development in Culicoides vectors 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.

    The replication of the BTV viral RNA is entirely mediated by the viral polymerase, which is active over the range 10 to 45 degrees, with an optima around 31 degrees. This may help to explain the temperature dependence of BTV replication in the vector insects.

    GAPS:

    • Culicoides life cycle, BTV development in the midge and seasonal distribution of BT outbreaks taking also into account environmental conditions, farm/animal density in different parts of Europe / the world.
    • Modelling the potential effects of climate change on the distribution of culicoides vectors and BTV into the future.
    • Investigate the vector competence of different Culicoides species and how this is affected by increases in temperature.
    • Investigate how the replication of different virus strains/lineages responds to changes in ambient temperature, and the molecular basis for such variations.
  • Route of Transmission

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

    Insects are biological vectors of the disease. Bluetongue virus (BTV) is transmitted between mammalian hosts via bites from adults of certain species of Culicoides midges. Midges of certain species in the genus Culicoides transmit BTV between susceptible ruminants, having become infected by feeding on viraemic animals (the vertebrate host). After a replication period of 6–8 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 life. Infection of the midge is a relatively inefficient process with less than ~10% of insects that ingest a viraemic blood meal becoming infected. An even lower percentage may become fully infected and capable of transmitting the virus, depending on the insect vector species. However, transmission of virus from a fully infected insect to mammalian host is an efficient process (possibly up to 100% efficient). This may help to explain the transmission of virus by wind borne insects over large distances.

    GAPS:

    • Determination of likelihood of introduction of BT into new regions depending on the mode of transmission.
    • The Culicoides saliva contains multiple proteins, including proteases that can modify the virus capsid, influencing its cell binding properties and infectivity. Further information is required concerning the significance of these proteins/ modification during transmission from insect to host and from host to insect.
  • Occasional mode of transmission

    Transplacental transmission by the northern European strain of BTV-8 and lab adapted vaccine strains (live attenuated vaccine strains).

    The occasional occurrence of venereal transmission from infected male ruminants to females and their offspring.

    Oral transmission to ruminants (eating infected placenta, ingestion of virus-containing colostrum) and carnivores (eating infected meat).

    GAPS:

    • Further work is required in order to study oral / mechanical transmission of BTV and the significance of these transmission mechanisms in the field.
    • Investigate further a possible role for oral transmission, through infected colostrum or placenta, in the spread and over-wintering of BTV.
  • Conditions that favour spread

    High density of vector Culicoides and high livestock density in an area. High temperatures which enhance virus development in and transmission by vectors. Wind conditions which can blow the vector into new areas. Naive host populations; introduction of exotic BTV strains.

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

  • Detection and Immune response to infection

  • Mechanism of host response

    Complex: Humoral with neutralizing and non-neutralizing antibodies. Cell-mediated immunity. Inflammation.

    Immunity (naturally acquired after infection or induced by vaccination) against one serotype is often ineffective or less effective in case of infection due to a different serotype.

    BTV can persistently infect ovine γδ T-cells in vitro, a process that may also occur during infection in mammalian hosts, thus providing a mechanism for virus persistence.

    BTV can infect other cellular components of the mammalian immune system (dendritic cells), which may be involved in dissemination of the virus in the mammalian host.

    Cleavage of virus surface proteins by host protease enzymes associated with inflammation generates infectious sub-virus particles that have enhanced infectivity (100 times) for the insect vector.

    GAPS:

    • The nature of the antiviral response in the insect vector is almost entirely uncharacterised.
    • Increase knowledge concerning host immune responses to BTV, identify correlates of protection in vaccinated animals and determine immune evasion mechanisms as well as the role of immunity in pathogenesis of disease.
    • Increase understanding of the immune responses to BTV to improve vaccination strategies: including identification of viral epitopes involved in type specific and cross-reactive immune reactions and protection;
    • Identification of mechanisms by which viruses evade host innate and adaptive immune responses.
    • Understanding the mechanism of prolonged viraemia. Where is the virus for each serotype? In which form (infectious or non-infectious virions)? Where does the virus replicate in mammals?
    • What are the receptors in mammals and insects for all serotypes?
    • What is the importance of cell-mediated immunity and the precise mechanisms for protective immunity?
    • What viral proteins / sites are involved in a protective cell mediated response.
    • What are the activated signaling pathways during infection and/or vaccination?
    • In insects, what is the nature of the innate barriers? Are some viruses able to kill the vector? (this is the case for other arboviruses).
    • Are acquired immune mechanisms induced during infection in insects?
  • Immunological basis of diagnosis

    Neutralizing antibodies against VP2 and VP5. Antibodies against VP7 are detected in the current commercial ELISA tests. Antibodies against other conserved viral proteins could also serve as a basis to indicate a previous infection. Cellular immune responses against NS1, VP-2, VP3, VP5 and VP7.

    GAPS:

    • Development to serotype-specific ELISA assays.
    • The ability of existing ELISA to detect novel virus types and topotypes requires further investigation.
  • Main means of prevention, detection and control

  • Sanitary measures

    Quarantine and serological surveillance; vector control; zoning. The most important sanitary measure to avoid the introduction of BTV in a free country is the testing and safe importation of live animals (and semen and embryos). To control the disease and the spread of infection: prompt reporting of BT outbreaks; vaccination; presence of appropriate serological and entomological surveillance and monitoring programme. GAPS:
    • Development of vaccines against all BTV serotypes / topotypes.
    • Development of cross reactive vaccines.
  • 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 and the use of vaccines.

    Restriction of movements and the use of vaccines are the most important control measures.

    GAP: Development of more effective insecticides and protective measures like impregnated netting.

  • Diagnostic tools

    Antibody Detection: ELISA, Virus neutralisation.

    Antigen detection: Real time RT-PCR or conventional RT-PCR, type specific RT-PCR, virus isolation and direct ELISA.

    Serogroup specific conventional and real-time RT-PCR assays are available.

    Serotype-specific PCR assays exist for all 6 serotypes.

    GAPS:

    • Development of serotype specific ELISAs,
    • Check cross reactivity between topotypes,
    • Development of DIVA serology assays in combination with DIVA vaccine,
    • Development of molecular-based DIVA assays in combination with DIVA vaccines,
    • RT-PCR assays need to be tested / validated against a wider range of strains and updated as required.
  • Vaccines

    Three types of vaccines can be considered: inactivated (killed), attenuated (‘live’) and recombinant virus vaccines but only killed and live vaccines are currently on the market.

    When vaccinating with modified live virus vaccines the serotypes incorporated into the vaccine must be the same as those causing infection in the field.

    Different vaccines have been applied since the disease started in the EU. During the outbreaks of 2000-2005 sheep in France were vaccinated with live attenuated vaccines against serotypes 2, 4 and 16 and sheep in Spain were vaccinated against serotypes 2 and 4. In Italy from 2002-2005 domestic ruminant (cattle, goats and sheep) population was vaccinated with live attenuated vaccine against serotypes 2, 4, 9, 16. The use of these ‘live’ vaccines does have some drawbacks They may revert to virulence or may already be virulent in naïve populations; they may induce abortion when given to pregnant females, they cause viraemia and can circulate in the field in Culicoides midge populations and the vaccine virus may undergo reassortment with circulating field strains of another serotype or topotype. However despite these drawbacks, live attenuated vaccines have sometimes been used successfully in controlling and in some circumstances (Balearic islands) eradicating the infection. These vaccines have been used successfully for many years to protect animals in endemic areas (e.g. in Southern Africa).

    Inactivated vaccines to BTV-2 and BTV-4 became available in 2005 – 2006 as an alternative to live attenuated vaccines. From 2007 / 2008 inactivated vaccines against BTV-1, BTV-8 and BTV-9 came onto the market and during 2008 a mass vaccination campaign was introduced in many EU countries against BTV-8 and BTV-1, which has been very successful.

    Modified attenuated vaccines have also been developed in Italy, where they have been used widely with good results.

    GAPS:

    • Development of vaccines that protect against all BTV serotypes. This could be achieved through cross reactive vaccines, or serotype specific vaccines against all serotypes.
    • Development of inactivated (DIVA) vaccines for each of the 24 BTV serotype. This could potentially be achieved through cross reactive vaccines.
    • Development of recombinant / subunit (DIVA) vaccines against individual and multiple serotypes of BTV. Again the scope for cross-reactive vaccines needs to be explored.
    • Develop novel subunit vaccines and associated DIVA assays.
    • Increase understanding of the immune responses to BTV to improve vaccination strategies: including identification of viral epitopes involved in type specific and cross-reactive immune protection;
    • Further understanding is needed of the significance of strain / topotype variation in the specificity, efficacy of neutralizing antibody and cell mediated responses.
    • More work is required in the development / evaluation of novel / appropriate antigen delivery platforms / adjuvants.
  • Therapeutics

    No efficient treatment.

    GAP: A better understanding of the biochemistry and replication of the virus could lead to opportunities to develop antiviral agents. However, it is not considered likely that these will play a major role in protection against BTV infection in the field.

  • Biosecurity measures effective as a preventive measure

    Ensuring no contact between vector and susceptible animals which can be difficult. Quarantine of animal hosts to prevent movement of infected animals into new areas. Quarantine in Culicoides proof stables and negative results to BTV RT-PCR assay or c-ELISA.

    GAP: Development of more effective insecticides and protective measures like impregnated netting.

  • Border/trade/movement control sufficient for control

    EU regulation based on animal movement and vector control.

    Vaccination, serological / entomological surveillance and monitoring programs.

    GAPS:

    • Appropriate size of control and surveillance zones in case of BT outbreaks.
    • The mechanism for long distance movement of BTV strains e.g. BTV-8 to northern Europe) still needs to be understood. Without this information it is difficult to develop appropriate controls/regulations to prevent further similar events.
  • Prevention tools

    Movement controls and vaccination.

    GAPS:

    • Development of vaccines that protect against all BTV serotypes. This could be achieved through cross reactive vaccines, or serotype specific vaccines against all serotypes.
    • Development of inactivated (DIVA) vaccines for each of the 24 BTV serotype. This could potentially be achieved through cross reactive vaccines.
    • Development of recombinant / subunit (DIVA) vaccines against individual and multiple serotypes of BTV. Again the scope for cross-reactive vaccines needs to be explored
    • Develop novel subunit vaccines and associated DIVA assays.
    • Increase understanding of the immune responses to BTV to improve vaccination strategies: including identification of viral epitopes involved in type specific and cross-reactive immune protection;
    • Further understanding is needed of the significance of strain / topotype variation in the specificity, efficacy of neutralizing antibody and cell mediated responses.
    • More work is required in the development / evaluation of novel / appropriate antigen delivery platforms / adjuvants.
  • Surveillance

    Surveys to identify infected areas, testing of imported or moved animals, notification of clinical disease.

    Entomological surveillance to know the species and abundance of Culicoides populations.

    Although there is no effective serological DIVA assay for use with the inactivated vaccines, the existing conventional RT-PCR assays can be used to detect animals that have recently been infected (and therefore represent a potential infection risk) regardless of the vaccination status of the animal. In some respects these assays are more effective than more conventional DIVA assays.

    GAPS:

    • Surveillance strategies taking into account limited resources and local conditions of disease and vector occurrence as well as climatic and environmental conditions.
    • Need for DIVA serological tests to differentiate vaccinated from infected animals independent of time of sampling, and/or a genetic DIVA assay for use during or directly after the BTV season.
    • Serological DIVA assays should be easier to develop for subunit and recombinant vaccines that use a depleted repertoire of the viral proteins as vaccine antigens.
    • All assays will need continued evaluation/validation, to ensure they are effective for target/novel virus strains.
  • Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

    Vaccination effective in reducing mortality and morbidity. Once infected and endemic difficult to eradicate, although it does also spontaneously clear without any vaccination after incursions of single serotypes – e.g. Canada.

    Successful eradication has been achieved (Spain, BTV-4, Balearic Islands) through high vaccine coverage (>80%) over an extended period of time (3-5 years).

    Vaccination with inactivated vaccines in the recent northern European outbreak has been extremely successful, for example the UK completely prevented re-emergence of the BTV outbreak in 2008. The number of infected farms in France was also reduced from 29,000 to <100 between 2008 and 2009. This was achieved through high levels of vaccine coverage (>80%) using a compulsory vaccination programme. Similar reductions in the incidence of disease have been achieved in Holland, Germany, Belgium and the UK through vaccination.

    There is clear evidence for the circulation and reassortment of multiple live BTV vaccine strains in the field within Europe. These viruses can experimentally cause severe clinical signs in naive ruminants. Although they may be useful in protection against the clinical signs of disease in endemic areas, they may be less effective in protection against virus spread, or in eradication.

    GAP: Modelling the use of vaccination as an effective control measure.

  • Costs of above measures

    Costs of vaccine and impact of movement controls.

  • Disease information from the OIE

  • Disease notifiable to the OIE

    Yes.

  • Socio-economic impact

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

    No effect on Human movement or activities.

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

    None.

  • Direct impact (a) on production

    Direct economic loss through diseased animals both morbidityand mortality, loss of productivity, loss of milk yield, abortion, loss of fertility.

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

    Cost of vaccine, costs of application, testing, impact of movement controls, reduced ability to export or to move within a country.

  • Indirect impact

    High indirect economic impacts through trade barriers.

  • Trade implications

  • Impact on international trade/exports from the EU

    The only internationally accepted diagnostic technique for the identification of the agent for international trade is reverse-transcription Polymerase Chain Reaction (RT-PCR); nevertheless there are other techniques that allow the identification of the agent, detailed in the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals, such as virus isolation or immunological methods.

  • Impact on EU intra-community trade

    Restrictions on free movement of animals due to restricted areas and testing requirements

  • Impact on national trade

    The duration of BTV viraemia in domestic ruminants has been a critical issue in international trade and placement of trade barriers. The OIE currently recognizes a 60 day infective period.

  • Main perceived obstacles for effective prevention and control

    • Diversity and variability of virus strains / serotypes / topotypes. Potential for reassortment.
    • Diversity of vector (many 100s of potentially competent Culicoides species).
    • Domestic and wild ruminants act as reservoirs with a long-lasting viraemia
    • Vector control almost impossible
    • Likely to be at least 26 serotypes, vaccines are serotype specific and are not available for all serotypes (live-attenuated vaccines are multi-serotype vaccines).
    • Uncertain elements of the BTV life cycle, including potential role of vertical and/or oral transmission of animals.

    GAPS:

    • Investigate the degree of reassortment that is occurring in the field in areas where BTV is endemic.
    • Further understanding of the diversity and global distribution of different virus strains /serotypes / topotypes.
    • Further understanding of cross-reaction and potential for cross protective vaccines between different strains, and the underlying immune mechanisms involved.
  • Main perceived facilitators for effective prevention and control

    GAPS:

    • Studies on the duration of viraemia in susceptible species, the determination of the infective titre and the mechanisms of overwintering would help to facilitate prevention and control. Virus is relatively well known but there is a need to develop new safe killed / recombinant vaccines against all the BTV serotypes.
    • In particular the development of effective cross serotype / cross topotype vaccines would be extremely useful and could potentially lead to an effective wider eradication campaign.

Risk

  • The recent spread of BTV (such as BTV-8) across the whole of Europe confirms the presence of suitable vectors in each of the affected countries. The whole of Europe must therefore be considered at risk from further incursions of BTV and other Culicoides transmitted orbiviruses, such as AHSV, EEV, EHDV. Local climate change could lead to increasing local temperatures, exacerbating these risks.

    In infected areas, monovalent live virus vaccines or subunit vaccines could potentially allow/force selection of new variant strains of BTV through genetic drift or shift (reassortment).

    Reassortment can occur between existing field strains in the field in Europe, including both eastern and western lineages, potentially leading to the emergence of progeny strains with novel biological characteristics.

    The recent isolate of BTV-4 from Morocco and Spain (2010) is a reassortant involving earlier strains of BTV-1 and BTV-4, and may have enhanced virulence in cattle.

    From 1998-2010, BT occurred in 20 countries in Europe; 14 of these countries reported BT to the OIE for the first time. The outbreaks were primarily caused by serotypes BTV- 1, 2, 4, 8. 9 and 16 . BTV-1 spread from northern Africa to Spain then as far as the north coast of France. BTV- 2 spread from northern Africa to France and then into Italy. BTV-4, 9 and 16 were first reported from the southeastern Mediterranean basin, and moved north and east to Italy. BTV-8 was reported recently in Netherlands, Germany, Belgium and north of France before spreading across the whole of Europe.

    Mechanisms for spread of BTV are thought to include illegal movement of viraemic animals and wind translocation of infected vector Culicoides spp. During the outbreaks, several southernn European countries implemented emergency mass vaccination using attenuated virus vaccines. Preliminary evidence indicates that mass vaccination was a useful tool in controlling the outbreaks, although outbreaks caused by live vaccine strains were also recorded.

    Traditional control measures for BT include animal movement restrictions, vector control, slaughter of viraemic animals, and management to reduce animal:vector exposure.

    GAPS:

    • Additional research is needed regarding use of vaccines during outbreaks.
    • Emergence of a novel reassorted BTV strain during a mixed infection of two parental strains, implies that it has some selective advantage over both parents and other progeny strains generated in the same outbresk. This implies that the new virus could have enhanced transmission or replication characteristics that might make it more dangerous.
    • Several reassortant strains have been identified in Europe. However, the potential for existing BTV strains in north Africa / the Mediteranean region /Europe to generate new strains, and the threat that these novel viruses might pose has not been fully evaluated.

Main critical gaps

Conclusion

  • Bluetongue remains a major health and trade problem for sheep and cattle industries. In infected countries, BT is a priority for Veterinary Services. Surveillance as well as vaccination remains principle tools for prevention and control, depending on the context. A number of vaccines and diagnostic tests are available in Europe and worldwide but technological advancement in both domains would be desirable. Due to a relatively high numbers of products on the market, it is unlikely that industry will invest in new technologies, unless external funding sources can be mobilized within the context of formal collaborations.

Sources of information

  • Expert group composition

    Dr Chris Oura - University of the West Indies, Trinidad and Tobago - [Leader]

    Expert group members have been included where permission has been given to do so

    Professor N James Maclachlan University of California, Davis, USA Dr Giovanni Savini, IZS, Teramo, Italy Dr Eileen N. Ostlund, USDA, USA Professor Philip Mellor, Institute for Animal Health, UK Dr. Christoph Staubach, Friedrich-Loeffler-Institut; Germany Professor Peter Mertens,The Pirbright Institute, UK Dr Ariane Cagienard ,Merial, France. Mariano Domingo, CReSA, Spain

  • Reviewed by

    Project Management Board.

  • Date of submission by expert group

    31st August, 2011.

  • References

    30th September, 2011.