Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  Diagnostics for FMD are available from a limited number of commercial suppliers. Some reference materials and reagents can be obtained from International Reference Laboratories or are produced in National Laboratories. Commercial reagents include stable and simplified ELISA kits for FMDV detection and serotyping, Lateral Flow Devices for pan-serotype detection and ELISA kits for FMD serology; the latter include kits for NSP-Ab testing and ELISA kits for structural antibodies specific to different serotypes. Availability and quality of commercial kits and robotics for extraction of analytes from clinical samples continues to improve.

  GAP:

  Molecular tests are largely unavailable as kits. Diagnostic kits have not been tested in all possible hosts, in particular in wildlife. LFD are needed for typing of FMDV. Improved validation and completion of the portfolio of diagnostic kits for all SATs antibody and antigen detection.

  See also gaps identified in Section “Main means of prevention, detection and control – Diagnostic tools”.

• Commercial diagnostic kits available in Europe

  See above.

• Diagnostic kits validated by International, European or National Standards

  See above. A small number of laboratories, such as The World Reference Laboratory, hold a wide range of materials for validating tests.

  GAP:

  Sufficient panels of samples for test validation across all serotypes and species are lacking. More studies could be conducted in endemic settings to test and validate new diagnostic kits and devices. Only a few diagnostic tests have been fully validated. Problems when different labs produce their own reagents based on published information and lack of guidelines to show equivalence.

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

  Virus isolation, antigen-ELISA, antibody-ELISAs, virus neutralization test, RT-PCR, sequencing, LFDs.

• Commercial potential for diagnostic kits in Europe

  Low, unless an epidemic occurs.

• DIVA tests required and/or available

  Serological tests can be used to help detect vaccinated and infected animals that show minimal or no disease. These tests rely on the fact that replicating virus, but not immunisation with purified vaccines, elicits an antibody response to the viral NSPs. An advantage of NSP serology tests is that they are not serotype specific and a single test can detect antibodies induced by all serotypes of FMDV.

  Several NSP tests are available as commercial kits and scientific evidence of an adequate validation is needed for new assays.

  DIVA testing can help monitor the effectiveness of control measures in reducing the prevalence of infection or to show that eradication has been successful.

  GAP:

  Improved methods for confirming the specificity of positive test findings are needed. Availability and access to sample panels for validation of new tests are difficult. Lack of knowledge about virus transmission and persistence in vaccinated populations and this creates uncertainty about reliability of NSP tests alone to detect undisclosed infection in vaccinated populations. Alternative methods are needed to test vaccines directly for levels of NSP contamination.

• Opportunities for new developments

  New and innovative diagnostic technologies have been developed, such as next generation sequencing, multiplexing testing systems (microarrays, Luminex, etc), detection of interaction between molecules based on physical/optical variation (ex Bioacore, Blitz, Cantilevers, Attana), new detection systems (Alpha technology, TRF, TR-FRET, …)

  GAP:

  Only some of the new technologies are being evaluated for FMD; investigations on potential benefits for FMD diagnosis could be opportune.

• Vaccines availability

• Commercial vaccines availability (globally)

  Inactivated, non purified or semi-purified FMD virus vaccines with either aluminium hydroxide and saponin adjuvants (aqueous vaccine) or as an oil vaccine (usually double oil emulsion (DOE) or single oil emulsions). Vaccines are usually inactivated by binary ethylenimine. Aqueous vaccines are generally applied subcutaneously while oil adjuvant vaccines are applied intramuscularly.

  GAP:

  Potency and stability of several vaccines globally produced can be poor depending on the producer. Lack of easy standardised and uniform testing systems to discriminated good quality vaccines from poor(er) quality vaccines. New strains of FMDV may emerge for which no adequate vaccines are available. New delivery systems need more study.

• Commercial vaccines authorised in Europe

  Two companies produce inactivated vaccines with market authorisation in EU Member States. EU and some Member States maintain reserves of deep frozen vaccine antigens that can be formulated into many doses of vaccine within a few days.

  GAP:

  Limited number of vaccine strains commercially available and potential exists for new virus variants that are not covered by current vaccine strains. Long pathway for introduction and use of new vaccine strains.

• Marker vaccines available worldwide

  Inactivated, whole virion FMD vaccines can be considered as “a marker vaccine” provided that the purification process has removed most viral non-structural proteins and the animals being tested have not been vaccinated many times. Sufficiently purified vaccines will only raise a host reaction against the structural proteins while a reaction towards the non-structural proteins, e.g. 3-ABC, can be used as a marker indicating infection rather than vaccination. The adenovirus vectored FMD vaccine that has been newly licensed in USA is also an NSP-based DIVA vaccine.

  GAP:

  Improved marker vaccines and associated diagnostic assays needed. However, the downside of ‘marker vaccines’ (higher cost and risk of lower quality) is poorly understood and proper education is needed to discourage the request for marker vaccines in countries or regions where the disease is endemic and eradication is far off.

• Marker vaccines authorised in Europe

  See above.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Current vaccines are rather efficient provided that they are applied before exposure to live virus (at least 1 week before exposure) and provided that: 1) the vaccine strain has been carefully selected to match the outbreak strain; 2) that the sufficient amount of intact antigen is included in the vaccine and 3) that the vaccine is of good quality.. Consequently, the shortcomings of current vaccines are the need to vaccinate ahead of virus exposure and the need of either knowing the antigenic characteristics of the outbreak virus strain or instead add multiple antigens to the vaccine, thereby increasing the costs significantly. In endemic settings, the need for regular booster vaccinations is a major constraint to maintaining protective levels of immunity, as is the heat labile nature of the vaccine, necessitating provision of a cold chain. There is a danger of virus escape from vaccine plants and from inadequately inactivated vaccines.

  GAP:

  See “Main means of prevention, detection and control”. Since FMD vaccines of acceptable quality are amongst the more difficult vaccines to produce from a technical perspective, more expertise in vaccine technology is required in particular with several small local vaccine producers. Review of limitations of current system (patenting, licencing, generic release) and exploration of new models to allow fuller genetic and antigenic matching of isolates and vaccines would be beneficial.

• Commercial potential for vaccines in Europe

  The commercial potential for FMD vaccines in Europe appears to be low. However, National and International antigen vaccine banks for emergency vaccination represent an existing commercial opportunity.

• Regulatory and/or policy challenges to approval

  A number of challenges including the current requirement for market authorisation and for potency testing in live animals.

  GAP:

  Absence of a suitable regulatory system, which deals with the strain differences, strain variability and the emergency character of the disease / strains. Non-sentient models needed for potency determination.

• Commercial feasibility (e.g manufacturing)

  Commercially feasible but return on investment for expensive new vaccines may be limited. Multistrain registration has become possible in Europe and would make registration more affordable.

  GAP:

  Governments should support the development of new vaccines, as there is no market in Europe and America for new products that might help developing countries to control FMD more easily.

• Opportunity for barrier protection

  Feasible to produce buffer zones with vaccination to protect free areas from endemic areas.

  GAP: information on the cost effective application of buffer zones scanty.

• Opportunity for new developments

  In the USA, adenovirus vectored vaccines have been registered for use during an outbreak in the USA and may become commercially available within the next five years with potential advantages in their speed of onset of protection and with a reduced risk for FMDV escape during production or from incomplete inactivation. Another promising line of research is the development of recombinant empty capsids which may have enhanced stability and can be produced without the need to handle live FMDV. There is potential to create master seed vaccines for production of inactivated vaccines using recombinant technology to facilitate rapid changes in the vaccine, e.g. to alter antigenicity to better match emerging strains of FMD virus. Methods to directly measure the NSP and intact capsid content of vaccine antigen batches are areas of current interest, so that purity and potency can be estimated directly and without a requirement for animal tests.

  GAP:

  Understanding the way epitope dominance is expressed and the interplay between the immune system and different antigenic sites on the virus surface, in order to better predict the antigenic match and cross-protection to field strains. Identification of sub-dominant conserved epitopes may lead to the development of more cross-protective vaccines. More studies are needed to explore the application and potential of novel vaccines, especially the adenovirus vectored and the recombinant capsid vaccines.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None.

• Future therapy

  Interferons such as INF-alpha or gamma. Inhibitors of FMD virus replication, e.g. inhibitors of the viral RNA polymerase.

  GAP:

  Better therapeutics could have limited market in developed countries.

• Commercial potential for pharmaceuticals in Europe

  Very low at present.

• Regulatory and/or policy challenges to approval

  Not applicable at present.

• Commercial feasibility (e.g manufacturing)

  Not applicable at present.

• Opportunities for new developments

  Possible developments of antivirals or immune system stimulants. Antivirals could have a limited role in limiting excretion of FMD virus in infected animals and bridging the time gap between infection and immunity after immunisation in an epidemic.

  GAP:

  Commercially minimally attractive to develop due to great uncertainty about likely use.

• New developments for diagnostic tests

• Requirements for diagnostics development

  Diagnostic tools for SATs are not well standardized and International Standards not available.New approaches to genetic characterisation allow tracing of the origin of infection down to the farm level. Pen-side tests have been available for several years but their usage has not been well integrated into diagnostic workflows. Serotype-specific RT-PCR are available only for few serotypes and few virus pools.

  GAPS:

  In addition to gaps already identified in "Main means for prevention, detection and control - diagnostic tools". Practical methods to screen herds for animals incubating disease are not available, even if RT-PCR tests have been used to look for preclinical viraemia or presence in milk and the oropharynx. Limited knowledge on the genetic and antigenic variation in viruses especially in Africa limit the sensitivity of assays. Enough and suited samples for validation of SAT strain diagnostics in particular are lacking. Better vaccine matching tests and better prediction of vaccine protection in the field. More effective and specific DIVA tests, faster diagnostics and field pen-side tests. Application of next generation sequencing to study transmission chains and better understand epidemiology in the field. Further development of molecular assays for serotyping of strains present in different geographical areas (virus pools) should be encouraged.

• Time to develop new or improved diagnostics

  2-5 years.

• Cost of developing new or improved diagnostics and their validation

  Medium.

• Research requirements for new or improved diagnostics

  Economical support for animal studies is essential. Such studies are very costly and it is of utmost importance that funding is available in order to make significant progress. Economic support and twinning projects are useful to facilitate accessibility to samples needed for diagnostics development and validation.

• Technology to determine virus freedom in animals

  GAP: new internationally validated (trade) methodologies for confirming freedom from virus are required.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  Vaccines can be improved in relation to several different properties. One could hope to increase the heat stability of the vaccines, or to e.g. make the response wider and thus covering more outbreak strains (subtypes) or even covering several serotypes. Vaccines may also be improved to provide a more rapid response and to include e.g. components of the innate of cellular immunity in order to potentially also protect against persistent infection. Mucosal vaccination might block virus entry.

  GAPS: FMD Vaccine needs for the future:

  • Improved stability of antigen (non-endemic) and vaccines (endemic)
  • Greater cross-protection (both)
  • Longer DOI (endemic)
  • Better negative markers (non-endemic – currently use absence of NSPs)
  • Rapid onset of immunity (non-endemic)
  Improved methods are needed to directly measure the NSP and capsid content of vaccine antigen batches and formulated vaccines.

• Time to develop new or improved vaccines

  10 years +

• Cost of developing new or improved vaccines and their validation

  Very high.

• Research requirements for new or improved vaccines

  Economical support for fundamental immunology and for animal studies is essential. Such studies are very costly and it is of utmost importance that funding is available in order to get significant progress.

  Economical support for vaccine technology studies is essential.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  A limited number of studies have been reported concerning the evaluation of anti-virals for FMD therapy. Potential drugs can be screened in cell cultures or by directly measuring interference with certain biochemical pathways (such as FMDV 3C protease activity). Some candidate drugs have been tested in small animal models and in pigs. Developing safe and orally effective products for ruminants may be challenging. Some studies have evaluated alternative immunostimulants to complement existing vaccines to improve effectiveness.

• Time to develop new or improved pharmaceuticals

  Long term.

• Cost of developing new or improved pharmaceuticals and their validation

  High.

• Research requirements for new or improved pharmaceuticals

  Limited at present due to perceived difficulties in efficacy, application and uptake.

Disease details

• Description and characteristics

• Pathogen

  A virus of the family Picornaviridae, genus Aphthovirus. Seven immunologically distinct serotypes: A, O, C, SAT1, SAT2, SAT3, Asia1. Serotype C has not been isolated since 2004.

  GAP:

  FMD has been studied for many years, but despite this there are still significant areas of uncertainty in relation to pathogenesis, immunology, vaccinology, epidemiology and control. This is partly due to the limited number of places where such research can be performed under suitable containment conditions as well as limited field investigations in endemic areas. Consequently, significant research contributions are still needed to prove or disprove a number of dogmas on FMD before rational disease control, including vaccination, can be optimised. More research is now being done in economically emerging countries such as China and India. It is unknown whether serotype C has been eradicated or might still be circulating in areas with poor surveillance, where equivocal serological evidence for the serotype has been found.

• Variability of the disease

  A wide range of variants is seen within the distinct serotypes. Different serotypes and strains are associated with different regions; some have a restricted distribution and others are widespread, differences occur between isolates in terms of pathogenesis, virulence and host range. Some serotypes such as the SAT types are less well understood from the antigenic variability and epidemiological aspects.

  GAPS:

  Differences in host adaptation and preference of different FMDV strains are mostly not defined or understood. The reasons for the geographical distribution of different variants and the mechanisms that drive strain diversification are not fully elucidated. Methods to identify viral phenotypes such as pandemic potential or escape from immune protection afforded by existing vaccines, are not optimal.

• Stability of the agent/pathogen in the environment

  Preserved by refrigeration and freezing and progressively inactivated by temperatures above 50°C. Inactivated by pH <6.0 or >9.0. Inactivated by sodium hydroxide (2%), sodium carbonate (4%), and citric acid (0.2%). Relatively resistant to iodophores, quaternary ammonium compounds, hypoclorite and phenol, especially in the presence of organic matter. Survives in lymph nodes and bone marrow at neutral pH, but destroyed in muscle when is pH <6.0 i.e. after rigor mortis. Can persist in contaminated fodder and the environment for up to 1 month, depending on the temperature and pH conditions. Humidity and other specific climatic, host and virus isolate conditions favour long distance aerosol spread.

  GAPS:

  Uncertainty over degree of FMDV surveillance and control needed for safe trade in animal products from regions where the virus has not been completely eradicated. Capsid stability and its role in vaccine efficacy and capacity for transmission is not clear. Relatively incomplete knowledge about the extent of virus survival in animal products after different treatments. The effect of High Pressure Processing (HPP) on virus survival is unknown.

• Species involved

• Animal infected/carrier/disease

  FMD virus has a very broad host range and may infect both large and small ruminants as well as porcine species including domestic and wildlife species. Ruminants, especially large ruminants, appear to play a special role as long time carriers of the virus and wildlife, such as the African buffalo, are likely to play a significant role in maintaining the SAT serotypes of FMD virus. Other wildlife reservoirs may include various gazelles such as impala and Ugandan kop although these species are more likely to play a role in transmission of acute infection. Various species of deer can also be infected but do not usually play a significant role in viral maintenance. Pigs appear not to become carriers, however, during acute infection the excretion of virus from pigs are at a very high level and they are likely to play an important role as amplifiers of virus during acute infection. There are breed differences in susceptibility to FMD within a particular host species. Different husbandry systems and contact networks also influence the likelihood of virus transmission and persistence.

  GAPS:

  More studies are still needed to describe infection and disease in various hosts including the role of different livestock species within different ecosystems as well as for various species of the camelidae and a number of wildlife species.

  The priority for disease control in different species in order to affect overall control at a regional level is not always understood, e.g. the question whether it is necessary to vaccinate sheep as well as cattle, and when is it necessary to control infection in wildlife? The basis for differences in susceptibility and immunity in different host species has not been determined. The underlying mechanisms for differences in the susceptibility of different hosts with respect to infection, disease and shedding are not understood.

  Although studied for many years, the precise roles and importance of carrier animals are basically unknown. There are still considerable amounts of research to be done within this field and in particular the molecular mechanisms of establishment of persistent infection as well as the actual potential transfer of virus from such carriers needs to be better established. Ways to prevent the establishment of carrier status in domestic animals during outbreaks or the absolute clearance of persistence need to be investigated. Novel indicators of carrier status could be useful adjuncts to virological and serological approaches.

• Human infected/disease

  Human infection is extremely rare. A number of cases associated with mild illness have been reported but very few are fully documented by isolation of virus and an increase in antibody titre. In one such case in 1966, the infection only resulted in a transient and mild disease with minor blisters which quickly healed. During the 2001and 2007 FMD outbreaks in the UK, there were cases of people suspected of being infected with FMD virus, however, where samples were evaluated using sensitive RT-PCR, the virus was not detected.

• Vector cyclical/non-cyclical

  Transmission by e.g. stable flies is unlikely but has not been studied extensively and can therefore not completely be excluded.

  GAP:

  Studies on mechanical transmission by vectors.

• Reservoir (animal, environment)

  There are significant regional differences in the importance of wildlife for the epidemiology of FMD. Impala and African buffalo can be involved in the epidemiology of FMD especially SAT strains in southern Africa. A wide range of wildlife can become infected with FMD virus including but not limited to African buffalo, deer, antelope, feral swine, and wild boar. . Their significance in the epidemiology of FMD most likely depends upon not only their susceptibility, but their distribution, density and contacts with domestic species. Animals that scavenge for meat, such as wild boar could be a risk factor for disease introduction.

  GAPS:

  The role of wildlife reservoirs and carriers needs to be better quantified. The potential for serotypes other than the SAT types to be maintained by buffalo in sub-Saharan Africa warrant further investigation. The role of wildlife other than buffalo and impala in disease spread and persistence is poorly described, although wild boar infection was demonstrated in Turkey after 2011. Non-invasive sampling methods need continued development to improve surveillance of wildlife species.

• Description of infection & disease in natural hosts

• Transmissibility

  Direct or indirect contact (droplets), animate vectors (humans, etc.), inanimate vectors (vehicles, implements), foodborne via contaminated animal products (swill). Airborne, especially in temperate zones (importance of long distant spread is controversial but up to 60 km overland and 300 km by sea have been reported).

  GAP:

  The relative importance of different mechanisms by which virus spreads between herds and flocks is uncertain. The role of illegal imports of animal products in introducing infection is hard to determine.

  The transmission of the virus among African buffalo and small and large wildlife ruminants (such as impala, Kop, kudu, blue wildebeest, gazelle) and the threat this poses to domestic cattle and small ruminants is still poorly understood. The mechanism by which FMDV, maintained in African buffalo, spreads to cattle is poorly understood. In particular, does this require the intermediary of acutely infected buffalo calves?

• Pathogenic life cycle stages

  Not applicable.

• Signs/Morbidity

  Cattle

  • Pyrexia, anorexia, shivering, reduction in milk production for 2-3 days;
  • Signs associated with vesicular lesions principally affecting the mouth, feet and mammary glands: smacking of the lips, grinding of the teeth, drooling, lameness, stamping or kicking of the feet, after 24 hours: rupture of vesicles leaving erosions
  • Recovery generally occurs within 8-15 days
  • Complications: tongue erosions, superinfection of lesions, hoof deformation, mastitis and permanent impairment of milk production, abortion, myocarditis associated with death of young animals, permanent loss of weight, loss of heat control ('panters')

  Sheep and goats

  • Lesions in mouth and on feet are less pronounced and may go unrecognised. Agalactia in milking sheep and goats is a feature. Death of young stock.

  Pigs

  • May develop severe foot lesions particularly when housed on concrete. Lesions form on areas of friction such as elbows and snout.High mortality in piglets a frequent occurrence
  GAP:

  The clinical signs are well understood, with the possible exception of the so-called “hairy panter” condition that has been ascribed to FMD in certain geographical locations.

  There is a need to continue running courses that train veterinarians from FMD-free countries in the recognition of clinical signs (as well as ageing lesions and conducting epidemiological evaluations).

• Incubation period

  Short incubation period; generally 2 to 14 days, but can be as short as 1 day if pigs are infected through skin abrasions.

  GAP:

  Limited knowledge on effect of infectious dose, virus isolate and adaptation during outbreaks on incubation period.

• Mortality

  Frequently non-fatal disease for adult animals (2-5% mortality), though young animals can have a high mortality

  GAP:

  Limited knowledge on effect of infection on foetuses and abortion.

• Shedding kinetic patterns

  Incubating and clinically affected animals shed virus in breath, saliva, faeces, nasal excretions and urine; milk and semen (up to 4 days before clinical signs); some animal products from animals killed during acute infection contain virus (including prior to development of clinical signs) that may or may not be inactivated during rigor mortis.

  GAP:

  Transmission potential of infected aborted carcasses not known. The risk has not been quantified for transmission of FMDV from vaccinated livestock that subsequently become infected with minimal disease. This gap weakens models to predict disease-spread in vaccinated populations.

• Mechanism of pathogenicity

  Rapidly replicating lytic virus and damage from inflammatory immune response

  GAP:

  Mechanisms not fully understood, especially innate immune response component.

• Zoonotic potential

• Reported incidence in humans

  Extremely rare. No indication of human infection playing any role in the epidemiology of FMD.

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

  Extremely low.

• Symptoms described in humans

  Mild vesicular condition.

• Estimated level of under-reporting in humans

  Probably low.

• Likelihood of spread in humans

  Extremely low.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  Very high impact on animal welfare which is intolerable in modern highly productive breeds of livestock. Control measures severely disrupt the care and movement of animals leading to significant welfare problems. Mass slaughter may be used for control. The severity of trade and movement restrictions may have more impact on animal welfare than the disease by itself.

  GAPS:

  • Contingency plans to deal with logistical challenges that arise during outbreaks not developed for all situations.
  • Better information on the risk of vaccinated infected animals to disease spread could lead to fewer animals culled during outbreaks.
  • Internationally accepted control tools, which allow rapid return to the status “free from FMD” based on risk quantification.

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

  Potential to affect zoo animals and endangered species if these are culled as part of a control programme. High mortality has occurred in rare gazelle species.

  GAP: We do not know how vaccines perform in most wild species.

• Slaughter necessity according to EU rules or other regions

  Slaughter of infected, recovered, and FMD-susceptible contact animals. Trade restrictions due to vaccination are still more severe than after culling. Culling remains the preferred option in many countries to maintain or regain FMD-free status.

  GAPS:

  • Alternative and less draconian control measures would be highly desirable.
  • Epidemiological knowledge to quantity the risks of culling versus vaccination.

• Geographical distribution and spread

• Current occurence/distribution

  FMD is widely distributed with only the rich (exporting) countries of Northern Europe, North America and Australia/New Zealand being completely free while many developing countries in Asia, the Middle East and in Africa, in particular, have significant problems with endemic FMD. After implementing a widespread vaccination program for many years, South America is approaching FMD freedom with no outbreaks reported since 2012. [See comments on serotype C in section Disease characteristics - pathogen]

  GAPS:

  Although starting to be addressed, there remains limited knowledge of circulating isolates in endemic countries, especially in Africa, and the potential for new variants to arise and spread.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Can be a high frequency but with controls can be limited. Ro may be from 4 to 80 depending on circumstances.

  GAPS:

  Limited knowledge of patterns of virus spread and persistence within many endemically affected regions; for example, impact of pastoral husbandry systems. Need better understanding of trade patterns and movements and their changes to help predict threats. More research needed to correlate this type of information with inferences on patterns of spread derived from viral sequence data (phylogeography).

• Seasonality

  Not specifically related to season but in temperate climates virus may persist and spread more readily during the winter months. Outbreaks may be linked to seasonal animal movements and trade practices, e.g. religious festivals in the Middle East. Climatic conditions such as drought and floods with subsequent changes in wildlife movement patterns and contact with domestic animals could lead to seasonal cycles especially in sub-Saharan Africa.

  GAPS:

  Seasonal impacts on trade patterns. Poor understanding of factors impacting on wildlife movement patterns and what drive these. Poor understanding of climatic factors impacting on livestock movement patterns in Africa.

• Speed of spatial spread during an outbreak

  High.

  GAP:

  Conditions that favour the spatial spread not fully elucidated. Models that are able to predict patterns of disease spread are available, but as based on parameters of past outbreaks, they may not be fully relevant in different circumstances/husbandry conditions/countries.

• Transboundary potential of the disease

  High.

  GAP:

  Movement patterns (both animal and human) and the factors that drive those not clear in endemic regions.

• Route of Transmission

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

  FMD virus can be transmitted by a number of routes including movement of infected animals (and possibly by movement of carrier animals), by contaminated animal products e.g. by contaminated straw and fodder or by swill feeding, or by physical transfer on any contaminated surface including vehicles and people. Close contact between livestock provides the conditions for the most efficient transmission. Escape of virus from facilities conducting research, diagnosis or vaccine manufacture has been documented.

  GAP:

  The relative importance of different mechanisms in transfer of infection between farms is hard to determine. The role of transmission by humans/pets/vermin should be studied more in detail. In relation to severity of trade restrictions: risk of carriers and wildlife needs to be better quantified.

• Occasional mode of transmission

  In addition to these routes of transfer, FMD virus can occasionally be transferred as an infectious aerosol from the breath of an infected animal. Infected pigs are the most likely to emit sufficient virus for the infectious aerosol to be transported by the wind for long distances under favourable epidemiological and climatic conditions. Transmission by wildlife could also fit into this category of "occasional" transmission

  GAP:

  Very difficult to prove causation for airborne long-distance spread of FMD virus. Lack of certainty about transmission from carriers and of mechanism of spread from African buffalo to cattle.

• Conditions that favour spread

  Close contact between animals, high density farming.

  Trade patterns induce price differences, which lead to more and longer distance transport of animals and animal products.

  Relatively high humidity, cold inversion conditions, little wind and relatively smooth topography.

  Socio-economic drivers such as using cattle as a ‘bank’.

  GAP:

  • Economical knowledge of drivers in the private sector, which lead to more transport from FMD-infected to FMD-free areas.
  • Conditions are not fully understood making predictions for spread difficult.
  • Socio-economic drivers for livestock movement are poorly understood in most endemic parts of the world.

• Detection and Immune response to infection

• Mechanism of host response

  Serum antibody appears quickly after infection and is associated with virus clearance. Furthermore, protection can be transferred between animals by antibody transfusion. Similarly, several current vaccines elicit an antibody response that correlates quite well with protection.

  GAPS:

  In order to develop vaccines that elicit a longer lasting, more potent and antigenically cross-reactive immunity, there is a need to better understand the role and mechanisms of innate and mucosal immunity and memory induction, as well as the viral determinants of protection. The importance of non-neutralising antibodies and of different antibody isotypes requires further study. The role of cellular immunity in protection is poorly understood. The role of antigen stability in eliciting longer lasting immunity in vaccinated animals also needs further understanding.

• Immunological basis of diagnosis

  Antibody responses can be used to identify past infection and to help differentiate between infection and vaccination.

  GAP:

  DIVA tests are discussed in section [Diagnostic availability]. Mucosal IgA responses are starting to be studied as indicators of ongoing viral replication and IgM responses might help to identify recent infection.

• Main means of prevention, detection and control

• Sanitary measures

  Protection of free zones by border animal movement control and surveillance; Slaughter of infected, recovered, and FMD-susceptible contact animals; Disinfection of premises and all infected material (implements, cars, clothes, etc.); Destruction of dead animals, litter, and susceptible animal products in the infected area; Quarantine measures (Code Chapter 2.1.1.); Swill feeding restrictions.

  GAP:

  Protection prior to vaccine induced immunity (0-7 days) is needed.

• Mechanical and biological control

  Not applicable.

• Diagnostic tools

  Identification of the agent

  • ELISA
  • RT-PCR, RT-LAMP
  • Virus isolation: inoculation of primary bovine thyroid cells and primary pig, calf and lamb kidney cells; inoculation of BHK-21, IB-RS-2, ZZR and LFBK cell lines
  • Lateral Flow Devices (LFD)
  • Pen-side tests

  Agent characterization

  • Genetic sequencing
  • Vaccine matching by serology (ELISA and virus neutralisation test)

  Serological tests

  • ELISA for antibodies to structural and non-structural viral proteins
  • Virus neutralisation test

  GAP:

  Assays for use in the field: some pen-side tests for antigen detection and non-structural proteins (NSP) serology are available, but need improvement, whilst serotyping tests are needed and remain under development/evaluation. A number of molecular technologies (e.g. RT-PCR and RT-LAMP) for high sensitivity virus detection in the field are under evaluation but not yet widely used.

  Identification of preclinically or subclinically infected animals and of carriers remains difficult on a large-scale. Various approaches are theoretically possible such as through risk-based placement of aerosol samplers or in-milk-pipe alert technologies. Also measurement of non-specific indicators (acute phase proteins, thermal imaging etc) to identify very high morbidity pathogen incursions at earliest time points.

  DIVA tests are commercially available, but non-specific results may hamper the substantiation of disease freedom in vaccinated populations and therefore better confirmatory tests that maintain sensitivity would be advantageous.

  New developments in sequencing may add to the resolution with which we can trace the spread of the virus between farms.

  Better ways are needed to predict levels of post-vaccination protective immunity against incursions by antigenically different virus strains. Current serological methods have rather crudely improvised thresholds and vaccine matching tests are poorly reproducible.

  Validation is needed for the different purposes of use of recently commercialised ELISA kits for serotype-specific antibodies. Wider use could be made in endemic settings of recently developed and commercialized ELISA kits for antigen detection and serotyping.

  Multiplexed assays are not yet fully developed and validated.

• Vaccines

  Inactivated virus vaccine grown in cell cultures and containing an adjuvant. Antibodies against the structural proteins of the virus capsid are an important component of protection. Protective immunity lasts up to 6 months after an initial course of vaccination, depending on the vaccine potency and the antigenic relationship between vaccine and outbreak strains. An initial course of two vaccinations improves the strength and duration of the antibody response. Longer lasting protection may develop once animals have received multiple vaccine doses. Purification of the vaccine virus capsids reduces the likelihood of inducing antibodies to viral non-structural proteins (NSP) so that NSP serology can be used for DIVA testing. However, the purification process reduces the yield, increasing cost. Care must also be taken to ensure that the purification process is not associated with capsid degradation and reduced vaccine efficacy.

  A new adenovirus-vectored vaccine has been licensed in the USA. Many other vaccine candidates are under development and both peptide vaccines and vaccines based on recombinant FMD virus like particles have been used in China.

  GAPS:

  Vaccines that induce a longer lasting immunity that don’t have to be administered frequently, that provide rapid and better protection, that provide sterile immunity, that allow reliable distinction between vaccinated and infected animals will assist in more effective disease control. Further research into improved adjuvants and more stable vaccines is needed as well as in vaccines that can be produced cost-effectively and safely without the need for high containment facilities. Direct methods to test and evaluate the quality of vaccine antigens and formulated FMD vaccines, their purity and the amount of vaccine degradation would be highly beneficial for quality control. Vaccine efficacy is often not well established for species other than cattle. New experimental infection models are needed that more accurately measure the ability of vaccines to block virus transmission. Better methods are needed to predict vaccine match to outbreak strains.

• Therapeutics

  Potential for e.g. interferons or specific inhibitors of viral replication

  Adenovirus vectored interferon type 1 provides some early protection.

  3Cpro inhibitors have been identified.

  GAP:

  Little data available. More therapeutics should be identified and promising studies in cell cultures and small animal models need to be followed with trials involving natural hosts. The FMDV polymerase is a potential target for inhibitors. Finding a compound that would be effective and cheap enough to administer on a large scale limits current potential usage to high-genetic merit populations only.

• Biosecurity measures effective as a preventive measure

  Advice given by Defra:

  • Avoid visiting other farms unless absolutely necessary and follow biosecurity procedures when you do.
  • Keep different species of livestock separate where possible.
  • When handling animals, be aware that sheep and goats do not always show obvious signs of the disease and you could inadvertently infect other animals.
  • Keep everything clean – materials like mud or bedding on clothes, boots equipment or vehicles can carry the virus from farm to farm or between different groups of livestock on the farm.
  • It is essential that you clean yourself, your vehicle and everything you carry thoroughly when you move between different groups of livestock on the farm.
  • Make sure you have disinfectant and cleaning material ready at your farm entrance, so that essential visitors can disinfect themselves before entering the premises and as they leave.

  GAP:

  The risks from aerosols generated by using power hoses in clean-up of infected premises needs to be taken account of.

  Quantitative analysis of secretion and excretion would help to identify the importance of different indirect transmission routes. The probability of infection by fomites is not known.

  The efficacy of different disinfection regimes in "real-life" situations needs further study.

• Border/trade/movement control sufficient for control

  Protection of free zones by border animal movement control and surveillance and restrictions on trade in animal products GAP: Risk of treated animal products not always known. Treatments for certain cultural products such as jerky, biltong etc not tested for virus inactivation. It would be useful to know how much bone marrow and lymph node remains in cuts of deboned beef, in order to quantify the risk of trading this product from FMDV infected areas.

• Prevention tools

  Vaccines, routine movement controls, wildlife cordon fences, animal identification, movement records, biosecurity regimens

  GAPS:

  See above for gaps in vaccines. Better decision support tools are needed to help triage different control options. Handheld apps could be developed to support farmer actions/reactions. These need to take account of costs as well as benefits. In many countries with endemic FMD, animal movement controls are not possible and the feasibility of controlling and eradicating FMD under these circumstances, using vaccination alone is questionable, but needs further study. More study of the cost-benefit of control measures in relation to wildlife management and its potential to generate income.

• Surveillance

  Notification and education, sero-surveillance in some circumstances.

  GAPS:

  More information for farmers on a regular basis to keep them alert, they are the first line of defence. Training of vets and other animal health staff. Improved rapid, inexpensive and pen-side diagnostic assays would assist in surveillance. Implementation of the FMD Progressive Control Pathway needs encouragement in countries with endemic FMD.

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

  Variable. Needs good surveillance, vaccines and diagnostic tests, associated with control measures as in section [Sanitary measures] for eradication. In recent FMD incursions into Japan and Korea, use of vaccination was delayed with possible adverse consequences.

  GAP: Critical success factors for eradication programmes in endemically infected countries.

• Costs of above measures

  High but variable depending on the size and extent of an outbreak.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes.

• WOAH disease card available

  Currently OIE recognises 67 countries as free from FMD without vaccination, and 1 as free with vaccination. In addition, 6 countries have one or several zones that are free without vaccination, 2 countries have one or two zones that are free with vaccination and 6 countries have several zones that are free without or with vaccination. Around 100 countries are endemically or sporadically FMD infected. Eight countries have OIE endorsed FMD control programmes. FMD is endemic and widespread in large parts of Africa, Asia and the Middle East including e.g. Turkey (Anatolia) and consequently constitute a significant threat of introduction into the EU. FMD has also spread recently across North Africa, from where many refugees seek asylum in Europe . Progressive control in South America in moving towards eradication.

  The endemic FMD world map is divided into 7 remaining geographically distinct virus pools which have independently variable topotypes within serotypes, with occasional but continuing epidemic incursions into ‘free’ areas:

  Pool 1 China & SE Asia: has Types O, A & Asia 1

  Pool 2 India: has Types O, A & Asia 1

  Pool 3 West Eurasia: has Types O, A & Asia 1

  Pool 4 E Africa: has Types O, A & SATs 1&2

  Pool 5 W Africa: has Types O, A & SAT 2

  Pool 6 S Africa: has Types SATs 1, 2 & 3

  Pool 7 S America: has Types O & A (no outbreaks since 2012)

  GAPS:

  Better knowledge on the antigenic and genetic variants within each pool and the impact on vaccination and diagnostic assays is needed. Better knowledge on what drives virus evolution in each pool is needed. The effects of vaccination in selecting for variants in the field is not known.

• WOAH Terrestrial Animal Health Code

  http://www.oie.int/index.php?id=169&L=0&htmfile=chapitre_1.8.5.htm

• WOAH Terrestrial Manual

  http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.05_FMD.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

  FMD causes considerable losses in livestock production by severely reducing animal productivity and reducing the value of affected animals.

  GAP:

  Accurate figures on production losses especially on poor farmers are lacking. Little knowledge on the recovery to prior production in milking cattle breeds (important in endemic situations).

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

  The economic impact is significant and prolonged for countries or regions with endemic FMD while epidemics, such as in the UK in 2001, are extremely costly in terms of disease control, proving freedom from infection and by short or long term trade implications.

  GAP:

  The cost of vaccination campaigns and other control measures such as fences and registration systems to trace movements of animals is not quantified in many countries and regions.

• Indirect impact

  Major economic impacts with disruption of food supply, constraints on production and impact on the welfare of animals subject to the controls. Control measures have a major impact.

  FMD is closely associated with poverty and is widespread in many developing countries. Control of FMD in such settings will provide a significant economical boost to both the local animal keepers as well as the countries in general. It is of utmost importance to bring FMD under control in these settings, taking account the situation in wildlife, as the reduction of infectious virus in these areas will provide a significant reduction in the risk of introduction of FMD virus to previously free areas.

  GAP:

  Accurate figures on the impact of FMD on poor farmers and the resultant positive impact on market access and the economy if the disease is controlled are not sufficiently available, in particular in endemic situations.

• Trade implications

• Impact on international trade/exports from the EU

  Severe trade difficulties especially with overreaction in some circumstances.

  GAP: Accurate figures are lacking.

• Impact on EU intra-community trade

  Can cause major disruption to trade within the community with subsequent impact on the economy.

• Impact on national trade

  The internal control measures cause major disruption especially with movement standstills and controls on animal.

  GAP: Accurate figures on such impacts are unavailable.

• Main perceived obstacles for effective prevention and control

  The main obstacle for effective prevention and control, in particular in the developing world, are the availability of HIGH QUALITY and AFFORDABLE vaccines that have been accurately selected and matched to the circulating virus strains. This needs to be supported by sufficient resources to the veterinary services in order to ensure an adequate and rapid response in relation to outbreak surveillance and examination and for establishing movement controls and improved biosecurity measures etc. Developing countries have many other priorities and limited resources so incentives to tackle FMD control are needed. The transboundary nature of disease requires concerted regional approaches to control. Lack of knowledge on circulating isolates, or logistics such as cold chain, in endemic regions may impact on the efficacy of vaccination campaigns.

  GAP:

  Gaps regarding FMD vaccines and knowledge on circulating viruses have been mentioned.

  Accurate impact and cost benefit analysis that could act as incentive for investment in control has not been done in most endemic regions. The costs to perform effective surveillance have to be evaluated against the potential gain.

• Main perceived facilitators for effective prevention and control

  Incentives, regional cooperation, better vaccines, diagnostic tools and evidence of cost-benefits for control schemes.

  GAPS:

  Information regarding effective incentives are scanty. Regional road maps should continue, in order to foster collegiate action by neighbouring countries. Such efforts need to be better coordinated with efforts to control other significant livestock diseases.

• Links to climate

  Seasonal cycle linked to climate

  See above (Section seasonal cycle).

• Distribution of disease or vector linked to climate

  Not known at present.

• Outbreaks linked to extreme weather

  Not known. Drought-induced migrations might be significant

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

  Not known.

Risk

• Significant funding for the above mentioned activities will clearly improve our understanding of FMD epidemiology and control and will have a very good chance of leading to improved disease control. The next 2-5 years may not necessarily lead to any significant new and improved products, but will anyhow provide a better background for using current vaccines and diagnostic methods.

Main critical gaps

Conclusion

• FMD is a very important animal disease with a considerable impact on the economy of many developing countries with endemic infection and also having considerable trade implications when an outbreak occurs in a previously free region. Increased funding to study this infection in detail, in particular for studies focusing on improved vaccines, treatment or disease control, is likely to result in significant progress in terms of reducing the presence of endemic FMD worldwide and in reducing the risk of introduction to previously free regions. Different approaches are required for the free countries and the endemic countries. Some other issues: enhanced risk for free countries due to globalization (animals, products, human movement, legal and illegal); cooperation activities in endemic countries to improve knowledge and control of the disease provide mutual benefits; implementation of the Progressive Control Pathway.

  GAP:

  Opportunities for Commodity based trade should be explored as a means of minimizing trade damage due to FMD.

Sources of information

• Expert group composition

  David Paton - Private Consultant, UK (leader)

  Wilna Vosloo - CSIRO, Australian Animal Health Laboratory, Australia

  Danny Goovaerts - DGVAC consultancy, Belgium

  Emiliana Brocchi - Istituto Zooprofilattico Sperimentale della Lombardia e dell' Emilia Romagna (IZSLER), Italy

  Ronan O' Neill - CVRL, Department of Food, Agriculture and the Marine, Ireland

• Reviewed by

  Project Management Board.

• Date of submission by expert group

  20th March 2015

• References

  Defra

  http://www.defra.gov.uk/animalh/diseases/vetsurveillance/az_index.htm

  OIE

  http://www.oie.int/eng/normes/MMANUAL/A_index.htm

  http://www.oie.int/eng/maladies/fiches/a_a080.htm

  http://www.oie.int/eng/ressources/en_diseasecards.htm

  http://www.oie.int/eng/maladies/en_alpha.htm?e1d7

STAR-IDAZ Research Road Maps

• Development of diagnostic tests

  Development of candidate vaccines

  Development of control strategies