ROYAL SOCIETY INQUIRY INTO INFECTIOUS DISEASES OF LIVESTOCK
Response from Institute for Animal Health (IAH) to call for detailed evidence
It is suggested that the priority exotic viral diseases which should be addressed by the Committee are those shown in Table 1. Emerging diseases should also be considered e.g. Nipah.
This document focuses primarily on foot-and-mouth disease (FMD) but the principles can equally well be applied to other diseases. The main features of bluetongue and African horse sickness, virus diseases transmitted by biting midges, are presented separately in Annex 1.
Table 1. The major livestock diseases of importance to the UK.
Present in EU
Risk for the UK
IAH research effort
Swine vesicular disease
Classical swine fever
African swine fever
African horse sickness
Sheep & goatpox
Peste des petits ruminants
West Nile Fever
1Key: Y = yes M = medium
N = no H = high
S = sporadic L = low
2 present in Italy only
3 most of the UKs research effort is at the VLA, Weybridge
4present in Sardinia only
5Greece, Spain, France and Italy
6sporadic in Greece
7present in Asiatic Turkey
8present in France
9attenuated vaccine available but not considered safe
10a zoonotic disease so important public health considerations
11 low at present but will increase with global warming
7 Almost all of the diseases listed above are classified by the Office International des Ipizooties (OIE; world Organisation for Animal Health) as List A diseases.
7 By definition they have the potential for rapid and extensive spread, are likely to have serious socio-economic or public health consequence and are of major importance in the international trade of animals and animal products.
7 The UK does not vaccinate against any of these diseases and so its livestock population is fully susceptible. Any incursion would have devastating economic consequences on the industry as evidenced by the 2001 epidemic of FMD in the UK and by the 19978 epidemic of CSF centred on The Netherlands. Several of these diseases, e.g. classical swine fever (CSF), swine vesicular disease (SVD), African swine fever (ASF) and bluetongue (BT) are present in the EU. Others, e.g. foot-and-mouth disease (FMD), sheep and goat pox (SGP) and Newcastle disease (ND) occur sporadically and are mostly confined to the EUs borders with eastern and central Europe. Greece is the EU member state most often affected and outbreaks of FMD and SGP there have been attributed to the illegal movement of infected sheep or goats from Asiatic Turkey where those diseases are endemic. Other exotic viruses, including peste des petits ruminants (PPR) virus and ephemeral fever virus have also been isolated in Asiatic Turkey, increasing the risk that they might be introduced into the EU at any time.
7 The risk of entry of an exotic virus into the UK has increased during recent years. The demise of the Iron Curtain has created opportunities for animals and their products to be transported from central to western Europe. At the same time, the formation of the single market within the EU has facilitated movement across the member states. Illegal trade has also increased, with smugglers being attracted by the prospect of higher profits. The increase in travel, particularly to and from far-distant countries, is increasing the chances of importation of virus in products brought from those countries where the viruses are endemic. Global warming is likely to increase the northerly distribution of the insect vectors of bluetongue, African horse sickness and West Nile Fever virus and the risk for the UK of those diseases (see Annex 1).
2 DISEASE FREE STATUS
2.1 Should the country abandon the disease free concept?
No. FMDV causes severe suffering in UK breeds of cattle and pigs and long-term loss of yield. Although mortality in FMD is generally low, severe losses have been reported among young animals in epidemics outside the UK with mortality levels between 50% and 90%. Not controlling the disease is therefore not an option. Moreover, the virus is so infectious that there can only be one rational objective when dealing with an outbreak: eradication. Therefore, the UK cannot abandon the "disease-free concept" in its wider sense.
2.2 Is it realistic to maintain the disease free status?
Yes. This answer anticipates much of the evidence to come in later sections, but a powerful case for maintaining disease-free status can be made simply by looking at the successful record of the policy. Essentially the argument is as follows:
The only way to demonstrate convincingly that livestock are free of FMDV is for animals to be, not just healthy, but also susceptible (see 5.10). For this reason, disease-free status, according to OIE criteria which this Institute supports, is incompatible with the presence of anti-FMDV antibodies in livestock. This means that a country cannot both vaccinate and be accredited virus-free at the same time. It is unlikely that this rule will be relaxed until science has provided the means to prevent or reliably detect the carrier state (see 5.10).
In the light of this the above question can be rephrased: Will it be practicable for the UK to control FMD without relying on permanent vaccine cover? Many factors limit the usefulness of current vaccines (see 5.3), in addition to their inability to confer sterile immunity (5.3(i)). The need for permanent vaccine cover should be assessed in the light of those factors and of the record of vaccine-free control policies in the UK, and globally.
How have the non-vaccine-using countries fared over the past ten years?
Fifty eight nations world-wide either qualify currently for disease-free status or, like the UK, have been traditionally disease-free. These countries include the whole of the developed world. Over the past decade since continental Europe ceased routine vaccination, there have been a total of 13 virus introductions from outside this group of 58 countries and a further four cross-infections between members of the group. Most outbreaks were restricted to a small number of cases per country (in Europe the median = 12), with just four very large-scale epidemics of over 1,000 cases (Taiwan 1997, Uruguay 2000, Argentina 2001, UK 2001) recorded over the period. According to that record, a country can expect to be infected on average once every 34 years and to suffer a really serious epidemic once in almost two centuries. Most, at least, of the traditionally disease-free countries will view a strategy delivering that level of control as cost-effective, and are unlikely to abandon it collectively on either a global or regional basis, at least under present circumstances.
As for the UKs own history, it is noteworthy that the two worst epidemics on record, 1967/68 and 2001, were almost certainly associated with the importation of contaminated animal products. This is FMDVs classic mode of intercontinental travel (e.g. Durban 2000) and it is preventable by cheaper and more effective measures than routine, mass vaccination. In any case, the UK has little room for unilateral action. This is not to prejudge the usefulness of vaccination as a temporary adjunct to other eradication measures, but it can not make sense for a major trading nation like the UK, with geographical advantages of insularity and remoteness from endemic areas, to put her livestock industry at a perpetual disadvantage by abandoning accreditation unilaterally.
In summary, we do not judge the aim of maintaining disease-free status to be unrealistic. Rather the reverse.
2.3 What are the economic drivers influencing the possibility of disease-free status?
Below are listed the economic arguments for, and against, policies aimed at maintaining disease-free status; followed by arguments for, and against, policies that would forfeit disease-free status by relying on some level of permanent vaccine cover.
7 Long-term access to export trade in animals and animal products to other disease-free countries
7 Lower recurrent costs compared with alternative option of 'permanent vaccine coverage'
7 Potentially very heavy costs of measures to contain and eradicate sporadic incursions of disease, itemised as follows:
maintaining contingency reserve of vaccine (if applicable)
enhanced controls on importation of animal products
One-off costs caused by an outbreak:
damage to tourist industry
loss to farm incomes due to animal movement restrictions
destruction of livestock:
- as a disease control measure
- on welfare grounds
- to eliminate any vaccinated individuals (if applicable)
- to eliminate animals rendered unmarketable by trade embargo
extended embargo if vaccinated animals not eliminated
costs of policy implementation, including:
- diagnosis; slaughter, disposal of animals, and disinfection
- serum surveillance
restocking vaccine reserve (if depleted)
Permanent vaccine cover:
7 Reduced risk of severe epidemics compared with alternative option of maintaining disease-free status and lower one-off costs resulting from outbreaks.
7 Higher recurrent costs due to:
Permanent loss of export trade to disease-free countries
Requirement for regular mass vaccination
It is difficult to prioritise the above drivers, since the individual costs of either strategy depend on policy choices, in particular, the role assigned to vaccination. A trade-off exists between the degree to which risks are abated by vaccination and the level of vaccine cover chosen (see 5.3(i)). For example, the tourist industry is said to have been a major casualty of the 2001 UK epizootic, but it is possible to imagine a different scenario in which prompt and massive application of vaccine might leave tourism largely unscathed, while incurring very much heavier costs under other headings. Finally, although we were asked only for economic drivers, important non-economic interests - animal welfare, civil liberties, environment, and popular sensibilities - have also been damaged by FMD control measures. These interests will tend to be affected by policy decisions in a similar way to tourism.
3. SURVEILLANCE AND DIAGNOSIS
3.1.1 How effective are existing methods of disease surveillance ?
For exotic diseases, surveillance consists of both worldwide information gathering and monitoring in ones own back-yard. The former is necessary to identify threats and quantify risks, whilst the latter should safeguard against introductions and ensure early recognition if the virus is imported. International surveillance is supported by bodies such as the OIE and the Food and Agriculture Organisation (FAO). The FAO is involved in global disease eradication campaigns such as that for rinderpest in which Pirbright, as WRL for Rinderpest, has played a major role. FAO also sponsors a number of world reference laboratories (WRL) such as that for FMD, rinderpest and peste des petits ruminants at the Pirbright Laboratory of the Institute for Animal health. The WRL for FMD maintains a surveillance service for FMD strains worldwide by providing a diagnostic and serotyping referral service, developing improved diagnostic techniques and providing a centre of excellence for training veterinarians and technical staff from national laboratories. For example, the FMD WRL at Pirbright supplies reagents for the most widely used serological assay for strain-specific antibody detection and has developed a generic FMD assay that can also differentiate between infection and vaccinally derived antibodies based upon reactivity to non-structural viral proteins. This latter test has been commercially developed by Intervet. For antigen detection, the success of Pirbrights pen-side chromatographic pen-side test for Rinderpest has been followed up by a similar development for FMD. Contacts overseas are used to evaluate these assays under field conditions. The WRLs also play a leading role in international test validation and harmonisation. Using molecular techniques for individually characterising strains of virus, the WRL can trace the movement of viruses across international borders and warn of their appearance in new areas. Antigenic and genetic typing also identifies emerging strains of virus and ensures that vaccines incorporate the most appropriate antigens. The OIE collates information on the occurrence of its OIE List A diseases (the most important ones affecting international trade) from national governments around the world. It also produces a manual of diagnostic tests recommended for use in controlling the spread of diseases by international trade as well as a set of codes recommending measures for the control of these diseases. OIE nominates a number of reference laboratories to provide specialist input to these tasks, but does not provide financial support for their work. There are also European Union reference laboratories for many of the OIE List A diseases. These carry out many of the functions of the WRL and OIE reference laboratories, but with an emphasis on harmonisation of diagnostic approaches within the EU. A certain amount of funding is provided. Although some important diseases (including FMD) are not currently covered, Pirbright has recently been nominated to take on the role of Community Reference Laboratory for FMD.
There are two major weaknesses with the arrangements for international surveillance. (1) It relies heavily on information and samples provided by national governments, which may not have the resources to investigate animal diseases thoroughly, and whose nationals will lose out in terms of international trade if they report the occurrence of OIE List A diseases (i.e. there is a disincentive for them to co-operate). (2) The international bodies responsible for promoting animal health have inadequate resources available to support their initiatives in the field and at reference laboratories. Even existing levels of international reference laboratory work, such as is carried out at Pirbright and Weybridge are subsidised by the UK National Government via DEFRA.
At the UK level, surveillance for exotic diseases can be divided into the monitoring of imports and of the national livestock herd. Laboratory tests for exotic viruses in support of this work are mainly done at Pirbright and Weybridge by the Institute for Animal Health and the Veterinary Laboratories Agency respectively. International agreements and EU legislation require that import control measures that limit trade must have a scientifically demonstrable justification. Different rules apply to trade within the European Community and between the EU and the outside world. In the former case there is more scope for demanding assurances from exporting countries as well as requiring pre-import testing to be carried out. Live animals can only enter via designated entry points and may be subject to full veterinary checks. In the latter case the onus is on the exporter to provide the necessary information regarding the health status of traded livestock. Furthermore, entry can occur by many routes and is subject to spot checking only. Once an animal is brought into the community it can be traded internally between member states as if it had originated within the EU. Control of animal products is even more problematic. There are few checks and controls on the international trading of meat and meat products. The travelling public may also bring animal products home from abroad. This is subject to little or no scrutiny and there is a lack of advice on the dangers this may pose to animal health. Above all, there seems to be little interest in carrying out the investigations required to quantify what is actually occurring with respect to the movement of animal products by undeclared or unorthodox routes.
National surveillance for exotic livestock pathogens relies on the recognition and investigation of suspicious signs of disease. Serological surveys are useful at the end of outbreaks to ensure that all infection has been recognised, but are of very little use in recognising primary cases. In the first instance it is the farmer and his/her veterinarian who needs to be able to recognise the signs of notifiable diseases if they are to actually be notified to the state veterinary service. This requires training and in the case of the veterinarian, adequate on-farm access. Referral centres such as VLAs regional laboratories should provide further veterinary input with a strong focus on exotic diseases. The inspection of live animals and carcases at abattoirs is also of paramount importance. A number of exotic virus diseases have the potential for transmission amongst various wildlife species present in Britain, such as free-living deer and wild boar. Disease surveillance in such species is fragmentary and there is a lack of detailed knowledge concerning the range and distribution of such species for risk assessment purposes during outbreaks.
3.1.2 What are the barriers, implications and costs of moving to more active surveillance ?
Internationally, more active surveillance can be brought about by better funding of international animal health bodies and their reference laboratories and by supporting disease control programmes in developing countries. Money spent on controlling disease in third countries before it spreads to other parts of the world could have a significant cost benefit, but requires a co-operative approach between (developed) countries. There is no animal disease equivalent to the Communicable Disease Centre in Atlanta which sends out teams to different parts of the world to investigate emerging human pathogens.
Nationally, more active surveillance needs more farm visits to be made by veterinarians. Steps could also be taken to encourage an increased frequency of submission of diagnostic specimens to referral laboratories.
3.1.3 How can science help surveillance at points of entry (import controls) ?
See also 4.1.4
7 Improved international surveillance could help to identify high risk imports so that preventive measures could be appropriately targeted.
7 Better means of permanent animal identification would help control illegal animal movements and identify animals that had been trans-shipped through various countries.
7 Better tests including pen-side tests that could be performed as part of on-the-spot health checks.
3.1.4 Do we need to improve education/communications between different sectors of the industry and government ?
Such communications are vital and must be established before crises unfold. This is a topic on which the IAH does not feel that it is sufficiently well qualified to comment in detail. We do, however, consider that greater awareness and knowledge of exotic virus diseases is essential among farmers and veterinarians in the front line and we expand on this in Section 7.
3.2.1 How good are existing techniques; what research is needed to improve them?
7 Specimens from animals suspected to be infected with any of the diseases listed in Table 1, with the exception of CSF, avian influenza, Newcastle disease, rabies and West Nile Fever virus would be sent to IAH, Pirbright since it is the only laboratory permitted by DEFRA to manipulate them under the Specified Pathogens Order. Pirbright is an OIE or FAO reference laboratory for all of the exotic diseases for which it provides a diagnostic service. It is the World Reference Laboratory for FMD and for rinderpest and peste des petits ruminants.
7 The protocols for the tests used at Pirbright are described in the OIE Manual of Standards for Diagnostic Tests and Vaccines. In regard to FMD, the tests were developed at Pirbright and the Chapter in the Manual was written by authors from Pirbright.
7 The techniques and systems used for FMD diagnosis at Pirbright are highly sensitive and specific and the best currently available. They are kept under constant review (see also Section 4) and where opportunities arise for improvement these are implemented and the new tests validated as soon as possible. Pirbright has for many years co-ordinated an FAO sponsored programme involving FMD laboratories in around twenty countries world-wide which aims to standardise diagnostic methods for FMD. This programme has provided a valuable forum for exchanging information about new techniques and developments and for comparing and analysing results obtained by the different participating laboratories.
7 A positive ELISA result for FMD can be obtained in around 3 hours when the clinical specimen submitted is of good quality, taken from an animal in the early acute stage of disease and transported to the laboratory under appropriate conditions for the preservation of virus (viral antigen). However, for specimens of poor quality i.e those which are too small in amount or collected from old lesions, the initial ELISA for detecting viral antigen is likely to give a weak, inconclusive or negative result. In these circumstances the inoculation of cell cultures will be required to determine whether any virus is present. The bovine thyroid cell system developed at Pirbright is highly sensitive for the isolation and growth of FMD virus but a cell passage takes 36 to 48 hours. Since two passage are required before a definitive negative result is given the total test time is 96 hours. To reduce this test period real-time RT-PCR methods have been developed at Pirbright. They have been found to be more sensitive than ELISA and as sensitive as ELISA combined with virus isolation. Further tests are currently in progress to establish precise values for the sensitivity and specificity of the method.
7 An approach which would accelerate the speed of investigation of suspected cases of FMD would be to perform the diagnostic tests on-farm or near-farm, perhaps in a biosecure mobile laboratory. Results obtained at Pirbright with real-time RT-PCR and with immuno-capture (penside; dipstick) tests using specimens from experimentally infected animals have shown that both diagnostic methods are rapid, sensitive and specific. A limited number of immuno-capture kits developed at Pirbright were used during the recent outbreak to analyse specimens from field cases. The results were promising and much more work is now required to fully validate the test. Developmental work is also required to optimise prototype real-time RT-PCR methods. The number of PCR steps needs to be simplified and PCR machines need to be designed to handle many more samples and incorporate features that minimise cross-contamination.
7 It is IAH policy that whenever possible, opportunities are taken to transfer reagents and knowledge from fundamental studies of the function and structure of viruses to diagnostic applications. This policy has proved to be very rewarding. For example, nucelotide sequence analysis was used to demonstrate that the cause of the UK 2001 epidemic was a type O Pan Asia strain virus. Such approaches could be enhanced by additional support to increase the effort being made both to examine more isolates and the lengths of the genomes sequenced. It is particularly important to extend sequencing to the non-structural proteins of FMDV where specific mutations have been linked to virulence (see also Section 4). This would generate the essential data for producing more diagnostic probes and primers and the information for genetically engineering diagnostic antigens and peptides. There is also a need to generate a wider range of monoclonal antibodies. These reagents would further increase the sensitivity and specificity of diagnostic tests and their standardisation. Any new methods would have to be fully validated to ensure that they performed as well as or better than existing methods.
3.2.2. How should individual animal diagnosis be linked to decision making?
7 The point behind this question is not clear. We are not aware of the circumstance when a diagnosis would be based on an individual animal. If a single animal was suspected to be showing the signs of a disease listed in Table 1 the farm should be placed under movement restriction and samples taken for laboratory investigation. The sampling would extend to other animals, especially cohorts. Further inspections and epidemiological investigations would be undertaken by the State Veterinary Service. In the case of the diseases listed it is highly improbable that just one animal would show signs of disease or infection. If disease was confirmed it would be dealt with as specified in the relevant Animal Health Order. All outbreaks of notifiable diseases should be reported to the Commission of the EU, to OIE and FAO.
7 Crucial to diagnosis is individual animal identification. This is essential to ensure a reliable audit trail from the animal to the laboratory as well as the capability to trace back to the animal for repeat sampling (see 3.2.3).
3.2.3 Are there developments in other sciences or technologies that might help?
7 As stated in Section 3.2.1, the diagnostic tests used at Pirbright are state-of-the-art. However, developments in computing and electronics are likely to increase the speed with which tests can be performed. Progress in molecular biology and genetic engineering will generate an increased array of molecular probes and of genetically expressed proteins and peptides for use as antigens and reagents. Microarray technologies are likely to be used much more widely for rapid disease diagnosis and the characterisation of virus isolates. The miniaturisation of electronics will increase the practicality of diagnosis in the field by PCR technologies. Thus, smaller, faster, automated and large capacity PCR equipment is likely to be developed within a few years. Especially important will be the development of equipment capable of automatically processing a sample all the way from receipt to final result without any intervention or any possibility of contamination. New technologies such as biosensors and micro-volume assays may be adapted for such assays. The use of biosecure mobile laboratories on or near to farms would accelerate the speed of diagnosis.
7 While not in the high tech category, bar code identification is a simple measure which should be used to identify individual animals to ensure the security of the audit trail from farm to laboratory and to facilitate the management of samples within the receiving laboratory, especially when automated robotic systems are employed for processing samples.
Tele-medicine and tele-detection systems are attractive but untested ideas. During a large epidemic they would have to be extremely robust if they were to help rather than hinder the procedures. Rather than tying up specialists with the diagnosis of disease over the Internet a more efficient way of using their skill might be to use them for training those in the front line so that they have a better disease awareness. An accurate clinical diagnosis of FMD often requires careful examination of the animal or animals by an experienced clinician - it is not just a matter of seeing a picture of a lesion. These comments are based on the current state of the quality of tele-diagnosis in the veterinary field, future developments, perhaps including 3-D images, may lead to wider acceptability. Nevertheless, the quality will need to be very high in order to be of any significant practical help or to compete with the alternative of the improved training of field personnel.
3.2.4 Who should manage the national diagnostic service?
7 The management of the national diagnostic service should be under the control of the State Veterinary Service but the performance of diagnostic tests could be done by sub-contracted agencies. It would be essential for the diagnostic activities to be done according to approved standards and under the required level of biosecurity. It is very important that the data generated is freely available for research purposes so that lessons can be learned and improved disease control strategies developed.
3.2.5 Who should undertake the actual diagnosis?
7 Veterinarians with appropriate training in exotic diseases and epidemiological principles are required for the primary assessment. With regard to confirmatory tests the ideal situation would be on-farm diagnosis beside the animal or animals under investigation using a fast, accurate method. Until that is practical and acceptable to the State Veterinary Service the diagnostic tests should be performed by competent laboratory diagnosticians operating within a laboratory under biosecure conditions which comply with the requirements of the Specified Pathogens Order. The laboratories could be governmental or sub-contracted agency establishments. Pirbright is uniquely placed to provide these services since it has large biosecure facilities, including those suitable for animal experiments. It has a cadre of internationally recognised experts and over seventy years of research experience in the field of exotic virus diseases which extends across the whole research spectrum from research on the molecular structure of the aetiological agents to the determinants of transmission in animal populations.
Clearly, all diagnostic activities should be done in close collaboration with the State Veterinary Service, DEFRA. During peace time all the diagnostic activity for exotic virus diseases can easily be handled by Pirbright alone. However, there should be national contingency plans for dealing with a large-scale epidemic and for the co-ordination of the diagnostic laboratory effort. It is important that the necessary, trained personnel and other resources are available or can be deployed. There should be provision for increased laboratory space to meet the demands of a large epidemic. This should be sufficient to accommodate virological and serological activities at biocontainment level 4.
7 The IT system used to transfer electronically laboratory results from the diagnostic laboratory or laboratories to DEFRA should operate in a seamless and efficient manner. This was not the situation during the 2001 FMD epidemic and was never satisfactorily resolved.
4. PREDICTION, PREVENTION AND EPIDEMIOLOGY
7 Spread of existing diseases: how good is our present predictive capability (early warning radar)? And what are the implications of long term climate change? what evidence exists on the impact of mobility of people and animals and of changing trade patterns?
7 The creation of the single market, the removal of the Iron Curtain and the efforts by the World Trade Organisation to liberalise north-south trade will all increase the risk of dissemination of animal diseases. The increased incidence of FMD and sheep and goat pox in south east Europe (e.g. Bulgaria) are examples of diseases which have been repeatedly introduced by illegal trade since the removal of the Iron Curtain.
Liberalisation of trade in animals and animal products will have to be balanced by greater efforts to determine the risks and to develop appropriate safeguards. Pirbright, in its capacity as a reference laboratory for eight of the OIE List A diseases regularly receives diagnostic specimens from around the world. It also has an excellent world-wide communication network. However, it is dependent on the enthusiasm, efficiency and reliability of the countries collecting and shipping the samples. Many countries around the world are handicapped by having insufficient resource to carry out effective surveillance. There is a need to improve this situation. This could be through aid programmes or the through assistance from trading partners.
The characterisation of isolates of virus received from around the world by the reference laboratories at Pirbright provides and early warning system about new and potentially dangerous variants of virus or those which may not be covered by available vaccines. Further financial support is needed to expand and strengthen these activities.
Pirbright, in collaboration with Oxford University and other centres, has developed satellite remote sensing systems which can identify regions suitable as insect breeding areas and where epidemics may occur. These have proved very accurate for giving advance warning of the spread of bluetongue disease in Europe and African horse sickness in Africa (see Annex 1).
7 Introduction or re-emergence of disease: what is the risk of importing diseases from overseas?, what is effect of changes in livestock production methods on the introduction or re-emergence of diseases?
7 The risk is high and has increased with more liberal and increased illegal trade see above. Increased air travel, increased tourism and the use of containers for moving freight - over 2 million enter the UK each year - has made it more difficult to check and prevent the entry of animal products. The increased settlement of ethnic minority groups has increased the probability that animal products will be illegally introduced when immigrants make return visits to their homelands since very often they have contact with rural communities. Increased tourism and the entry of camper vans in which tourists bring their own food stuffs are a risk since they may discard stale food in rural settings. The move towards free-range pig production has increased the likelihood that animals will contact discarded waste food.
7 The routes of entry of FMD into the UK in the past have generally been either through the entry of contaminated waste food or airborne spread from outbreaks on the nearby continent. The only times when animals have introduced the disease was when infected beef cattle were imported from Ireland. This occurred when the disease was endemic on both sides of the Irish Sea. When waste food has been the source of virus entry then pigs have been the species first affected. Cattle have been the species first affected when virus has gained entry on the wind. The risk to pigs can be addressed by either banning the feeding of swill or ensuring that it is properly heat-treated to inactive the virus. The entry of airborne virus cannot be prevented but the consequences can be minimised by ensuring good co-operation with our continental neighbours to ensure that they report any outbreaks. Airborne prediction models, such as those developed by Pirbright in collaboration with the UK Met Office and used successfully to predict the Isle of Wight and Jersey outbreaks in 1981, can be used to give early warnings and direct control measures in the most effective manner. The models have been refined since the 1981 outbreaks through collaboration with the Danish Meteorological Institute and the Riso National Institute, Denmark and validated using data from outbreaks in northwestern Europe in which airborne spread was a feature, including France and the UK in 1981 and Eastern Germany and Denmark in 1982. However additional work is required to investigate experimentally whether infectious doses can be accumulated over time and, if so, how this can be incorporated in the models.
7 The unrestricted movement of animals, especially sheep, through markets was clearly an important factor in the wide-scale spread of FMD during the UK 2001 epidemic. Animals in trade should be required to spend at least 28 days in residency after purchase - as was recommended in the Gower Report of 1954, following the 1952-54 FMD epidemic. Had this recommendation been enacted in law and implemented the infected sheep from Ponteland in Northumberland would have stayed in that county and would not have moved on to Longton market in Cumbria in mid-February. Subsequent outbreaks would have been limited to Northumberland and the spread to Scotland, Ireland, Devon and other parts on the UK would have been avoided.
7 Novel agents: how good is scientific basis for predicting (a) wholly new disease agents or (b) existing agents occurring in new hosts or changing form to become more virulent? How could it be improved?
7 a). Wholly new disease agents. The extensive database of FMDV sequences generated at Pirbright allows the laboratory to identify all known strains of FMDV, and to determine the origins of FMD outbreaks. Here the scientific basis is excellent because the test relies on a molecular analysis of the virus genome. The current method requires that a segment of the genome encoding the capsid protein is sequenced and the same small area (less than 10% of the genome) is examined for antibody binding. The World Reference Laboratory also provides serological and PCR tests for many other exotic virus infections of farm animals currently endemic throughout the world. Importantly, the laboratory is familiar with the location of endemic areas and the clinical signs that viruses cause. Any change in the norm, or the emergence of a disease that could not be diagnosed at Pirbright would provide early evidence for a potential emerging disease.
7 b). Existing agents occurring in new hosts or changing form to become more virulent. The sequencing of FMDV strains that cause outbreaks around the world is ongoing. This strategy has the potential to detect any major changes in the virus genome and this can be correlated with virulence and tropism. Collaboration between Pirbright and Plum Island has shown, for example, that mutations within the non-structural protein 3A in the isolate responsible for the 1997 outbreak in Taiwan, correlate with high virulence within pigs. These results highlight the need for fast and detailed molecular characterisation of the genomes of outbreak strains in conjunction with controlled studies of virulence, tropism and excretion levels. In the future this will require the development of faster and more sensitive methods for full length viral genome sequencing. Detailed characterisation may also involve micro-arrays designed to detect specific serotypes and/or mutations in virulence hotspots. Taken together such studies should permit faster characterisation of new outbreak isolates and lead to an increased accuracy in risk predictions including the risk of emerging virus infections.
4.1.1 What role might exist for prophylactic (preventative) vaccination?
7 Preventative vaccination may be needed in certain circumstances, but should only be contemplated when the risk of introduction is significant. At the outset it should only be used as a step towards an eradication strategy, unless the situations in neighbouring countries are such that continued preventative vaccination is justified (high risk).
7 FMD viruses are highly variable and divided into seven serotypes with a significant degree of variation within serotypes. This makes preventative vaccination very difficult, as vaccine would have to cover all specific strains likely to present a risk. To cover all the FMD virus strains currently circulating worldwide, as many as 10 antigens should be incorporated into the vaccine to give full protection. For practical and economical reasons, current vaccines most often incorporate 3 or 4 antigens selected on the basis of local risk assessments.
7 There is a role for preventative vaccination under certain circumstances. Countries at very high and constant risk of introduction or which are endemically or sporadically infected and have no possibility of implementing a cull policy are clearly better off employing vaccine. Thus, their strategy is aimed at minimising the livestock production losses. This can be especially important where the animals at risk are valuable e.g. high producing dairy cattle or animals being used for breed improvement. However, vaccination alone will not eradicate FMD virus. That requires additional measures during outbreaks such as stamping out, movement restrictions, carcase disposal and disinfection. Generally countries using prophylactic vaccination as part of a national or regional programme do so to control rather than eradicate the disease. However, if they can maintain the programme over a long period it took about 20 years in Europe they may be able to reduce the incidence of disease to a level where it becomes economically acceptable to bring in stamping out and other zoo-sanitary measures which will eradicate the virus.
4.1.2 What lessons can be learn from other countries?
7 The countries of western continental Europe progressively introduced prophylactic vaccination of cattle during the 1950s when it became possible to produce FMD vaccine on a mass scale. At that time the number of outbreaks per year was around 300,000 and the productivity losses were enormous. By the mid-70s the number of outbreaks in western Europe had been reduced to below a hundred per year. Additional measures in the event of outbreaks were introduced including stamping out of infected premises, ring vaccination around them and movement control. Although outbreaks continued around 2,000 in total during the 1980s the general trend for most countries continued downwards. In 1989 the EU, seeking a harmonised policy for FMD control in the community ahead of the creation of the single market, decided that it would be more cost effective to cease vaccination than to have pan-vaccination. The decision was taken that vaccination should cease during 1990-91 so that there could be a period of one year before the single market came into operation on 1 January 1993. The estimated saving to the community between 1991 and 1996 of ceasing vaccination has been estimated to have been in excess of 800 million ECU at 1996 prices. Before the policy was implemented it was stated that the money saved by ceasing vaccination would be used to strengthen the periphery of the community against the risk of future virus entry, but that did not happen. On the contrary the borders of the community, especially on the east and southeast are much more porous (see Section 4).
7 In the EU, the UK and Ireland have never vaccinated. Greece and Denmark used vaccine for a short period and then abandoned it. It is generally accepted that preventative vaccination should only be considered if the risk of introduction or spread indicates a significant risk. Otherwise, experiences over many years indicates that it is possible and better to prevent the introduction of FMD virus. If the number of introductions are few and the control measures are effectively applied it should be possible to eradicate the virus without resorting to vaccination. The only exemption to this pattern is where a severe epidemic develops. This is most likely to occur when there is a long delay in the reporting of disease due to poor awareness or negligence on the part of farmers. In the 2001 UK epidemic the situation was worsened by the extensive trade in livestock as well as poor biosafety on many farms. Thus, initiation of preventative vaccination represents a total lack of confidence in the ability to sustain good animal husbandry, including biosafety. The example of the Dutch 2001 FMD vaccination has no scientific weight, as their cases most likely could have been eradicated relatively easily and with a minimal amount of culling. The Dutch had the considerable advantage in that they already been warned by the UK and only ruminant animals were affected.
4.1.3 What is the role of preventive measures such as changes in stocking densities?
7 Clearly a high stocking density will favour the spread of a contagious disease such as FMD and increase the problems of disposal. The distance between herds is also an important consideration since short distance will favour virus spread. Analysis of the UK epidemic should provide useful data on the influence of these parameters. Crucial to any consideration in this regard is the efficiency of the biosecurity of a farm. Preliminary data indicating that a very high proportion of the spread during the 2001 UK epidemic was local which indicates that either airborne spread was more common than expected or that there were frequent failures of biosecurity.
4.1.4 How good are present import control? What is needed to improve? Can new science or technology help?
7 Apart from commenting that two exotic viral diseases (classical swine fever and FMD) have recently entered the UK and that the most probable mechanisms of entry were contaminated animal products being fed to pigs the IAH does not consider that it is well placed to make a judgement about this.
7 In the case of imports entering the UK from other member states of the EU, responsibility for the certification of the health of animals resides with the exporter. Improved controls could be achieved by the establishment of voluntary testing by UK animal breed organisations. Such an arrangement would make it possible to check a number of samples from animals and animal products after importation. In combination with new, sensitive diagnostic techniques, it may even be possible to envision a significant screening of batches of imported animals and animal products before release.
4.1.5 How good are other countries import control? what can we learn from them?
7 Several countries have more stringent import controls. For example, the USA, Australia and New Zealand vigorously enforce import controls and use x-ray equipment that can detect animal products. Certain other countries have concluded that the risks from the importation of live animals far outweigh those from the other possible routes of virus entry and so the authorities focus their efforts on live animal imports and vehicles used to transport live animals. Since EU rules do not allow any special screening of imported live animals (apart form the tests provided by the exporter) any additional screening cannot be done by Government. However, the animal breed organisations could organise and fund post import live animal testing.
4.1.6 Are there wholly new approaches to prevention?
7 There is the possibility of the future development of a specific treatment or a sterilising vaccine capable of curing or preventing the establishment of the carrier state in FMD.
With more basic knowledge of the molecular-mechanisms underlying viral tropism (Section 4 (i)), it may be possible to develop drugs to prevent a virus from infecting an animal and likewise, it may be possible to devise a vaccine that efficiently prevents both acute disease and the establishment of persistent infection (carriers). If establishment of the carrier state can be prevented, many of the negative effects of emergency vaccination would no longer be relevant. Nevertheless, it is most likely that if such vaccines or drugs were available they would be used to control an outbreak instead of being used for preventative purposes. In order to be accepted for use the vaccine or drug would have to be cheap.
4.1.7 What are the prospects for breeding animals with higher resistance, route forward?
7 At present this is not a viable proposition, however future developments may create opportunities.
4.2 Modelling of diseases spread
4.2.1 Is there sufficient scenario planning?
7 No. For many years, Pirbright staff organised exercises on the epidemiology and control of FMD. These were held on a rotating basis around the different regions of the country. However, the overall frequency of these courses has declined in recent years due to the severe reductions of experienced veterinary staff at Pirbright.
4.2.2 What is the role of predictive modelling?
7 Predictive modelling can play a very important role. As previously described in the Section Introduction or re-emergence of disease, models produced by Pirbright and the Met Office were used successfully to predict that the Channel Islands and the southern coast of the UK were a risk in 1981 when outbreaks were reported in Brittany, France. The information was passed to MAFF who issued advance warnings to the farming community. When disease subsequently occurred on Jersey and the Isle of Wight it was quickly reported and dealt with and no further spread took place.
7 Predictive modelling can also be useful as an aid to decision making. For example when examining the possible outcomes of different disease control strategies.
7 There is a need to improve the accuracy of existing prediction models and to develop new models which can simulate the outcomes of different emergency vaccination strategies.
4.2.3 How good are the present models?
7 The models developed originally at Pirbright in collaboration with the UK Met Office for predicting the airborne spread of FMD have been considerably refined and improved through subsequent collaboration with the Danish Meteorological Institute and the Riso National Institute, Denmark. Two short-range and two long-range models are available. The impetus for the development of these models has come from concern about the atmospheric dispersion of radioactivity following nuclear accidents. In a field trial during which an inert gas was released off the west coast of continental Europe the Danish model Rimpuff, which is used to predict airborne spread of FMD virus, gave the most accurate prediction of atmospheric dispersion of 19 models which were tested.
7 IAH is not in a position to judge the quality of other predictive models but suggests that it should be possible to determine this when the data from outbreaks during the UK epidemic are analysed in detail and it is determined which farms of those culled were actually infected.
4.2.4 What precise evidence is needed to underpin the models?
7 Much more detailed biological input data are required. This will require a considerable amount of research effort into the time course of the infectiousness of FMD in different species of animals, the minimum doses to infect different species by various routes and investigations to determine in detail the rates of decay of FMD virus under different conditions.
7 For airborne transmission predictions, data on minimal concentrations as well as the importance of accumulated dose over time is needed. Provided the necessary resources can be obtained, such studies will be a natural continuation of ongoing activities at IAH.
4.2.5 How can they be made flexible enough to cover all eventualities?
7 The full flexibility of modelling requires the close integration of modelling and disease/infection expertise. It is, therefore, of utmost importance that the predictions made by biomathematicians are scrutinised by experts in the veterinary or other scientific fields. We consider it essential that there is close collaboration between modellers and disease experts, especially those experts who have actually generated the biological/virological data for models.
4.2.6 How can we improve our databases and livestock demography?
7 It is essential that the various databases are compatible and that all serious stakeholders can have free access to them. Farm location data and demographic data should be available to researchers in the public sector. It is important that all entries in the databases are accurate and up-to-date and can be made available quickly in the event of a national emergency.
4.2.7 Do other countries use similar or better ones?
7 New Zealand, Ireland, The Netherlands and Denmark are among the countries that are more advanced than the UK in the systems they have available for managing data relating to land parcels and demography.
4.2.8 Are there new techniques from other fields (eg operational research) that could help?
7 IAH does not feel that it is competent to comment on this.
4.3 Control if an outbreak occurs
4.3.1 Are present methods compatible with modern ethical views?
IAH does not consider it unethical per se to kill a farm animal since, in the case of food animals, that will be their inevitable fate. The question presumably is should culling be employed to control disease? The traditional method of controlling FMD, which is to slaughter all the cloven-hoofed animals on an infected premises and those which can be identified as dangerous contacts, has been demonstrated on very many occasions in different countries to be an effective method of eliminating the virus. Modifying the procedure and only killing the clinically affected animals has been attempted e.g. in the UK during 1922-24 and in Italy during the 1980s, but was abandoned because outbreaks continued in some cases months later when animals were moved to new farms, presumably because some animals were convalescent carriers. On the grounds of effective disease control and the greater good of saving the lives of healthy animals on non affected farms these actions can be considered ethical.
The control measures introduced during the 2001 epidemic, in particular the 24/48 hour cull can only be judged as being ethical or not when the data from culled farms has been analysed to determine whether the mathematical predictions for spread made by the modellers were actually accurate or not.
4.3.2 Has the socio-economic climate (including the CAP) altered the fundamentals of the national strategy?
7 IAH has no comments on this question which falls outside its expertise.
4.3.3 Do control procedures incorporate recent developments in science and technology?
7 The traditional method for eradicating FMD from a country which is normally free from the disease is stamping out. As has been mentioned previously (see Section 4.3.1) any compromise to that policy risks the possibility of the recrudescence of disease. Historically, the UK has been country which has been the main promoter and driver of stamping out. The policy has stood the test of time and farmers in developed countries are well aware of what will happen if their herds or flocks are affected. They can also accept the culling of their animals when their farms are dangerous contacts.
7 A development in science arising from work at Pirbright which has been taken on board by DEFRA and other veterinary authorities has been the demonstration that pigs can excrete large amounts of airborne virus. Consequently when pig farms have been affected they have been culled out as fast as possible to reduce the risk of downwind spread.
7 The airborne prediction models for FMD developed at Pirbright have also been used during outbreaks to analyse the risk of downwind spread of disease and to direct surveillance activities in the most probable direction of spread. The value of these models during the 1981 outbreaks has been outlined in Section 4.1.2. During the 2001 epidemic the prediction models were used when any pig premises was involved and the plume predictions were given to DEFRA. Fortunately airborne spread, at least over long distance, was not a feature during the epidemic because few pigs were involved and also because the UK 2001 strain of virus was found to be excreted in relatively low amounts.
7 The improvement of emergency vaccines and the methods for their storage have made it more feasible to consider the option of using emergency vaccination as an adjunct to stamping out.
7 The 24/48 hour culling policy went against the available scientific evidence which showed that the virus was unlikely to spread over significant distances provided the control measures, in particular movement control, were enforced effectively. The fact that extensive local spread did occur indicates either that the predictions for airborne (uncontrollable) spread were too conservative or that there was widespread failure of biosecurity.
7 Serological testing during the UK FMD epidemic was based on state-of-the-art methods developed at Pirbright but DEFRA was reluctant to use any methods that were not fully validated under field conditions. Consequently considerable time and effort was expended in validating them during the epidemic. Several additional rapid on-site methods were also developed at IAH. These techniques included a penside antigen-detection kit as well as a real-time RT-PCR. These methods were tested and gave excellent results with samples from experimentally infected animals. Around 300 of the on-site kits were distributed to veterinarians in Northumberland and Cumbria for testing under field conditions, but, disappointingly, very few kits were returned to the lab (less than 2%). During the outbreak field samples were tested by the real-time RT-PCR methods in a research setting with good results, but were not used for final diagnosis. Nevertheless, the results obtained are valuable and will support validation of RT-PCR methods for future use.
4.3.4 How effective is the present national infrastructure and logistical support?
7 The failure to identify the breaches of the swill feeding requirements on the primary infected premises indicates that the infrastructure responsible for inspections in that area was ineffective.
7 The chaos at the start of the epidemic clearly showed that the national infrastructure and logistical support was inadequate for dealing with an epidemic of the scale encountered.
7 The IT for linking Pirbright and DEFRA for the electronic transfer of results was unsatisfactory and inefficient and was never properly corrected.
4.3.5 What are the key elements of a strategy to control and eradicate important infectious diseases within the current trading policies?
7 The key elements are:
- Having available the best possible intelligence about the present whereabouts of the diseases which pose a threat and up-to-date information about the characteristics of the causal organisms. This requires knowledge about the trustworthiness of trading partners in terms of their reliability to survey for and report disease outbreaks.
- Controls and checks at ports, airports other points of entry to prevent the illegal entry of animals and animal products.
- A policy for waste food. Either destroy all or if swill feeding is permitted take measures to ensure that it is properly heat treated (e.g. by local government authority).
- Ensure by proper and frequent training that those in the front line are aware and familiar with the signs of animal diseases.
- Ensure by training and publicity that the farming community is familiar with the diseases that pose a threat and with basic biosecurity methods.
- Ensure that the farming community and others in the front line are aware of the need for rapid reporting of suspected cases of exotic disease.
- Enact a residency requirement of at least 28 days for animals that have been purchased.
- Ensure that there is an adequate infrastructure and logistical support to deal with epidemics.
- Implement an appropriate series of control and eradication measures when any outbreaks occur.
- Have in place a national contingency plan for dealing with disease emergencies.
- Ensure that the different arms of the national emergency response are effectively co-ordinated.
- Instigate a programme of extensive surveillance to determine whether the causal agent has been eradicated.
4.3.6 How effective is culling? How good are the techniques and what are the alternatives?
7 The culling of animals infected with FMD dramatically reduces the amount of virus they are liberating into the environment. This is especially important when pigs are infected because they are powerful emitters of virus. Culling will eliminate carrier animals and eliminates the possibility of carrier animals causing the recrudescence of disease. Culling on a large scale presents considerable practical problems. In The Netherlands mobile electrocution trucks were developed and used in 1997 when 10 million pigs were slaughtered.
4.3.7 What are the environmental and public health implications of disposal technique
7 Disposal by burial is the preferred disposal method but there was strong opposition to this method during the UK epidemic. The concerns related to the risk of water contamination by chemicals, BSE and other agents. Burning causes smoke and chemical pollution and possible risk to human health. Disposal by rendering or burial in safe sites seem to be the only practical options. Both of these activities require the manipulation and transport of infected carcasses and so the risk of spread of virus will be increased.
5. 1 What roles do vaccines play.
Mass vaccination. FMD vaccines can be broadly grouped into mass vaccines and emergency vaccines. Either can be employed in various ways to achieve different objectives. Mass vaccines are used in infected countries to reduce productivity losses. This may be the loss of milk and meat production in cattle husbandry or the deaths of piglets in pig production systems. In developing countries FMD vaccine is usually used selectively due to the limited financial resources. Therefore, in South America, Africa and India vaccination is usually focussed on the cattle, especially the dairy animals, whereas in south east Asia the focus is on pigs and cattle.
Countries infected with FMD face severe constraints on the export of live animals and animal products, especially of fresh meat. The desire to improve earning potential, especially of hard currency, is the driver for countries embarking on FMD eradication programmes. They key elements of such programmes are a high and sustained vaccination coverage, the prompt reporting of outbreaks and zoo-sanitary actions which will reduce the amount of circulating virus. The objective of mass vaccination in those circumstances is to reduce the incidence of disease to a level where it is economically acceptable to introduce stamping out (culling). Farmers will only accept the stamping out policy if they are fully and promptly compensated for the loss of their animals. Thus, vaccination per se will not eradicate the virus it must be combined with other zoo-sanitary actions.
Regions and countries in which such campaigns have reached a successful conclusion include the continent of Europe, Chile and Indonesia. The Philippines is making steady, island-by-island, progress. Typically, the duration of eradication campaigns can be measured in decades rather than years. For example, it took from the mid-50s until the late-80s to eradicate FMD from Europe (see Section 4.1.2).
Barrier vaccination zone is a measure entailing the mass vaccination of animals along a defensive wall, typically at a national boundary, to minimise the risk of spread of FMDV from an infected area on one side to a free area on the other. For example, from the mid-60s to1989 a barrier vaccination zone was maintained along the borders of Bulgaria and Greece with Turkish Thrace and successfully protected south-eastern Europe from exotic strains of FMDV present in Asiatic Turkey.
Emergency vaccination: Emergency vaccination can be used in different ways and with different objectives. In general, emergency vaccines are formulated so that they induce a rapid and strong immune response. In ring vaccination a zone is selected beyond the infected area and all species are vaccinated to create an immune belt. The objective is to contain infection inside the ring. This strategy will only work if the ring is small and can be clearly defined. In dampening down or suppressive vaccination the vaccine is applied in and around an infected area. The objective in this case is to reduce the amount of virus being liberated into the environment. This was the strategy used in the 2001 Dutch epidemic. The Dutch had disposal problems and so they decided to vaccinate to reduce the amount of virus that would be released during the delay before the animals were slaughtered.
Levels of vaccine cover: Whatever the role/strategy, choices must be made with regard to the livestock species that are to be vaccinated, and the FMDV strains that these species are to be protected against. Such decisions involve weighing likely benefits against risks and costs, and inevitably produce a compromise. For example, when mass vaccination was used on continental Europe in 1991, the entire cattle population of the region was regularly vaccinated against strains of the three European serotypes, O, A, and C. However, the cattle were allowed to remain susceptible to strains of the other four serotypes, and pigs, sheep and goats were totally unprotected from FMDV. To provide an adequate level of protection against all the major antigenic groups of strains circulating in the world today would require vaccines prepared from around ten different strains.
5. 2 What are the implications of vaccination for animals entering the food chain?
The primary consideration here is the safety of any food products derived from vaccinated animals. Other than the type of inactivated antigen contained in the formulation they are no different from any other vaccines routinely given to animals from which food for human consumption is derived. There has been some resistance to meat from animals inoculated with oil-adjuvanted vaccine, although the oils used nowadays are not considered a hazard to human health. The FSA and VMD have both assessed the safety of FMD vaccines for human consumers and concludes that the vaccines do not represent a hazard in terms of consumer safety. However they may be subject to food safety legislation.
5. 3 How good are the present vaccines and how could they be improved?
Current vaccines are made from inactivated, virulent virus, and suffer from several limitations, listed (i) (x), below. Ways in which these deficiencies might be addressed are considered in section 5.4.
(i) Vaccines protect animals from clinical disease but do not confer sterile immunity, i.e. prevent infection and virus replication in the oro-pharynx in ruminants. They therefore may not prevent some transmission of the virus between animals. Vaccinated animals, although protected from the development of clinical signs, should be considered potentially infected by FMDV, and in the case of ruminants, such infected animals can become carriers with the potential to spread the disease to naive animals.
(ii) The protection provided is serotype specific. At present there are seven different serotypes circulating throughout the world. A vaccine based on one serotype does not protect against another, or even against some strains within the same serotype.
(iii) The immunity conferred is of short duration. Antibodies play a key role in immunity to FMDV, and protection requires a high resting levels of antibody (hence the serotype specificity noted in (ii)). Maintaining protective immunity thus necessitates booster vaccination at regular intervals of four to six months (see 5.7). It is this factor, above all, that makes FMD control by vaccination extremely expensive.
(iv) Vaccine protection is delayed (see 5.7). High potency vaccines can induce protective immunity in as little as four days, but even that delay is a major impediment to the emergency control of an infection which spreads as rapidly as FMD.
(v) Mammalian species differ in their responses to vaccines. The adjuvant of choice for vaccines for ruminants, aluminium hydroxide, is less effective for pigs. Oil adjuvanted vaccines will protect either, but are more expensive.
(vi) FMDV vaccine antigen is unstable as immunogenicity is greatly impaired when the virion breaks down or when antigenic determinants on the surface of the virion are cleaved by adventitious proteases. This causes several problems. Once formulated for use, vaccines cannot be frozen, have a limited shelf life, and require a cold chain for delivery to infected areas. This is a serious limitation in many areas of the world where FMD is endemic, and where vaccines would otherwise be most useful.
(vii) Vaccines made from live, virulent FMDV pose risks to safety. Their manufacture requires a high level of bio-containment and strict control of the inactivation process, the latter to ensure the safety of both the production staff and the product. As noted in 5.9(iv), FMD outbreaks have been attributed both to leaks of virus and, more importantly, to the use of incompletely inactivated vaccine. Currently only one European manufacturer is licensed to market vaccine. While the safety of that product is not in doubt, safety is a concern in parts of the world where locally produced vaccine is used.
(viii) Repeated vaccination eventually leads to the production of antibodies against the replicatory viral proteins (the non-structural proteins or nsps) which are present at low levels in commercial vaccines. This complicates the development of serum tests for distinguishing infected animals from uninfected vaccinated animals.
(ix) Virus strains used in vaccine manufacture are adapted to growth in suspension BHK cells. Some of the changes that arise during adaptation, e.g. in receptor usage, alter the antigenic properties of the virus and in some cases these significantly reduce the efficacy and coverage of the resulting vaccine.
(x) Vaccines have to be injected. Novel approaches e.g. oral or aerosol vaccination would be advantageous.
5. 4 What research is needed to improve existing vaccines or their delivery?
The major aim should be the design of stable vaccines that produce rapid and long term sterile immunity in all host species. The factors that limit the efficacy of current vaccines are listed in 5.3. The first five, (i) (v), relate to the nature of the immune responses in livestock. As we shall see below, some of these will require basic immunological research before practical solutions can be devised. This is particularly true of the carrier state (see (i), below). The remainder, (vi) (ix), raise an assortment of issues which are more amenable to attack from the vantage point of molecular and structural biology of FMDV. Here we offer brief suggestions on how to address each issue in turn, in the light of recent scientific developments.
(i) Vaccines able to confer sterile immunity? Lack of sterile immunity is a major problem (see 5.10). However serious the other limitations of vaccines may be in practice, they can generally be accommodated given sufficient resources. Not so the regulatory problem posed by carriers! The epithelial tissue that serves as the initial site of infection in ruminants is also the one in which the virus persists. Since the (clinical) immunity conferred by natural FMD fails to prevent (sub-clinical) re-infection at that same site, the carrier state would appear to result from an intrinsic deficiency in the ruminant immune response to FMDV. In these circumstances it is unclear how vaccinology alone is going to solve the carrier problem. How can a vaccine induce an immune response that FMDV itself does not? Research into live vaccines which combine appropriate tissue targetting with enhanced potency (see iii, below) might yield a solution to the problem. Equally, however, it might not. Rather, we believe that the way forward is to pursue vigorously the aims of our basic, multidisciplinary research programme to gain an intimate understanding of the molecular, immunological, and cellular interactions that determine the tropism of FMDV and that take place in those particular pharyngeal cells in the living animal.
(ii) Broad antigenic spectrum vaccines? Currently these are produced as multivalent vaccines, i.e. containing mixtures of FMDV strains. There is a fundamental obstacle to broad-spectrum vaccines, and that is the dependence of protective immunity on the humoral arm of the immune system (5.3(iii)). More research is needed to understand the contribution that cytotoxic immune responses make to protection. Certainly, high levels of neutralising antibody are not always sufficient to protect cattle - this has been shown in a number of experiments with peptide immunogens at IAH Pirbright - but antibodies are surely necessary.
In (iii), below, we offer specific suggestions for biotechnology aimed at delivering more potent vaccines. Some improvement in antigenic coverage can be expected to accompany any increase in potency and duration of immunity, which are desirable properties anyway. In particular, extending the range of immune responses to include e.g. conserved MHC class I epitopes, as live vaccines should do (see (iii)), may well result in some broadening of strain coverage.
What about peptide vaccines? An alternative approach to a multivalent vaccine might be one displaying multiple serotypic forms of the FMDV loop (the G-H loop of capsid protein VP1). This was the first example of an anti-viral peptide vaccine to be reported and, over the twenty years since, the sequence has been incorporated in a vast number of live, subunit, virus-chimaera, and synthetic, vaccines (including several at this Institute); novel peptoid chemistries have also been explored. Unfortunately, peptides are fundamentally unsuited to the demands, stipulated above, of an FMDV vaccine. Any peptide immunogen must be presumed to possess (a) a narrow range of epitopes, (b) a wide range of mainly inappropriate molecular conformations, and (c) a molecular setting, if any, that is inappropriate. None of the extensive research reported to date, nor our unpublished research, encourages us to believe that these deficiencies collectively can easily be overcome.
In conclusion, while research can be expected to produce some welcome improvements in strain coverage, it is difficult to imagine these ever bridging the antigenic gulf that divides the serotypes. It is likely, therefore, that multivalent vaccines will continue to be needed when multiple serotypes threaten.
(iii) Vaccines conferring extended duration of immunity? The scientific issues relating to humoral immunity which underlie broad-spectrum vaccines ((ii), above) are also relevant to duration. The period of cover is limited because of the decline in antibody levels. However, protection tends to last longer following natural FMD than it does post-vaccination, presumably owing to stimulation by the former of CTL responses. Vaccines that express the FMDV immunogen within the tissues of the animal, including live and DNA vaccines, ought therefore to provide a way of extending the duration of cover.
What live/DNA vaccines?
Live attenuated FMDVs, analogous to the Sabin oral poliovirus vaccine, were developed many years ago at IAH Pirbright and in several other laboratories. However, on occasions, the consequences were disastrous when they reverted to virulence and caused severe outbreaks. There are several ways in which attenuation could be engineered into FMDV by site-directed mutagenesis, but such vaccines might also encounter regulatory hurdles.
Vector (virus or bacterial) or DNA vaccines ought to be more acceptable. Eukaryotic expression systems for making capsid-like particles of FMDV were pioneered several years ago at IAH Pirbright. The type of cDNA expression cassette in those vectors has since been used at Plum Island in experimental vaccines expressed from a defective adenovirus vector or naked DNA. The work, as reported, appears to be at an early stage, but both systems merit further development. Attenuated herpesvirus vectors should also be considered. So, too, should attenuated capripoxvirus vectors, for use in the extensive areas of the world where FMDV and capripoxviruses are both endemic; capripoxvirus vaccine technology has been developed at the IAH, and found to be effective in stimulating responses in cattle to foreign gene products. In speculating about live vector-based vaccines, a note of caution should be sounded, as the biotechnological challenges are far from trivial. There appears not to be any eukaryotic vector (vaccinia virus, baculovirus, and a rinderpest virus vector developed in-house have all been tried at the IAH) that will tolerate the insertion of an FMDV (or any picornaviral) capsid expression cassette unless expression is either inefficient or under the control of an inducible promoter.
Longer term, improvements should be sought by enhancing immune responses through the inclusion of stimulatory viral sequences (B- and T-cell epitopes), and cytokines for stimulating the appropriate types of TH lymphocyte response. These developments should be underpinned by basic research on the ruminant and porcine immune systems, as e.g. is ongoing in the substantial research programmes at IAH Compton and Pirbright, respectively. The rational design of vaccines for farm animals benefits greatly from our current understanding of murine and human immune systems. It is important to point out, however, that pigs and ruminants have many unique immunological features such as heterogenous lymphocyte populations and very large numbers of gd T-cells and natural killer (NK) cells. These cells are rare and difficult to study in murine and human immune systems and until recently been overlooked as important arms of the immune system. The precise role these cells play during infection and vaccination of pigs and ruminants needs to be investigated (see 5.6)
An alternative way of giving long-lasting protection might be by means of a slow-release implant, although we have no experience of these devices.
(iv) More rapidly acting vaccines? It is difficult to see how the response time might be significantly reduced for ruminants, but better vaccines for pigs can be envisaged, and are certainly needed (see 5.7) to ensure a rapid response.
(v) Vaccines effective for a broad spectrum of mammals? The oil-based vaccines that are protective for pigs also protect cattle, but are not the cheapest. Better adjuvants should continue to be explored. They should be versatile and work in all host species, provide better immogenicity, and be easier to deliver, or offer alternative delivery systems. They should also be safe to both host and consumer.
(vi) Stable vaccines?
(vii) Safe vaccines?
(viii) Vaccines free of replicatory antigens?
(ix) Vaccines with the authentic antigenicity of field strains?
Biotechnology provides realistic routes towards all these four goals, the main limitation to progress in recent years having been the paucity of governmental support in the UK and EU. (vi) Regarding stable vaccines, candidate virus vectors are suggested in (iii), some of which, like poxviruses, are comparatively stable and amenable to freeze-drying. Alternatively, technology has been developed at the IAH for making FMDV capsids in reasonably large amounts in tissue culture, and this product is, as we have shown, amenable to site-directed mutagenesis to enhance physical robustness. (vii) Any cDNA-derived immunogen is safe in the sense that it is free of live FMDV. (viii) Assembly of FMDV capsids requires the viral 3C protease, but no other replicatory protein. It is therefore possible to guarantee exclusion of all the latter, undesirable, antigens, and so avoid inducing responses that might be confused with FMDV infection. (ix) Similarly, the authenticity of the antigen will be precisely that of the virus isolate from which the cDNA was copied. The antigenic deficit that occurs when FMDVs are passaged in tissue culture is therefore not a problem.
5.5 What is the role for marker vaccines combined with differential diagnosis?
A marker vaccine could be used as a way of distinguishing vaccinated animals from animals whose immunity had been acquired through natural infection, but crucially it would not identify among vaccinated animals those that had subsequently become infected and were carrying the virus. We would envisage little role for such technology, were it to be developed, for two reasons:
(i) serum tests already exist for distinguishing infected animals from uninfected, vaccinated animals (although they become less reliable after repeated vaccination).
(ii) A more fundamental objection is that the test would only be helpful if one could confidently infer from the presence of anti-marker antibodies that the animal was free from infection. For that to be true, several stringent conditions would need to be met, among them, that the vaccine is able to confer sterile immunity. No such vaccine exists or is in immediate prospect.
5.6 Do we have the tools to evaluate vaccine efficiency (challenge models, correlates of immunity)?
The evaluation of vaccine efficacy is currently undertaken at IAH Pirbright by the use of in-vivo models normally encompassing one of the target hosts, usually cattle, and in-vitro assessment, primarily through the quantification of a virus neutralising antibody response. The relationship of a field isolate to the vaccine strain also encompasses a serological approach.
The evaluation of correlates of immunity requires analysis of two arms of the immune response. The evaluation of the acquired immune response involves analysis of circulating antibody and the detection of T and B cell populations recognising FMDV or vaccine components. For these the basic methodologies of ELISA, virus neutralisation and cellular proliferation assay are available. In the future this analysis should be refined through development of MHC tetramers to follow he induction of virus-specific T-cells, and the use of ELISPOT technology to follow the dynamics of cells producing antiviral cytokines.
The evaluation of the innate immune response of ruminants and pigs to vaccination is more difficult, but remains an important area for investigation. In young animals as many as 50% of the circulating lymphocytes are either gd T cells or natural killer (NK) cells. This is in contrast to man and mouse where such cells are rare in the circulation. The reasons for these differences are not known, but the innate ability of these cells to respond to antigen, and their ability to secrete cytokines, gives them the potential to respond rapidly to FMDV. This may explain the rapid action of the FMDV emergency vaccine that can protect ruminants within 4 days. These provocative observations show that there is an urgent need to understand how stimulation of these cell populations in ruminants and pigs, correlates with protection against FMDV. In the past the prediction of the efficiency of FMDV vaccines has been based on serology, most usually the induction of neutralising antibodies. It is important to point out that these methods have not yet provided a vaccine able to prevent persistent infection of ruminants (see 5.10). The development of alternative correlates of protection is therefore an urgent priority, and those based on the stimulation of innate antiviral responses offer much promise for the future. To do this we need to develop markers and functional assays for the NK cells and gdT cells of farm animals, and use them to guide future vaccine trials.
5. 7 What is the time course of protection offered by the vaccines?
The most potent vaccines (high dose, emergency formulation) induce protection in ruminants within 4 days of a single vaccination, whereas vaccines to the standard specification may take up to a week to protect. During this period ruminant species are still susceptible to infection. This means that ring vaccination is less effective at preventing virus spread than ring culling, which removes all susceptible animals immediately. Response times in pigs are much more variable, and can be as long as three weeks. Vaccines do not protect animals that have been exposed to the virus and are already incubating the disease.
A primary course of conventional vaccine comprises an initial vaccination followed by a boost vaccination around 4 weeks later. Depending on the vaccine, its potency, and the number of doses given, protection lasts 6 12 months. With high potency vaccines immunity can be maintained in sheep for at least 6 months following a single injection, and in pigs for 7 months. Sustained protection against FMD from the use of conventional, aqueous vaccines requires booster injections at 4-6 monthly intervals; with oil adjuvented vaccines annual re-vaccinations may suffice.
5.8 Should vaccination be used for rare breeds and for zoological collections?
Possibly. In principle, vaccination of high-value individuals or collections might be justified by a risk/benefit analysis that acknowledges the low risk of infection from carrier animals. Unfortunately, animals such as African buffalo can carry FMD all their lives, and so pose a risk for many years. The dangers of permitting potential carriers to survive possibly long after the country has regained disease-free status, are too great to contemplate without stringent controls. The issue raises severe, as yet unresolved, regulatory problems, although in principle we feel that these problems could be overcome. To minimise risk to an acceptable level the following conditions would have to be met:
(i) Since vaccination merely masks, but does not prevent, infection, it would be necessary to avoid contact between vaccinated and susceptible animals. This may be difficult to sustain long-term.
(ii) Different mammalian species possess very different immune systems, and there is very little direct evidence for the response of wild animals to FMD vaccination. Where a variety of exotic cloven-hoofed species are housed together, as in a zoo, it would be important to monitor serum antibody levels to ensure all individuals are protected.
(iii) This raises the issue of how these antibody tests would be done. Hopefully a competitive ELISA could be used, but such assays have not been validated for exotic species of mammal.
(iv) Once the external threat of infection ceases, previously vaccinated animals would have to remain in quarantine until their virus-free status has been verified. This might be achieved either by repeated negative testing for virus in oro-pharyngeal secretions sampled by probang, or by monitoring declining antibody levels until they become undetectable. An individual with a persistently raised antibody titre would have to be slaughtered as a presumed carrier.
(v) Systems for policing these quarantining and testing arrangements would need to be put in place to the satisfaction, not only of DEFRA, but also OIE.
The current OIE ruling is that a country which has any vaccinated animals on its territory, irrespective of their species, forfeits its disease-free non-vaccinated status. Any exceptions policy for high-value animals, were one to be agreed, would inevitably be very expensive to implement, but we would not rule out the possibility altogether.
5.9 What can we learn from other countries?
Current policies on vaccination are largely informed by the example of other countries.
Eradication by vaccination: The experience of continental European countries following World War II taught that mass vaccination can be successful in reducing the incidence of disease, but that additional zoo-sanitary measures, such as movement controls and culling on infected premises, were required to eradicate the virus. Progress towards eradication took several decades. More recent experience tends to confirm that using mass vaccination to eradicate FMDV can be a long and arduous process. For example, vaccination was used in Taiwan 1997 and yet the disease is still there today. It is too soon to tell how successful the use of mass vaccination was in Uruguay at the beginning of 2001. At best the expedient will have cost that country her disease-free status for ~2 years. Suppressive vaccination, followed by culling of all vaccinated animals, was adopted in The Netherlands this year but had very limited objectives (see Section 5.1). To summarise, the main lessons from other countries are as follows:
(i) Success requires that neighbouring countries in a region work together to operate a common policy. That policy, moreover, must be rigorously enforced.
(ii) It is not possible to eradicate FMDV by vaccination alone. Sporadic outbreaks are liable to continue for many years (e.g. see iii, iv), unless vaccination is accompanied by stamping out measures.
(iii) Carrier animals can start outbreaks of acute disease in susceptible livestock. That was a lesson of the Danish outbreak of 1983.
(iv) Stringent safety controls are necessary on the manufacture and inactivation of vaccine virus; outbreaks have been attributed, both to leaks of virus, and to the use of incompletely inactivated vaccine.
5. 10 What is the importance of the carrier state in vaccinated animals?
The pernicious ability of the virus, not only to spread with devastating speed, but also to persist, is what makes this the worlds most economically important animal virus. The carrier state is the chief regulatory barrier to the use of vaccination against FMD. The reasons are as follows:
The carrier state is a persistent, asymptomatic FMDV infection which commonly follows the acute phase of the disease. It can be detected by assaying for live virus, or viral RNA, in the oro-pharyngeal secretions of the infected animal sampled using a probang. The condition arises very commonly in ruminants (up to 50% of cattle) but has not been demonstrated in pigs. Importantly, it also arises in vaccinated (or recovered) animals upon subsequent exposure to FMDV. Indeed vaccination confers little, if any, protection against the carrier state.
It has been argued that carrier animals pose a negligible risk of infection on several grounds: (i) The amount of virus shed during the persistent phase of infection (<104 infectious units per ml oro-pharyngeal fluid) is much lower than during acute disease. (ii) Transmission from carrier cattle or sheep, whether vaccinated or not, has never been demonstrated experimentally, only from African buffalo.
Despite these arguments, we believe that the reasons for caution are overwhelming. (i) Probang sampling has shown that the practice of vaccinating in the face of ongoing disease does tend to create significant numbers of carrier animals. The number is likely to be underestimated, moreover, because the appearance of live virus in probang samples is often only intermittent, so that infection can be missed unless sampling is repeated. (ii) The low transmission rate from carriers is partly balanced by a very much longer risk period. Cattle can carry FMDV for up to 3.5 years, sheep for 9 months. (iii) It cannot be assumed that virus shed by carriers is entirely harmless. Not all of it is neutralised by antibody, and even that which is neutralised (i.e. is unable to infect cells in culture) must still be regarded as potentially infectious for animals. (iv) Circumstantial evidence does exist for transmission from carrier animals in the field in the UK, Denmark and Zimbabwe.
Given these risks, it is unrealistic to expect countries with susceptible livestock to recognise the disease-free status of those that practice vaccination, and the right of the former to embargo the agricultural products of the latter is upheld by the OIE. In principle, some relaxation of this rule might be possible if the vaccinating country could demonstrate that every carrier animal had been eliminated. Carriage, however, is an elusive state. Serum tests for distinguishing infected from vaccinated animals do not identify all infected vaccinates because these animals do not always mount a detectable antibody response to replicatory viral antigens . We therefore lack a reliable means of mass-screening for carriers.
It is sometimes claimed that use of a synthetic or bio-synthetic vaccine (see e.g. 5.4(iii)) would overcome the detection problem. It would not. Moreover, no validated and licensed vaccine of that kind exists or is in prospect.
Conclusion: Until science can produce a vaccine capable of preventing the carrier state, or a serum test sensitive enough to detect all carriers, any ruminant carrying antibodies to FMDV has to be regarded as a risk.
6. ANIMAL DISEASE RESEARCH IN THE UK AND EUROPE
6.1 How does UK animal disease research rate on a world scale of 1 (lowest) 5?
Rating = 5
The Institute for Animal Health, at its Pirbright Laboratory, is the only institution in the UK able to work on FMD and along with the VLA at Weybridge, carries out virtually all of the UK research on exotic viral diseases of livestock. Pirbright research ranges from the fundamental to the applied, whereas the work at VLA focuses on applied aspects only. A recent review of the Institute recognised the Epidemiology and Diagnosis of Exotic Infections, Structural Biology of Viruses, Molecular Biology of Viruses and Host-Virus Interactions programmes, which cover most of the work done on exotic viruses at IAH, as being of either high international or international standard. The remainder of the Institutes infectious disease programme was also, with the exception of 2 small areas, rated as being of a high international or international standard. The quality of the IAHs research on exotic virus diseases is recognised by the Reference Laboratory status conferred by OIE, FAO and EU.
A survey of articles published between 1996 and 2001 on the exotic animal virus diseases worked on at IAH Pirbright shows that almost 9% (246 out of 2860) of world publications in this area arise from the work of Pirbright scientists. A quick survey of papers published on FMDV since 1997, by the IAH Pirbright and the Plum Island facility shows that Pirbright publishes twice the number of papers as its US counterpart.
6.2 Where are the strengths and weaknesses?
IAH carries out fundamental and applied research on the experimental aspects of many of the diseases listed in Table 1. The strengths of its research programme lie in the multi-disciplinary approach to these diseases involving molecular biologists, cell biologists, virologists, pathologists, immunologists and veterinarians. The main scientific goal is to understand host-pathogen interactions at a molecular level. This has involved the sequencing of host and pathogen genomes, the identification of proteins important for pathogen replication and virulence, and in the case of viruses, generation of crystal structures that reveal pathogens in atomic detail. This has required a heavy investment in genome technology, structural biology, and more recently, cell biology and bioimaging. The result is a holistic view of the diseases and the disease agents. In the case of foot-and-mouth disease, the work at IAH Pirbright focuses on the structural biology of FMDV, allowing the molecular characterisation of antibody and receptor binding sites, and cell biological and immunological studies aimed at understanding how tissue tropism, and immune evasion, contribute to persistent infection. This information will underpin the rational design of better vaccines against FMDV. Disease surveillance is also an important area of research at Pirbright leading to the development of improved diagnostics tools, and methods of studying airborne spread, data that are integrated into developing predictive models. The Institute itself is not strong in mathematical modelling but this gap in expertise has been successfully addressed over many years through collaboration with Oxford University and, latterly, with Professor Woolhouse in Edinburgh.
6.3 Is the situation changing and what needs to be done to improve it
As with all biological topics, research into animal diseases is moving fast. The sequences of the genomes of farm animals, and the pathogens that infect them, are either completed or being generated. This explosion of information needs to be integrated into future research programmes. Those working on animal diseases will have to invest heavily in post genomic technologies such as microarray analysis and proteomics, and get to grips with the disciplines of cell biology and structural biology that underpin the future success of functional genomics.
It should not be forgotten that it is the immune system that ultimately eliminates pathogens. Much is to be learned in the near future from a careful comparison of human, mouse and farm animal genomes with respect to the regulation and organisation of genetic loci and proteins of immunological importance. Understanding the functional consequences of these similarities and differences will underpin the rational design of vaccines for farm animals.
There is a shortage of skilled, trained personnel in all aspects of infectious disease research. It is essential for the public sector to be able to recruit and retain these individuals in competition with the private sector so that high quality, independent research is carried out and Government receives appropriate and sound policy advice. There is, therefore, a need to ensure that the career prospects on offer to those studying animal diseases is able to attract high calibre people to publicly funded research establishments.
Given that there are very tight constraints on where work on these diseases can be undertaken (e.g. DEFRA category 4) it is unlikely that several centres for experimental work can be established. Nevertheless the IAH has developed a policy of external collaboration to bring into the research arena expertise that is present in the university sector and elsewhere
6.4 How does funding compare with comparable countries?
We do not have information on funding in other countries.
The budget for the whole of the Institute for Animal Health is approximately #27M per annum [figures taken for 2000/01 financial year]. This is made up of a core grant from BBSRC (#6.3M), research funding from DEFRA (#8.4M), other responsive mode public funding, mostly BBSRC and EU, (#3M) and funding from all other sources, including industry (#9.3M). The Pirbright budget is approximately #8.1M p.a. made up of #2.4M core funding, #3.9M DEFRA, #0.6M responsive mode and #1.2M other. We cannot say how this compares with other institutions in other countries, but clearly with more resources more research could be carried out both in-house as well as through collaboration with external groups.
6.5 Is research sufficiently coordinated on (a) a European (b) a world level?
We do not have information on official initiatives to coordinate infectious disease research. However the Institute participates in a wide range of collaborations in Europe and the rest of the world. We are currently partners in 24 projects funded by the EU, worth to IAH #1M p.a. and with a total of 95 European partners. In addition, through the status of our reference laboratories we inevitably work with research laboratories around the world. For example, the WRL for FMD is the collaborating for one project which in 2000 involved the participation of 30 other laboratories worldwide.
6.6 Is it optimally organised (BBSRC/DEFRA, Scotland and Universities)? (is university-institute collaboration good enough?)
The IAH has had approximately 300 formal (that is, funded or producing publications) collaborations in the period 1996-2001 mainly with university groups in the UK and overseas and an uncountable number of informal collaborations. These have largely been initiated by the Institute and the researchers themselves, although funding initiatives, such as those of the EU which require several partners, clearly encourage the formation of collaborations across the EU.
6.7 Who is the customer for applied research? Are they capable of specifying the national requirements?
apart from the broad scientific community, the customers for IAHs research include:
7 Other Government Departments e.g. DFID
7 Animal Health Pharmaceutical Industry (vaccine and diagnostic kit manufacturers)
7 Agricultural Livestock Sector
7 International Animal Health Organisations (FAO, IAEA, OIE)
7 European Union
One would expect these bodies through their contacts to be able to define their, and the national, needs. However, in some cases there is a tension between what is identified as a priority in the national interest and priorities established by market forces.
7. EDUCATION AND TRAINING
The difficulties experienced in the field during the FMD outbreak in 2001 and the experiences of many members of Pirbright staff have highlighted a number of areas for which basic training for DEFRA and other UK veterinary staff is required.
In the past basic training has been provided at Pirbright Laboratory which consisted of a series of lectures covering the major exotic virus diseases that threaten the UK. These lectures contained up-to-date information on each disease including information relevant to those likely to involved as the first line of defence in that they are expected to be those who would have to make critical decisions based on clinical and epidemiological evidence in the field about the likely introduction of any of these exotic virus diseases. In addition the opportunity was provided for direct observation and clinical examination of animals that have been infected with foot-and-mouth disease as part of Home Office licensed experiments carried out within the biosecurity facilities at Pirbright. In addition Pirbright staff have also been involved in carrying out simulation exercises in different regions of the country. These courses have not been carried out for some time.
Basic training courses covering all the major exotic diseases that pose a threat to the UK. should now be resumed. In particular they should include the following key elements:
(i) The geographical distribution and likely risk areas from which disease may be introduced.
(ii) Details of routes and doses needed to infect the different susceptible species.
(iii) Clinical and post-mortem examination of infected animals.
The problems encountered in reaching a sound diagnosis of foot-and-mouth disease in the field based on clinical examination of some species, particularly sheep, have made it clear that there can be no real substitute for direct examination of the clinical signs in known infected animals. This can only be achieved in the UK by allowing veterinary field staff to observe animals that have been infected with foot-and-mouth disease as part of Home Office licensed experiments carried out within the biosecurity facilities at the Institute for Animal Health, Pirbright Laboratory.
(iv) Diagnostic tests and details of the collection of appropriate good quality samples packed and transferred under the appropriate conditions.
(v) Fundamental epidemiological information covering the ways in which disease control must be based on a clear understanding of the basic mechanisms involved in the spread of virus through different animal populations.
(vi) Biosecurity. The use of appropriate disinfectants and procedures to reduce or eliminate the risk of introduction of disease onto premises with susceptible livestock.
(vii) Simulation exercises in collaboration with DEFRA to be carried out under field conditions in different regions of the UK
IAH RESPONSE IN RELATION TO ARBOVIRAL DISEASES WITH SPECIAL REFERENCE TO BLUETONGUE AND AFRICAN HORSE SICKNESS
The Royal Society call for detailed evidence cites a number of diseases to address in the first instance. In addition to these we suggest a number of other, vector-borne, diseases should also be addressed. In this context, of prime importance are the diseases bluetongue (BT) and African horse sickness (AHS). Both of these are designated OIE List A diseases and therefore are of international significance, and both have a recent track record of incursion into the European Union and therefore are of immediate importance. Both diseases are transmitted between their respective ruminant and equid hosts by species of Culicoides biting midge and have similar epidemiologies, therefore they will be dealt with here together.
SCIENTIFIC NEEDS TO ENHANCE CONTROL/ERADICATION OF BTV AND AHSV
The UK is BT and AHS-free and should strive to maintain that status. Despite the continuing expansion of vector-borne diseases such as BT, in response to climate-change and the increasing international movements of animals, maintenance of a disease-free status is both possible and desirable. The consequences of not maintaining this status would be extreme both in terms of disease and animal welfare, and in terms of economic and other costs. AHS causes 90-95% mortality in naove horses BT causes up to 50% mortality and severe disease in British breeds of sheep. Presence of AHS in the UK would prevent most international horse racing and other equine competitions while presence of BT would significantly curtail international trade in ovines and bovines and their germ plasms. Worldwide it has been estimated that BTV alone causes losses in excess of $3 billion per year.
SURVEILLANCE AND DIAGNOSIS
7 There is no formal surveillance system for BT/AHS operating in the UK at present
7 Improved, more speedy, more sensitive diagnostic tests are required
There is no real surveillance system for BT/AHS operating in the UK although OIE regulations covering importation of ruminants/equids and their products, prior to their import, are observed. Detection of a disease incursion into the UK (either via an infected animal or infected vectors) would depend mainly upon clinical recognition by farmers or veterinarians. In this context a more formal surveillance system, such as is adopted by other at-risk countries may be of value (see section on Prevention below).
With regard to international surveillance, there is a European Community Reference Laboratory for each of the diseases, at Pirbright for BT and Madrid for AHS. Pirbright is an OIE reference laboratory for both diseases.
It is often not possible to confirm a diagnosis of BTV or AHSV infection on clinical evidence alone. Laboratory confirmation is usually necessary and can take many days.
The selection of the appropriate vaccines usually cannot be made until the results of the type specific neutralisation tests are known. The delay of up to 50 days in obtaining these results can cause significant problems in applying effective control procedures.
The existing techniques are good but much more is required. What are needed are rapid and reliable group specific and type specific tests. Such group specific tests (group specific PCRs) for BTV and AHSV are in use elsewhere but not in the UK. A type specific test for AHSV is also in occasional use elsewhere (the type specific PCR), though this has not yet been optimised for all serotypes of the virus and has not been validated. A similar test for BTV is under development at IAH (Orbivirus Group) but is so far only available for 2 BTV serotypes and has not been validated. The development and validation of improved group and type specific tests for BTV and AHSV needs to be speeded up so that they are available for routine use in the UK as quickly as possible.
PREDICTION, PREVENTION AND EPIDEMIOLOGY
7 Improved predictive modelling based upon temperature, and the bioclimatic envelopes of the traditional and novel vector species of Culicoides is required
7 Confirmation of the identity of the suspected, novel vectors, is required
7 The vector capacity of British potential vector species of Culicoides requires detailed investigation
7 Establishment of a sequence database for BTV (and AHSV) to enable backtracking of incursions and to identify vaccine breakdown is required
7 The novel overwintering ability of BTV, which is facilitating its northwards extension in range, requires elucidation
7 Existing live virus vaccines require testing for safety and efficacy, and novel inherently safe, inactivated virus vaccines, require development
Each of these areas relies upon a clear and detailed understanding of the way in which BTV/AHSV are maintained and transmitted in the field. A crucial part of this understanding involves the vectors and the effects of climatic variables upon them. Such an understanding will enable areas at risk to be identified and the level of risk to be assessed. It will also enable alterations in the distribution of the viruses (as a result of climate-change for instance) to be predicted thus enabling the targeted deployment of control measures before disease incursions occur. Such a predictive capability depends upon a knowledge of the virus vectors (their identity, levels of vector competence, distribution, abundance, seasonal incidence, climatological requirements etc) and the virus itself (overwintering mechanisms, duration of viraemia, temperature required for replication in the vector etc.). These requirements are particularly urgent in the case of BTV since this virus appears to have established itself for the first time in southern Europe (1998-2001) and has now penetrated over 500 kms further north than ever before. Four serotypes of the virus are involved and have infected regions of Spain, Italy, Bulgaria, Kosovo, Serbia, Greece, Macedonia and France so far killing over 300,000 sheep - the most severe epizootic of BT ever recorded. The situation is of particular concern because one or more novel vector species of Culicoides are involved in some of the infected areas. Circumstantial evidence suggests that these are likely to be C. obsoletus and/or C. pulicaris group midges. Worryingly these are also the commonest Culicoides species present in the UK.
Spread of BTV and AHSV: Predictive capability for these viruses is at present poorly developed although it is improving as a result of several programmes of work that have either recently begun at IAH or are planned for the future.
The implications of long-term (and short-term) climate change on insect-transmitted pathogens such as BTV and AHSV are likely to be major. Palaeoclimatic records show that most shifts in the distribution of insect taxa have been associated with temperature change and that these changes occur very rapidly. However, the precise effects of temperature upon the dynamics of arboviral transmission can be difficult to predict and are likely to vary with each virus-vector combination. Generally speaking at higher temperatures a vector may blood-feed more frequently and the rate of virogenesis within it is usually faster, leading to enhanced probability of transmission. On the other hand increased environmental temperature may shorten the lifespan of the vector, which would lessen the transmission potential. As temperature decreases, virogenesis usually slows and at some point (specific for each arbovirus) may cease altogether; however, at lower temperatures the life span of the vector may be extended. The likelihood of arbovirus transmission by insect vectors is therefore a function of the interaction of these two opposing sets of trends.
In the case of BTV, specifically, since 1998 there has been a dramatic change in its epidemiology. The virus has gained entrance to Europe, has established itself in several parts of this continent, has extended its range over 500 kms further north than ever before, has gained access to novel vector species of Culicoides and has succeeded in overwintering in regions where previously it could not even survive. These changes, particularly in respect of the novel vectors and its new overwintering ability, make it very difficult to identify northern limits and suggest that, potentially, it could extend as far as Scandinavia. Such extensions in the range of BTV are compounded by the advent of the single market with its increased movement of potentially viraemic or otherwise infected animals.
An additional requirement to enhance our ability to monitor the spread of BTV/AHSV involves a molecular epidemiological approach. This will involve the establishment of a sequence database that is sufficiently comprehensive to permit regional variations between viruses of the same serotype to be detected (topotyping) thereby enabling virus incursions to be "backtracked" to source. It should also enable differentiation between vaccine viruses and field strains of the same serotype thus allowing the early detection of reversion of live virus vaccines should they be used in the field (see section on vaccines).
Programmes of work to enable the prediction of BTV spread and to facilitate backtracking of virus incursions are now underway at IAH-P, funded by the EU. The predictive work is based upon the bioclimatic envelope of C. imicola the traditional Old World BTV vector. However, with the involvement of novel vector species of Culicoides this work will require expansion to confirm their identity and to incorporate their bioclimatic requirements. It will also be necessary to determine and "factor-in" the minimum temperature requirements to achieve a patent BTV infection in the novel vectors since it is this parameter that is now likely to govern the northern limits of the disease.
Introduction or re-emergence of disease: The advent of the single European market and the establishment of BTV in certain member states have increased the likelihood of importing potentially infected and infectious animals. This is compounded by the modification of import regulations, as outlined in recent OIE publications, to facilitate enhanced international trade in animals and their products, and the attempts of certain other trading partners to downgrade the importance of BT, despite it having been the cause of over 300,000 sheep deaths in Europe since 1998.
Of great importance in the context of BTV is the recently demonstrated ability of the virus to overwinter in the cooler areas of Europe. This may be connected to the persistent infection of ovine and bovine γδT cells by the virus (publication in press). In such animals BTV is able to persist, covertly, for periods of many months ("overwinter") prior to recrudescence through a mechanism initiated by the bites of vector Culicoides. There is no obvious test that would detect, reliably, such a non-viraemic but virus-positive animal. In such a situation it might be better to proscribe the importation of all sero-positive ruminants rather than import a potentially infectious animal. The BTV overwintering ability clearly requires further study to elucidate the mechanisms involved. On the basis of this work a safe importation strategy, for sero-positive and other ruminant animals should be able to be developed.
Import procedures for ruminants (BTV) and equids (AHSV) and their germ plasms are in place. However, the novel overwintering mechanism cited above could confound these procedures.
Importantly, both BTV and AHSV are transmitted by vector species of Culicoides, insects that can be transported as aerial plankton on the wind for scores and probably hundreds of kilometres. These viruses can therefore be introduced and can establish widely without obvious warning. Indeed, such has been the case in all of the 9 recently infected European countries. It is important, therefore, for the veterinary authorities to be aware of the risk from these viruses and for their staff to be able to recognise suggestive clinical signs. In most of the infected European countries the local government veterinarian was the first source of suspicion. In other countries first indication of a virus incursion came from sero-conversion in sentinel animals. The UK has no such sentinel system.
In the context of vectors it is the case that recent work at IAH-Pirbright has shown that the bite of a single Culicoides midge is easily sufficient to infect an animal and initiate an outbreak. Therefore, the number of infected vectors arriving on the wind, as described above, need not be large to initiate an outbreak. The controlling requirement for a major outbreak is the presence of a local population of vector Culicoides. At the moment information on the vector potential of British Culicoides species for BTV and AHSV is minimal. We know that we have 48 resident species of Culicoides present in the UK and that C. obsoletus and C. pulicaris group midges (the suspect major vectors in Eastern Europe) are our commonest species. However, we know very little indeed about their levels of vector competence in the UK or how those levels vary from population to population across the country. This gap in our knowledge requires rectification.
Prophylactic vaccination is not an option for BTV or AHSV (see section on vaccination).
Modelling of disease spread
A programme of work designed to develop a predictive capacity for BTV and AHSV is now underway at IAH funded by the EC. This work is based upon data from several cross-Europe surveys for C. imicola (the major BTV/AHSV vector) and certain remotely sensed proxy climatic variables. Preliminary risk maps have already been produced that have accurately identified many areas of Europe as being at high risk to BT, prior to actual disease incursions occurring. These maps are now being used to target control in many areas of southern Europe. This work is continuing, to enhance predictive accuracy under existing and anticipated climatic scenarios (i.e. according to the recent IPCC projections, up to 6oC rise in mean annual temperature).
The above work is based upon the "bioclimatic envelope" of C. imicola the traditional BTV/AHSV vector. However, in the light of the recent extensions of BTV in eastern Europe, to be applicable to the UK, the work requires extension to include both the bioclimatic envelopes of the novel vectors (C. obsoletus/C. pulicaris) and the temperature requirements to enable virus transmission. This new model will then require validation.
Control if an outbreak occurs
Traditional zoosanitary methods are used in many areas to control BT/AHS epizootics. These include movement of animal restrictions, husbandry modifications (to separate vectors and hosts), slaughter of potentially infected animals (to prevent them being a source of virus for vectors) and vector abatement measures. Vaccination will be dealt with in the next section.
The traditional zoosanitary control measures have never been used against BT/AHS in the UK and may require modification to be effective here. For example, it is known that C. imicola the major European vector is exophilic and therefore housing stock during its times of activity (crepuscular) significantly reduces biting rates and hence risk of transmission. Such information is not available for the potential UK vectors. It is also the case that there are no data outlining the most appropriate vector abatement measures (for C. obsoletus/C. pulicaris midges) in the UK and indeed optimised strategies for vector Culicoides abatement are not available anywhere.
Neither as yet do we have data identifying the most vulnerable areas of the UK.
All of these deficiencies require rectification before appropriate control and eradication strategies can be devised for the UK.
Vaccination is a vital element in the control of most infectious diseases. However, in the case of BT and AHS it is an issue that is fraught with difficulty and there are both short and long term requirements that must be met before safe efficacious vaccination strategies can be devised and implemented:
No BTV/AHSV vaccines are manufactured in Europe. The only commercially available vaccines are South African and are live tissue culture attenuated preparations. These are available in specific polyvalent combinations appropriate to South Africa. Vaccines specific for other areas may take 2-3 months to prepare and deliver.
The vaccine viruses are teratogenic and are therefore not recommended during early pregnancy.
The vaccine viruses tend to cause a viraemia in vaccinated animals. There is therefore a risk that vector insects may ingest vaccine virus and transmit it to other animals. No data exist concerning the likelihood of insect transmission of these vaccine viruses or the risk of reversion to virulence during insect passage.
The vaccine viruses may reassort with field viruses generating new viruses with uncertain virulence characteristics. There are no data assessing the risks posed by these changes.
The South African BTV vaccines are designed for use in sheep, to protect this disease vulnerable species. Cattle and goats are not vaccinated in South Africa because although they are virus amplifiers they do not usually suffer from clinical disease. However, we would want to vaccinate cattle and goats in addition to sheep in order to eradicate the virus, otherwise it will continue to circulate through the non-sheep ruminants. However, there are no data on the safety and efficacy (i.e. ability to prevent a viraemia on subsequent field infection) of the attenuated BTV vaccines in cattle and goats.
Because of these drawbacks many countries refuse to use the existing live virus vaccines and will continue to refuse until it has been determined whether or not they are efficacious in a European situation and can be used with safety. However, in the absence of a coherent vaccination strategy it has not been possible to eradicate BTV from Europe by traditional zoosanitary measures alone.
In the long term what is required is the development of inactivated whole virus or non-replicating subunit vaccines for BT/AHS that are inherently safe and efficacious. A programme of work funded by the ECUand based at IAH-P is planned to develop and test such new vaccines.