Aftosa, Aphthous Fever

Foot-and-mouth disease virus

Foot-and-mouth disease virus (FMDV) is the prototype member of the Aphthovirus genus of the family Picornaviridae.

Picornaviridae are nonenveloped viruses with single-stranded RNA genome of positive polarity. In addition, they are highly labile and rapidly lose infectivity at pH values of less than 7.0.

The virus exists in the form of seven different serotypes: A, O, C, Asia1, and South African Territories 1 (SAT1), SAT2, and SAT3, but a large number of subtypes have evolved within each serotype. Based upon the pioneering poliovirus genotyping studies of Rico-Hesse, FMDVs have been divided into genotypes based on comparisons of VP1 sequence data. For example, in a comprehensive study of FMD type O viruses they could be grouped into eight topotypes based on nucleotide differences of up to 15%. Similar studies are in progress for type A, C and Asia 1.

Foot and Mouth Disease is endemic in parts of Asia, Africa, the Middle East and South America.

Outbreaks have occurred in every livestock-containing region of the world with the exception of New Zealand, and the disease is currently enzootic in all countries except Australia and North America. The disease affects domestic cloven-hoofed animals, including cattle, swine, sheep, and goats, as well as more than 70 species of wild animals, including deer. The recent outbreaks of foot-and-mouth disease (FMD) in a number of FMD-free countries, in particular Taiwan in 1997 and the United Kingdom in 2001, have significantly increased public awareness of this highly infectious disease of cloven-hoofed livestock. Furthermore, world concern following the terrorist attacks in the United States has raised the possibility that terrorist organizations or rogue states might target the $100 billion/year U.S. livestock industry by employing the etiologic agent of FMD. Although FMD does not result in high mortality in adult animals, the disease has debilitating effects, including weight loss, decrease in milk production, and loss of draught power, resulting in a loss in productivity for a considerable amount of time. Mortality, however, can be high in young animals, where the virus can affect the heart. In addition, cattle, sheep, and goats can become carriers, and cattle can harbor the virus for up to 2 to 3 years. FMD is one of the most highly contagious diseases of animals or humans, and FMDV rapidly replicates and spreads within the infected animal, among in-contact susceptible animals, and by aerosol.

Foot-and-mouth disease virus A

Foot and mouth disease type A viruses have always been considered to be antigenically the most diverse of the European serotypes and up to 32 subtypes had been defined by the early 1970s. Some of these subtypes have been shown to be genetically distinct (eg. A22, A24), although many have not been examined. Although this system of subtyping was discontinued type A viruses are still considered to be extremely antigenically and genetically diverse. Comparison of almost 300 complete, or nearly complete, Vp1 sequences has shown that type A viruses can be grouped into three major geographically restricted genotypes, (i) Euro-SA, (ii) Asia, and (iii) Africa, although occasional spread between these continents may take place.

One of the many questions being raised for future research is why do so many of the new strains for serotype A disappear just as regularly as they appear?

Foot-and-mouth disease virus (strain A10-61)

Foot-and-mouth disease virus (strain A12)

Foot-and-mouth disease virus (strain A22/550 Azerbaijan 65)

Foot-and-mouth disease virus (strain A24 Cruzeiro)

Foot-and-mouth disease virus (strain A5)

Foot-and-mouth disease virus A22/India/17/77

Foot-and-mouth disease virus GAM/51/88/A

Foot-and-mouth disease virus K/37/84/A

Foot-and-mouth disease virus KEN/1/76/A

Foot-and-mouth disease virus Asia 1

Asia 1 normally only occurs in southern Asia. Antigenically FMD Asia 1 viruses have been considered less diverse than those belonging to types O, A or C. Only three antigenic subtypes were defined in the 1960s. Although two major genotypes could be distinguished, relationships were generally above 85% and it was concluded that all the isolates could be included in a single topotype. It is clear that genetic variation amongst FMD Asia 1 viruses is much lower than that found within other serotypes. This may indicate that the serotype has a more recent origin than the others, or that it has been through a severe bottleneck purification with only a single topotype surviving. The latter would seem unlikely unless this serotype was once confined to a much smaller area than it is at present.

Aphthovirus Asia

Foot-and-mouth disease virus C

Type C appears to have become confined to the Indian sub-continent. FMDV type C has a very limited distribution compared with most of the other serotypes. Historically, it has been recorded in Europe, South America, EA, North Africa, Angola and southern Asia. However, it now appears to be limited to the Indian sub-continent and only appears intermittently. It is not clear why type C is apparently disappearing, although vaccination and control campaigns have been responsible for its eradication in Europe and South America, where the last outbreaks occurred in 1989 (Italy) and 1994 (Argentina), respectively. However, this is not the case in Asia. Using the criterion employed to classify FMD type O viruses, all the classical type C subtypes can be placed into a single topotype, which we have named EuroSA. More recent unpublished studies have shown that comparisons of partial VP1 sequences can be used to classify FMD type C viruses into eight topotypes: EuroSA, Angola, Philippines, ME-SA, Sri Lanka, EA and Tadjikistan. Type C was introduced into the Philippines for the first time in 1976. The virus strain, which caused these first outbreaks was shown to be very closely related to the South American vaccine strain, C3/Resende/Brazil/55. Over the subsequent 18 years the virus evolved to become a new topotype C-Philippines; however, following the re-introduction of type O into the Philippine Islands in 1994, the incidence of type C decreased and no outbreaks have been recorded since 1996. It is also apparent that the Angolan type C virus lineage evolved from South American viruses. The topotypes named MESA, Sri Lanka, EA and Tadjikistan also form a group consistent with their geographic proximity and viruses sometimes spread between these areas (e.g. C/K221/83, a Kenyan virus in the MESA topotype and C/SAU/1/84, a Saudi Arabian virus, in the EA topotype). When more complete sequence data is available, it may be possible to combine some of the topotypes. There have been no outbreaks of type C in Europe since 1989 (Italy), South America since 1994 (Argentina), Asia since 1996 (India and the Philippines) and Africa since 1996 (Kenya). It is likely that many type C virus lineages existed in the recent past, but have now become extinct. Since there are no known natural reservoirs, this serotype would be an excellent candidate for global eradication.

Foot-and-mouth disease virus (strain C1-Santa Pau)

Foot-and-mouth disease virus (strain C3 Indaial)

Foot-and-mouth disease virus C-S8c1

Foot-and-mouth disease virus C1

Foot-and-mouth disease virus C2

Foot-and-mouth disease virus C3

Foot-and-mouth disease virus C4

Foot-and-mouth disease virus C5

Foot-and-mouth disease virus O

Serotype O is the most prevalent of the seven serotypes of foot-and-mouth disease virus and occurs in many parts of the world.

FMD type O viruses were classically divided in 10 or 11 antigenic subtypes although it is now recognised that antigenic variation with this serotype is not as extensive as once thought and relatively few vaccine strains are able to protect against most field outbreaks. However, genetic diversity is much greater, allowing the classification of many distinct lineages.

Researchers have identified eight distinct genetic lineages, which fall into geographically distinct regions. These have been designated topotypes and named EuropeSouth America (Euro-SA), Middle EastSouth Asia (ME-SA), South-East Asia (SEA), Cathay (an ancient and poetic name for China and east Tartary), West Africa (WA), East Africa (EA), Indonesia-1 (ISA-1) and Indonesia-2 (ISA-2). This discrimination is indicative of genetic lineages that have evolved independently.

Foot-and-mouth disease virus (strain O1)

Foot-and-mouth disease virus BFK/2/92/O

Foot-and-mouth disease virus HKN/2002

Foot-and-mouth disease virus KEN/1/91/O

Foot-and-mouth disease virus O/IND146/99

Foot-and-mouth disease virus O/IND148/99

Foot-and-mouth disease virus O/IND153/99

Foot-and-mouth disease virus O/IND160/99

Foot-and-mouth disease virus O/IND164/99

Foot-and-mouth disease virus O/IND170/97

Foot-and-mouth disease virus O/IND175/99

Foot-and-mouth disease virus O/IND185/99

Foot-and-mouth disease virus O/IND205/99

Foot-and-mouth disease virus O/IND207/99

Foot-and-mouth disease virus O/IND208/99

Foot-and-mouth disease virus O/IND210/99

Foot-and-mouth disease virus O/IND23/99

Foot-and-mouth disease virus O/IND249/99

Foot-and-mouth disease virus O/IND256/99

Foot-and-mouth disease virus O/IND27/97

Foot-and-mouth disease virus O/IND275/97

Foot-and-mouth disease virus O/IND278/97

Foot-and-mouth disease virus O/IND28/97

Foot-and-mouth disease virus O/IND281/97

Foot-and-mouth disease virus O/IND282/99

Foot-and-mouth disease virus O/IND285/99

Foot-and-mouth disease virus O/IND287/99

Foot-and-mouth disease virus O/IND296/97

Foot-and-mouth disease virus O/IND31/97

Foot-and-mouth disease virus O/IND33/97

Foot-and-mouth disease virus O/IND352/97

Foot-and-mouth disease virus O/IND37/97

Foot-and-mouth disease virus O/IND38/97

Foot-and-mouth disease virus O/IND380/97

Foot-and-mouth disease virus O/IND384/97

Foot-and-mouth disease virus O/IND39/97

Foot-and-mouth disease virus O/IND391/97

Foot-and-mouth disease virus O/IND399/97

Foot-and-mouth disease virus O/IND407/97

Foot-and-mouth disease virus O/IND409/97

Foot-and-mouth disease virus O/IND410/97

Foot-and-mouth disease virus O/IND411/97

Foot-and-mouth disease virus O/IND414/97

Foot-and-mouth disease virus O/IND420/97

Foot-and-mouth disease virus O/IND423/97

Foot-and-mouth disease virus O/IND424/97

Foot-and-mouth disease virus O/IND427/98

Foot-and-mouth disease virus O/IND461/97

Foot-and-mouth disease virus O/IND463/97

Foot-and-mouth disease virus O/IND464/97

Foot-and-mouth disease virus O/IND465/97

Foot-and-mouth disease virus O/IND469/98

Foot-and-mouth disease virus O/IND47/98

Foot-and-mouth disease virus O/IND48/98

Foot-and-mouth disease virus O/IND485/97

Foot-and-mouth disease virus O/IND49/97

Foot-and-mouth disease virus O/IND54/98

Foot-and-mouth disease virus O/IND55/98

Foot-and-mouth disease virus O/IND56/98

Foot-and-mouth disease virus O/IND57/98

Foot-and-mouth disease virus O/IND61/97

Foot-and-mouth disease virus O/IND63/97

Foot-and-mouth disease virus O/IND64/97

Foot-and-mouth disease virus O/IND64/98

Foot-and-mouth disease virus O/IND65/98

Foot-and-mouth disease virus O/IND66/98

Foot-and-mouth disease virus O/IND70/97

Foot-and-mouth disease virus O/IND74/97

Foot-and-mouth disease virus O/IND75/97

Foot-and-mouth disease virus O/IND78/97

Foot-and-mouth disease virus O/IND79/97

Foot-and-mouth disease virus O/IND81/98

Foot-and-mouth disease virus O/IND81/99

Foot-and-mouth disease virus O/IND82/97

Foot-and-mouth disease virus O/SKR/2000

Foot-and-mouth disease virus O5India

Foot-and-mouth disease virus SAT 1

Three serotypes, South African Territories (SAT) types 1-3 are endemic to southern Africa. The three SAT types differ from each other with regard to geographic distribution, infection rates and wildlife involvement in the FMD outbreaks of livestock. SAT-1 is of particular importance due to its extensive distribution throughout sub-Saharan Africa and previous incursion into North Africa and the Middle East. In addition, SAT-1 has the highest seroprevalence rate in the maintenance host, the African buffalo. Despite the high incidence of SAT-1 type virus in buffalo, this serotype has accounted for only 36% of the SAT-type outbreaks of FMD in cattle in southern Africa this century, with most outbreaks (48%) begin caused by the SAT-2 type viruses and the SAT-3 accounting for only 16% of outbreaks.

Serotype SAT 1 is widespread throughout sub-Saharan Africa and has also been introduced into the Middle East periodically, but has not become established in that region. Genetic characterisation of viruses from African buffalo in southern and East Africa has shown that distinct evolutionarily viral lineages occur. Three distinct southern Africa lineages have been defined and two East African topotypes identified. Of note was the identification of three unrelated topotypes occurring within a single country, Zimbabwe. A retrospective analysis of viruses from West Africa, revealed that a further two SAT 1 topotypes occur on the continent, bringing the total number of SAT 1 topotypes identified in Africa to six. This number will probably increase when further viruses representative of Central and north-east Africa are characterised.

Foot-and-mouth disease virus SAT 2

Serotype SAT 2 occurs throughout sub-Saharan Africa and has made recent incursions into the Middle East from north-east Africa. This serotype has been studied more intensively than the other two SAT serotypes, given the frequent association of the serotype with outbreaks of the disease in southern and West Africa. These studies have not only been useful for determining relationships of viruses recovered from different outbreaks, but have also conclusively shown that buffalo in defined areas of southern Africa transmitted SAT 2 type virus to cattle and impala within their immediate vicinity. The conclusion of a comprehensive survey of SAT 2 type viruses from all major regions on the continent has revealed the presence of eleven distinct topotypes. Four topotypes occur in southern Africa, two in East Africa, two in Central Africa, one in the Horn of Africa and two in West Africa.

SAT 2 is also the virus type most frequently associated with outbreaks of the disease in livestock in southern and West Africa and with clinical cases of the disease in wildlife. Despite the regular involvement of this serotype in outbreaks and evidence that buffalo are the primary source of infection for other cloven-hoofed species in southern Africa, it is not the serotype most frequently recovered from foot-and-mouth disease (FMD)-infected buffalo populations in South Africa (records of the Onderstepoort Veterinary Institute). Consequently, it has been proposed that the different SAT virus types may have differential abilities in crossing species barriers and that SAT 2 appears to be the most efficient in doing so.

Foot-and-mouth disease virus SAT 3

Of the three SAT types, SAT 3 has the most restricted distribution with relatively few topotypes. Nonetheless, it is notable that five different topotypes have been identified to date, despite the viruses studied being derived from just seven countries, namely: South Africa, Zimbabwe, Zambia, Namibia, Botswana, Malawi, and Uganda. Three of the five topotypes occur within different regions of Zimbabwe, whilst the remaining countries have a single topotype within their borders. In the southern African region, SAT 3 is the serotype least frequently associated with outbreaks of FMD in domestic or wild cloven-hoofed animals.

Unclassified Foot-and mouth disease virus

Foot-and-mouth disease virus A10 Holland

The FMD virion has a diameter of about 25 nm.

By electron microscopy, the FMD virion appears to be a round particle with a smooth surface. FMDV is distinguished from other picornaviruses by the lack of a surface canyon, or pit, which has been shown to be the receptor binding site for the entero-and cardioviruses. Another feature of the virion is the presence of a channel at the fivefold axis which permits the entry of small molecules, such as CsCl, into the capsid, resulting in FMDV having the highest buoyant density of the picornaviruses.

FMDV, like other members of the Picornaviridae, has a relatively short infectious cycle in cultured cells. Depending on the multiplicity of infection, newly formed infectious virions begin to appear at between 4 and 6 hours after infection. The virus is cytocidal, and infected cells exhibit morphological alterations, commonly called cytopathic effects, which include cell rounding and alteration and redistribution of internal cellular membranes. The virus also causes biochemical alterations, including inhibition of host translation and transcription.

The virion is a 140S particle.

The genome of FMDV, which is over 8000 bases in length, is covalently bound at its 5-terminus to a 2324 amino acid residue genome-linked protein, 3B. In the mature virus, the genome is encapsidated in an icosahedral structure composed of 60 copies of four proteins (1A, 1B, 1C, and 1D). The genome contains a single long open reading frame (ORF), that has two alternative initiation sites, and the encoded polyprotein can be processed into over a dozen well-described mature polypeptides as well as a variety of partial cleavage intermediates. Most of the proteolytic events that produce these mature products are mediated by three viral proteinases, Lpro, 2A, and 3Cpro. The precise nature of the cleavage mechanisms utilized by 2A and the maturation cleavage of capsid protein 1AB into 1A and 1B remains unclear.

8161 bp

The genome contains a single long open reading frame (ORF), that has two alternative initiation sites, and the encoded polyprotein can be processed into over a dozen well-described mature polypeptides as well as a variety of partial cleavage intermediates.

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8173 bp

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8203 bp

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8170 bp

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8167 bp

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8134 bp

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8115 bp

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General: More than 50 of the 162 Member Countries of the Office International des Epizooties (OIE), the World Organisation for Animal Health, have obtained recognition from the OIE for freedom from foot and mouth disease (FMD) without vaccination. The virus continues to circulate in two-thirds of the remaining countries, thus dividing the globe into two zones. This has significant effects on international trade patterns in susceptible animals and animal products. Consequently, countries that do not have FMD-free status continue to suffer a severe handicap in terms of access to international markets. This situation was highlighted by the sudden and largely unexpected resurgence of FMD in Europe, South America and Asia at the beginning of the 21st Century. This endemic situation with respect to FMD in many parts of the world is a constant threat to countries that have acquired FMD-free status at considerable cost and effort. The threat has been exacerbated over the last decade by accelerated trade and movements of people due to globalization. At the same time, developed countries have either decreased or discontinued vaccination. The dangerous cocktail of globalization and non-immunised animals exploded in 2001, first in South America and then in the United Kingdom and other countries of the European Union.

In 1997 an FMD outbreak was reported in Taiwan, a country that had been free of the disease for 68 years. This devastating outbreak resulted in the slaughter of more than 4 million pigs, almost 38% of the entire pig population, at a cost of approximately U.S $6 billion and reminded the international animal health community of the severe economic consequences that a FMD outbreak could have for a previously disease-free country. Starting in late 1999 and 2000, a series of FMD outbreaks occurred in a number of countries in East Asia. This was followed by an outbreak in South Africa and culminated in the destructive outbreak in the United Kingdom, which then spread to the European continent. These outbreaks reemphasized the extreme virulence of the FMDV in a variety of animal species, the vulnerability of FMD-free countries as well as countries where FMD is enzootic to new viral strains, the efforts of globalization on increasing the risks of disease incursion, and hence the need for countries to more closely monitor for the presence of exotic disease.

Europe and Central Asia: In the past, the disease has ravaged European livestock, but has been gradually brought under control, at great cost, by preventive vaccination programmes, supplemented by the destruction of infected herds in most of the countries of continental Europe and, in the United Kingdom (UK) and Nordic countries, by destruction of infected herds alone. After careful evaluation of the two possible options for preventing the re-occurrence of the disease in Europe to either continue or discontinue mass vaccination the European Union decided to prohibit all vaccination after 1991. FMD remained and is still endemic in the Middle East, including Asian Turkey (Anatolia), and despite efforts of the Governments of Turkey and Europe, Anatolia appears to be a permanent source of sporadic outbreaks in the Balkans and a threat to Europe. In recent years, FMD was reported mainly in the Balkans. Despite these occasional incursions of FMD into south-east Europe, in all cases, the control measures were efficient and the disease never spread to such an extent as to become endemic. A major outbreak, which affected 2,030 farms occurred in the UK between February and September 2001. This was the first major epidemic of FMD in Europe since preventive vaccination had been abandoned in continental Europe in 1991. The disease also spread to Ireland, France and the Netherlands although the number of outbreaks was limited in these countries.

South America: Since the signing in 1987 of the Hemispheric Plan for the Eradication of Foot-and-Mouth Disease by the countries of South America, clinical cases of foot and mouth disease have decreased significantly throughout the continent. During the early 1990s, national laboratories diagnosed an average of 766 cases per year in South America. By the late 1990s, this continent-wide average had fallen to 130. By the end of the 1990s, the international community recognized Argentina, Chile, Guyana, and Uruguay as free of FMD without vaccination. In 1999, clinical signs of FMD were absent in 60% of all cattle on the continent. These cattle represented 41% of all herds in South America and extended over 60% of the geographical area of the continent. However, in the spring of 2001, FMD re-appeared in certain countries of the Southern Cone. This wide-spread re-occurrence of the disease in Argentina, Uruguay and the State of the Rio Grande do Sul in Brazil called into question whether countries in South America can achieve and maintain FMD-free status, with or without vaccination.

Middle East and North Africa: Only one country in the Middle East (Cyprus) is presently included in the OIE list of foot and mouth disease-free countries. The region is regarded as that most affected by FMD in the world. FMD has been recorded in all countries in the Middle East on numerous occasions between 1960 and 2000, serotype O being the most prevalent. In the past, exotic FMD viruses were the cause of panzootics, which spread to many areas of the region, even extending to the frontier of Europe. A remarkable example was the rapid dissemination of serotype SAT 1 virus, which occurred initially in Bahrain in December 1961. The virus spread north-westwards to reach Iraq, Jordan, Israel, and Syria by April 1962, continuing to Iran and Turkey. In September 1962, this serotype crossed the Bosporus to enter Europe for the first time, and in November, caused an outbreak further west, near the border between Turkey and Greece. Historically, epidemics mainly affected cattle and spread from east to the west in the Middle East. The slow spread of FMD from Tunisia in 1989 to Morocco in 1991 exemplifies the difficulty in controlling the disease since unregulated movements of herds of small ruminants may play an important role in spreading infection. The situation in the Middle East and North Africa constitutes a threat to other regions of the world, especially Europe.

East Asia: Japan regained the status of freedom from foot and mouth disease without vaccination in September 2000 and the Republic of Korea likewise obtained this status in September 20001. However, new outbreaks of FMD caused by the Pan-Asian topotype have occurred in pigs in the Republic of Korea since May 20002. Taipei China has not experienced an outbreak of FMD since February 20001 and the country is currently implementing and eradication programme. These countries had been free from FMD for many decades when in 1997, the FMD virus once again invaded the region, particularly in 2000; this resulted in widespread occurrence of the disease. The types of FMDV were investigated by genome analysis, and in each case the virus concerned was found to be a member of the pan-Asian O lineage.

South-East Asia: Of the ten countries in South-East Asia, FMD is endemic is seven (Cambodia, Laos, Malaysia, Myanmar, the Philippines, Thailand, and Vietnam) and three are free of the disease (Brunei, Indonesia and Singapore). Part of the Philippines is also recognized internationally as being free of FMD. From 1996 to 2001, serotype O viruses caused outbreaks in all seven of the endemically infected countries. On the mainland, three different type O lineages have been recorded, namely: the South-East Asian topotype, the pig-adapted or Cathay topotype and the pan-Asian topotype. Prior to 1999, one group of SEA topotype viruses occurred in the eastern part of the region and another group in the western part. However, in 1999, the pan-Asian lineage was introduced to the region and has become widespread. The Cathay topotype was reported from Vietnam in 1997 and is the only FMD virus currently endemic I the Philippines. Type Asia 1 has never been reported from the Philippines but was reported from all countries on the mainland except Vietnam between 1996 and 2001. Type A virus has not been reported east of the Mekong River in the past six years and seems to be mainly confined to Thailand with occasional spillover into Malaysia. The distribution and movement of FMD in the region is a reflection of the trade-driven movement of livestock.

Sub-Saharan Africa: Six of the seven serotypes of FMDV (i.e. all but Asia 1) are prevalent in Africa although there are marked regional differences in distribution. Three of these serotypes are unique in Africa -- the three SAT serotypes. Serotype C may also now be confined to Africa because it has not been reported elsewhere recently. In southern Africa at least, the SAT serotypes have an intimate and probably ancient association with African buffalo (Syncerus caffer) that is instrumental in their maintenance. Within each of the six prevalent serotypes, with the possible exception of C, there are a number of different lineages with more or less defined distributions (topotypes) that in some cases are sufficiently immunologically different from one another to require specific vaccines to ensure efficient control. This immunological diversity in prevalent serotypes and topotypes, in addition to the uncontrolled animal movement in most parts of the continent, render FMD difficult to control in present circumstances. This fact, together with poorly developed intercontinental trade in animals and animal products has resulted in the control of FMD being afforded a low priority in most parts of the continent, although the northern and southern regions of the continent are an exception. As a consequence, eradication of FMD from Africa as a whole is not a prospect within the foreseeable future

The circumstances in which it does occur in humans are not well defined, though all reported cases have had close contact with infected animals. There is one report from 1834 of three veterinarians acquiring the disease from deliberately drinking raw milk from infected cows. There is no report of infection from pasteurized milk, and the Food Standards Agency considers that foot and mouth disease has no implications for the human food chain.

People in contact with infected animals are exposed to enormous amounts of virus. Using large-volume air samplers, Sellers found that in a period of 30 minutes 10 million IU could be collected from the air of a stable housing infected pigs.

Sampling of human subjects, who had been in contact with diseased animals, showed that virus could be recovered from the nose, throat, and saliva of these people immediately after leaving the room. Nasal swabs of such persons usually contain 100-1000 IU, but some may contain as many as 10,000 IU.

Nonsusceptible animals, such as horses, foxes, rats, birds, and humans, are a means of mechanical spread of the virus.

During the FMD outbreak that took place in the UK in 2001, disease spread was reported to occur frequently by mechanical carriage of virus between flocks by humans or vehicles.

People who work with infected animals or materials will carry FMD virus on their hair and skin and on clothes. If contaminating virus is not removed by showering and change of clothes there is a high probability that a susceptible animal will receive sufficient virus to become infected by fomites, aerosol or handling. In the 1967-68 epidemic in UK, veterinarians were incriminated in 6 of 51 outbreaks and in 4 other cases non-veterinary personnel were involved. Sellers reported that, under exceptional circumstances, FMD virus carried in the nose and throat could be transmitted from man to animals. Shortly after begin in contact with infected animals, these researchers discarded clothes, showered and moved to a different compound and succeeded, in transmitting and infecting one steer by examining the animals and at the same time sneezing, snorting, coughing and breathing a the muzzles of the animals. The exposure of each animal to this treatment lasted 30s for each person. However, in practice, such intimate contacts between people and susceptible cloven-hoofed animals is unlikely.

Susceptible cattle coming into contact with an infected animal, whether sheep, goat, pig or wildlife species may be infected by the respiratory rout or through an abrasion on the skin or mucous membranes.

Infection of cattle generally occurs via the respiratory route by aerosolized virus. Infection can also occur through abrasions on the skin or mucous membranes, but is very inefficient, requiring almost 10,000 times more virus. Virus is excreted into the milk of dairy cattle as well as in semen, urine and feces, and calves can become infected by inhaling milk droplets

In 1981, cattle on the Isle of Wight in the United Kingdom were infected by windborne aerosol virus produced by infected pigs in Brittany, France and the virus was carried over 250 km across the English channel.

The transmission of FMD virus within an unvaccinated herd is usually rapid, as was seen during the recent outbreak in the UK win which over 90% of a group could be showing clinical signs by the time the disease was first identified. Even within a vaccinated herd, the aerosol production of virus from a single infected animal can overcome the immunity of others in the herd resulting in a further increase in the level of challenge and the appearance of clinical disease.

In all parts of the world with the exception of sub-Saharan Africa, FMD in free-ranging or captive wildlife appears to be an extension of the disease in lifestock. This has been documented for free-ranging moose, Alces alces, as well as in fallow, roe and red deer in Europe. In the former Soviet Union, FMD was described in free-ranging reindeer Rangifer tarandus and saiga Saiga tatarica, while in India severe clinical signs and mortality were reported in the blackbuck Antilope cervicapra. High ranging mortality also occurred in free-ranging mountain gazelles in Israel during epidemics in cattle. Similarly, outbreaks of FMD in zoological gardens in Paris, Zurich, and Buenos Aires coincided with outbreaks in FMD in domestic animals.

Infected cattle also aerosolize large amounts of virus, which can infect other cattle in addition to other species.

Infected cattle also produce up to log10 5.1 TCID50 of aerosol virus per day, and a large dairy herd could infect neighboring herds with their combined output of virus.

Cattle with FMD are usually the greatest producers of FMD virus of all species. It can be estimated that one infected cow, in addition to exhaled air, contaminates the environment with some 10 billion or more IU during the first week of disease with excretions (faeces, urine, milk), salivation, sloughed-off blister epithelium and vesicular fluid. The total amount of virus excreted by pigs and sheep is, in general, much smaller than cattle.

Pigs usually become infected with the virus by eating FMDV-contaminated products, by direct contact with another infected animal, or by being placed in a heavily contaminated environment, for example a pen, an abattoir lairage or a transport lorry that has previously housed or transported infected animals. Pigs are considerably less susceptible to aerosol infection than ruminants, and recent studies using several virus strains indicated that a pig may require up to 6,000 50% tissue culture infective doses TCID50, possibly as much as 600 times more than the exposure to aerosol virus required by a bovine or an ovine, to cause infection. While this figure may vary with individual pigs and potentially could be different for certain FMDV strains, it was consistent with many field and experimental observations which described situations in which pigs were not infected when physically separated from infected animals. Once infection is established within a pig herd, transmission by direct contact between infected and susceptible animals can be very rapid, and many routes of viral entry bay be involved, i.e. aerosol, oral, mucosal, and through damaged epithelium which may play an important role under intensive conditions or other conditions (transportation and at abattoirs) where aggression among pigs may be increased.

In the United States, feral pig populations are very large and widespread. Foot and mouth disease in feral pigs has been the subject of considerable research and modeling. For example, Australian scientists have estimated that FMD will spread among feral pigs at a rate of 2.8 km per day when pigs are at a fairly low population density (1 to 2/km2)

Pigs infected with FMDV do produce more aerosol virus than ruminants, and the same studies showed that the aerosol production from infected pigs infected with different stains also differed considerably. Maximum excretion of aerosol virus coincides with development of clinical disease and lesions on the snout, tongue and feet, and declines over the following 3 to 5 days as the antibody response develops.

In 1981, cattle on the Isle of Wight in the United Kingdom were infected by windborne aerosol virus produced by infected pigs in Brittan, France and the virus was carried over 250 km across the English Channel.

Sheep are highly susceptible to virus infection via aerosol and can excrete airborne virus; however during outbreaks they are most like infected by contact with other animals.

As is the case with other ruminants, sheep and goats are highly susceptible to infection with FMD virus by the aerosol route. Aerosol production by pigs can be as high as log10 8.6 TCID50 per day, theoretically sufficient to infect over 20 million sheep. But sheep are less likely to become infected by airborne virus than cattle because of their lower respiratory volume. Sheep and goats are probably most often infected by direct contact with infected animals. The virus may infect sheep and goats through abrasions on the skin or mucous membranes, through contaminated food, as well as by the respiratory route.

Aerosol production by infected sheep is considerably less. Aerosol transmission from infected sheep is unlikely to occur over distances greater than 100 meters. Sheep-to-sheep spread by contact appears to be restricted, to the extent that the rate of transmission within an affected flock is lower than that observed in infected pig or cattle herds. A good example of this phenomenon is illustrated by the outbreak of FMD that took place in Greece during 1994. Serological investigations showed that in many of the affected flocks not all individuals had sero-converted to the virus, indicating that the virus had not disseminated sufficiently to infect entire flocks. Similarly, evidence from the recent UK epidemic shows considerable variation in the level of intra-flock infection rates. On one farm visited, only 5% of 237 sheep that were blood tested were sero-positive, and 3% were virus-positive, whereas 91% of the 75 cattle present were clinically affected.

The probability of transmission of FMD virus from infected sheep is highest during the viraemic phase and peaks at or just before the appearance of clinical signs. This period correlates well with the period of virus excretion, which ends at the point of sero-conversion. Levels of virus excretion are strain specific.

Because it is very difficult to make a clinical diagnosis of FMD in sheep, the disease can be spread to other livestock prior to detection

A recent study by Hughes has provided supportive evidence for the observed difference between the dynamics of FMD transmission in sheep populations as compared with cattle and pigs. The study showed that, using the 1994 Greek outbreak strain, there was significant reduction in the level of infection and estimated transmission rates over time during serial passage though groups of sheep. These results infer that some, possibly most, strains of FMD virus may die out if they are restricted to sheep. Infection of cattle and pigs may be sufficient to increase the level of circulating virus and consequently the probability of transmission of infection to in-contact sheep, thereby re-establishing the disease. This hypothesis requires further investigation using other strains of FMD virus.

Most infections are believed to occur as a result of childhood epidemics within buffalo breeding herds when large numbers of juveniles (about 10% of each breeding herd) are recruited annually into the susceptible populations. They can become infected on the waning of maternally-derived immunity obtained from colostrum.

Infection of individual animals within the breeding herds of buffalo usually occurs when maternal immunity starts to wane at 2-4 months of age. Calves are not necessarily infected by their dams, and it is presumed that SAT viruses spread mainly during minor epidemics among animals in breeding herds, with carriers ensuring that the viruses survive interepidemic periods. Transmission of SAT type viruses between individual buffaloes appears to occur by two processes: (1) contact transmission between acutely infected and susceptible individuals, which is likely to account for most infections, and (2) occasional transmission between carrier buffaloes and susceptible individuals. However, the mechanism whereby carrier transmission occurs between buffaloes is obscure. A possibility, for which the evidence is still obscure, is sexual transmission.

Transmission of SAT-type virus from persistently infected African buffalo to cattle under experimental and natural conditions has been unequivocally demonstrated.

Buffalo calves lose their maternal antibodies at 2-6 months of age and thereafter show seroconversion for one or more of the three types of SAT virus. Apparently during that period they acquire the infection from their dams. It has been quite difficult to show that the infection can pass from buffalo to domestic livestock species, but studies of Thomson in 1992 indicated that young buffalo in the acute stage of infection are likely to be the most infectious animals in the herd. Those contagious calves are responsible for maintaining FMD virus in the herd and the spread of FMD to other wildlife or domestic livestock species.

Buffalo bulls in the field have been observed by farmers to mount domestic cows on occasion and it is possible that sexual activity may be a way in which SAT-type viruses are transmitted form African buffaloes to cattle.

African buffaloes in the KNP in south Africa have been shown to be the usual source of infection for impala on the basis of sequencing studies.

Other susceptible species, principally impala, probably become exposed while infection is circulating among buffalo calves, possibly around permanent water points, where animals congregate.

There is evidence suggesting transmission in both directions between cattle and European hedgehogs Erinaceus europaeus, and for latent infections of hibernating hedgehogs. However, these reports should be viewed with caution, because there is not evidence that hedgehogs have participated in the propagation of FMD viruses in Europe or Africa in recent times.

During and outbreak in Norfolk in 1946 nine hedgehogs were found dying from FMD over an 11-week period. It was thought that there had been hedgehog to hedgehog transmission and that they had contributed to local spread of the disease. The authors considered that the outbreak could have originated in the hedgehogs as they had access to kitchen scraps containing imported meat products.

It might be considered that they could act as ideal hosts for the virus and that they might well acts as excellent reservoirs of infection. In the 1924 outbreak in California, over 20,000 deer were shot in order to control the spread of disease and over 2,000 had active or healed lesions. Yet in Europe, deer do not appear to act as disseminators of virus. In the UK during periodic outbreaks of FMD over the past fifty years, there has never been any suggestion that deer have directly involved. In an area such as the New Forest in the south of England, which is over 1000 square miles in extend, cattle and pigs share the forest grazings with at least four species of deer. Despite outbreaks in the farm livestock, no deer has ever been seen to be infected clinically. Many years ago, many deer were culled during an outbreak so that they could be examined by veterinary experts none were found with lesions.

Roe deer Capreolus capreolus, fallow deer Dama dama, sika deer Cervus Nippon, red deer Cervus elaphus and muntjac Muntiacus muntjac excreted FMD virus following experimental infection in approximately the same quantities as sheep and cattle. It has furthermore been shown that infection between deer and domestic livestock may occur in either direction.

White-tailed deer were shown to be susceptible to infection with FMD virus type O. The disease was transmitted by contact from deer to other deer, from deer to cattle, and from cattle to deer. White-tailed deer were clearly susceptible to infection from this strain of FMD virus both by intranasal inoculation and by contact exposure.

Most deer, including white-tailed deer and mule deer like those found in North America, were assigned a high hazard category because of demonstration of FMDV transmission. At least one white-tailed deer remained a carrier of FMDV for 11 weeks after infection. Exotic deer, including red, sika, and fallow, have been gaining popularity for use on deer farms or game ranches. Such deer have been found to both acquire and transmit FMDV under natural conditions. There is no information on transmission from other cervids such as moose and elk. Accordingly, those cervids were placed in a moderate category.

The opinion that FMD infected deer constitutes a low risk because sick animals hide and probably die, is not valid. Like cattle or sheep, susceptible deer are very infectious prior to the development of the lesions while they still actively move and graze. Also deer with sub-clinical or minor lesions will still roam around.

Llama

Foot-and-mouth disease virus was shown to be transmitted from either cattle to llamas, llamas to swine or llamas to llamas.

In a large experimental study where llamas were exposed to FMD infected pigs and cattle, the llamas were poorly susceptible to FMD and the few infected llamas only had virus in their pharyngeal mucosa for a short time. Moreover, recovered animals did not transmit virus to other susceptible species. Clearly, to become infected llamas need exceptional infection pressure. The lack of sero-conversion, when exposed to normal outbreak situations, indicates that llamas do not play a role in FMD epidemics.

Rodents

Capybaras (Hydrochaeris hydrochaeris) are susceptible to FMD and they may play a role in the epidemiology of FMD in cattle in South America.

The capybara, a large rodent that lives in groups in close contact with grazing livestock, has been shown to develop clinical disease. Capybaras were exposed to FMDV type O by the intramuscular route and virus was isolated from most of the organs collected from four animals slaughtered 24-48 hours post-inoculation. The remaining capybaras developed vesicular lesions on their feet between 72 and 96 hours post-infection and virus was shed in feces until at least 10 days post-infection. The susceptibility to capybaras to this strain of FMDV by intramuscular inoculation does not necessarily mean that they constitute an actual reservoir and the epidemiological significance of FMD in the species is unknown. Most likely cattle are the primary host and capybaras a dead-end host.

Rodents

Rats, mice and birds might transmit the disease mechanically. FMDV has been found in rat feces and urine and in bird droppings. The maximum titer found in rat feces was 1000 ID50 per g. Sellers states that the feces from 160 rats would be required to attain sufficient virus to infect cattle by ingestion. However, the chance of infection will also depend on the numbers of animals contacting the infectious source, raising the likelihood of a transmission occurring with sources containing low viral loads. It has also been suggested that contamination of dust by rat feces or urine may lead to infection by inhalation. In this instance only a few IU would be required. It must be emphasized that the role of vermin such as rats is insignificant under conditions of extensive cattle management as occur in South America. Vermin might spread FMD from infected premises, particularly when cleaning and decontaminating have eliminated normally available feed sources.

Invertebrates

Although the role of flies and ticks in the epizootiology of FMD is not usually large, it has been demonstrated that ticks and some species of biting flies can transmit the virus through bite. Tick, flies, and biting flies were categorized as high hazards, based either on transmission capability or long carrier status (whether mechanically or biologically). Houseflies can carry FMDV both externally and internally; whether they can transmit the virus is unknown. It is unlikely that the virus multiplies in the cells of invertebrates. However, experimental transovarial infection of a portion of a population of Dermacentor ticks has been reported.

Currently, carrier animals are defined as those from which live virus can be isolated at 28 days, or later, after infection. The role of carrier animals in the spread of virus in the filed is still controversial. The mechanisms for the establishment and maintenance of the carrier state are not well understood, since persistence can occur in animals exposed to virus after either acute disease or vaccination. It does appear that the immune status of the animal probably controls the level of virus replication. Alexanderson and colleagues have proposed two mechanisms for the development of persistence in the pharynx. One suggests that FMDV can infect immune system cells, such as macrophages, or other immunologically privileged sites, leading to evasion of the immune response. The second mechanism proposes that the virus exploits the host response to provide favorable intracellular conditions for long-term persistence, possibly by utilizing cytokine signalling.

In the late 50s and early 60s it was shown that in countries with endemic FMD, virus could be isolated from the mucous and cell debris form oropharyngeal mucosa in as much as half of the cattle population. However, dependent on the virus strain, type of cattle and local circumstances figures may vary and individual cattle will show differences in duration and level of virus excretion. The long-term persistence of FMDV in the pharyngeal area of cattle is measured in years rather than in months.

More than 50% of cattle have recovered from infection with FMD virus and vaccinated cattle that have had contact with live virus become carriers. The FMD virus persists particularly in the basal epithelial cells of the pharynx and dorsal soft palate, and can be recovered from some animals for over three years, although the carrier state does not usually extend beyond a year.

The FMD virus is pH sensitive, with an optimal pH between 7.2 and 7.6, and is inactivated at a pH less than 6.0 and greater than 9.0. The FMD virus is fairly stable at low temperatures, surviving for 1 year at 4 degrees C, but can survive for progressively shorter times as temperature increases. For instance, survival times at 37 degrees and 56 degrees C are 10 days and less than 30 minutes, respectively. However, the virus is not inactivated during pasteurization at 72 degrees C for 15 seconds. Milk from naturally infected cows must be heated to 100 degrees C for greater than 20 minutes for virus inactivation. The virus can be persistent in the environment and survives in the soil for 3 days in the summer and 28 days in the winter. In dry fecal material, the virus survives for 14 days in the summer, whereas it can survive for 6 months in manure slurry in winter conditions. The virus survives for up to 39 days in urine. To inactivate the FMD virus in slurry, the slurry must be heated to 67C for 3 minutes.

Unlike those of other picornoviruses, the FMDV capsid is dissociated at pHs of below 6.5 into 12S pentameric subunits. The reason for this instability is thought to be a cluster of His residues at the interface between BP2 and VP3, which become protonated at low pH, weakening the capsid through electrostatic repulsion. This low-pH-induced instability of FMDV leads to difference in the mechanism of its uncoating upon infection of cells compared to that for other picornaviruses and also probably plays a role in the targeting of the virus to specific tissues and organs in susceptible hosts.

Preserved by refrigeration and freezing and progressively inactivated by temperatures above 50C. Inactivated by sodium hydroxide (2%), sodium carbonate (4%), and citric acid (0.2%). Resistant to iodophores, quaternary ammonium compounds, hypochlorite and phenol, especially in the presence of organic matter. Survives in lymph nodes and bone marrow at neutral pH, but destroyed in muscle when pH is less than 6.0 i.e. after rigor mortis. Can persist in contaminated fodder and the environment for up to 1 month, depending on the temperature and pH conditions.

When compared with viruses such as the smallpox virus, FMD virus is relatively fragile, but under the cool, moist, and often cloudy conditions (low ultraviolet light concentration) of winter and spring in the UK, it survives for several days and often longer.

Sheep and goats less frequently become a carrier and for shorter periods of than cattle often lasting for only 1-5 months. However, in some animals the carrier state may last up to 12 months. Unequivocal evidence of transmission form carrier sheep or goats has neither been demonstrated under experimental conditions or in the field.

FMDV was seldom recovered from the pharynx from red and roe deer beyond 14 days post-exposure. Fallow deer carried the virus for a minimum of 5 weeks. Two months after exposure 6 from the 12 deer were still positive. White tailed deer in the USA carried FMD virus regularly up to 5 weeks after exposure, but one deer had virus in the OP fluid as long as 11 weeks post-exposure.

Exotic deer, including red, sika, and fallow, have been gaining popularity for use on deer farms or game ranches. Such deer have been found to both acquire and transmit FMDV under natural conditions. There is no information from other cervids such as moose and elk.

All of the deer tested 4 weeks after exposure had virus in the OPF and therefore could be classified as carriers. Generalization is not possible with such a small experimental group but he presence of virus in the OPF of one animal 11 weeks after exposure makes the existence of relatively long term carriers a distinct possibility.

Individual animals may maintain the infection for periods of at least 5 years, but in most buffalo the rates peak in the 1-3 year age-group. Individual buffalo may be persistently infected with more than one type of FMDV in the pharyngeal region.

African buffalo are efficient maintenance hosts of the SAT type viruses, with individual animals maintaining the virus for up to 5 years, and isolated herds for up to 24 years although persistence in individual buffaloes is probably not lifelong.

Many animal-origin products and other fomites or vehicles can serve as possible modes of FMDV transmission. A total of 76 products (15 nonfood and 61 food) and 21 fomites were identified by the USDA in this publication.

Diseased animals excrete the virus in tremendous quantities. The most common way of dissemination is by infected live animal and contaminated animal products. Indirect transmission can be made by people, vehicles, equipment, hay or bedding contaminated with feces or urine of diseased animals. Over the years, illegal activities, have often been attributed to introductions of FFMD into non-infected countries, such as the importation of infected meat and feeding to pigs of non-heat treated swill.

The virus has a remarkable capacity for remaining viable in carcasses, in animal byproducts, in water, in such materials as straw and bedding, even in pastures. In 1994, USDA examined the source of all primary FMD outbreaks worldwide from 1870 through 1993. The study found that of the 558 outbreaks with a reported source, contaminated meat, meat products or garbage caused 66 percent of the outbreaks. For the latter 25 years under the study, the sources of most of the 69 primary FMD outbreaks were livestock importations, animal vaccines (including both contaminated vaccines and escapes of virus from vaccine production facilities), and contaminated meat, meat products or garbage.

Primary infections in FMD free countries have frequently involved pigs, often on swill feeding holdings. Swill from ships and aircrafts forms a special risk in this respect. Therefore, swill feeding practices are not compatible with a FMD free status unless the swill is processed in officially validated plants that are well-controlled by the government.

The primary role of biologics in the transmission of FMDV has been through the use of improperly inactivated FMD vaccine. Outbreaks have occurred primarily in Europe due to the use of formalin-inactivated vaccines. In the early 1900's other biologics were found to be contaminated with FMDV. It is less likely that problems with inactivation or contamination of vaccines could occur today given the techniques now used by most manufacturers.

During the past 20 years on at least at two occasions FMDV escaped from technically well-equipped high-containment laboratories causing outbreaks outside the facilities. Therefore, regular international inspection of FMD laboratories and vaccine production plants is needed. Inspection must be carried out on the status of facilities and equipment, on logistics, and on the execution of the internal control on bio-containment and biosafety. This is particularly important for such laboratories in countries with a FMD free status.

FMDV was found in semen as early as 12 hours after inoculation of bulls and as long as 42 days after contact exposure. In addition, heifers artificially inseminated with infected semen have developed FMD. In swine, FMDV has not been transmitted through artificial insemination even though semen from infected swine contains FMDV. Consequently, although further transmissibility studies in swine may be warranted, porcine semen was categorized as a low hazard.

FMDV remained infective in hides preserved by 4 conventional methods for varying lengths of time, all over 14 days. The authors of the study noted that these experimentally observed time periods should not be considered maximum survival times. Further, imported hides were suspected of causing the 1914 outbreak in the United States, in which at least 22 states and the District of Columbia were affected. Untanned hides and skins are currently allowed into the United States if they are hard dried, pickled in a solution of salt containing mineral acid or treated with lime in such a manner and for such a period as to have become dehaired. No studies were found in which the effect of such processing on FMDV was examined.

Ninety-nine animals were identified as possible sources of FMDV Of those, 31 were characterized as high, 50 as moderate, and 18 as low. A complete listing of all 99 animals can be found in this publication.

While there is no evidence to suggest that the recent epidemic of foot-and-mouth disease (FMD) in the UK and its subsequent spread to continental Europe were caused by bioterrorism, the extent of the epidemic shows that FMD could be a very powerful weapon for a bioterrorist wishing to cause widespread disease in livestock and economic disruption for the targeted country. A report by the National Academies has highlighted the vulnerability of the nations food supply. FMD was identified as the most important animal disease that the US must be prepared for. The potential use of FMD to physically cripple livestock and to economically cripple a country has been recognized for many years. Few know that in the 1970s the Irish Republican Army threatened to release FMD virus in the UK; in the 1980s Australia had to respond to an extortionist who similarly threatened to use FMD virus. Not surprisingly, there are unsubstantiated reports that al Qaeda has also studied the malevolent use of the virus.

Due to FMDs highly infectious nature, any detection of the disease in the United States would warrant immediate activation of APHIS Emergency Operations Center. If FMD is found in the United States, the U.S. Department of Agricultures (USDA) Animal and Plant Health Inspection Service (APHIS) officials stationed in the Center would help to coordinate local, State, and Federal response and eradication efforts, coordinate inter-agency planning, and implement national communication and information-sharing strategies. APHIS has already established a toll-free telephone number that concerned citizens and cooperators can call to obtain information on FMD and APHIS response efforts. 1-800-6-1-9327.

Ways by which the virus or infectious RNA may escape or be carried out from laboratories include: Personnel, Air Effluent and other waste Equipment.

Compared to bio-terror, agro-terror is appallingly easy. Animal diseases of greatest concern are those that, by nature, are very infectious and spread rapidly through herds and flocks. FMD, for instance, is the most contagious disease known to exist, spreading from animal to animal with incredible rapidity and in a more efficient manner than even the most contagious of human diseases. Bringing FMDV into a naive area is surprisingly simple, and once introduced, it will spread quite readily, without any requirement for weaponization to facilitate spread.

Were FMD to occur through bioterrorism, it is probable that terrorists would trigger several outbreaks in different parts of the country, possibly caused by several serotypes of the virus. Multiple routes of transmission demand complex disease control responses and disruption of society.

FMD is one of the most contagious diseases known and manipulating the virus in the laboratory without adequate precautions is a hazard. The escape of a single infectious unit of FMDV from a laboratory could potentially cause an outbreak. The main sources of virus or infectious RNA (in increasing risk of hazard) are: infected tissue cultures, infected baby mice, guinea pigs, rabbits etc., physical and chemical processing of large quantities of virus outside closed vessels (e.g., concentration, purification, inactivation, etc.), infected pigs, cattle, sheep, goats and other susceptible animals. Ways by which the virus or infectious RNA may escape or be carried out from laboratories include: Personnel, Air Effluent and other waste Equipment. Therefore all laboratories manipulating FMD virus must work under high containment conditions. The safety precautions must preclude any escape of virus and special attention must be given to: the prevention of illegal entry into the restricted area, the presence of changing and showering facilities, the responsible behaviour of personnel within and when they leave the laboratory, application of rules for primary containment, the use of inactivated virus where possible, the maintenance of negative air pressure where virus is manipulated and decontamination of exhaust air, the decontamination of effluent, the disposal of carcasses in a safe manner, the decontamination of equipment and materials before removal from the restricted area. To achieve this containment a variety of technical installations and a comprehensive set of disease security regulations are required under the supervision of a Disease Security Officer.

The evidence that the virus can be transmitted by aerosol alerted workers for the need to operate under negative pressure, particularly when large amounts of the agent are involved. Circulating air should be filtered appropriately.

U.S. research and diagnostic work with live foot-and-mouth disease virus is permitted only in an island-based laboratory.

The proven strategy for controlling an FMD outbreak includes several key actions: Quarantine and stop movement of animals and products. Disinfect vehicles and personnel. Slaughter infected and contact animals. Destroy infected carcasses. Assess the need for strategic vaccination of animals and implement this action as appropriate.

Human

Homo sapiens

Foot and mouth disease is a zoonosis, but it crosses the species barrier with difficulty and with little effect. Given the high incidence of the disease in animals, both in the past and in recent outbreaks worldwide, its occurrence in man is rare so experience of the human infection is limited. The last human case reported in Britain occurred in 1966. The type of virus most often isolated in humans is type O followed by type C and rarely A. The incubation period in humans is 2-6 days.

Sampling of human subjects, who had been in contact with diseased animals, showed that virus could be recovered from the nose, throat, and saliva of these people, immediately after leaving the room. Nasal swabs of such persons usually contain 100-1000 IU, but some may contain as many as 10,000 IU.

The route of transmission of FMDV from animals to man is unclear, although the virus has been detected in the upper respiratory tract of exposed individuals who did not contract infection.

Travelers can make sure they do not bring in prohibited food items and other products, such as soiled footwear and soiled clothing items, that could present a risk of transmitting FMD and other diseases. Travelers should ensure that luggage, packages, and mail are free of any prohibited meats, dairy products, and other at-risk materials before they are shipped to the United States. Travelers should also shower and shampoo prior to and again after returning to the United States from an FMD-affected country. Launder and/or dry clean clothes before your return to the United States if possible. If you visited a farm or had any contact with livestock on your trip, you should avoid all contact with livestock, zoo animals, or wildlife for 5 days after your return to the United States.

The incubation period in humans is 2-6 days.

Symptoms have been mild and self-limiting. Patients have usually recovered about a week after the last blister formation.

Symptoms have been mild and self-limiting, mainly uncomfortable tingling blisters on the hands, but also fever, sore throat, and blisters on the feet and in the mouth, including the tongue.

Proven cases of FMD have occurred in several countries in Europe, Africa and South America.

Human infection with FMDV has been described but only a few cases have been confirmed virologically by the isolation of virus and detection of a specific immune response.

Vesicles develop on the hands, mostly on the fingers, occasionally on the feet and in the region of the mouth, especially on the tongue and palate. A tingling, burning sensation of the fingers and palms precedes the development of vesicles between fingers at the lateral sites of the hand and the volar surfaces of terminal phalanges. Similar sensations are felt in the feet if they are involved. Sometimes the only blisters occur in the oral cavity. Here the greatest discomfort arises. The pain involved in eating, drinking and talking is intense. Excessive salivation adds to the distress. The aphthae may be as small as a pin head or as large as 2 cm in diameter. In this area the spinose layer of the epidermis experiences a colliquative necrosis. Initially the blisterfluid is clear and yellowish but soon becomes inspissated. Blisters dry up within two or three days with skin being sloughed, sowing the red basal layer of the epidermis. Secondary blisters may appear up to five days after the primary ones have developed.

The onset is characterized by mild headache, malaise with fever that reaches as high as 39.5 degrees celcius.

Criteria for establishing a diagnosis of FMD in man are the isolation of the virus from the patient and or identification of specific antibodies after infection. Laboratory tests for diagnosis of human FMD are the same as for animals.

Rodent

The intraperitoneal inoculation of FMDV produces death in suckling mice, and this has been extensively exploited to titrate virus infectivity. Likewise, FMDV can be adapted, by serial passages, to produce clinical symptoms in guinea-pigs, an animal model that has been used mostly for immunological analysis.

Cattle

Bos taurus

FMD in the highly productive beef and dairy breeds of Europe, North America and Australia is characterized by severe clinical signs. Index cases on farms exposed to low level aerosol virus may develop only mild or even subclinical infection, but as the virus replicates in the first infected animal and is produced in large quantities, so the remaining animals in the herd appear with multiple vesicles in the mouth and on the feet and udder. The disease is considerably less obvious in the breeds of cattle indigenous to Africa and Asia, where FMD is mostly endemic. However, FMD is also economically important in these regions, further reducing an already low milk yield, causing the death of young calves, and interfering with the function of adult cattle to pull a plough or cart.

Cattle injected in the tongue epithelium with only 1IU may become infected, while a higher dose of 10-100 IU is required for aerosol exposure.

Cattle are very susceptible by the respiratory route, requiring as little as 20 TCID50 of virus to establish infection, but may require 10,000 times more to become infected by the oral route.

The FMD virus replicates at the site of entry, either in the mucosa and lymphoid tissue of the upper respiratory tract or in the dermal and subdermal tissue of a skin abrasion. The virus enters the blood circulation as free virus or associated with mononuclear cells and is distributed around the body to glandular tissue and predilection sites in the stratum spinosum, where secondary replication takes occurs.

A number of studies have suggested that the lung or pharyngeal areas are the sites of initial virus replication with rapid dissemination of the virus to oral and pedal epithelial areas, possibly mediated by cells of monocyte/macrophage origin. In cattle experimentally infected via aerosol, it was found, by in situ hybridization, that within the first 24 hours, virus was present in respiratory bronchiolar epithelium, subepithelium, and interstitial areas of the lung. By 72 hours, signal was detected in epithelial cells of the tongue, soft palate, feet, tonsils, and tracheobronchial lymph nodes. Other studies, however, have suggested that the pharynx, not the lungs, may be the initial site of replication in infected cattle. The conflicting observations about the region of the respiratory tract that is initially infected in cattle exposed to aerosols may be the result of a number of variables, including aerosol particle size, strain of virus, or how the aerosol was generated.

Stamping-out consists of the killing and disposal of all susceptible livestock on the infected farms and their immediate contact farms that most likely infected followed by a thorough disinfection, cleaning, disinfection procedure of the premises, the first disinfection begin to prevent the production of virus aerosols during the cleaning. In traditionally FMD free countries, stamping-out is the first option to eradicate the disease. As a first line of defense it is often quite successful, at least if the disease has not yet spread too widely and if the density of the livestock in the area is relatively low. Also, during the first days of an outbreak the proper vaccine may not be available. The choice of the stamping-out option should also depend on the possibility of tracing dangerous contacts, political will and available resources.

In countries free of the disease, a policy of slaughter of all infected and in-contact susceptible animals is usually employed.

The slaughter of infected or at-risk herds should be the primary means for controlling diseases such as FMD as long as they are detected at an early stage

This stamping out policy is standard and is recognized by the Office International des Epizooties (OIE) as the most appropriate way to break the chain of virus transmission and thus control and eradicate the disease in industrialized countries.

Control of the disease in FMD-free countries include an exclusion and slaughter policy. However, stamping out of infected and contact animals alone may not be sufficient to eradicate the virus promptly and vaccination is now considered an acceptable alternative or adjunct.

Cattle have been infected by entry into decontaminated premises, up to four months after culling, cleaning and disinfection had occurred: 12 occurrences of this were reported in the winter of 1967-1968 in the UK. The mechanisms of such infection are unclear, but apparently the virus was able to survive that length of time in the environment or in some unknown other host.

Heavy equipment used in these operations is difficult to decontaminate and might be a source of infection or contamination of roads when being driven to another job or back home Disposal of cadavers also presents a risk since virus in lesions, excrements and excretions is not rapidly destroyed after death and might be disseminated by transport of cadavers, by pyres, at burial sites or digester plants. Transport systems for carcasses are not bio-secure, neither is the handling of the carcasses at the rendering plants. The highest risk comes probably from the involvement of large numbers of contractors not trained in disease containment.

After the 2001 outbreak in the UK, public reaction, questioned the need for large-scale slaughter of susceptible animals, particularly the slaughter of vaccinated animals that were healthy.

So-called circle culling and culling of contiguous farms has been applied in the UK and in the Netherlands as an extension of usual stamping-out procedures. The aim of the circle is to eliminate incubating infections that may have spread from the outbreak farm(s) and create a fire break around the outbreak. The diameter of the circle was based on the analysis of spread of FMD during the outbreak using computer models. However, the calculated distance of spread must include spread due largely to the culling process itself as an additional transmission mechanism.

In countries free of the disease, a policy of slaughter of all infected and in-contact susceptible animals is usually employed.

The slaughter of infected or at-risk herds should be the primary means for controlling diseases such as FMD as long as they are detected at an early stage

Although ring culling reduces the need for surveillance, it creates potentially much higher numbers of cadavers, some of which might be infected.

Most culled farms within the circle are not infected and do not represent a risk of further spread of the disease and, therefore, are culled unnecessarily. The operation itself has a high-risk of disseminating FMDV over short and long distances. A long drawn-out campaign is very disruptive for the rural society as a whole, including sectors like tourism. The rural community may fear the control measures more than the disease, and live under this fear for several months after the last case. The consequent application of circle and of contiguous culls pose a threat to zoological collections and valuable (rare) breeding stock. Massive killing and destruction of livestock usually is not done with adequate respect for animal welfare and bio-ethical principles. The small risk represented by hobby farms and smallholdings is not taken into account. An enormous serological surveillance exercise is often required to detect residual infection since new cases could easily re-start the epidemic at its tail end, particularly if movement controls are prematurely lifted. Finally, many culls represent a human tragedy and traumatic experience not only for farmers and their families but for many veterinarians as well. The risk-avoidance behavior of farmers leads to social isolation and breakdown of the socialeconomic and trading patterns of rural communities.

In endemic or epi-endemic regions, strategic or general vaccination is required with vaccine containing the FMD subtypes that are active in the area. This could be carried out with the more classical aqueous vaccine or with oil-adjuvant vaccine.

The current FMD vaccine is an inactivated whole-virus preparation that is formulated with adjuvant prior to use in the field. A number of countries have established vaccine banks, which contain concentrated antigen stored in the gaseous phase of liquid nitrogen. Banks contain antigen against a number of virus serotypes and provide member countries with an almost immediate source of vaccine.

Vaccination would be used to control an outbreak in an endemic area. Vaccination may also be used to surround a focal outbreak of a disease to prevent the virus from spreading and the vaccinated animals may be subsequently slaughtered to reduce the delay in re-establishing trading status. A buffer zone containing vaccinated animals may be used to separate an area within a country in which FMD is endemic from an FMD-free area, from which exports of cattle and cattle products are sourced.

Aqueous vaccines must be applied twice yearly. In general, current oil-adjuvant vaccines protect cattle of different breeds more effectively. Cattle up to 2 years should be vaccinated twice yearly. Thereafter, a yearly vaccination will maintain their immune status.

Normally, when a number of animals are vaccinated, some animals fail to develop immunity. Should these animals become infected and develop clinical FMD, they can excrete large amounts of virus, which may overcome the vaccinal immunity of the other animals in the group.

Intensive vaccination does not always prevent the appearance of clinical FMD. Some very high yielding diary herds in the Middle East are vaccinated every ten weeks with vaccine produced under European standards containing eight strains of FMDV. However, because of severe challenge originating predominantly from the nomadic herds of sheep, goats and cattle, which graze freely in the area, introduction of virus into the dairies is inevitable. When these dairy cattle become infected, they frequently exhibit a very severe form of disease, in which the tongue swells and protrudes from the mouth and the majority of the tongue epithelium is shed.

Since cattle that are exposed to infection can become persistently infected, whether vaccinated or not, all seropositive animals are considered a risk, which explains, in part, the distinction established by the OIE. The objective of improved serological tests, therefore, must be to reliably detect animals that have been infected with FMD, regardless of whether they have also been vaccinated. A serological test that detects antibodies to the nonstructural polyprotein 3-ABC can be used on a herd basis to detect viral circulation in vaccinated populations. However, there is evidence that not all animals that have been vaccinated and are infected seroconvert to nonstructural proteins.

The duration of immunity following a single dose of high-potency vaccine in a previously naive animal is usually less than a few months against homologous challenge, and shorter for heterologous challenge. A booster dose given 3 to 4 wk after the initial dose will prolong the immunity for up to 6 mo, but this can be dependent on the level of exposure of the vaccinated animals to live virus challenge.

Freedom from disease, as established through stamping out, allowed exports to open in 3 months, compared with 12 months when vaccine was used. While the Netherlands used emergency vaccination to control the epidemic, it subsequently culled all vaccinated animals to allow its markets to open early. With the knowledge that vaccination could significantly delay resumption of the UK export market, the question of whether or not to vaccinate created considerable controversy during the (2001) epidemic

High-containment facilities are required for the production of vaccine. Vaccinated animals develop antibody responses against the contaminating proteins, in addition to the viral structural proteins, making it difficult to reliably distinguish vaccinated from infected or convalescent animals with currently approved diagnostic tests. Most Virus preparations are concentrated cell culture supernatants from FMDV-infected cells and, depending on the manufacturer, contain various amounts of contaminating viral NS proteins. The vaccine does not induce rapid protection against challenge by direct inoculation or direct contact. Vaccinated animals can become long-term carriers following contact with FMDV.

Interference in response to vaccination by young animals with high levels of maternally derived antibody. Only when it is below a LPBE titer of 1:45 will the calf respond to vaccination. The problem of the approximately one month time gap between susceptibility to infection and vaccination can only be managed by keeping the calves isolated from any source of FMD virus during that period.

A misconception is that vaccination causes the carrier status. This is impossible since FMD vaccine is an inactivated, safe vaccine. A vaccinated animal must be exposed to a large quantity of FMDV in order to become a carrier, for instance when vaccinated cattle come in contact with large numbers of diseased pigs. Because vaccination suppresses the amount of FMDV that is released into the environment (low morbidity!) it is very unlikely that vaccinated animals will become carriers. It is also unlikely that vaccinated animals become carriers through infection by FMDV transmitted by fomites or people and brought from infected farms. It is thus very unlikely that new carriers will be induced in vaccinated herds. Carriers among vaccinated cattle have not caused FMD outbreaks among susceptible non-vaccinated livestock populations nor have they hampered FMD eradication efforts.

It has been demonstrated that early FMD vaccination of herds or flocks round the infected premise creates a cordon of protective animals that can stop effectively the diffusion of the disease. The size of the ring required depends on the rapidity of action of the vaccine and the anticipated rapidity of potential spread of infection from the IP, and location of high-risk farms, which might amplify infection for onward spread. For example, to get ahead of the disease with a vaccine would require 45 days to stimulate immunity and create an area in which farms/animals are protected before the anticipated first contact with virus. The higher the anticipated aerosol transmission, the larger the area that would be required to ensure an adequately immunised ring. Therefore, ring vaccinations should be performed without delay and should include all susceptible species. Preferably, the vaccination should be carried out from the outside of the ring towards the center of the outbreak. Simultaneously, to protect the most endangered farms as soon as possible, vaccination should proceed from the center towards the outside. In the immediate vicinity of the outbreak farm, the large (cattle) holdings should be vaccinated first because potentially, those are the largest aerosol collectors.

Outbreaks in the vaccinated zone or ring will usually cease within 10 days of effective herd immunity being reached, and frequently cease well before this.

This control option is heavily penalized by present OIE regulations because of the 1224 months waiting period to regain the status of freedom from FMD, depending on whether or not stamping-out was applied.

Fear of carriers among vaccinated animals has led to suppressive vaccination. In that approach, vaccination is used to control the outbreak(s), but all vaccinated animals have to be killed before FMD free status can be regained. It was used in The Netherlands in the main outbreak area to control the recent outbreak.

Four to six days after vaccination all vaccinated animals will have sufficient protection to prevent dissemination of virus. The vaccinated animals can be killed over a more extended period, depending on incinerator capacity.

Suppressive vaccination creates several of the problems mentioned for circle culling, with the exception of the risk of dissemination of the virus. This risk is much reduced, because 46 days after vaccination all vaccinated animals will have sufficient protection to prevent dissemination of virus. The vaccinated animals can be killed over a more extended period, depending on incinerator capacity. It is interesting to note that, although vaccinated pigs do not become carriers they still must be slaughtered as well!

The establishment of wildlife conservancies has created a problem with regard to FMD because the Office International des Epizooties (OIE) presently considers any territory on which buffalo infected with FMD viruses occur as infected. Zones recognized as free of FMD by the OIE need to be separated from infected zones by a defined surveillance zone of at least 10km deep (International Health Code, 1992). According to the OIE recommendations this means that landowners acquiring even one infected buffalo cause their land to be in an infected zone and, by implication, their neighbors to be in a surveillance zone. However, in May 1997 it was accepted by the OIE that infected and free zones may be separated by a barrier instead of a surveillance zone. It appears that modified low-maintenance buffalo control fence complemented with buffer zones or vaccination zones may be a cost-effective solution to the containment of FMD in wildlife zones.

The floods of 2000 in southern Africa damaged the Kruger National Park game fence extensively, and there were several accounts of buffalo that had escaped from the park. The VPI gene, which codes for the major antigenic determinant of the FMD virus, was used to determine phylogenetic relationships between virus isolates obtained from the outbreaks and those previously obtained from buffalo in the KNP. These results demonstrate that buffalo were most probably the source of the outbreaks, indicating that disease control using fencing as well as vaccination is extremely important to ensure that FMD does not become established in domestic livestock.

The construction of a game fence along international borders if there are no wildlife areas in the neighboring countries would serve no purpose as far as FMD control is concerned.

In principle, wildlife fences should not be constructed only between wildlife zones and the farming areas. They should not run through the middle of any wildlife zones, but between them and any commercial farms or communal lands. Also from a FMD control point of view there is no need to fence through communal lands or along international borders.

Fences are supposed to prevent close contact between infected animals and noninfected animals from the same species or from different species. However, other transmission mechanisms, such as intermediate hosts, must be accounted for.

The use of fencing has been severely criticised by conservationists, because the fences sometimes have blocked migration routes and access of wildlife to water, resulting in ecological disturbances and wildlife mortality. The necessity for fencing is increasingly questioned -- the argument being that vaccination alone should be sufficient to protect livestock from infection.