Development of a Foot‐and‐Mouth Disease Infection Model in Severe Combined Immunodeficient Mice for the Preliminary Evaluation of Antiviral Drugs

Recent European guidelines facilitate the use of emergency vaccines during outbreaks of foot‐and‐mouth disease. Antiviral drugs could be used as a complementary measure. This study aimed at developing a small animal model to assess the in vivo activity of early antiviral lead molecules with anti‐foot‐and‐mouth disease virus (FMDV) activity in vitro. In a first attempt, several FMDV strains were titrated in Balb/c mice. Inoculations with O₁ Manisa or C₁ Noville did not induce clinical disease, whereas Asia1 Shamir induced death too rapidly [i.e. within 4 days post‐inoculation (dpi)]. Therefore, we switched to severe combined immunodeficient mice which are frequently used as a model for viral infections and experimental therapeutics. Strain O₁ Manisa did not induce clinical disease, but titrations with A₂₂ Iraq, C₁ Noville or Asia1 Shamir resulted in virus‐induced morbidity (including respiratory problems and weight loss) with subsequent mortality. Inoculations with strain A₂₂ Iraq resulted in a reproducible mean time of death of 6 dpi (this was shorter for the other strains). In this newly developed rodent model, strain A₂₂ Iraq seems the most suited to assess the in vivo anti‐FMDV activity of selective inhibitors of FMDV.     

Foot‐and‐Mouth Disease Virus Concentrations in Products of Animal Origin

Foot‐and‐mouth disease (FMD) is a highly contagious disease of cloven‐hoofed animals which can have devastating economic consequences. Maintaining an FMD‐free status is a priority for non‐endemic countries, which restrict importation of animals and animal products from countries in which the disease is present or sporadic, thus presenting a considerable barrier to international trade. This review examines the concentration of FMD virus in animal tissues during the viraemic stage of disease and in animal products derived from infected animals.     

Emergence and Distribution of Foot‐and‐Mouth Disease Virus Serotype A and O in Bangladesh

Foot‐and‐mouth disease (FMD) is endemic in Bangladesh and is predominantly due to FMDV serotype O. In 2012, FMD outbreaks were identified in five different districts of Bangladesh. Of 56 symptomatic cattle epithelial tissue samples, diagnostic PCR assay based on 5′‐URT detected 38 FMDV infections. Viral genotyping targeting VP1‐encoding region confirmed emergence of two distinct serotypes, A and O with an abundance of serotype A in Chittagong and Gazipur districts and serotype O in Pabna and Faridpur. Only single lineage of both A and O was retrieved from samples of five different regions. Sequencing and phylogenetic analysis of VP1 sequences revealed that serotype O sequences were closely related to the Ind 2001 sublineage of Middle East–South Asia (ME‐SA) topotype that was previously circulating in Bangladesh, and serotype A sequences belonging to the genotype VII that was dominant in India during the last decade. The results suggest that extensive cross‐border animal movement from neighbouring countries is the most likely source of FMDV serotypes in Bangladesh.     

Epidemiological Patterns of Foot‐and‐Mouth Disease Worldwide

Foot‐and‐Mouth Disease (FMD) is a clinical syndrome in animals due to FMD virus that exists in seven serotypes, whereby recovery from one sero‐type does not confer immunity against the other six. So when considering intervention strategies in endemic settings, it is important to take account of the characteristics of the different serotypes in different ecological systems. FMD serotypes are not uniformly distributed in the regions of the world where the disease still occurs. For example, the cumulative incidence of FMD serotypes show that six of the seven serotypes of FMD (O, A, C, SAT‐1, SAT‐2, SAT‐3) have occurred in Africa, while Asia contends with four sero‐types (O, A, C, Asia‐1), and South America with only three (O, A, C). Periodically there have been incursions of Types SAT‐1 and SAT‐2 from Africa into the Middle East. This paper describes the global dynamics for the seven sero‐types and attempts to define FMD epidemiological clusters in the different regions of the world. These have been described on a continent by continent basis. The review has reaffirmed that the movement of infected animals is the most important factor in the spread of FMD within the endemically infected regions. It also shows that the eco‐system based approach for defining the epidemiological patterns of FMD in endemic, which was originally described in South America, can apply readily to other parts of the world. It is proposed that any coordinated regional or global strategy for FMD control should be based on a sound epidemiological assessment of the incidence and distribution of FMD, identifying risk sources as either primary or secondary endemic eco‐systems.     

Review of the Global Distribution of Foot‐and‐Mouth Disease Virus from 2007 to 2014

Foot‐and‐mouth disease (FMD) virus affects livestock worldwide. There are seven different serotypes, each with a diversity of topotypes, genetic lineages and strains. Some lineages have different properties that may contribute to sporadic spread beyond their recognized endemic areas. The objective of this study was to review the most significant FMD epidemiological events that took place worldwide between 2007 and 2014. Severe epidemics were caused by FMD virus (FMDV) lineage O/Asia/Mya‐98 in Japan and South Korea in 2010, both previously free of disease. In India, where FMD is endemic, the most important event was the re‐emergence of lineage O/ME‐SA/Ind‐2001 in 2008. Notably, this lineage, normally restricted to India, Bangladesh, Nepal and Bhutan, was also found in Saudi Arabia and Libya in 2013 and has caused several outbreaks in Tunisia and Algeria in 2014–2015. In January 2011, FMDV‐positive wild boars were found in Bulgaria, where the disease last occurred in 1996, followed by 12 outbreaks in livestock infected with FMDV O/ME‐SA/PanAsia2. In 2012, FMDV SAT2 caused outbreaks in Egypt and the Palestinian Autonomous Territories. Another significant event was the emergence of FMDV Asia1 Sindh‐08 in the Middle East. In South America, one outbreak of FMDV serotype O, topotype Euro‐SA was reported in Paraguay in 2011, which was recognized as FMD‐free with vaccination at the time. Lessons learned from past events, point out the need for an integrated strategy that comprises coordinated global and regional efforts for FMDV control and surveillance. Specific local characteristics related to host, environment and virus that condition FMD occurrence should be carefully considered and incorporated to adapt appropriate strategies into local plans. In this review, we compiled relevant epidemiological FMD events to provide a global overview of the current situation. We further discussed current challenges present in different FMD areas.     

Molecular Characterization of Foot‐and‐Mouth Disease Virus: Implications for Disease Control in Bangladesh

Foot‐and‐mouth disease (FMD) is endemic in Bangladesh, and to implement an effective FMD control programme, it is essential to understand the complex epidemiology of the disease. Here, we report on the characterization of FMD virus (FMDV) recovered from FMD outbreaks in Bangladesh in late 2009. All isolated viruses belonged to the FMDV serotype O. The phylogenetic reconstruction showed that all isolates belonged to the Middle East–South Asia (ME–SA) topotype, but fell into two distinct sublineages, one named Ind‐2001 (the other has not been named). Within both sublineages, the 2009 Bangladesh isolates were most closely related to viruses from Nepal collected during 2008 and 2009. Additionally, both sublineages contained older viruses from India collected in 2000 and 2001. In South Asia, there is extensive cross‐border cattle movement from Nepal and India to Bangladesh. Both these findings have implications for the control of FMD in Bangladesh. Because of the porous borders, a regional FMD control strategy should be developed. Further, animal identification and monitoring animal movements are necessary to identify the cross‐border movements and market chain interactions of ruminants, leading to improved border and movement controls. Additionally, a vaccination strategy should be developed with the initial objective of protecting small‐scale dairy herds from disease. For any successful FMD control programme, long‐term Government commitment and adequate resources are necessary. A sustainable programme will also need farmer education, commitment and financial contributions.     

Experimental Infection of Giraffe (Giraffa camelopardalis) With SAT‐1 and SAT‐2 Foot‐and‐Mouth Disease Virus

The potential role of giraffe (Giraffa camelopardalis) in the epidemiology and spread of foot‐and‐mouth disease (FMD) SAT types was investigated by experimental infection and detection of virus in excretions using virus isolation on primary pig kidney cell cultures. In two experiments separated by a period of 24 months, groups of four animals were needle infected with a SAT‐1 or SAT‐2 virus, respectively and two in‐contact controls were kept with each group. Viraemia was detected 3–9 days post‐infection and virus isolated from mouth washes and faeces only occasionally up to day 13. The SAT‐1 virus was transmitted to only one in‐contact control animal, probably via saliva that contained virus from vesicles in the mouth of a needle‐infected animal. None of the animals infected with the SAT‐2 virus had any vesicles in the mouth, and there was no evidence of transmission to the in‐contact controls. No virus was detected in probang samples for the duration of the experiments (60 days post‐infection), indicating that persistent infection probably did not establish with either of these isolates. Giraffe most likely do not play an important role in FMD dissemination. Transmission of infection would possibly occur only during close contact with other animals when mouth vesicles are evident.     

Collection of Oral Fluids Using Cotton Ropes as a Sampling Method to Detect Foot‐and‐Mouth Disease Virus Infection in Pigs

In high‐density farming practices, it is important to constantly monitor for infectious diseases, especially diseases that have the potential to spread rapidly between holdings. Pigs are known to amplify foot‐and‐mouth disease (FMD) by excreting large amounts of virus, and it is therefore important to detect the virus quickly and accurately to minimize the spread of disease. Ropes were used to collect oral fluid samples from pigs, and each sample was compared to saliva samples collected from individual animals by detecting FMD virus RNA using real‐time PCR. Two different experiments are described where groups of pigs were infected with different serotypes of FMD virus, either with or without vaccination, and unvaccinated pigs were kept in aerosol contact. The sensitivity of the rope sampling varied between 0.67 and 0.92, and the statistical agreement between this method and individual sampling ranged from substantial to moderate for the two different serotypes. The ease of collecting oral fluids using ropes together with the high sensitivity of subsequent FMD detection through PCR indicates that this could be a useful method to monitor pig populations for FMD virus infection. With further validation of the sensitivity of detection of FMD virus RNA, this can be a cost‐effective, non‐invasive diagnostic tool.     

Proof of Concept for the Inhibition of Foot‐and‐Mouth Disease Virus Replication by the Anti‐Viral Drug 2′‐C‐Methylcytidine in Severe Combined Immunodeficient Mice

Recent European contingency plans envisage emergency vaccination as an animal‐friendly control strategy for foot‐and‐mouth disease (FMD). Anti‐viral drugs may be used as an alternative or complementary measure. We here demonstrate that the nucleoside analogue 2′‐C‐methylcytidine (2′CMC) protects severe combined immunodeficient (SCID) mice against lethal FMD virus infection. In brief, SCID mice were inoculated with serotype A FMD virus and treated for five consecutive days with 2′CMC. All 15 treated mice remained healthy until the end of the study at 14 days post‐infection (dpi). At that time, viral RNA was no longer detected in 13 of 15 treated mice. All eight untreated mice suffered from an acute generalized disease and were euthanized for ethical reasons on average at 4 dpi. These results illustrate the potential of small molecules to control FMD.     

Foot‐and‐Mouth Disease Seroprevalence in Cattle in Eritrea

Information about seroprevalence of foot‐and‐mouth disease (FMD) and virus serotypes in Eritrea is unavailable, but is very important as it may guide the choice of intervention measures including vaccination to be implemented. We carried out a cross‐sectional study from February to June 2011 in Eritrea with a two‐stage cluster design, sampling cattle in 155 villages with the objective of determining the seroprevalence of FMD in four administrative regions of the country. We analysed cattle sera (n = 2429) for FMD virus antibodies using the non‐structural ELISA (NS ELISA) and virus neutralization test (VNT). The overall seroprevalence was 26% and 30% for the NS ELISA and VNT, respectively. FMD virus serotypes O (14%) and A (11%) were the most prevalent. Gash Barka showed the highest (39%) seroprevalence both in NS ELISA and VNT compared to the other three administrative regions. Strategic FMD virus vaccination with type O and A (matching circulating strains) in combination of zoo‐sanitary measures would be the best control option for Eritrea which could be started in areas where the disease is less endemic.     

Serological Evidence of Foot‐and‐Mouth Disease Virus Infection in Randomly Surveyed Goat Population of Orissa,India

India is endemic for foot‐and‐mouth disease (FMD), and goats constitute the second largest susceptible population of domestic livestock. FMD surveillance and control strategies in the country largely ignore small ruminants, known to be critical in the epidemiology of the disease. Here, serological investigations were carried out to generate estimates of antibody prevalence in goats of Orissa state to both non‐structural (NSP‐Ab) and structural proteins (SP‐Ab) of FMD. The apparent overall NSP‐Ab and SP‐Ab seroprevalences were 38% and 20.7%, respectively, which signifies a very high level of FMD virus circulation in the goat population despite the lack of clinical signs in this species. The apparent prevalence of NSP‐Ab and SP‐Ab was positively correlated in the sampling areas. Interestingly, the values found for NSP‐Ab prevalence were almost consistently higher than those found for SP‐Ab prevalence. This could have been attributable to either issues related to sensitivity and specificity of the test systems employed or differences in the post‐infection kinetics of NSP‐ and SP‐Ab. The pattern that emerged from SP‐Ab analysis indicated goats being infected with all three prevalent serotypes (O, A and Asia 1) and reinforces the concept that non‐vaccinated goats can be exploited as tracer animals for detecting serotypes involved in outbreaks. The results underscore the requirement to bring caprine species under comprehensive surveillance and vaccination campaigns to check silent amplification, excretion and transmission of the virus.     

Data‐Driven Models of Foot‐and‐Mouth Disease Dynamics: A Review

Foot‐and‐mouth disease virus (FMDV) threatens animal health and leads to considerable economic losses worldwide. Progress towards minimizing both veterinary and financial impact of the disease will be made with targeted disease control policies. To move towards targeted control, specific targets and detailed control strategies must be defined. One approach for identifying targets is to use mathematical and simulation models quantified with accurate and fine‐scale data to design and evaluate alternative control policies. Nevertheless, published models of FMDV vary in modelling techniques and resolution of data incorporated. In order to determine which models and data sources contain enough detail to represent realistic control policy alternatives, we performed a systematic literature review of all FMDV dynamical models that use host data, disease data or both data types. For the purpose of evaluating modelling methodology, we classified models by control strategy represented, resolution of models and data, and location modelled. We found that modelling methodology has been well developed to the point where multiple methods are available to represent detailed and contact‐specific transmission and targeted control. However, detailed host and disease data needed to quantify these models are only available from a few outbreaks. To address existing challenges in data collection, novel data sources should be considered and integrated into models of FMDV transmission and control. We suggest modelling multiple endemic areas to advance local control and global control and better understand FMDV transmission dynamics. With incorporation of additional data, models can assist with both the design of targeted control and identification of transmission drivers across geographic boundaries.     

Review: Evaluation of Foot‐and‐Mouth Disease Control Using Fault Tree Analysis

An outbreak of foot‐and‐mouth disease (FMD) causes huge economic losses and animal welfare problems. Although much can be learnt from past FMD outbreaks, several countries are not satisfied with their degree of contingency planning and aiming at more assurance that their control measures will be effective. The purpose of the present article was to develop a generic fault tree framework for the control of an FMD outbreak as a basis for systematic improvement and refinement of control activities and general preparedness. Fault trees are typically used in engineering to document pathways that can lead to an undesired event, that is, ineffective FMD control. The fault tree method allows risk managers to identify immature parts of the control system and to analyse the events or steps that will most probably delay rapid and effective disease control during a real outbreak. The present developed fault tree is generic and can be tailored to fit the specific needs of countries. For instance, the specific fault tree for the 2001 FMD outbreak in the UK was refined based on control weaknesses discussed in peer‐reviewed articles. Furthermore, the specific fault tree based on the 2001 outbreak was applied to the subsequent FMD outbreak in 2007 to assess the refinement of control measures following the earlier, major outbreak. The FMD fault tree can assist risk managers to develop more refined and adequate control activities against FMD outbreaks and to find optimum strategies for rapid control. Further application using the current tree will be one of the basic measures for FMD control worldwide.     

Epidemiology of the 2010 Outbreak of Foot‐and‐Mouth Disease in Mongolia

Foot‐and‐mouth disease (FMD) occurred in five provinces and 24 counties as part of the FMD incursion into Mongolia during 2010. The first detection occurred on 21 April 2010 (confirmed 26 April 2010) with the last detection occurring approximately 8 months later on 13 December 2010. The number of livestock detected in the spring phase of the outbreak was 323 cattle and in the summer phase was 13 485 sheep, 6748 cattle, 5692 goats and 10 camels (total livestock summer phase = 25 935; for spring and summer phases combined = 26 258). Infection of livestock was confirmed by PCR for each affected county but not necessarily for every outbreak cluster involving more than one herder. It is likely that the summer phase of the outbreak was a continuation of the spring event. In the summer phase, the spatio‐temporal pattern of spread suggested an extension of infection from the main cluster in the Sukhbaatar county. There was also a number of long‐distance clusters established. The relative importance of spread by three potential pathways of gazelle, livestock, animal product and fomite movements has not been determined and will require further study. The estimated dissemination ratio (EDR) did not provide evidence of high rate of transmission of infection between herders; however, the data are limited by the quality of surveillance and the method of calculation which used the date of detection rather than the date of infection.     

Outbreaks of Foot‐and‐Mouth Disease in Libya and Saudi Arabia During 2013 Due to an Exotic O/ME‐SA/Ind‐2001 Lineage Virus

Foot‐and‐mouth disease viruses are often restricted to specific geographical regions and spread to new areas may lead to significant epidemics. Phylogenetic analysis of sequences of the VP1 genome region of recent outbreak viruses from Libya and Saudi Arabia has revealed a lineage, O‐Ind‐2001, normally found in the Indian subcontinent. This paper describes the characterization of field viruses collected from these cases and provides information about a new real‐time RT‐PCR assay that can be used to detect viruses from this lineage and discriminate them from other endemic FMD viruses that are co‐circulating in North Africa and western Eurasia.     

Serotype Specificity of Antibodies against Foot‐and‐Mouth Disease Virus in Cattle in Selected Districts in Uganda

Uganda had an unusually large number of foot‐and‐mouth disease (FMD) outbreaks in 2006, and all clinical reports were in cattle. A serological investigation was carried out to confirm circulating antibodies against foot‐and‐mouth disease virus (FMDV) by ELISA for antibodies against non‐structural proteins and structural proteins. Three hundred and forty‐nine cattle sera were collected from seven districts in Uganda, and 65% of these were found positive for antibodies against the non‐structural proteins of FMDV. A subset of these samples were analysed for serotype specificity of the identified antibodies. High prevalences of antibodies against non‐structural proteins and structural proteins of FMDV serotype O were demonstrated in herds with typical visible clinical signs of FMD, while prevalences were low in herds without clinical signs of FMD. Antibody titres were higher against serotype O than against serotypes SAT 1, SAT 2 and SAT 3 in the sera investigated for serotype‐specific antibodies. Only FMDV serotype O virus was isolated from one probang sample. This study shows that the majority of the FMD outbreaks in 2006 in the region studied were caused by FMDV serotype O; however, there was also evidence of antibodies to both SAT 1 and SAT 3 in one outbreak in a herd inside Queen Elizabeth national park area.