Understanding foot-and-mouth disease virus transmission biology: identification of the indicators of infectiousness.

The control of foot-and-mouth disease virus (FMDV) outbreaks in non-endemic countries relies on the rapid detection and removal of infected animals. In this paper we use the observed relationship between the onset of clinical signs and direct contact transmission of FMDV to identify predictors for the onset of clinical signs and identify possible approaches to preclinical screening in the field. Threshold levels for various virological and immunological variables were determined using Receiver Operating Characteristic (ROC) curve analysis and then tested using generalized linear mixed models to determine their ability to predict the onset of clinical signs. In addition, concordance statistics between qualitative real time PCR test results and virus isolation results were evaluated. For the majority of animals (71%), the onset of clinical signs occurred 3-4 days post infection. The onset of clinical signs was associated with high levels of virus in the blood, oropharyngeal fluid and nasal fluid. Virus is first detectable in the oropharyngeal fluid, but detection of virus in the blood and nasal fluid may also be good candidates for preclinical indicators. Detection of virus in the air was also significantly associated with transmission. This study is the first to identify statistically significant indicators of infectiousness for FMDV at defined time periods during disease progression in a natural host species. Identifying factors associated with infectiousness will advance our understanding of transmission mechanisms and refine intra-herd and inter-herd disease transmission models.

The performance of approximations of farm contiguity compared to contiguity defined using detailed geographical information in two sample areas in Scotland: implications for foot-and-mouth disease modelling.

BACKGROUND: When modelling infectious diseases, accurately capturing the pattern of dissemination through space is key to providing optimal recommendations for control. Mathematical models of disease spread in livestock, such as for foot-and-mouth disease (FMD), have done this by incorporating a transmission kernel which describes the decay in transmission rate with increasing Euclidean distance from an infected premises (IP). However, this assumes a homogenous landscape, and is based on the distance between point locations of farms. Indeed, underlying the spatial pattern of spread are the contact networks involved in transmission. Accordingly, area-weighted tessellation around farm point locations has been used to approximate field-contiguity and simulate the effect of contiguous premises (CP) culling for FMD. Here, geographic data were used to determine contiguity based on distance between premises' fields and presence of landscape features for two sample areas in Scotland. Sensitivity, positive predictive value, and the True Skill Statistic (TSS) were calculated to determine how point distance measures and area-weighted tessellation compared to the 'gold standard' of the map-based measures in identifying CPs. In addition, the mean degree and density of the different contact networks were calculated. RESULTS: Utilising point distances <1 km and <5 km as a measure for contiguity resulted in poor discrimination between map-based CPs/non-CPs (TSS 0.279-0.344 and 0.385-0.400, respectively). Point distance <1 km missed a high proportion of map-based CPs; <5 km point distance picked up a high proportion of map-based non-CPs as CPs. Area-weighted tessellation performed best, with reasonable discrimination between map-based CPs/non-CPs (TSS 0.617-0.737) and comparable mean degree and density. Landscape features altered network properties considerably when taken into account. CONCLUSION: The farming landscape is not homogeneous. Basing contiguity on geographic locations of field boundaries and including landscape features known to affect transmission into FMD models are likely to improve individual farm-level accuracy of spatial predictions in the event of future outbreaks. If a substantial proportion of FMD transmission events are by contiguous spread, and CPs should be assigned an elevated relative transmission rate, the shape of the kernel could be significantly altered since ability to discriminate between map-based CPs and non-CPs is different over different Euclidean distances.

Optimal reactive vaccination strategies for a foot-and-mouth outbreak in the UK.

Foot-and-mouth disease (FMD) in the UK provides an ideal opportunity to explore optimal control measures for an infectious disease. The presence of fine-scale spatio-temporal data for the 2001 epidemic has allowed the development of epidemiological models that are more accurate than those generally created for other epidemics and provide the opportunity to explore a variety of alternative control measures. Vaccination was not used during the 2001 epidemic; however, the recent DEFRA (Department for Environment Food and Rural Affairs) contingency plan details how reactive vaccination would be considered in future. Here, using the data from the 2001 epidemic, we consider the optimal deployment of limited vaccination capacity in a complex heterogeneous environment. We use a model of FMD spread to investigate the optimal deployment of reactive ring vaccination of cattle constrained by logistical resources. The predicted optimal ring size is highly dependent upon logistical constraints but is more robust to epidemiological parameters. Other ways of targeting reactive vaccination can significantly reduce the epidemic size; in particular, ignoring the order in which infections are reported and vaccinating those farms closest to any previously reported case can substantially reduce the epidemic. This strategy has the advantage that it rapidly targets new foci of infection and that determining an optimal ring size is unnecessary.

INFERENCE FOR INDIVIDUAL-LEVEL MODELS OF INFECTIOUS DISEASES IN LARGE POPULATIONS.

Individual Level Models (ILMs), a new class of models, are being applied to infectious epidemic data to aid in the understanding of the spatio-temporal dynamics of infectious diseases. These models are highly flexible and intuitive, and can be parameterised under a Bayesian framework via Markov chain Monte Carlo (MCMC) methods. Unfortunately, this parameterisation can be difficult to implement due to intense computational requirements when calculating the full posterior for large, or even moderately large, susceptible populations, or when missing data are present. Here we detail a methodology that can be used to estimate parameters for such large, and/or incomplete, data sets. This is done in the context of a study of the UK 2001 foot-and-mouth disease (FMD) epidemic.

The role of pre-emptive culling in the control of foot-and-mouth disease.

The 2001 foot-and-mouth disease epidemic was controlled by culling of infectious premises and pre-emptive culling intended to limit the spread of disease. Of the control strategies adopted, routine culling of farms that were contiguous to infected premises caused the most controversy. Here we perform a retrospective analysis of the culling of contiguous premises as performed in 2001 and a simulation study of the effects of this policy on reducing the number of farms affected by disease. Our simulation results support previous studies and show that a national policy of contiguous premises (CPs) culling leads to fewer farms losing livestock. The optimal national policy for controlling the 2001 epidemic is found to be the targeting of all contiguous premises, whereas for localized outbreaks in high animal density regions, more extensive fixed radius ring culling is optimal. Analysis of the 2001 data suggests that the lowest-risk CPs were generally prioritized for culling, however, even in this case, the policy is predicted to be effective. A sensitivity analysis and the development of a spatially heterogeneous policy show that the optimal culling level depends upon the basic reproductive ratio of the infection and the width of the dispersal kernel. These analyses highlight an important and probably quite general result: optimal control is highly dependent upon the distance over which the pathogen can be transmitted, the transmission rate of infection and local demography where the disease is introduced.

Accuracy of models for the 2001 foot-and-mouth epidemic.

Since 2001 models of the spread of foot-and-mouth disease, supported by the data from the UK epidemic, have been expounded as some of the best examples of problem-driven epidemic models. These claims are generally based on a comparison between model results and epidemic data at fairly coarse spatio-temporal resolution. Here, we focus on a comparison between model and data at the individual farm level, assessing the potential of the model to predict the infectious status of farms in both the short and long terms. Although the accuracy with which the model predicts farms reporting infection is between 5 and 15%, these low levels are attributable to the expected level of variation between epidemics, and are comparable to the agreement between two independent model simulations. By contrast, while the accuracy of predicting culls is higher (20-30%), this is lower than expected from the comparison between model epidemics. These results generally support the contention that the type of the model used in 2001 was a reliable representation of the epidemic process, but highlight the difficulties of predicting the complex human response, in terms of control strategies to the perceived epidemic risk.

Geographic and topographic determinants of local FMD transmission applied to the 2001 UK FMD epidemic.

BACKGROUND: Models of Foot and Mouth Disease (FMD) transmission have assumed a homogeneous landscape across which Euclidean distance is a suitable measure of the spatial dependency of transmission. This paper investigated features of the landscape and their impact on transmission during the period of predominantly local spread which followed the implementation of the national movement ban during the 2001 UK FMD epidemic. In this study 113 farms diagnosed with FMD which had a known source of infection within 3 km (cases) were matched to 188 control farms which were either uninfected or infected at a later timepoint. Cases were matched to controls by Euclidean distance to the source of infection and farm size. Intervening geographical features and connectivity between the source of infection and case and controls were compared. RESULTS: Road distance between holdings, access to holdings, presence of forest, elevation change between holdings and the presence of intervening roads had no impact on the risk of local FMD transmission (p > 0.2). However the presence of linear features in the form of rivers and railways acted as barriers to FMD transmission (odds ratio = 0.507, 95% CIs = 0.297,0.887, p = 0.018). CONCLUSION: This paper demonstrated that although FMD spread can generally be modelled using Euclidean distance and numbers of animals on susceptible holdings, the presence of rivers and railways has an additional protective effect reducing the probability of transmission between holdings.

Effect of data quality on estimates of farm infectiousness trends in the UK 2001 foot-and-mouth disease epidemic.

Most of the mathematical models that were developed to study the UK 2001 foot-and-mouth disease epidemic assumed that the infectiousness of infected premises was constant over their infectious periods. However, there is some controversy over whether this assumption is appropriate. Uncertainty about which farm infected which in 2001 means that the only method to determine if there were trends in farm infectiousness is the fitting of mechanistic mathematical models to the epidemic data. The parameter values that are estimated using this technique, however, may be influenced by missing and inaccurate data. In particular to the UK 2001 epidemic, this includes unreported infectives, inaccurate farm infection dates and unknown farm latent periods. Here, we show that such data degradation prevents successful determination of trends in farm infectiousness.

Topographic determinants of foot and mouth disease transmission in the UK 2001 epidemic.

BACKGROUND: A key challenge for modelling infectious disease dynamics is to understand the spatial spread of infection in real landscapes. This ideally requires a parallel record of spatial epidemic spread and a detailed map of susceptible host density along with relevant transport links and geographical features. RESULTS: Here we analyse the most detailed such data to date arising from the UK 2001 foot and mouth epidemic. We show that Euclidean distance between infectious and susceptible premises is a better predictor of transmission risk than shortest and quickest routes via road, except where major geographical features intervene. CONCLUSION: Thus, a simple spatial transmission kernel based on Euclidean distance suffices in most regions, probably reflecting the multiplicity of transmission routes during the epidemic.

Reconstructing geographical movements and host species transitions of foot-and-mouth disease virus serotype SAT 2.

UNLABELLED: Of the three foot-and-mouth-disease virus SAT serotypes mainly confined to sub-Saharan Africa, SAT 2 is the strain most often recorded in domestic animals and has caused outbreaks in North Africa and the Middle East six times in the last 25 years, with three apparently separate events occurring in 2012. This study updates the picture of SAT 2 phylogenetics by using all available sequences for the VP1 section of the genome available at the time of writing and uses phylogeographic methods to trace the origin of all outbreaks occurring north of the Sahara since 1990 and identify patterns of spread among countries of endemicity. Transitions between different host species are also enumerated. Outbreaks in North Africa appear to have origins in countries immediately south of the Sahara, whereas those in the Middle East are more often from East Africa. The results of the analysis of spread within sub-Saharan Africa are consistent with it being driven by relatively short-distance movements of animals across national borders, and the analysis of host species transitions supports the role of the African buffalo (Syncerus caffer) as an important natural reservoir. IMPORTANCE: Foot-and-mouth disease virus is a livestock pathogen of major economic importance, with seven distinct serotypes occurring globally. The SAT 2 serotype, endemic in sub-Saharan Africa, has caused a number of outbreaks in North Africa and the Middle East during the last decades, including three separate incidents in 2012. A comprehensive analysis of all available RNA sequences for SAT 2 has not been published for some years. In this work, we performed this analysis using all previously published sequences and 49 newly determined examples. We also used phylogenetic methods to infer the source country for all outbreaks occurring outside sub-Saharan Africa since 1990 and to reconstruct the spread of viral lineages between countries where it is endemic and movements between different host species.

Vaccination against foot-and-mouth disease: do initial conditions affect its benefit?

When facing incursion of a major livestock infectious disease, the decision to implement a vaccination programme is made at the national level. To make this decision, governments must consider whether the benefits of vaccination are sufficient to outweigh potential additional costs, including further trade restrictions that may be imposed due to the implementation of vaccination. However, little consensus exists on the factors triggering its implementation on the field. This work explores the effect of several triggers in the implementation of a reactive vaccination-to-live policy when facing epidemics of foot-and-mouth disease. In particular, we tested whether changes in the location of the incursion and the delay of implementation would affect the epidemiological benefit of such a policy in the context of Scotland. To reach this goal, we used a spatial, premises-based model that has been extensively used to investigate the effectiveness of mitigation procedures in Great Britain. The results show that the decision to vaccinate, or not, is not straightforward and strongly depends on the underlying local structure of the population-at-risk. With regards to disease incursion preparedness, simply identifying areas of highest population density may not capture all complexities that may influence the spread of disease as well as the benefit of implementing vaccination. However, if a decision to vaccinate is made, we show that delaying its implementation in the field may markedly reduce its benefit. This work provides guidelines to support policy makers in their decision to implement, or not, a vaccination-to-live policy when facing epidemics of infectious livestock disease.

Modelling the within-host dynamics of the foot-and-mouth disease virus in cattle.

In this paper we investigate the within-host dynamics of the foot-and-mouth disease virus (FMDV) in cattle using previously published data for 8 experimentally infected cows. An 8-compartment, 14-parameter differential equation model was fitted to data collected from each cow every 24 h over the course of an infection on: (i) the concentration of FMDV genomes in the blood, (ii) the concentration of infectious virus in the blood, (iii) antibody levels, and (iv) interferon levels. Model parameters were estimated using maximum-likelihood methods. The likelihood surface was sampled using Markov chain Monte Carlo methods giving credible intervals for each of the model parameters. The model was able to capture the within-host dynamics well for 6 of the infections, with both the innate (type 1 interferon) and antibody responses playing key roles in determining the height and duration of peak levels of virus. There was considerable variation between virus dynamics in individual cattle which was only partly accounted for by inferred differences in the dose of virus received. A better understanding of the within-host dynamics also provides insights into the dynamics of infectiousness and the transmission of virus to new hosts.

Risk-targeted selection of agricultural holdings for post-epidemic surveillance: estimation of efficiency gains.

Current post-epidemic sero-surveillance uses random selection of animal holdings. A better strategy may be to estimate the benefits gained by sampling each farm and use this to target selection. In this study we estimate the probability of undiscovered infection for sheep farms in Devon after the 2001 foot-and-mouth disease outbreak using the combination of a previously published model of daily infection risk and a simple model of probability of discovery of infection during the outbreak. This allows comparison of the system sensitivity (ability to detect infection in the area) of arbitrary, random sampling compared to risk-targeted selection across a full range of sampling budgets. We show that it is possible to achieve 95% system sensitivity by sampling, on average, 945 farms with random sampling and 184 farms with risk-targeted sampling. We also examine the effect of ordering samples by risk to expedite return to a disease-free status. Risk ordering the sampling process results in detection of positive farms, if present, 15.6 days sooner than with randomly ordered sampling, assuming 50 farms are tested per day.

Relationship between clinical signs and transmission of an infectious disease and the implications for control.

Control of many infectious diseases relies on the detection of clinical cases and the isolation, removal, or treatment of cases and their contacts. The success of such "reactive" strategies is influenced by the fraction of transmission occurring before signs appear. We performed experimental studies of foot-and-mouth disease transmission in cattle and estimated this fraction at less than half the value expected from detecting virus in body fluids, the standard proxy measure of infectiousness. This is because the infectious period is shorter (mean 1.7 days) than currently realized, and animals are not infectious until, on average, 0.5 days after clinical signs appear. These results imply that controversial preemptive control measures may be unnecessary; instead, efforts should be directed at early detection of infection and rapid intervention.

Estimating risk factors for farm-level transmission of disease: foot and mouth disease during the 2001 epidemic in Great Britain.

Controlling an epidemic would be aided by establishing whether particular individuals in infected populations are more likely to transmit infection. However, few analyses have characterised such individuals. Such analyses require both data on who infected whom and on the likely determinants of transmission; data that are available at the farm level for the 2001 Foot and Mouth Disease epidemic in Great Britain. Using these data a putative number of daughter infected premises (IPs) resulting from each IP was calculated where these daughters were within 3km of the IP. A set of possible epidemiological, demographic, spatial and temporal risk factors were analysed, with the final multivariate generalised linear model (Poisson error term) having 6 statistically significant (p<0.05) main effects including geographic area, local cattle and sheep densities, and the number of non-IP culls. This model demonstrates that farms are heterogeneous in their propensity to transmit infection to other farms and, importantly, that it may be possible to identify holdings that are at high risk of spreading disease a priori. Such information could be used to help prioritise the response to an epidemic.

Statistical modeling of holding level susceptibility to infection during the 2001 foot and mouth disease epidemic in Great Britain.

BACKGROUND: An understanding of the factors that determine the risk of members of a susceptible population becoming infected is essential for estimating the potential for disease spread, as opposed to just focusing on transmission from an infected population. Furthermore, analysis of the risk factors can reveal important characteristics of an epidemic and further develop understanding of the processes operating. METHODS: This paper describes the development of a mixed effects logistic regression model of susceptibility of holdings to foot and mouth disease (FMD) during the 2001 epidemic in Great Britain following the imposition of a national ban on the movements of susceptible animals (NMB). RESULTS: The principal risk factors identified in the model were shorter distances to the nearest infectious seed (a holding infected before the NMB) and the county of the holding (principally Cumbria). Additional risk factors included holdings that are mixed species rather than single species, the surface area of the holding, and the number of cattle within 10km (all p<0.001), but not surrounding sheep densities (p>0.1). The fit of the model was evaluated using the area under the receiver operator characteristic curve (ROC) and the Hosmer and Lemeshow Chi-squared statistic; the fit was good with both tests (area under the ROC=0.962 and Hosmer and Lemeshow Chi-squared statistic=49.98 (p>0.1)). CONCLUSIONS: Holdings at greatest risk of infection can be identified using simple readily available risk factors; this information could be employed in the control of future FMD epidemics.

Serial passage of foot-and-mouth disease virus in sheep reveals declining levels of viraemia over time.

If an infectious agent is to maintain itself within a closed population by means of an unbroken serial chain of infections, it must maintain the level of infectiousness of individuals through time, or termination of the transmission chain is inevitable. One possible cause of diminution in infectiousness along serial chains of transmission may be that individuals are unable to amplify and transmit comparable levels of the infectious agent. Here, the results are reported of a novel experiment designed specifically to assess the effects of serial passage of foot-and-mouth disease virus (FMDV) in experimental groups of sheep. A virus isolate taken from an epidemic of foot-and-mouth disease (FMD) characterized by rapid fade-out of infection was passed serially through four groups of sheep housed in an isolation unit. Although it was not possible to measure individual infectiousness directly, blood virus load from infected individuals was quantified using a real-time PCR assay and used as an underlying indicator of the level of infection. The results of this assay concurred well with those of the traditional tissue-culture assay and were shown to be highly repeatable. The level of peak viraemia was shown to fall significantly with the time of infection and with passage group, both in terms of the group mean and regression analysis of individual values, suggesting that this isolate of FMDV may, under certain conditions, be unable to maintain itself indefinitely in susceptible sheep populations. The results of these experiments are discussed in terms of the epidemiology of FMD in sheep.