Inferring Mycobacterium bovis transmission between cattle and badgers using isolates from the Randomised Badger Culling Trial.

Mycobacterium bovis (M. bovis) is a causative agent of bovine tuberculosis, a significant source of morbidity and mortality in the global cattle industry. The Randomised Badger Culling Trial was a field experiment carried out between 1998 and 2005 in the South West of England. As part of this trial, M. bovis isolates were collected from contemporaneous and overlapping populations of badgers and cattle within ten defined trial areas. We combined whole genome sequences from 1,442 isolates with location and cattle movement data, identifying transmission clusters and inferred rates and routes of transmission of M. bovis. Most trial areas contained a single transmission cluster that had been established shortly before sampling, often contemporaneous with the expansion of bovine tuberculosis in the 1980s. The estimated rate of transmission from badger to cattle was approximately two times higher than from cattle to badger, and the rate of within-species transmission considerably exceeded these for both species. We identified long distance transmission events linked to cattle movement, recurrence of herd breakdown by infection within the same transmission clusters and superspreader events driven by cattle but not badgers. Overall, our data suggests that the transmission clusters in different parts of South West England that are still evident today were established by long-distance seeding events involving cattle movement, not by recrudescence from a long-established wildlife reservoir. Clusters are maintained primarily by within-species transmission, with less frequent spill-over both from badger to cattle and cattle to badger.

Risk factors and variations in detection of new bovine tuberculosis breakdowns via slaughterhouse surveillance in Great Britain.

Slaughterhouse surveillance through post-mortem meat inspection provides an important mechanism for detecting bovine tuberculosis (bTB) infections in cattle herds in Great Britain (GB), complementary to the live animal skin test based programme. We explore patterns in the numbers of herd breakdowns detected through slaughterhouse surveillance and develop a Bayesian hierarchical regression model to assess the associations of animal-level factors with the odds of an infected animal being detected in the slaughterhouse, allowing us to highlight slaughterhouses that show atypical patterns of detection. The analyses demonstrate that the numbers and proportions of breakdowns detected in slaughterhouses increased in GB over the period of study (1998-2013). The odds of an animal being a slaughterhouse case was strongly associated with the region of the country that the animal spent most of its life, with animals living in high-frequency testing areas of England having on average 21 times the odds of detection compared to animals living in Scotland. There was also a strong effect of age, with animals slaughtered at > 60 months of age having 5.3 times the odds of detection compared to animals slaughtered between 0-18 months of age. Smaller effects were observed for cattle having spent time on farms with a history of bTB, quarter of the year that the animal was slaughtered, movement and test history. Over-and-above these risks, the odds of detection increased by a factor of 1.1 for each year of the study. After adjustment for these variables, there were additional variations in risk between slaughterhouses and breed. Our framework has been adopted into the routine annual surveillance reporting carried out by the Animal Plant Health Agency and may be used to target more detailed investigation of meat inspection practices.

Potential benefits of cattle vaccination as a supplementary control for bovine tuberculosis.

Vaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette-Guérin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers' willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post-mortem detection.

The effect of badger culling on breakdown prolongation and recurrence of bovine tuberculosis in cattle herds in Great Britain.

Bovine tuberculosis is endemic in cattle herds in Great Britain, with a substantial economic impact. A reservoir of Mycobacterium bovis within the Eurasian badger (Meles meles) population is thought to have hindered disease control. Cattle herd incidents, termed breakdowns, that are either 'prolonged' (lasting ≥ 240 days) or 'recurrent' (with another breakdown within a specified time period) may be important foci for onward spread of infection. They drain veterinary resources and can be demoralising for farmers. Randomised Badger Culling Trial (RBCT) data were re-analysed to examine the effects of two culling strategies on breakdown prolongation and recurrence, during and after culling, using a Bayesian hierarchical model. Separate effect estimates were obtained for the 'core' trial areas (where culling occurred) and the 'buffer' zones (up to 2 km outside of the core areas). For breakdowns that started during the culling period, 'reactive' (localised) culling was associated with marginally increased odds of prolongation, with an odds ratio (OR) of 1.7 (95% credible interval [CI] 1.1-2.4) within the core areas. This effect was not present after the culling ceased. There was no notable effect of 'proactive' culling on prolongation. In contrast, reactive culling had no effect on breakdown recurrence, though there was evidence of a reduced risk of recurrence in proactive core areas during the culling period (ORs and 95% CIs: 0.82 (0.64-1.0) and 0.69 (0.54-0.86) for 24- and 36-month recurrence respectively). Again these effects were not present after the culling ceased. There seemed to be no effect of culling on breakdown prolongation or recurrence in the buffer zones. These results suggest that the RBCT badger culling strategies are unlikely to reduce either the prolongation or recurrence of breakdowns in the long term, and that reactive strategies (such as employed during the RBCT) are, if anything, likely to impact detrimentally on breakdown persistence.

Estimating the hidden burden of bovine tuberculosis in Great Britain.

The number of cattle herds placed under movement restrictions in Great Britain (GB) due to the suspected presence of bovine tuberculosis (bTB) has progressively increased over the past 25 years despite an intensive and costly test-and-slaughter control program. Around 38% of herds that clear movement restrictions experience a recurrent incident (breakdown) within 24 months, suggesting that infection may be persisting within herds. Reactivity to tuberculin, the basis of diagnostic testing, is dependent on the time from infection. Thus, testing efficiency varies between outbreaks, depending on weight of transmission and cannot be directly estimated. In this paper, we use Approximate Bayesian Computation (ABC) to parameterize two within-herd transmission models within a rigorous inferential framework. Previous within-herd models of bTB have relied on ad-hoc methods of parameterization and used a single model structure (SORI) where animals are assumed to become detectable by testing before they become infectious. We study such a conventional within-herd model of bTB and an alternative model, motivated by recent animal challenge studies, where there is no period of epidemiological latency before animals become infectious (SOR). Under both models we estimate that cattle-to-cattle transmission rates are non-linearly density dependent. The basic reproductive ratio for our conventional within-herd model, estimated for scenarios with no statutory controls, increases from 1.5 (0.26-4.9; 95% CI) in a herd of 30 cattle up to 4.9 (0.99-14.0) in a herd of 400. Under this model we estimate that 50% (33-67) of recurrent breakdowns in Britain can be attributed to infection missed by tuberculin testing. However this figure falls to 24% (11-42) of recurrent breakdowns under our alternative model. Under both models the estimated extrinsic force of infection increases with the burden of missed infection. Hence, improved herd-level testing is unlikely to reduce recurrence unless this extrinsic infectious pressure is simultaneously addressed.

Estimation of the relative sensitivity of the comparative tuberculin skin test in tuberculous cattle herds subjected to depopulation.

Bovine tuberculosis (bTB) is one of the most serious economic animal health problems affecting the cattle industry in Great Britain (GB), with incidence in cattle herds increasing since the mid-1980s. The single intradermal comparative cervical tuberculin (SICCT) test is the primary screening test in the bTB surveillance and control programme in GB and Ireland. The sensitivity (ability to detect infected cattle) of this test is central to the efficacy of the current testing regime, but most previous studies that have estimated test sensitivity (relative to the number of slaughtered cattle with visible lesions [VL] and/or positive culture results) lacked post-mortem data for SICCT test-negative cattle. The slaughter of entire herds ("whole herd slaughters" or "depopulations") that are infected by bTB are occasionally conducted in GB as a last-resort control measure to resolve intractable bTB herd breakdowns. These provide additional post-mortem data for SICCT test-negative cattle, allowing a rare opportunity to calculate the animal-level sensitivity of the test relative to the total number of SICCT test-positive and negative VL animals identified post-mortem (rSe). In this study, data were analysed from 16 whole herd slaughters (748 SICCT test-positive and 1031 SICCT test-negative cattle) conducted in GB between 1988 and 2010, using a bayesian hierarchical model. The overall rSe estimate of the SICCT test at the severe interpretation was 85% (95% credible interval [CI]: 78-91%), and at standard interpretation was 81% (95% CI: 70-89%). These estimates are more robust than those previously reported in GB due to inclusion of post-mortem data from SICCT test-negative cattle.

Estimates for local and movement-based transmission of bovine tuberculosis in British cattle.

Both badgers and livestock movements have been implicated in contributing to the ongoing epidemic of bovine tuberculosis (BTB) in British cattle. However, the relative contributions of these and other causes are not well quantified. We used cattle movement data to construct an individual (premises)-based model of BTB spread within Great Britain, accounting for spread due to recorded cattle movements and other causes. Outbreak data for 2004 were best explained by a model attributing 16% of herd infections directly to cattle movements, and a further 9% unexplained, potentially including spread from unrecorded movements. The best-fit model assumed low levels of cattle-to-cattle transmission. The remaining 75% of infection was attributed to local effects within specific high-risk areas. Annual and biennial testing is mandatory for herds deemed at high risk of infection, as is pre-movement testing from such herds. The herds identified as high risk in 2004 by our model are in broad agreement with those officially designated as such at that time. However, border areas at the edges of high-risk regions are different, suggesting possible areas that should be targeted to prevent further geographical spread of disease. With these areas expanding rapidly over the last decade, their close surveillance is important to both identify infected herds qucikly, and limit their further growth.