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In Ireland, the interferon-gamma (IFN-γ) assay is routinely used as an ancillary test interpreted in parallel with the single intradermal comparative tuberculin test (SICTT) to maximize the detection of bovine tuberculosis (bTB) infected animals. Up until 2018, a positive test result was recorded in the IFN-γ ELISA assay following whole blood stimulation with purified protein derivative (PPD)-bovine (B), PPD-avian (A) and nil sample (N), using the interpretation criteria, B-N > 50 optical density units (OD), B > 100 and B-A > 0. Following a review of available data, the threshold of the B-A component changed to B-A > 80. As predicting the impact of changing the cut-off thresholds for the IFN-γ test de novo is challenging, the aims of this study were to follow animals that initially tested negative using the new IFN-γ assay interpretation criteria and investigate their future risk of disclosure with bTB, with a focus on animals that otherwise would have been removed when using the older interpretation criteria (0 < B-A ≤ 80). Enrolled animals (n = 28,669 cattle from 527 herds) were followed up for two years (2019-2021), or to point of bTB detection or death. At the end of follow-up, 1151 (4.0%) of enrolled animals were bTB cases. The majority of these cases were diagnosed using SICTT (80.5%). The cumulative number of positive animals that would have been removed if the old cut-off (0 < B-A ≤ 80) was used amounted to 1680 cattle (5.9% of the enrolled cohort). Of these, 127 (7.5%) were diagnosed with bTB during follow-up. In contrast, 1024 of the 1151 cattle which subsequently tested positive during the study period following a negative IFN-γ test would not have been identified with the old or new IFN-γ cut-off criteria. Survival analysis showed that animals that would have been removed under the old interpretation criteria were at increased risk of a positive diagnosis with bTB during follow-up compared to other test negative animals. A newly developed risk prediction model (using a Cox proportional hazard model) showed that age, animal number of SICTT tests, number of inconclusive SICTT tests, B-A (IFN-γ assay), B-N (IFN-γ assay), animals from store herds and the percentage of the rest of the herd that were positive during the breakdown were statistically significantly associated with bTB detection. However, inclusion of the IFN-γ OD variables did not show added value in terms of prediction performance of the model., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bovine tuberculosis, caused by Mycobacterium bovis (M. bovis), is a globally distributed chronic disease of animals. The bacteria can be transmitted to humans via the consumption of unpasteurised (raw) milk, thus representing an important public health risk. To investigate the risk of zoonotic transmission of M. bovis via raw milk, this study systematically reviewed published studies to estimate the prevalence of M. bovis in on-farm bulk-tank milk (BTM) and individual cow's milk (IM) by meta-analysis. In total, 1,339 articles were identified through seven electronic databases and initially screened using titles and abstracts. The quality of 108 potentially relevant articles was assessed using full texts, and 67 articles comprising 83 studies (76 IM and 7 BTM), were included in the meta-analysis. The prevalence of M. bovis in IM and BTM was summarised according to the diagnostic test used, and the tuberculin skin test (TST) infection status of the individual cows (for IM) or herds (for BTM). Heterogeneity was quantified using the I-squared statistic. Prediction intervals (95% PIs) were also estimated. For IM, the overall prevalence was summarised at 5% (95%CI: 3%-7%). In TST positive cows, prevalence was summarised at 8% (95%CI: 4%-13%). For BTM, the overall prevalence independent of individual herd TST infection status was summarised at 5% (95%CI: 0%-21%). There was considerable heterogeneity evident among the included studies, while PIs were also wide. Inconsistency in the quality of reporting was also observed resulting in missing information, such as the TST infection status of the individual animal/herd. No study reported the number of M. bovis bacteria in test-positive milk samples. Several studies reported the detection of M. tuberculosis and M. africanum in milk. Despite international efforts to control tuberculosis, this study highlights the risk of zoonotic transmission of M. bovis via unpasteurised milk and dairy products made using raw milk., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bovine tuberculosis (bTB) is a chronic infectious disease caused by Mycobacterium bovis which results in a significant economic cost to cattle industries and governments where it is endemic. In Ireland, the European badger is the main wildlife reservoir of infection. In this study, we investigated whether (motorway) road construction was associated with an increased risk of bTB in associated cattle herds. For this study, we considered three observation periods: pre-construction (2011-2014), construction (2015-2017) and post-construction (2018-2019). We selected 1543 herds situated, based on proximity, between >50 m and <5 km of the roadworks, and extracted information about their herd-size, herd-type, inward animal movements, bTB history, and distance to the roadworks. Generalized linear mixed models were performed, whose outcome were whether a herd experienced a bTB breakdown with ≥1 or ≥3 standard reactor/s, respectively. Herds located at a distance of >3 km from the roadworks were found to be at reduced risk of a bTB breakdown over the construction period compared with those situated within 1 km of the roadworks for ≥1 reactor/s (>3 km and construction vs. <1 km: OR: 0.595, 95 % Confidence Interval (CI): 0.354-0.999) or ≥3 reactors (>3 km and construction vs. <1 km: OR: 0.431, 95 % CI: 0.174-1.067). Other previously reported risk factors such as inward movements, herd-size and herd-type were also associated with bTB risk in the final models (≥1 reactor/s and ≥3 reactors). These findings appear to be consistent with bTB breakdowns being a consequence as opposed to coincident to road construction, given the temporal and spatial consistency of the evidence. The potential for badger social group disturbance leading to the spatial spread of infection to cattle herds, as previously described in the United Kingdom, could be a hypothetical mechanism to explain these findings. However, our findings are not consistent with previous Irish studies, including recent work from another road construction project, albeit running alongside and cross over an existing road rather than construction of a new road as in this case, or experiences from national targeted badger removal. Further research is warranted to verify this pattern occurs elsewhere, and the underlying biological mechanism. Until further data are available, we recommend that badgers are vaccinated, as a precautionary measure, in advance of the commencement of major roadworks., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A field trial was conducted to investigate the impact of oral vaccination of free-living badgers against natural-transmitted Mycobacterium bovis infection. For a period of three years badgers were captured over seven sweeps in three zones and assigned for oral vaccination with a lipid-encapsulated BCG vaccine (Liporale-BCG) or with placebo. Badgers enrolled in Zone A were administered placebo while all badgers enrolled in Zone C were vaccinated with BCG. Badgers enrolled in the middle area, Zone B, were randomly assigned 50:50 for treatment with vaccine or placebo. Treatment in each zone remained blinded until the end of the study period. The outcome of interest was incident cases of tuberculosis measured as time to seroconversion events using the BrockTB Stat-Pak lateral flow serology test, supplemented with post-mortem examination. Among the vaccinated badgers that seroconverted, the median time to seroconversion (413 days) was significantly longer (p = 0.04) when compared with non-vaccinated animals (230 days). Survival analysis (modelling time to seroconversion) revealed that there was a significant difference in the rate of seroconversion between vaccinated and non-vaccinated badgers in Zones A and C throughout the trial period (p = 0.015). For badgers enrolled during sweeps 1-2 the Vaccine Efficacy (VE) determined from hazard rate ratios was 36% (95% CI: -62%- 75%). For badgers enrolled in these zones during sweeps 3-6, the VE was 84% (95% CI: 29%- 97%). This indicated that VE increased with the level of vaccine coverage. Post-mortem examination of badgers at the end of the trial also revealed a significant difference in the proportion of animals presenting with M. bovis culture confirmed lesions in vaccinated Zone C (9%) compared with non-vaccinated Zone A (26%). These results demonstrate that oral BCG vaccination confers protection to badgers and could be used to reduce incident rates in tuberculosis-infected populations of badgers., Competing Interests: FEA is an Inventor on a patent related to the Liporale technology and is a Director on a company (Immune Solutions Ltd) which has a vested interest in commercializing Liporale as an oral delivery platform. Liporale is covered by the following pending patents and applications: “Antigenic Compositions” WIPO WO/2003/009868, PCT/NZ2002/00132, NZ 546141, AU 2002/326233, US 2004/0234533, EP 02760915.5, CA 2454920, ZA 2004/1211, CN 02817408.9, IN 00302/DELNP/2004, JP 2003-515260, HK 04109263.7. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

A long-term research programme has been underway in Ireland to evaluate the usefulness of badger vaccination as part of the national bTB (bovine tuberculosis) control strategy. This culminated in a field trial which commenced in county Kilkenny in 2009 to determine the effects of badger vaccination on Mycobacterium bovis transmission in badgers under field conditions. In the present study, we sought to optimise the characteristics of a multiplex chemiluminescent assay for detection of M. bovis infection in live badgers. Our goal was to maximise specificity, and therefore statistical power, during evaluation of the badger vaccine trial data. In addition, we also aimed to explore the effects of vaccination on test characteristics. For the test optimisation, we ran a stepwise logistic regression with analytical weights on the converted Relative Light Units (RLU) obtained from testing blood samples from 215 badgers captured as part of culling operations by the national Department of Agriculture, Food and the Marine (DAFM). The optimised test was applied to two other datasets obtained from two captive badger studies (Study 1 and Study 2), and the sensitivity and specificity of the test was attained separately for vaccinated and non-vaccinated badgers. During optimisation, test sensitivity was maximised (30.77%), while retaining specificity at 99.99%. When the optimised test was then applied to the captive badger studies data, we observed that test characteristics did not vary greatly between vaccinated and non-vaccinated badgers. However, a different time lag between infection and a positive test result was observed in vaccinated and non-vaccinated badgers. We propose that the optimized multiplex immunoassay be used to analyse the vaccine trial data. In relation to the difference in the time lag observed for vaccinated and non-vaccinated badgers, we also present a strategy to enable the test to be used during trial evaluation.

The gamma-interferon assay (IFNγ) is often used as an ancillary diagnostic test alongside the tuberculin skin test in order to detect Mycobacterium bovis infected cattle. The performance of the IFNγ test has been evaluated in many countries worldwide and wider usage as a disease surveillance tool is constrained due to the relatively low and inconsistent specificity at a herd and area level. This results in disclosure of a higher proportion of false positive reactors when compared with the skin test. In this study, we used cohorts of animals from low prevalence tuberculosis herds (n = 136) to assess a range of risk factors that might influence the specificity of the test. Univariate and multivariate logistic generalised estimating-equation (GEE) models were used to evaluate potential risk factors associated with a false positive IFNγ test result. In these herds, the univariate model revealed that the region of herd origin, the time of year when the testing was carried out, and the age of the animal were all significant risk factors. In the final multivariate models only animal age and region of herd origin were found to be significant risk factors. A high proportion of herds with multiple IFNγ false positive animals were located in one county, with evidence of within-herd clustering, suggesting a localised source of non-specific sensitization. Knowledge of the underlying factors influencing the IFNγ test specificity could be used to optimize the test performance in different disease level scenarios in order to reduce the disclosure rate of false positive reactors.

Local persistence of infection is a key feature of bovine tuberculosis (bTB) among cattle herds in the Republic of Ireland. The aim of this study was to determine the relative importance of 'neighbourhood', specifically farm-to-farm spread and spread from wildlife, in the persistence of bTB by investigating herds having a bTB episode in 2006. A case-control study was conducted on the association between the occurrence of a bTB episode in 2006 and the occurrence of bTB in previous years among neighbouring herd(s) within 1 km, while controlling for each herd's bTB history and other risk factors. Neighbouring herds were grouped into three zones, based on distance, and bTB incidence measures summarised within each zone and by calendar year (2001-2005). The incidence of bTB was associated with an increased animal incidence in two subsets of neighbouring herds: (i) herds directly contiguous during the previous 2 years (attributable fraction=0.20), and (ii) herds at a distance of >25 m in the previous year (attributable fraction=0.19). Other predictors of bTB in a herd in 2006 included the occurrence of a bTB episode within that herd in any of the previous 5 years, herd size, and the number of animals purchased at age greater than 12 months. An infected wildlife source best explains the existence of a "neighbouring herd risk" for bTB at distances greater than 25 m. Further studies will be necessary to determine to what extent neighbouring herd risk within 25 m may be confounded by the same wildlife (badger) source., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This paper reports changes in the cattle population and the incidence of bovine tuberculosis in the Republic of Korea between 1960 and 2007, and discusses potential factors contributing to the recently observed increase in disease incidence, particularly in beef cattle and deer. Although there have been ongoing refinements to the existing programme, further improvements in current strategies are needed, including surveillance of susceptible animal species, both domestic and wild, and ongoing surveillance of the human population., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Within the European Union (EU), detailed legislation has been developed for cattle, but not deer, to minimise disease risks associated with trade in animals and animal products. This legislation is expressed as input-based standards, providing a detailed outline of the activity required (for example, testing of animals and application of defined control measures), on the expectation that an adequate output (for example, confidence in freedom) will be achieved. Input-based standards are at odds with the increasing shift towards output-based standards, particularly in OIE rules governing international trade. In this paper, we define output-based standards to achieve and maintain freedom from tuberculosis (TB) in farmed deer, with reference to EU member states. After considering the probability of freedom achieved for cattle under existing EU legislation, we defined a 'free farmed deer holding' as one with a probability of freedom from infection of at least 99%. We then developed an epidemiological model of TB surveillance systems for deer holdings, incorporating different surveillance strategies, including combinations of diagnostic tests, and a variety of different scenarios relating to the potential for introduction of infection. A range of surveillance strategies were identified to achieve and maintain a free farmed deer holding, and worked examples are presented. The surveillance system sensitivity for varying combinations of screening and confirmatory tests in live animals, animals at slaughter and on-farm deaths is also presented. Using a single test at a single point in time, none of the TB tests routinely used in farmed deer is able to achieve an acceptable probability of TB freedom. If repeat testing were undertaken, an acceptable probability of TB freedom could be achieved, with differing combinations of the surveillance system sensitivity, frequency of testing and risk of introduction. The probability of introduction of infection through the importation of infected deer was influenced by the use of a pre-movement test (assumed 90% test sensitivity and negative test results), the TB prevalence in the source herd and the number of animals imported. A surveillance system sensitivity of at least 81% was achieved with different combinations of annual live animal surveillance and surveillance of animals at slaughter or on-farm deaths. This methodology has broad applicability and could also be extended to other diseases in both deer and other species with relevance to trade in animals and animal products.

Background: Infection of livestock with bovine tuberculosis (bTB; Mycobacterium bovis) is of major economical concern in many countries; approximately 15 000 to 20 000 cattle are infected per year in Ireland. The objective of this study was to quantify the genetic variation for bTB susceptibility in Irish dairy and beef cattle. Methods: A total of 105 914 cow, 56 904 heifer and 21 872 steer single intra-dermal comparative tuberculin test records (i.e., binary trait) collected from the years 2001 to 2010 from dairy and beef herds were included in the analysis. Only animal level data pertaining to periods of herd bTB infection were retained. Variance components for bTB were estimated using animal linear and threshold mixed models and co-variances were estimated using sire linear mixed models. Results: Using a linear model, the heritability for susceptibility to bTB in the entire dataset was 0.11 and ranged from 0.08 (heifers in dairy herds) to 0.19 (heifers in beef herds) among the sub-populations investigated. Differences in susceptibility to bTB between breeds were clearly evident. Estimates of genetic correlations for bTB susceptibility between animal types (i.e., cows, heifers, steers) were all positive (0.10 to 0.64), yet different from one. Furthermore, genetic correlations for bTB susceptibility between environments that differed in herd prevalence of bTB ranged from 0.06 to 0.86 and were all different from one. Conclusions: Genetic trends for bTB susceptibility observed in this study suggest a slight increase in genetic susceptibility to bTB in recent years. Since bTB is of economic importance and because all animals are routinely tested at least once annually in Ireland and some other countries, the presence of genetic variation for bTB susceptibility suggests that bTB susceptibility should be included in a national breeding program to halt possible deterioration in genetic susceptibility to bTB infection. [ABSTRACT FROM AUTHOR]

A long-term research programme has been underway in Ireland to evaluate the usefulness of badger vaccination as part of the national bTB (bovine tuberculosis) control strategy. This culminated in a field trial which commenced in county Kilkenny in 2009 to determine the effects of badger vaccination on Mycobacterium bovis transmission in badgers under field conditions. In the present study, we sought to optimise the characteristics of a multiplex chemiluminescent assay for detection of M. bovis infection in live badgers. Our goal was to maximise specificity, and therefore statistical power, during evaluation of the badger vaccine trial data. In addition, we also aimed to explore the effects of vaccination on test characteristics. For the test optimisation, we ran a stepwise logistic regression with analytical weights on the converted Relative Light Units (RLU) obtained from testing blood samples from 215 badgers captured as part of culling operations by the national Department of Agriculture, Food and the Marine (DAFM). The optimised test was applied to two other datasets obtained from two captive badger studies (Study 1 and Study 2), and the sensitivity and specificity of the test was attained separately for vaccinated and non-vaccinated badgers. During optimisation, test sensitivity was maximised (30.77%), while retaining specificity at 99.99%. When the optimised test was then applied to the captive badger studies data, we observed that test characteristics did not vary greatly between vaccinated and non-vaccinated badgers. However, a different time lag between infection and a positive test result was observed in vaccinated and non-vaccinated badgers. We propose that the optimized multiplex immunoassay be used to analyse the vaccine trial data. In relation to the difference in the time lag observed for vaccinated and non-vaccinated badgers, we also present a strategy to enable the test to be used during trial evaluation. [ABSTRACT FROM AUTHOR]

Background: Here, we jointly summarise scientific evidence for genetic variation in resistance to infection with Mycobacterium bovis, the primary agent of bovine tuberculosis (TB), provided by two recent and separate studies of Holstein-Friesian dairy cow populations in Great Britain (GB) and Ireland. Methods: The studies quantified genetic variation within archived data from field and abattoir surveillance control programmes within each country. These data included results from the single intradermal comparative tuberculin test (SICTT), abattoir inspection for TB lesions and laboratory confirmation of disease status. Threshold animal models were used to estimate variance components for responsiveness to the SICTT and abattoir confirmed M. bovis infection. The link functions between the observed 0/1 scale and the liability scale were the complementary log-log in the GB, and logit link function in the Irish population. Results and discussion: The estimated heritability of susceptibility to TB, as judged by responsiveness to the SICTT, was 0.16 (0.012) and 0.14 (0.025) in the GB and Irish populations, respectively. For abattoir or laboratory confirmation of infection, estimates were 0.18 (0.044) and 0.18 (0.041) from the GB and the Irish populations, respectively. Conclusions: Estimates were all significantly different from zero and indicate that exploitable variation exists among GB and Irish Holstein Friesian dairy cows for resistance to TB. Epidemiological analysis suggests that factors such as variation in exposure or imperfect sensitivity and specificity would have resulted in underestimation of the true values. [ABSTRACT FROM AUTHOR]

Abstract: A national programme to eradicate bovine tuberculosis commenced in Ireland in 1954. During the last 15–20 years, research has been conducted to address gaps in knowledge of disease epidemiology, to objectively evaluate alternative strategy options, and to critically assess the implementation of disease control strategies. This paper provides a review of scientific and policy advances in Ireland since 1988, relevant to the tuberculosis eradication programme in Ireland. There have been substantial advances in knowledge of aspects of disease epidemiology, relating to cattle-to-cattle transmission, the role of wildlife, transmission of infection from wildlife and methods to minimise wildlife-to-cattle transmission. Further, scientific advances have been made both in the detection and management of infected herds. With respect to policy, the paper describes current policy and policy advances in both the detection and management of infected herds, as well as current strategies to prevent herd breakdowns. The Irish programme is a useful example of science-informed policy in a national context. [Copyright &y& Elsevier]

This paper reports changes in the cattle population and the incidence of bovine tuberculosis in the Republic of Korea between 1960 and 2007, and discusses potential factors contributing to the recently observed increase in disease incidence, particularly in beef cattle and deer. Although there have been ongoing refinements to the existing programme, further improvements in current strategies are needed, including surveillance of susceptible animal species, both domestic and wild, and ongoing surveillance of the human population. [ABSTRACT FROM AUTHOR]

Abstract: The principal wildlife reservoir of Mycobacterium bovis in Ireland is the European badger. Studies in the Republic of Ireland (RoI) have shown that badgers culled in association with cattle herd tuberculosis breakdowns (focal culling) have a higher prevalence of infection than the badger population at large. This observation is one rationale for the medium term national strategy of focal badger culling. A vaccination strategy for the control of bovine tuberculosis (bTB) in badgers is a preferred long-term option. The Bacillus Calmette-Guérin (BCG) vaccine has been shown to decrease disease severity in captive badgers under controlled conditions. As the vaccine has been tested in a controlled environment with precise information on infection pressure, it cannot be assumed a priori that the effects of vaccination are similar in the wild, where other environmental and/or ecological factors prevail. For this reason we have designed a vaccine field trial to assess the impact of vaccination on the incidence of TB infection in a wild badger population. The selected study area for the vaccine trial (approximately 755 square kilometers) is divided into three zones each of which has similar characteristics in terms of size, number of main badger setts, cattle herds, cattle and land classification type. Three vaccination levels (100%, 50% and 0%) will be allocated to the three zones in a way that a gradient of vaccination coverage North to South is achieved. The middle zone (zone B) will be vaccinated at a 50% coverage but zone A and C will be randomly allocated with 100% or 0% vaccination coverage. Vaccination within zone B will be done randomly at individual badger level. The objective of this paper is to describe the design of a field tuberculosis vaccination trial for badgers, the epidemiological methods that were used to design the trial and the subsequent data analysis. The analysis will enable us to quantify the magnitude of the observed vaccination effect on M. bovis transmission in badgers under field conditions and to improve our knowledge of the biological effects of vaccination on susceptibility and infectiousness. [Copyright &y& Elsevier]

Abstract: There is a good understanding of factors associated with bovine tuberculosis (BTB) risk in Irish herds. As yet, however, this knowledge has not been incorporated into predictive models with the potential for improved, risk-based surveillance. The goal of the study was to enhance the national herd scoring system for BTB risk, thus leading to improved identification of cattle herds at high risk of recurrent BTB episodes. A retrospective cohort study was conducted to develop a statistical model predictive of recurrent bovine tuberculosis episodes in cattle herds in the Republic of Ireland. Herd-level disease history data for the previous 12 years, the previous 3 years, the previous episode, and the current-episode were used in survival analyses to determine the aspects of disease history that were predictive of a recurrent breakdown within 3 years of a cleared BTB episode. Relative to herds with 0–1 standard reactors in the current BTB episode, hazard ratios increased to 1.3 and 1.6 for herds with 2–5 and >5 standard reactors, respectively. Compared to herds with <30 animals, hazard ratios increased from 1.8 to 2.5 and then to 3.1 for herds with 30–79, 80–173, and >174 animals respectively. Relative to herds with <4 herd-level tests in the previous 3 years, herds with 4–5 and >5 tests had 1.1 and 1.4 times greater hazard of a BTB breakdown. Herds that did not have a BTB episode in the 5 years prior to their 2001 episode were 0.8 times less likely to breakdown in the next 3 years than herds that did. Herds breaking down in the spring or summer were 0.8 times less likely to suffer a recurrent breakdown than herds breaking down in autumn or winter (this was likely due to seasonality in testing regimes). The presence of a confirmed BTB lesion was not predictive of increased risk of recurrent BTB. Despite the availability of detailed disease history, the predictive ability of the model was poor. One explanation for this was that herds suffering a recurrence of BTB on their first test after clearing a BTB episode were different from herds that broke down later in the period at risk. Future research might need to include additional variables to identify which subsets of herd BTB episodes, if any, have identifiable features that are predictive of recurrent breakdowns. [Copyright &y& Elsevier]