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Mycobacterium tuberculosis is recognised as the primary cause of human tuberculosis worldwide. However, substantial evidence suggests that the burden of Mycobacterium bovis, the cause of bovine tuberculosis, might be underestimated in human beings as the cause of zoonotic tuberculosis. In 2013, results from a systematic review and meta-analysis of global zoonotic tuberculosis showed that the same challenges and concerns expressed 15 years ago remain valid. These challenges faced by people with zoonotic tuberculosis might not be proportional to the scientific attention and resources allocated in recent years to other diseases. The burden of zoonotic tuberculosis in people needs important reassessment, especially in areas where bovine tuberculosis is endemic and where people live in conditions that favour direct contact with infected animals or animal products. As countries move towards detecting the 3 million tuberculosis cases estimated to be missed annually, and in view of WHO's end TB strategy endorsed by the health authorities of WHO Member States in 2014 to achieve a world free of tuberculosis by 2035, we call on all tuberculosis stakeholders to act to accurately diagnose and treat tuberculosis caused by M bovis in human beings.

Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.

Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity.

Transcription activator-like effector nuclease (TALEN)-mediated genome modification has been applied successfully to create transgenic animals in various species, such as mouse, pig, and even monkey. However, transgenic cattle with gene knockin have yet to be created using TALENs. Here, we report site-specific knockin of the transcription activator-like effector (TALE) nickase-mediated SP110 nuclear body protein gene ( SP110 ) via homologous recombination to produce tuberculosis-resistant cattle. In vitro and in vivo challenge and transmission experiments proved that the transgenic cattle are able to control the growth and multiplication of Mycobacterium bovis , turn on the apoptotic pathway of cell death instead of necrosis after infection, and efficiently resist the low dose of M . bovis transmitted from tuberculous cattle in nature. In this study, we developed TALE nickases to modify the genome of Holstein–Friesian cattle, thereby engineering a heritable genome modification that facilitates resistance to tuberculosis. Significance Bovine tuberculosis is a chronic infectious disease that affects a broad range of mammalian hosts. It is a serious threat to agriculture in many less-developed countries. In this study, we introduced a mutation to the FokI of the right hand of wild-type transcription activator-like effector nuclease and established a transcription activator-like effector nickase system that creates single-strand breaks in the genome. Then we used this system to add the mouse gene SP110 to a specific location in the bovine genome and created transgenic cattle with increased resistance to tuberculosis. Our results contribute to the control and prevention of bovine tuberculosis and provide a previously unidentified insight into breeding animals for disease resistance.

Bovine tuberculosis is a major economic burden on the cattle industry, and attempts to control it have been politically controversial; here farm movement and bovine tuberculosis incidence data are used to construct a mechanistic model and tease apart the factors contributing to epidemic bovine tuberculosis spread. Cattle are prime target in TB Bovine tuberculosis (TB) is a major economic burden on the cattle industry, particularly in the United Kingdom. Attempts to control it, especially by targeting the environmental reservoir in the badger population, have been politically controversial and largely unsuccessful. Ellen Brooks-Pollock, Gareth Roberts and Matt Keeling have used farm movement and bovine TB incidence data to construct a mechanistic model that they use to tease apart the factors contributing to epidemic bovine TB spread. Although the environmental reservoir is important for infection in the short term, it is not a major determinant of long-term spread, and most herd outbreaks are caused by several transmission routes. The authors find that only intensive control measures that focus on cattle are likely to be effective, and that control of local badger populations is unlikely to have a substantial impact. Bovine tuberculosis (TB) is one of the most complex, persistent and controversial problems facing the British cattle industry, costing the country an estimated £100 million per year 1 . The low sensitivity of the standard diagnostic test leads to considerable ambiguity in determining the main transmission routes of infection, which exacerbates the continuing scientific debate 2 , 3 , 4 , 5 , 6 . In turn this uncertainty fuels the fierce public and political disputes on the necessity of controlling badgers to limit the spread of infection. Here we present a dynamic stochastic spatial model for bovine TB in Great Britain that combines within-farm and between-farm transmission. At the farm scale the model incorporates stochastic transmission of infection, maintenance of infection in the environment and a testing protocol that mimics historical government policy. Between-farm transmission has a short-range environmental component and is explicitly driven by movements of individual cattle between farms, as recorded in the Cattle Tracing System 2 . The resultant model replicates the observed annual increase of infection over time as well as the spread of infection into new areas. Given that our model is mechanistic, it can ascribe transmission pathways to each new case; the majority of newly detected cases involve several transmission routes with moving infected cattle, reinfection from an environmental reservoir and poor sensitivity of the diagnostic test all having substantive roles. This underpins our findings on the implications of control measures. Very few of the control options tested have the potential to reverse the observed annual increase, with only intensive strategies such as whole-herd culling or additional national testing proving highly effective, whereas controls focused on a single transmission route are unlikely to be highly effective.

Bovine tuberculosis (BTB) has a significant impact on both the cattle industry and human health. Understanding its transmission, clinical signs, risk factors, and control measures is essential for prevention. This study aimed to evaluate the knowledge, attitudes, and practices regarding BTB in high-burden areas of Malawi. A stratified sampling design was employed to collect data from 463 butchers, dairy farmers and cattle farmers in different locations and settings in Malawi. Aggregate scores on knowledge, attitudes, and practices were taken as multivariate measurements and fitted with multivariate linear regression models. Participants displayed satisfactory knowledge (88.68%), negative attitudes towards risky behaviours (92.27%), and appropriate practices (86.83%) concerning BTB. Most were aware of its presence in cattle (85.71%) and potential transmission to humans (74.09%), yet exhibited gaps in understanding clinical signs and held misconceptions about hereditary transmission. Many participants demonstrated risky behaviours, such as consuming raw animal products and selling products from infected animals. Individuals with secondary (β: -2.148; 95% CI: -4.168, -0.127) and tertiary education (β: -3.488; 95% CI: -6.626, -0.349) exhibited more negative attitudes towards risky behaviours compared to those with informal education. Adults aged 18-30 (β: -2.777; 95% CI: -5.469, -0.085) and those aged 31-45 (β: -3.035; 95% CI: -5.752, -0.319) demonstrated better protective practices than youths under 18. There is an urgent need for targeted health education on BTB, focusing on clinical signs and the myth of hereditary transmission, particularly aimed at young people, individuals with limited formal education, and farmers, to enhance prevention efforts.

Bacillus Calmette-Guérin (BCG) Danish strain 1331 (CattleBCG) is currently the lead vaccine candidate for the control of bovine tuberculosis (TB) in cattle in GB, where prior vaccination has shown to result in a significant reduction in bovine TB pathology induced by infection with Mycobacterium bovis (M. bovis). A critical knowledge gap in our understanding of CattleBCG is the duration of immunity post vaccination at the minimum intended vaccine dose. To this end, we performed an experiment where calves were vaccinated with a targeted dose of 106 CFU and, after a period of 52 weeks, experimentally infected with M. bovis. Post mortem examination performed 13 weeks after infection revealed a statistically significant reduction in the severity of TB pathology in the CattleBCG vaccinated group compared with the unvaccinated control group. Additionally, this study allowed us to further assess the diagnostic performance of a defined antigen DIVA reagent (DST-F) developed to detect infected amongst vaccinated animals. Our results demonstrate that when used in a skin test format, DST-F showed high specificity (100 %) in BCG-vaccinated animals when tested prior to infection, whilst detecting all infected animals when re-tested after infection. Furthermore, we also present results supporting the use of the DST-F reagent in an interferon-gamma release assay. In conclusion, the results of this study demonstrate a 52-week duration of immunity following administration of a minimum dose of CattleBCG. This evidence will be a fundamental component in our efforts to apply for UK marketing authorisation to enable vaccination of cattle as a significant additional control measure in the ongoing fight against bovine TB in GB.

Persistent tuberculosis (TB) in cattle populations in England has been associated with an exchange of infection with badgers ( Meles meles ). A badger control policy (BCP) commenced in 2013. Its aim was to decrease TB incidence in cattle by reducing the badger population available to provide a wildlife reservoir for bovine TB. Monitoring data from 52 BCP intervention areas 200–1600 km 2 in size, starting over several years, were used to estimate the change in TB incidence rate in cattle herds, which was associated with time since the start of the BCP in each area. A difference in differences analysis addressed the non-random selection and starting sequence of the areas. The herd incidence rate of TB reduced by 56% (95% Confidence Interval 41–69%) up to the fourth year of BCP interventions, with the largest drops in the second and third years. There was insufficient evidence to judge whether the incidence rate reduced further beyond 4 years. These estimates are the most precise for the timing of declines in cattle TB associated with interventions primarily targeting badgers. They are within the range of previous estimates from England and Ireland. This analysis indicates the importance of reducing transmission from badgers to reduce the incidence of TB in cattle, noting that vaccination of badgers, fertility control and on farm biosecurity may also achieve this effect.

Bovine tuberculosis (bTB) is a chronic disease of cattle and the leading cause of zoonotic tuberculosis. In Bhutan, there is no dedicated program for bTB despite the country being situated in the bTB enzootic region, where a large section of population relies on cattle and raw milk and, dairy products are widely consumed.To contribute to the design of future education, surveillance, mitigation, and control programs, we investigated the knowledge, attitudes, and practices relevant to bTB among dairy farmers. We surveyed 264 farmers in Thimphu, Paro, and Haa Dzongkhags. These farmers contribute to supplying the eight milk outlets in the capital, Thimphu. We found that only 11 farmers (4.2%; confidence interval 95%: 2.1% - 7.3%) were aware that bTB existed, and only five of them (1.9%; CI 95%: 0.6% – 4.3%) were aware that bTB is a zoonosis. Risk perception and practice followed a gradient of variation from Thimphu to Haa, but overall, we found a correlation between bTB risk perception for animals and humans. Farmers and traders, along with the consumption of meat and sick animals, were perceived as occupations and activities involving the highest risk of zoonotic infection. Contact with animals entering the herd and with neighbouring cattle were perceived as the highest risk for animal infection. Most farmers in Haa consume raw milk and dairy products they produced by themselves, whereas farmers in Paro and Thimphu prefer powdered milk. Using generalised low-rank models and k-means clustering, we found that dzongkhag of residence and attitudes toward zoonotic infection prevention explained most variability in the data. The severe knowledge deficits about bTB are particularly concerning given the zoonosis is present in Bhutan, is prevalent in neighbouring countries, and negatively affects cattle health and well-being, diminishing fertility, milk, and overall productivity, ultimately impacting farmers’ livelihoods and undermining Bhutan’s nutritional and economic reliance on this sector. Urgent short and mid-term activities should be prioritised to identify bTB high-risk areas, educate farmers, and mitigate bTB impacts.

► BCG is particularly protective when administered to neonatal calves. ► Subunit vaccines may be used to boost immunity in cattle. ► T cell central memory responses correlate with protection to M. bovis challenge. ► DIVA approaches are feasible in cattle using in vitro or in vivo methods. ► BCG is being considered for use in several wildlife reservoirs of M. bovis. The emergence of wildlife reservoirs of Mycobacterium bovis infection in cattle as well as increased inter-regional trade with associated spread of M. bovis has led to renewed interest in the use of vaccines for the control of bovine tuberculosis (TB). Field efficacy trials performed in the early 20th century demonstrated the partial effectiveness of bacilli Calmette–Guerin (BCG) for the control of bovine TB. Recent experimental trials with cattle have demonstrated that: (1) subunit vaccines may boost immunity elicited by BCG in cattle, (2) T cell central memory immune responses evoked by protective vaccines correlate with protection upon subsequent M. bovis challenge, (3) BCG is particularly protective when administered to neonates, and (4) differentiation of infected from vaccinated animals (DIVA) is feasible in cattle using in vitro or in vivo methods. In regards to wildlife reservoirs, the efficacy of BCG delivered orally has been demonstrated for brushtail possums (in field trials) as well as Eurasian badgers, wild boar, and white-tailed deer (each in experimental challenge studies). Vaccine delivery to wildlife reservoirs will primarily be oral, although a parenteral route is being deployed for badgers in England. Vaccine efficacy trials, both experimental challenge and field studies, with cattle and their wildlife reservoirs represent a primary example of the one health approach, with outcomes relevant for both veterinary and medical applications.