Control of bovine tuberculosis is driven by the need to reduce the risk of zoonotic transmission of M bovis to people. And this is partly driven by the aspirations of the WHO, or the World Health Organization, who are aiming to eradicate human TB by 2030. And although there are animal health and welfare risks of bovine TB in cattle, this public health aspiration is the driver for controlling cattle. The OIE work with the WHO trying to eradicate bovine tuberculosis in cattle populations, primarily internationally by helping restrict trade between countries that are bovine TB infected with those that are TB free. They provide guidance for regional and national control programs as well as at local level in testing cull programs. So why don't we use antibiotics to control Mycobacterium bovis infections in cattle? Primarily because the same antibiotics would be used to treat people which require long protracted courses of at least a few months to six months, as well as reducing the chances of antibiotic resistance developing in Mycobacterium bovis, which is highly prevalent in Mycobacterium tuberculosis with multiple resistant forms. Also, do cattle really need to be treated in a lifetime, as clinically they are unlikely to develop clinical bovine tuberculosis during their lifetimes. And as well for dairy cattle, the majority of their lactation would be restricted if they were on milk withholds for long courses of antibiotics. So the mainstay of control programs in cattle populations is testing and identifying animals that are positive for bovine tuberculosis and removing them from the herd as soon as possible to prevent further onward transmission. These infected carcasses do not enter the food chain due to the zoonotic risk, or at least parts of their carcass do not. So in countries that are aiming to eradicate bovine tuberculosis, or at least control it in their cattle populations, test and slaughter programs are often conducted at herd level every one to four years, with any animal testing positive being slaughtered. Testing is conducted one to four years to allow animals to develop immune responses that are detectable either through skin testing, gamma interferon testing, or a combination of both depending on the sensitivity or specificity of the test required. Surveillance is conducted through this active testing program, cattle herds using these antemortem tests, but also often through passive surveillance, not only to protect public health, but also identify animals that may be missed through the active testing, and also to analyse epidemiologically the spread of disease within those populations, potentially through genotyping methods. Although the UK is yet to eradicate bovine tuberculosis, it has been on track for over a 100 years with reducing the levels of bovine tuberculosis in it's cattle population. In the early 1900's, the prevalence was unknown, and upon implementation of the Tuberculosis Order over a 100,000 infected cattle were slaughtered primarily through testing these cattle, but also slaughtering any clinical cases. By the 1930's, active surveillance was implemented across the cattle population in the UK, with over a third of dairy cattle being infected. Post, post-Second World War the eradication scheme was set up to actively aim towards eradicating bovine tuberculosis from the British Isles. And by 1950 an obligatory national herd testing scheme was conducted with movement restrictions and reactor compensation implemented. By 1960 all UK herds were tested annually and all testing was paid for exemption of movement and export tests. From the 1950's and 60's, the number of test positive animals, otherwise known as reactors, dramatically declined due to test and slaughter programs and surveillance. Although from the mid 1990's, the number of bovine tuberculosis reactors began to increase across the UK cattle population. There are a variety of reasons for this. Partly because of increased cattle movements across the UK. Partly because of the  infection getting into wildlife populations which act as a reservoir for infection, as well as the early 2000's outbreak of foot and mouth disease where cattle were slaughtered, and then replacement animals were moved across the UK that were potentially infected with bovine tuberculosis leading to a gap in test and slaughter programs. All these mechanisms have resulted in increasing bovine tuberculosis positive animals across the UK. And this results in a more difficult challenge to try and reduce bovine tuberculosis in the UK. So in response to this increase in reactor animals, being identified, a number changes were made. The cattle tracing system, which requires all cattle in the UK to have a passport was improved. So animals could be traced back to their herd of origin and tested if their herd of origin had a break down of bovine tuberculosis. Private vets worked with Government vets to increase the frequency of testing, and this has led to parts of the UK being officially free of tuberculosis, such as Scotland. England and Wales unfortunately, the hotspot of tuberculosis has increased across southern Wales, South Western England, up to the Cheshire border. And the number of herds testing positive on an annual basis resides around about 5%. Despite this increase in bovine tuberculosis in the UK, the UK still aiming towards eradication. And in response to that, testing needs to be continued to try and reduce infection being spread between herds and within herds, and thus was tendered out in the early 2010's to allow non-vets to test animals. Skin testing is used as the primary measure to determine if an animal is bTB positive, otherwise known as a reactor. This is to minimize the number of false positive animals and reduce the chances of animals being slaughtered that are not infected with bovine TB. And often animals are followed up with the gamma interferon test to increase the sensitivity of testing on that farm. So what happens if an animal tests positive for bovine tuberculosis in the UK using the single comparative intradermal skin test. Well, initially the whole herd is put under movement restrictions to prevent onward transmission, of bovine tuberculosis to other herds. Positive animals are slaughtered, and samples are taken from lesions to understand the molecular epidemiology and potential source of this breakdown. Government vets and epidemiologists visit the farm to try and understand the epidemiology of the disease on farm to implement further control measures. Disinfection is conducted to remove environmental contamination. Furthermore, public health is notified due to the zoonotic risk of bovine TB, both from any milk that is produced by the farm, but also to farm staff. As part of the wider investigation, any animals that have been sold within a period of time are traced and tested to prevent further contamination of farms within the area and beyond. And any animals that are contiguous or likely been infected from the original farm that may be in the local region will also be tested. For that herd to return negative short interval tests are then conducted every 60 days to try and estimate the number of animals that are infected and give them time to develop an immune, immunological response. If the herd has two clear tests of the whole herd, than the herd restrictions are lifted. This is quite a stringent control program in, with the aims trying to eliminate infection entirely. To a national level, if we focus on England as the example, active surveillance requires herds to be tested. And this, the frequency of testing is dependent on the risk for herd's been testing positive, as there is a hotspot in the southwest and western areas of England for bovine tuberculosis. This is a high risk area and the testing is conducted on an annual basis unless a herd is already broken down with TB. In the low-risk area of the UK, testing is either conducted on a four yearly basis or not at all. Like England, across the rest of the UK, frequency of testing is dependent on risk of transmission. For example, unofficially, tuberculosis free Scotland four yearly testing is conducted for breeding stock. Although most herds are of low risk, or are exempt from testing. In other high-risk areas such as Wales and Northern Ireland, annual testing is conducted every six weeks to six months to try and reduce the incidence of new herd breakdowns. Also in Northern Ireland, control measures are coordinated with Irish control measures, as control of TB is coordinated on a whole island basis. In addition, passive surveillance monitors all animals that are slaughtered in the UK to determine whether they've been infected with bovine TB or not, and whether they pose a risk to the food chain, but also feedback to the farm of origin to determine whether further testing is required. This flow diagram demonstrates the decision tree made for any animals that are slaughtered in the UK. Samples taken from passive surveillance from lesioned animals can be genotyped and used to try and map spatially the spread of bovine tuberculosis across the UK. This is helpful to describe the epidemiology locally of Mycobacterium bovis between herds, and helpful for local veterinary inspectors to implement control measures to prevent onward spread of infection. It's  also useful to determine whether a new breakdown is because of new, new animals entering the herd, or whether it is because of local onward transmission between herds. This information, both from active and passive surveillance is fed into the  ibTB website, that is present for all herds in England and Wales. This is useful to identify the pockets of infection and engage farmers in understanding the risk of bovine TB in their area. Farmers are also being encouraged in recent years to improve their biosecurity. Partly to prevent the spread of onward transmission between herds, and this has been through getting farmers to sign up to certification schemes to highlight all the control measures that they're conducting to reduce the risk of bovine tuberculosis in their stock. And also, so farmers can understand the risk of animals that they buy in to whether they are infected with bovine TB through pre and post movement testing. In some areas of the UK, this is obligatory, as well as pre and post movement tests if animals are exported or imported to the United Kingdom. There has also been an increased impetus to minimise contact with infected wildlife, and I'll come onto this in a few slides time. It is worth noting that risk-based trading schemes encourage buy-in from farmers to assist control of bovine tuberculosis at national level, and help them identify the risk of bovine tuberculosis being brought into their herd from cattle that they have purchased. Wildlife species can also be involved in the maintenance of M bovis infection within cattle populations. Some species are known as amplifier hosts, and they can be involved in onward transmission between cattle and the species themselves, and vice versa. In the UK, badgers are an amplifier host and they continue onward transmission to cattle due to the high prevalence of Mycobacterium bovis  in badgers. In certain areas of the world such as Michigan in the US, white-tailed deer are involved in onward transmission due to their close contact with cattle, as well as possums in New Zealand. Other species can be known as spill over hosts that become infected, but do not perpetuate onward transmission, and are not essential in the maintenance of M bovis infection in cattle. A large variety of species are susceptible to M bovis infection, and particularly in the UK, camelids and cats have been reported to be infected with M. bovis, where there is a high infection pressure. It is worth noting the diagnostics are not validated in all species, so interpretation of tests can be difficult. In the UK, badgers were first identified as a wildlife species infected with Mycobacterium bovis in the early 1970's. It is thought that badgers were infected from cattle, and due to their high susceptibility to M bovis infection became part of the transmission cycle. Transmission routes between cattle and badgers, and badgers and cattle respectively, is thought to be due to their close contact in the field or at feeding points where badgers feed on cattle feed and the secretions that are infected on cattle feed, and vice versa. To try and control infection from badgers. in areas where badger transmission was thought as a high risk, in the early 2000's a randomised badger culling trial was conducted. The results showed that it was efficacious, but it needed to be sustained to maintain the impacts from the culling trials because as soon as it was stopped badger reinfection occurred. This was partly due to badgers being territorial and moving from outside areas once badger numbers had been cleared from the original area, and become reinfected either from cattle or from original dwellings such as setts, where badgers live, and remaining secretions reinfecting badgers returning to those setts. This link here  describes the randomised culling trial and the limitations of the research conducted. Currently, various trials are being conducted to control onward transmission from badgers to cattle. In England, culling trials have been conducted since 2013 to try and understand not only whether culling can have a sustained impact on the incidence of herd breakdowns to bovine TB, but also to try and understand the incidence of bovine tuberculosis in badgers. In Wales, vaccination has been trialled since 2012 and is ongoing to try and demonstrate whether vaccination of badgers can help reduce M tuberculosis in cattle and positive results seem to be ongoing. The next steps towards bTB eradication in the UK are highlighted towards certifying the low-risk area is certified as officially bovine tuberculosis free, which was planned for 2019, and continued cattle and badger controls and monitor through surveillance programs. From a badger perspective, there are some papers here that describe the onwards badger culling trial, as this is controversial as the badger is a native species in the UK. So evidence of efficacy is important with any animal culls. And as this is a sustained program, it requires longitudinal review as the factors are multi-factorial in the transmission between badgers and cattle. There is local variations, so presence of badgers does not imply that cattle will always become infected from badgers, and their importance in transmitted infection between the two species. And the context of cattle control measures is important. Because if cattle are being moved from high risk areas into the area, this might have a larger impact than simply badgers being present in a bovine tuberculosis hotspot. Other factors have been identified that affect the risk of an animal testing positive for bovine tuberculosis. For example, certain genotypes of Holstein cattle appeared to be more susceptible or resistant to bovine tuberculosis infection. And breeding programs may be important in future as part of the toolkit for control of bovine tuberculosis. There is also an impact of co-infections in increasing the likelihood of false negatives cell mediated immunity test responses. For example, liver fluke infections, modulate the host immune response away from Th1 responses that are responsible for cell-mediated immune responses. And consequently, if animals are infected with bovine TB, while the parasite is present, it might lead to false negative test responses. Also, other immunosuppressive viruses such as BVD, may play a role in the false-negative test responses. And further research is ongoing to understand the impact of these infections. Vaccination has also been explored as a potential control measure where bovine tuberculosis is endemic. The primary candidate has been the BCG vaccine, which is used in humans with calves being shown to have a similar efficacy to protection as in humans. However, there are limitations in rolling out vaccine using cattle. For example. BCG is used extensively in humans and there was a global shortage recently, so this will limit the use in cattle. It's unclear how long the immunity lasts in cattle, and further trials are required to understand how long the immunity occurs and whether booster vaccinations are required. But the major limitation is how to identify animals that are vaccinated from animals that are infected, and might consequently further transmit infection. Subsequently, DIVA tests have been in the pipeline to differentiate infected animals, from vaccinated animals, and this is through amending the protein, or purified protein derivative used in cell mediated diagnostics. These vaccines and not currently licensed to be used due to the official TB free status definition, stated by the OIE. But recent publications have demonstrated that it is possible to differentiate infected animals from uninfected animals using modified cell-mediated immune tests. However, there are a variety of barriers for use, for example, defining and proving that the vaccine is working within these populations over a period of time. The efficacy of DIVA tests requires to have a high specificity in particular, to make sure the animals are definitively not falsely positive when the vaccine is used. Where does vaccination fit in current control measures? As it is no doubt that vaccine is not going to be the silver bullet in the control of bovine tuberculosis. So how does this fit in, in current and test and slaughter programs? Consequently, if we get over these barriers, legislation changes are required to ensure that further trading can be conducted between countries that are officially TB free and those that are vaccinating against bovine tuberculosis. And ultimately, is vaccination a stepping stone towards eradication of bovine TB in all countries, or is it more of a control measure in countries that are not wishing to eradicate bovine tuberculosis? And how does this fit in with the eradication of humans tuberculosis across the globe? Many of these questions are explored in this, in this insightful paper that's been published, which is a review of the variety of vaccines and DIVA tests that are available currently. So what can we learn from countries that have had sustained control programs when we're looking at a country such as Cameroon that currently does not conduct animal control measures. Firstly, we have to think about why we're trying to control disease in cattle. And unfortunately, it's unlikely that we're going to be there yet, due to other human infections taking prevalent precedence due to their significance. Other livestock diseases are maybe more important, such as Foot and Mouth Disease, which is commonly seen by herdsmen. And bovine  tuberculosis is relatively infrequently seen as a clinical disease. And also does it affect trade with other countries? Adjacent countries to Cameroon trade cattle without considering bovine tuberculosis status. So it's unlikely the trade will be impacted by tuberculosis risk. Also, secondly, we need to consider the tools available. Is surveillance feasible in a country where cattle are currently not traced or tracked, and animals are grazed on communal pasture. A test and slaughter program sustainable in areas where cattle are again nomadic, but also there is no program for compensation. What about the distribution of vets? If, if cattle in remote regions where veterinary, vets are not taking part in test and control programs, it is likely that pockets of infection are likely to remain. Again, tracking these cattle with vets is required and checking of tracked cattle through trading posts in markets is equally important. And having the infrastructure to be able to sustain that. Compensation methods need to be reserved by the Government over the same period of time to be able to implement these control programs. And what about the wildlife components? Is unclear how wildlife in such free range roaming systems in Cameroon could affect infection in wildlife. But could other control measures that are not currently used hold the answer, such as vaccination or identifying the risk of animals being infected through computer simulation. Is this feasible in this setting? So although the challenges are the same across the globe for control of bovine TB, the focus may differ between low income and high income countries. For example, often low-income countries have not had sustained animal control measures to reduce the risk of infection from cattle or other wildlife species to people. So the focus has been on protecting public health and maintaining trade in the local area. Challenges include the transmission to humans and the presence of HIV infections complicating the morbidity and mortality of infection in humans. There are challenges with the infrastructure and organisation of the cattle industry to try and implement any form of sustainable control measure, such as tracing animals and identify animals that need to be retested. In high-income countries often the incidence of human cases of zoonotic TB is low. So most of the focus is aiming towards eradication rather than just control. And so we have a focus on improving diagnostics and trying to reduce infection from wildlife species that are acting as maintenance hosts. It's worth bearing in mind that eradication is possible despite these challenges. And Australia achieved eradication of bovine tuberculosis in less than 30 years. The control program started in 1970, where all cattle were tested on a routine basis with reactors being slaughtered. A similar combination of tests we used such as the skin tests and gamma interferon assays, where increased sensitivity was required, and field post mortems were conducted to confirm infection. Field post mortems were required as cattle production, particularly in the northern territories of the country, is rather extension extensive where cattle are ranched. One major factor in the success of bovine tuberculosis control and Australia was that there was no significant wildlife host, which may have hindered control in the extensive ranching setting. However, while cattle were present and in particular in certain northern territories, and these cattle, slowed down control of bovine tuberculosis. As Australia could focus control in these areas, cattle were darted and tested up frequently on a routine basis, and positive animals with slaughtered. This helps eradicate bovine tuberculosis in these areas, leading to official TB free status in 1997, which is currently maintained. So overcoming these logistical, diagnostic and wildlife challenges is possible with a little bit of ingenuity. In summary, although there are a variety of challenges in controlling and/or eradicating bovine tuberculosis from cattle populations, the significance of these challenges depends on the aims of the control or eradication program, the local situation within that cattle population and dynamic between humans and wildlife, as well as what can be achieved in that setting. We need to bear in mind whether the goals set out by programs are realistic, and consider whether everyone engaged in the program is actually really engaged in the program. And what the needs and aspirations are of all stakeholders from farmers all the way through to policymakers. It is likely that we're going to have to embrace novel control practises to get towards control and eradication of bovine tuberculosis in the future. I would highlight these two articles as they tackle some of these challenges and highlight some of the current research in the battle against bovine tuberculosis globally. In addition to the references mentioned throughout this presentation, I've collated some other references that may help with background on bovine tuberculosis both in the global stage, but also in Great Britain itself. And the current diagnostic tests that are available and their limitations. If you have any questions for me after this talk, and please do not be afraid to email me or contact me via the discussion forums. Thank you for listening to this talk.