The nature of protective immunity to mycobacterial infection is complex and still only partly understood. Pathogenic mycobacteria evade and exploit the immune system of the host to their advantage ( Raja 2004 ), meaning that infected animals do not readily clear the infection. As a result of this evasion of the immune system, BCG does not induce full protective immunity in all individuals. Thus, a proportion of vaccinated humans and animals can still be infected and develop disease ( Barreto and others 2006 , Dye 2013 , Waters and others 2012 ). However, laboratory studies have demonstrated that vaccination with BCG can reduce the progression and severity of TB and the excretion of M bovis in both badgers and cattle ( Buddle and others 1995 , Lesellier and others 2011 ).

At present, the vaccine agent for tackling TB in both cattle and badgers is Bacille Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis. This has been given to people as a TB vaccine since 1927 and is one of the most widely used of all human vaccines. The BCG strain used in the badger and cattle experiments in the UK is BCG Danish strain 1331 produced by the Statens Serum Institut in Copenhagen, Denmark, which is the strain licensed for human vaccination in the UK. For simplicity, we will refer to this strain from now on as BCG, although not all of the experiments referenced in this review use this strain.

The aim of vaccination is to stimulate an immune response in the vaccinated animal, such that it is either resistant to infection or, if infection occurs, it is less susceptible to clinical disease and less likely to spread infection. Even a vaccine that only partially protects animals to the extent that they are less infectious to other animals over their lifetime may still eventually reduce disease prevalence in the population. There are significant gaps in our knowledge regarding the impact that the vaccination of either badgers or cattle could have in practice. For example, there is a lack of empirical data on the effect of vaccinating badgers with the licensed vaccine (BadgerBCG) on TB incidence in cattle.

This review focuses on one component of the English and Welsh eradication programmes; namely vaccination. Vaccination of cattle and/or badgers could contribute to TB control in Great Britain ( Delahay and others 2003 , Wilson and others 2011 ). The aim of this review is to set out current knowledge and experience regarding the development and application of vaccines against bovine TB for badgers and cattle. We highlight the most important gaps in our knowledge, where empirical data are lacking, and some of the more significant challenges to implementating vaccination.

‘BOVINE tuberculosis (TB) is one of the most complex animal health problems that the farming industry in Great Britain faces today’. This was the view of the Chief Veterinary Officer in 2006 ( Reynolds 2006 ) and, despite advances in our understanding of the disease and its epidemiology, this view still stands. The disease picture varies considerably within Great Britain; it is endemic and spreading in parts of England and Wales while Scotland has been officially TB-free since 2009 and only sees rare sporadic cases from imported cattle ( Abernethy and others 2013 ). Despite regional differences, annual fluctuations and different ways of presenting the data, the overall picture of bovine TB incidence in Great Britain is that it has been on the increase since the early 1980s, although there is evidence that the increase may have plateaued in the last couple of years ( Blake and Donnelly 2014 ). This implies that current TB control measures are slowing but not reversing the spread of disease. In addition, the significant financial and emotional impact bovine TB has on farmers and the cost to government in control (bovine TB has cost the taxpayer £500 million in England alone in the past 10 years [ Defra 2014a ]) means tackling this disease is a major animal health priority for government. Finally, its complex (and sometimes controversial) epidemiology, recently reviewed by Godfray and others (2013) , means only a comprehensive, multifaceted eradication programme is likely to have a significant impact on infection levels. Readers are encouraged to refer to the review by Godfray and colleagues, which provides an excellent understanding of the natural science evidence base relevant to the control of bovine TB in Great Britain, including vaccination.

Vaccination of badgers

In areas with a reservoir of infection in badgers, the goal of badger vaccination is to reduce the pressure of infection from badgers to cattle such that transmission between the two is eliminated or significantly reduced. A vaccine has the potential to achieve that goal either through preventing infection altogether or by reducing the infectiousness of vaccinated badgers that become infected with M bovis. Badger vaccination could also have a role in protecting uninfected badger populations at risk of disease spread, for example, in the face of advancing disease at the edge of bovine TB endemic areas. Both scenarios are novel, as vaccination has, so far, not been used extensively to control chronic bacterial infections such as TB in wildlife (Blancou and others 2009). The only available TB vaccine for badgers (BadgerBCG) was licensed by the UK competent authority the Veterinary Medicines Directorate (VMD) in 2010, following 10 years of studies carried out by the AHVLA (formerly the Veterinary Laboratories Agency [VLA] and the National Wildlife Management Centre of the Food and Environment Research Agency, now also part of AHVLA). It is an injectable vaccine with a Limited Marketing Authorisation and is currently available for use by vets and trained lay vaccinators under prescription from a veterinary surgeon. For more information see Brown and others (2013). Licensing of BadgerBCG required evidence of vaccine safety and efficacy, obtained from laboratory and field studies, but the duration of immunity from BadgerBCG remains unknown.

The value of a vaccination campaign can be assessed in three main ways, each providing a different measure of success (Blancou and others 2009). These are: quantification of vaccine uptake; assessment of the immune response in vaccinated individuals; and evaluation of the epidemiological consequences of vaccination. In the case of BCG vaccination where the vaccine is used as a national disease control tool, the principal interest is in the epidemiological consequences in cattle and badgers, although this is the hardest measure to assess. The likely impact of badger vaccination on TB incidence in cattle is poorly understood. Modelling studies have provided predictions of the effects of vaccination relative to other interventions (Smith and others 2012); however, in the absence of the necessary field data, it is not known whether mathematical predictions will be borne out in reality. Measuring this empirically and accurately would involve monitoring cattle TB incidence in areas where badgers were vaccinated and in other areas where they were not, ideally within a large randomised and controlled field experiment with an appropriately structured sampling framework.

Protective effect of badger vaccination Our understanding of the effects of vaccination on badger immune responses is derived from laboratory and field studies. Laboratory studies with captive badgers supported the claim that the vaccination of badgers by injection with BCG significantly reduces the number and severity of lesions of tuberculosis caused by M bovis (Lesellier and others 2011). The protection afforded to badgers by BCG in experimental challenge models such as these is rarely complete (defined as the absence of visible pathology and the isolation of M bovis from tissues), most likely because of the relatively high infection doses used in experimental studies in order to generate reproducible levels of infection. Hence the protection afforded in experimental challenge models may not reflect the level of protection afforded against ‘natural challenge’ in the wild, where animals may be exposed to lower numbers of virulent bacteria (see experimental evidence for BCG in cattle later in this review). The results of a four-year field study of BCG in wild badgers were consistent with the direct protective effect of BCG observed in experimental studies. Individual badgers that initially tested negative to a panel of diagnostic tests and were presumed uninfected were significantly less likely to subsequently test positive to serological and immunological tests for TB following vaccination, compared to non-vaccinated control animals (Chambers and others 2011, Carter and others 2012). The risk of yielding a positive result was reduced by 54 per cent using a combination of diagnostic tests (‘triple test’) to detect infection (bacterial culture for M bovis, the Brock (TB) Stat-Pak serological test and an interferon-gamma (IFN-γ) test based on the use of specific M bovis antigens ESAT-6 and CFP-10). When test results were restricted to culture and Stat-Pak, risk was reduced by 76 per cent, consistent with an additional impact of vaccination in the prevention of disease progression in vaccinated animals that still became infected (Carter and others 2012). The ‘triple test’ represents the most sensitive panel of tests available to detect infection in a live vaccinated animal, whereas positive Stat-Pak and culture results are better indicators of more advanced infection. Although the BadgerBCG field study was relatively small-scale and designed primarily as a field safety study, it also demonstrated an indirect beneficial effect of vaccination; evidence of the herd immunity effect of vaccination, whereby unvaccinated individuals are indirectly protected as the vaccine prevents circulation of an infectious agent in susceptible populations by increasing the prevalence of immunity (see review by Kim and others [2011]). In this case, non-vaccinated cubs captured in vaccinated social groups were significantly less likely to test positive to TB when more members of their group had been previously vaccinated. When more than a third of the social group had been previously vaccinated, the risk of non-vaccinated cubs testing positive by culture, Stat-Pak or the IFN-γ test was reduced by 79 per cent (Carter and others 2012). The most plausible explanation for this result is that vaccination had reduced the rate of transmission more effectively in social groups where a higher proportion of animals had been vaccinated during the four-year study. The indirect protective effect conferred to non-vaccinated cubs living in such groups was evident after the point that they had emerged from the sett, that is, at the point at which they could be caught and vaccinated themselves. There is no evidence of either a beneficial or detrimental effect of BCG in infected badgers. Assuming widespread annual deployment, the beneficial effects of vaccination should accrue over time as the proportion of the population vaccinated increases and animals with pre-existing infection die off naturally. There is no empirical evidence on the optimal size or duration for a badger vaccination programme. Benefits will start to accrue from the onset of immunity and most badgers (whether infected with TB or not) are expected to die off within five years (Wilkinson and others 2000).

Field delivery of an injectable badger vaccine BadgerBCG has been deployed in an area of Gloucestershire in each of the four years since it was licensed in 2010, as part of the five-year Defra-funded Badger Vaccine Deployment Project (BVDP) (Defra 2014b). The BVDP aims to increase knowledge of the practicalities and costs of deploying injectable BCG, train lay badger vaccinators and build confidence in the principle of badger vaccination. It was not designed to estimate the impact of badger vaccination on the incidence of TB breakdowns in cattle herds. Up until the end of 2013, 182 lay vaccinators from a range of organisations had been trained on the bespoke training course built into the BVDP. The project has provided an understanding of what is logistically possible in terms of injectable vaccine delivery. During the four-month field season in 2013, 834 badgers were vaccinated over an area of approximately 90 km2 of farmland, encompassing around 100 farm premises. This was carried out by a core team of five trapper/vaccinators. Nationally, BadgerBCG is being deployed under three main models: government agency-led (accounting for the largest share); voluntary and community sector organisations (with a degree of government support); and commercial operators. Combining deployment under all three models, a total of 2781 badgers were vaccinated in 2013 by 15 organisations. A total of 6788 badger BCG doses were delivered in England and Wales between 2010 and 2013 inclusive. The single largest vaccination project to date was that initiated in 2012 by the Welsh Government. In the first year of this five-year project the Welsh Government vaccinated 1424 badgers over 241 km2 of land in west Wales at a cost of approximately £945,000 (Government 2013). In the second year (2013), 1352 badgers were vaccinated over 258 km2 at a cost of approximately £927,000 (Government 2014). The cost of injectable vaccination has been estimated to be between £2000 to £4000 per km2, depending on a wide range of factors including the type of organisation delivering the work and environmental factors such as badger density and landscape characteristics. Incorporating emerging models of deployment into economic analyses will be useful as the costs (and benefits) associated with a government agency-led scheme may differ from a stakeholder initiative incorporating voluntary staffing input. The proportion of the badger population that receives and is protected by vaccination will influence the rate at which the incidence of disease changes in badgers (Wilkinson and others 2004). Estimations of the proportion of the badger population that is trapped are not built into current vaccination projects and therefore this remains a knowledge gap. Estimated trapping efficacy in triplets during the Randomised Badger Culling Trial (RBCT) varied from 35 per cent to 85 per cent (Smith and Cheeseman 2007). However, this is likely to have used a different pattern of trapping over the area and therefore may not be directly comparable.