Explore the vast range of titles available.

European badgers ( Meles meles ) are reservoirs for animal tuberculosis (TB) in some European countries, complicating TB control in cattle. Badger vaccination and a deeper understanding of the subsequent protection mechanisms are necessary for effective TB control. In a previous study, two of eight badgers immunized with the heat-inactivated Mycobacterium bovis (HIMB) vaccine exhibited an unusual immune response (divergent), developing exacerbated lesions. The present study aimed to describe the local immune response in divergent badgers (those with severe disease progression), with respect to that observed in standard (where the vaccine showed efficacy) and control badgers. Immunohistochemistry was performed to evaluate immune cells (macrophages, T and B lymphocytes, plasma cells), and proteins (TGF-β, IL-10, Fox-P3) within TB granulomas in the lung and bronchial lymph node (LN), after TB challenge. Lung lesion volume, bacterial load and immunological response were also evaluated. The divergent immune response was characterized by elevated IL-10 and Fox-P3, few macrophages and high B lymphocytes (mainly in lungs), suggesting a Th1/Th2 imbalance with reduced Th1 cellular immunity leading to severe TB. In contrast, vaccinated badgers with a standard immune response showed a balanced response, with significantly lower bacterial loads (85.5% LN and 99.9% lung) than control group. This study provides new insights into the immune mechanisms in HIMB-vaccinated badgers, to improve TB control strategies.

Bovine tuberculosis (bTB) is a costly disease in Britain and Ireland shared by cattle and badgers ( Meles meles ), and to reduce the infection in cattle to low levels some form of badger management is considered necessary. We compare the results of a badger field trial where test-positive badgers are culled, and test-negative badgers vaccinated (a TVR approach) with the results of the simulation model originally used to predict the effect of the trial in Northern Ireland. Initial model results depended strongly on whether social perturbation occurred in the badger population following culling, and the field study demonstrated no evidence for such behavior. Here we re-run the model with the initial conditions of the TVR study and with no social perturbation and predict a similar outcome in terms of number of badgers caught, number testing positive, and the substantial decline in prevalence. These results validate our model and demonstrate the utility of such predictive modelling for this disease system. This is particularly important as the UK government moves away from widespread badger culling in England toward more vaccination, as this combined approach of vaccination and selective culling based on test results may give a more robust method of disease management than just vaccination on its own.

Control of bovine tuberculosis (TB) in cattle has proven particularly challenging where reservoirs of infection exist in wildlife populations. In Britain and Ireland, control is hampered by a reservoir of infection in Eurasian badgers (Meles meles). Badger culling has positive and negative effects on bovine TB in cattle and is difficult, costly and controversial. Here we show that Bacillus Calmette-Guérin (BCG) vaccination of captive badgers reduced the progression, severity and excretion of Mycobacterium bovis infection after experimental challenge. In a clinical field study, BCG vaccination of free-living badgers reduced the incidence of positive serological test results by 73.8 per cent. In common with other species, BCG did not appear to prevent infection of badgers subjected to experimental challenge, but did significantly reduce the overall disease burden. BCG vaccination of badgers could comprise an important component of a comprehensive programme of measures to control bovine TB in cattle.

Senescence has been hypothesized to arise in part from age-related declines in immune performance, but the patterns and drivers of within-individual age-related changes in immunity remain virtually unexplored in natural populations. Here, using a long-term epidemiological study of wild European badgers (Meles meles), we (i) present evidence of a within-individual age-related decline in the response of a key immune-signalling cytokine, interferon-gamma (IFNγ), to ex vivo lymphocyte stimulation, and (ii) investigate three putative drivers of individual variation in the rate of this decline (sex, disease and immune cell telomere length; ICTL). That the within-individual rate of age-related decline markedly exceeded that at the population level suggests that individuals with weaker IFNγ responses are selectively lost from this population. IFNγ responses appeared to decrease with the progression of bovine tuberculosis infection (independent of age) and were weaker among males than females. However, neither sex nor disease influenced the rate of age-related decline in IFNγ response. Similarly, while ICTL also declines with age, variation in ICTL predicted neither among- nor within-individual variation in IFNγ response. Our findings provide evidence of within-individual age-related declines in immune performance in a wild mammal and highlight the likely complexity of the mechanisms that generate them.

Where wildlife disease requires management, culling is frequently considered but not always effective. In the British Isles, control of cattle tuberculosis (TB) is hindered by infection in wild badger (Meles meles) populations. Large-scale badger culling can reduce the incidence of confirmed cattle TB, but these benefits are undermined by culling-induced changes in badger behavior (termed perturbation), which can increase transmission among badgers and from badgers to cattle. Test–vaccinate/remove (TVR) is a novel approach that entails testing individual badgers for infection, vaccinating test-negative animals, and killing test-positive animals. Imperfect capture success, diagnostic sensitivity, and vaccine effectiveness mean that TVR would be expected to leave some infected and some susceptible badgers in the population. Existing simulation models predict that TVR could reduce cattle TB if such small-scale culling causes no perturbation, but could increase cattle TB if considerable perturbation occurs. Using data from a long-term study, we show that past small-scale culling was significantly associated with four metrics of perturbation in badgers: expanded ranging, more frequent immigration, lower genetic relatedness, and elevated prevalence of Mycobacterium bovis , the causative agent of TB. Though we could not reject the hypothesis that culling up to three badgers per social group might avoid perturbation, we also could not reject the hypothesis that killing a single badger prompted detectable perturbation. When considered alongside existing model predictions, our findings suggest that implementation of TVR, scheduled for 2014, risks exacerbating the TB problem rather than controlling it. Ongoing illegal badger culling is likewise expected to increase cattle TB risks.

In animal populations, males are commonly more susceptible to disease-induced mortality than females. However, three competing mechanisms can cause this sex bias: weak males may simultaneously be more prone to exposure to infection and mortality; being ‘male’ may be an imperfect proxy for the underlying driver of disease-induced mortality; or males may experience increased severity of disease-induced effects compared with females. Here, we infer the drivers of sex-specific epidemiology by decomposing fixed mortality rates into mortality trajectories and comparing their parameters. We applied Bayesian survival trajectory analysis to a 22-year longitudinal study of a population of badgers (Meles meles) naturally infected with bovine tuberculosis (bTB). At the point of infection, infected male and female badgers had equal mortality risk, refuting the hypothesis that acquisition of infection occurs in males with coincidentally high mortality. Males and females exhibited similar levels of heterogeneity in mortality risk, refuting the hypothesis that maleness is only a proxy for disease susceptibility. Instead, sex differences were caused by a more rapid increase in male mortality rates following infection. Males are indeed more susceptible to bTB, probably due to immunological differences between the sexes. We recommend this mortality trajectory approach for the study of infection in animal populations.

In developing an oral bait BCG vaccine against tuberculosis in badgers we wanted to understand the conditions of the gastrointestinal tract and their impact on vaccine viability. Conditions mimicking stomach and small-intestine caused substantial reduction in BCG viability. We performed in vivo experiments using a telemetric pH monitoring system and used the data to parameterise a dynamic in vitro system (TIM-1) of the stomach and small intestine. Some BCG died in the stomach compartment and through the duodenum and jejunum compartments. BCG survival in the stomach was greatest when bait was absent but by the time BCG reached the jejunum, BCG viability was not significantly affected by the presence of bait. Our data suggest that from a starting quantity of 2.85 ± 0.45 x 108 colony-forming units of BCG around 2 log10 may be killed before delivery to the intestinal lymphoid tissue. There are economic arguments for reducing the dose of BCG to vaccinate badgers orally. Our findings imply this could be achieved if we can protect BCG from the harsh environment of the stomach and duodenum. TIM-1 is a valuable, non-animal model with which to evaluate and optimise formulations to maximise BCG survival in the gastrointestinal tract.

•First report of a physically stable bait for the delivery of BCG to wild badgers.•BCG is stable within bait during storage and under simulated deployment conditions.•Bait used to deliver oral biomarker to badgers to simulate oral delivery of vaccine.•A highly palatable bait combined with a BCG-compatible vaccine carrier.•Discussion of requirements for the components of a successful oral wildlife vaccine. The oral vaccination of wild badgers (Meles meles) with live Bacillus Calmette–Guérin (BCG) is one of the tools being considered for the control of bovine tuberculosis (caused by Mycobacterium bovis) in the UK. The design of a product for oral vaccination requires that numerous, and often competing, conditions are met. These include the need for a highly palatable, but physically stable bait that will meet regulatory requirements, and one which is also compatible with the vaccine formulation; in this case live BCG. In collaboration with two commercial bait companies we have developed a highly attractive and palatable bait recipe designed specifically for European badgers (Meles meles) that meets these requirements. The palatability of different batches of bait was evaluated against a standardised palatable control bait using captive badgers. The physical properties of the bait are described e.g. firmness and colour. The microbial load in the bait was assessed against European and US Pharmacopoeias. The bait was combined with an edible vaccine carrier made of hydrogenated peanut oil in which BCG vaccine was stable during bait manufacture and cold storage, demonstrating <0.5 log10 reduction in titre after 117weeks’ storage at −20°C. BCG stability in bait was also evaluated at +4°C and under simulated environmental conditions (20°C, 98% Relative Humidity; RH). Finally, iophenoxic acid biomarkers were utilised as a surrogate for the BCG vaccine, to test variants of the vaccine-bait design for their ability to deliver biomarker to the gastrointestinal tract of individual animals. These data provide the first detailed description of a bait-vaccine delivery system developed specifically for the oral vaccination of badgers against Mycobacterium bovis using live BCG.

Wildlife is a global source of endemic and emerging infectious diseases. The control of tuberculosis (TB) in cattle in Britain and Ireland is hindered by persistent infection in wild badgers (Meles meles). Vaccination with Bacillus Calmette-Guérin (BCG) has been shown to reduce the severity and progression of experimentally induced TB in captive badgers. Analysis of data from a four-year clinical field study, conducted at the social group level, suggested a similar, direct protective effect of BCG in a wild badger population. Here we present new evidence from the same study identifying both a direct beneficial effect of vaccination in individual badgers and an indirect protective effect in unvaccinated cubs. We show that intramuscular injection of BCG reduced by 76% (Odds ratio = 0.24, 95% confidence interval (CI) 0.11-0.52) the risk of free-living vaccinated individuals testing positive to a diagnostic test combination to detect progressive infection. A more sensitive panel of tests for the detection of infection per se identified a reduction of 54% (Odds ratio = 0.46, 95% CI 0.26-0.88) in the risk of a positive result following vaccination. In addition, we show the risk of unvaccinated badger cubs, but not adults, testing positive to an even more sensitive panel of diagnostic tests decreased significantly as the proportion of vaccinated individuals in their social group increased (Odds ratio = 0.08, 95% CI 0.01-0.76; P = 0.03). When more than a third of their social group had been vaccinated, the risk to unvaccinated cubs was reduced by 79% (Odds ratio = 0.21, 95% CI 0.05-0.81; P = 0.02).

The innate immune system provides the primary vertebrate defence system against pathogen invasion, but it is energetically costly and can have immune pathological effects. A previous study in sticklebacks found that intermediate major histocompatibility complex (MHC) diversity correlated with a lower leukocyte coping capacity (LCC), compared to individuals with fewer, or many, MHC alleles. The organization of the MHC genes in mammals, however, differs to the highly duplicated MHC genes in sticklebacks by having far fewer loci. Using European badgers (Meles meles), we therefore investigated whether innate immune activity, estimated functionally as the ability of an individual's leukocytes to produce a respiratory burst, was influenced by MHC diversity. We also investigated whether LCC was influenced by factors such as age-class, sex, body condition, season, year, neutrophil and lymphocyte counts, and intensity of infection with five different pathogens. We found that LCC was not associated with specific MHC haplotypes, MHC alleles, or MHC diversity, indicating that the innate immune system did not compensate for the adaptive immune system even when there were susceptible MHC alleles/haplotypes, or when the MHC diversity was low. We also identified a seasonal and annual variation of LCC. This temporal variation of innate immunity was potentially due to physiological trade-offs or temporal variation in pathogen infections. The innate immunity, estimated as LCC, does not compensate for MHC diversity suggests that the immune system may function differently between vertebrates with different MHC organizations, with implications for the evolution of immune systems in different taxa.