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Bovine TB vaccinations and minimizing 'false positives'

PLOS

Bovine tuberculosis is a major economic disease of livestock worldwide. Despite an intensive, and costly, control program in the United Kingdom, bovine TB persists. Currently, vaccinating cattle with the human vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) offers some protection in cattle, but is currently illegal within the European Union (EU) due to its interference with the tuberculin skin test; the cornerstone test for surveillance and eradication strategies.

According to research in PLOS Computational Biology new diagnostic tests are need to make bovine TB vaccination viable. The study further recommends that the number of false positives from these tests must be below 15 out of every 10,000 cattle tested.

Researchers at the University of Cambridge and Animal & Plant Health Agency, Surrey, show that the specificity of the test - the proportion of uninfected animals that test negative - is more important than the efficacy of a vaccine when determining whether vaccination can provide a protective economic benefit when used to supplement existing controls.

Vaccination for the control of bovine tuberculosis in cattle is not currently used within any international control program, and is illegal within the EU. Currently, there is no gold standard test to diagnose TB in cattle. Cattle that test positive are slaughtered immediately and therefore have rarely developed any physical signs - in fact, only around a half of animals examined post-mortem show physical signs of infection even if they are, indeed, infected.

Dr Andrew Conlan from the Department of Veterinary Medicine at the University of Cambridge says: "In order for vaccination to be viable, we will need a 'Differentiate Infected from Vaccinated Animals' (DIVA) test that has extremely high specificity. If the specificity is not good enough, the test will find false positives, leading to restrictions being put in place and a significant financial burden for the farmer.

"But validating a test that has a very high specificity will in itself be an enormous challenge. We would potentially need to vaccinate, test and kill a large number of animals in order to be confident the test is accurate. This would be very expensive."

For vaccination to be feasible economically and useful within the context of European legislation, the benefits of vaccination must be great enough to outweigh any increase in testing. DIVA tests open up the opportunity for the use of BCG within current control programmes.

The EU has recently outlined the requirements for changes in legislation to allow cattle vaccination and a recent report from its European Food Safety Authority emphasized the importance of demonstrating that BCG is efficacious and that DIVA tests can be shown to have a comparable sensitivity to tuberculin testing in large-scale field trials. However, a key factor overlooked in this report was that the currently viable DIVA tests have a lower specificity than tuberculin testing; this could lead to vaccinated herds being unable to escape restrictions once a single test-positive animal has been detected, as the more times the herd is tested, the more likely the test is to record a false positive.

In the study funded by the Department for Environment, Food & Rural Affairs (Defra), the researchers from Cambridge and the Animal & Plant Health Agency used herd level mathematical models to show that the burden of infection can be reduced in vaccinated herds even when DIVA sensitivity is lower than tuberculin skin testing - provided that the individual level protection is great enough. However, in order to see this benefit of vaccination the DIVA test will need to achieve a specificity of greater than 99.85% to avoid increasing the duration and number of animals condemned during breakdowns. A data set of BCG vaccinated and BCG vaccinated/experimentally M. bovis infected cattle suggests that this specificity could be achievable with a relative sensitivity of the DIVA test of 73.3%. Defra are aware of these results and are considering the potential implications for the cattle vaccine programme.

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All works published in PLOS Computational Biology are Open Access, which means that all content is immediately and freely available. Use this URL in your coverage to provide readers access to the paper upon publication: http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004038

Press-only preview: http://www.plos.org/wp-content/uploads/2015/02/pcbi.1004038-1.pdf

Citation: Conlan AJK, Brooks Pollock E, McKinley TJ, Mitchell AP, Jones GJ, Vordermeier M, et al. (2015) Potential Benefits of Cattle Vaccination as a Supplementary Control for Bovine Tuberculosis. PLoS Comput Biol 11(2): e1004038. doi:10.1371/journal.pcbi.1004038

Funding: This study was funded by Defra project SE3127 and uses nationally collected incidence and cattle-movement data sets held by Defra. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

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