̽��ֱ�� of Cambridge - bovine tuberculosis

Cost and scale of field trials for bovine TB vaccine may make them unfeasible

cjb250 — Thu, 07 Jun 2018 10:50:07 +0000

Instead, the researchers suggest that the scale and cost of estimating the effect of a vaccine on transmission could be dramatically reduced by using smaller, less expensive experiments in controlled settings – using as few as 200 animals.

Bovine TB is an infectious disease that affects livestock and wildlife in many parts of the world. In the UK, it is largely spread between infected cattle; badgers are also involved, transmitting to and receiving infection from cattle. Culls to keep badger populations small and reduce the likelihood of infecting cattle have proven controversial both with the public and among scientists.

̽��ֱ��UK has a policy of ‘test and slaughter’ using the tuberculin test and slaughter of infected animals. A vaccine (BCG) exists, but can cause some vaccinated cattle to test positive falsely. As such, the vaccine is currently illegal in Europe. Researchers are trying to develop a so-called ‘DIVA test’ (‘Differentiates Infected from Vaccinated Animals’) that minimises the number of false positives, but none are yet licensed for use in the UK.

̽��ֱ��European Union has said it would consider relaxing its laws against bovine TB vaccination if the UK government were able to prove that a vaccine is effective on farms. Any field trials would need to follow requirements set by the European Food Safety Authority (EFSA).

In research published today, a team of researchers led by the ̽��ֱ�� of Cambridge has shown using mathematical modelling that satisfying two key EFSA requirements would have profound implications for the likely benefits and necessary scale of any field trials.

̽��ֱ��first of these requirements is that vaccination must be used only as a supplement, rather than replacement, to the existing test-and-slaughter policy. But use of vaccination as a supplement means that a successful vaccine which reduces the overall burden and transmission of disease may nonetheless provide only limited benefit for farmers – false positives could still result in animals being slaughtered and restrictions being placed on a farm.

̽��ֱ��second of the EFSA requirements is that field trials must demonstrate the impact of vaccination on transmission rather than just protecting individual animals.

̽��ֱ��team’s models suggest that a three year trial with 100 herds should provide sufficient to demonstrate that vaccination protects individual cattle. Such a trial would be viable within the UK. However, demonstrating the impact on vaccination on transmission would be almost impossible because the spread of bovine TB in the UK is slow and unpredictable.

If BCG were to be licensed for use in cattle in the UK, vaccination would be at the discretion of individual farmers. Farmers would have to bear the costs of vaccination and testing, as well as the period of time under restrictions if animals test positive. This means that they would be less interested in the benefit to individual cattle and more interested in the benefits at the herd level. Herd immunity is such that, even if the vaccine is not 100% effective in every individual animal, the vaccine has an overall protective effect on the herd.

Trying to demonstrate an economic benefit for farmers would prove challenging. Using their models, the researchers show that herd-level effectiveness would be exceptionally difficult to estimate from partially-vaccinated herds, requiring a sample size in excess of 2,000 herds. ̽��ֱ��number of herds required could be reduced by a ‘three arm design’ that includes fully-vaccinated, partially-vaccinated and unvaccinated control herds; however, such a design would still require around 500 fully-vaccinated herds and controls – presenting potential logistical and financial barriers – yet would still have a high risk of failure.

Instead, the researchers propose a natural transmission experiment involving housing a mixture of vaccinated and unvaccinated cattle with a number of infected cattle. Such an experiment, they argue, could provide robust evaluation of both the efficacy and mode of action of vaccination using as few as 200 animals. This would help screen any prospective vaccines before larger, more expensive and otherwise riskier trials in the field.

“We already know that the BCG vaccine has the potential to protect cattle from bovine TB infection,” says Dr Andrew Conlan from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge, the study’s first author. “Our results highlight the enormous scale of trials that would be necessary to evaluate BCG alongside continuing testing in the field.

“Such trials would be hugely expensive, and it isn’t even clear whether enough farms could be recruited. This scale could be dramatically reduced by using smaller scale natural transmission studies.”

Based on current knowledge of the likely efficacy of BCG, the researchers say their models do not predict a substantial benefit of vaccination at the herd level when used as a supplement to ongoing test-and-slaughter. Ruling out the use of vaccination as a replacement, rather than a supplement, to test-and-slaughter will inevitably limit the effectiveness and perceived benefits for farmers.

“If we could consider replacing test-and-slaughter with vaccination, then the economics becomes much more attractive, particularly those in lower income countries,” says Professor James Wood, Head of Cambridge’s Department of Veterinary Medicine. “Then, we would no longer need to carry out expensive testing, but could instead rely on passive surveillance through the slaughterhouses.”

̽��ֱ��study was funded by the UK Department for Environment, Food and Rural Affairs (Defra) and the Alborada Trust

Reference
Conlan, AJK, et al. ̽��ֱ��intractable challenge of evaluating cattle vaccination as a control for bovine Tuberculosis. eLife; 5 June 2018; DOI: 10.7554/eLife.27694.001

Field trials for a vaccine to protect cattle against bovine tuberculosis (bovine TB) would need to involve 500 herds – potentially as many as 75,000-100,000 cattle – to demonstrate cost effectiveness for farmers, concludes a study published today in the journal eLife.

Our results highlight the enormous scale of trials that would be necessary to evaluate BCG alongside continuing testing in the field. Such trials would be hugely expensive, and it isn’t even clear whether enough farms could be recruited

Andrew Conlan

Knarrhultpia

Curious cows

Researcher Profile: Dr Andrew Conlan

It may seem surprising to find a physicist in the Department of Veterinary Medicine, but this was how Dr Andrew Conlan began his career at the ̽��ֱ�� of Edinburgh. He is now an applied mathematician and statistician at in Cambridge’s Disease Dynamics Unit, engaged in work which he describes as “intensively multi-disciplinary”, requiring him to work within multiple environments with medics, veterinarians, farmers, policymakers – and even school children.

Andrew’s research sets out to use mathematics to predict the spread of infectious disease within populations and provide evidence to inform policy on the control of infectious diseases in humans and animals. His work centres around controlling the spread of diseases such as bovine TB and human diseases including, measles, whooping cough, scarlet fever, norovirus and meningitis.

“Policy decisions on the control of infectious diseases often have to be made quickly based on limited information and data,” he says. “I believe that government policy on infectious disease control should be based on evidence and good science.”

Although much of his research is office-based, involving analysing data, writing computational models and occasionally pen-and-paper work, he also does a lot of work with schools, working with pupils on research projects and delivering lessons on disease transmission.

“I’ve been involved in running citizen science projects for many years now, which have led to several peer reviewed papers on how social contact networks in schools could be useful to predict the spread of infectious disease,” he explains (while, ironically, nursing a cold picked up from his son, who had in turn picked it up at nursery). “I dreamed it up over a tea break with my colleague Ken Eames. At the time very little work had been down on contact patterns in school age children as they are a potentially vulnerable population that is difficult to access. We thought that getting them to do the research themselves and take ownership would be a way to address it – and it worked!”

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Minimising ‘false positives’ key to vaccinating against bovine TB

cjb250 — Thu, 19 Feb 2015 19:00:00 +0000

Using mathematical modelling, researchers at the ̽��ֱ�� of Cambridge and Animal & Plant Health Agency, Surrey, show that it is the specificity of the test – the proportion of uninfected animals that test negative – rather than the efficacy of a vaccine, that is the dominant factor in determining whether vaccination can provide a protective economic benefit when used to supplement existing controls.

Bovine TB is a major economic disease of livestock worldwide. Despite an intensive, and costly, control programme in the United Kingdom, the disease continues to persist. Vaccination using 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. This test is the cornerstone of surveillance and eradication strategies and is used to demonstrate progress towards national eradication and as the basis of international trade in cattle.

̽��ֱ��current tuberculin skin test has a very high estimated specificity of over 99.97%, which means that less than three animals in 10,000 will test falsely positive. ̽��ֱ��test as carried out in Great Britain is thought to have at best an 80% sensitivity – a measure of how many infected animals will correctly test positive – missing around 1 in 5 bovine TB-infected cattle. It is used to determine if animals, herds and countries are officially free of bovine TB.

Vaccinated animals that test positive have to be treated as infected animals. Under European law, if an animal tests positive, it must be slaughtered. ̽��ֱ��remaining herd is put under movement restrictions and tested repeatedly using both the skin test and post-mortem examinations until it can be shown to be officially clear of infection. ̽��ֱ��duration of movement restrictions is important due to the considerable economic burden they place on farms. ̽��ֱ��cost to the UK government alone, which depends on the number of visits to farms by veterinarians, tests carried out and compensation for the slaughter of infected animals, is estimated to be up to £0.5 billion pounds over the last ten years.

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. A new generation of diagnostic tests, known as ‘Differentiate Vaccinated from Infected Animals’ (DIVA) tests, opens up the opportunity for the use of BCG within current control programmes.

̽��ֱ��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 published today, 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%.

However, validating a test to such a high specificity will likely prove a challenge. 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 ̽��ֱ�� of Cambridge says: “In order for vaccination to be viable, we will need a 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.”

̽��ֱ��need for a better DIVA test was acknowledged by the Government at the end of last year. In a written statement to the House of Commons noting data from the ̽��ֱ�� of Cambridge and Animal Health and Veterinary Laboratories Agency, the Rt Hon Elizabeth Truss, Secretary of State for Environment, Food and Rural Affairs, said: “An independent report on the design of field trials of cattle vaccine and a test to detect infected cattle among vaccinated cattle (DIVA) shows that before cattle vaccination field trials can be contemplated, we need to develop a better DIVA test.”

̽��ֱ��study was funded by the Department for Environment, Food and Rural Affairs (Defra) in the UK.

Reference
Conlan, AJK et al. Potential benefits of cattle vaccination as a supplementary control for bovine tuberculosis. PLOS Comp Biol; 19 Feb 2015

New diagnostic tests are needed to make vaccination against bovine tuberculosis (bovine TB) viable and the number of false positives from these tests must be below 15 out of every 10,000 cattle tested, according to research published today in the journal PLOS Computational Biology.

Validating a test... 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

Andrew Conlan

bertknot

Cows

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First national model for bovine TB calls for greater focus on cattle

cjb250 — Wed, 02 Jul 2014 17:00:00 +0000

̽��ֱ��model, developed by researchers at the ̽��ֱ�� of Warwick and ̽��ֱ�� of Cambridge, suggests that improved testing, vaccination of cattle and culling of all cattle on infected farms would be the most effective strategies for controlling the disease. It found that whilst badgers – the subject of controversial culling plans to stem the spread of the disease – form part of the environmental reservoir, they only play a relatively minor role in the transmission of infection.

Based on a study of cattle and the causes of bovine TB in Great Britain, the model, published in the journal Nature, sought to ascertain how and why the epidemic has grown over the past 15 years. Using data from the Animal Health and Veterinary Laboratories Agency and the Department for the Environment, Food and Rural Affairs (Defra), the researchers developed a mathematical model that incorporated both within- and between-farm bovine TB transmission.

“Our model offers a dispassionate, unbiased view of the spread of bovine TB through the cattle industry of Great Britain,” says Professor Matthew Keeling, from the ̽��ֱ�� of Warwick’s School of Life Sciences and Department of Mathematics. “ ̽��ֱ��model is based on the recorded pattern of positive and negative tests and uses the known movement of cattle around the country. We aim for it to provide policy-makers with the best evidence possible from which to make decisions relating to bovine TB and to contribute to the ongoing discussions on this sensitive issue.”

̽��ֱ��model allowed the researchers to tease apart how different routes involved in transmission interact and overlap.

Dr Ellen Brooks-Pollock from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge adds: “By using the most recent data, our model predicts that it is most likely that both cattle movements and the local environment are driving the front of the epidemic. Imperfect cattle skin tests contribute to the spread by delaying the time until infected herds are detected for the first time and incorrectly identifying herds as clear of infection.”

One of the key results from the model is the large variation in what happens to farms once they are infected.

“We found that the vast majority of infected farms don’t spread the infection to any other farms before they clear infection themselves. Only a small number of farms spread the infection, and they can cause the majority of new cases”, says Dr Brooks-Pollock.

̽��ֱ��researchers argue that the findings are essential for improving the targeting of control measures. If infected farms can be identified and caught early then it might be possible to make substantial progress in tackling the epidemic.

“ ̽��ֱ��model we are putting forward can be used to address several potential control methods – but there is no single panacea,” says Professor Keeling. “All controls have advantages and disadvantages. However, we find only three controls have the power to reverse the current increase in cases: more frequent or more accurate testing, vaccination of cattle and culling all cattle on infected farms.”

̽��ֱ��control measures the researchers investigated were designed to be ‘idealised’ control options to understand what measures in theory could stop the increasing epidemic. ̽��ֱ��researchers did not consider the practicalities or economics of implementing control measures.

̽��ֱ��research was funded by the Biotechnology and Biological Sciences Research Council, the Wellcome Trust and the Engineering and Physical Sciences Research Council.

Adapted from a press release from the ̽��ֱ�� of Warwick.

̽��ֱ��majority of outbreaks of bovine TB within cattle herds are caused by multiple transmissions routes – including failed cattle infection tests, cattle movement and reinfection from environmental reservoirs such as infected pastures and wildlife – according to the first national model of bovine TB spread, published today.

It's most likely that both cattle movements and the local environment are driving the bovine TB epidemic

Ellen Brooks-Pollock

Giuseppe Milo

Cows (cropped image)

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