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Let's discuss the BCG vaccine



 Added by  Sally (Guest)
 21 Apr 2010, 3:44 PM


The BCG vaccine is frequently mentioned as the most common vaccine to help protect against TB. It has been used to protect people from the human form of the disease, although more recently in the UK the vaccination programme has been stopped owing to its poor cost effectiveness. An injectable form has recently been licensed for use on badgers. Could it be used for cattle? Is it a reliable vaccination and has it helped prevent the human form of TB?

geoffrey
Cattle bTB Vaccination could save the lives of thousands of cattle and the Taxpayer millions of pounds.
 
Calmette and Guerin, first reported the vaccination of cattle with BCG, to immunize them from bovine TB, in 1911. However, in 2011, one hundred years later, vaccination of cattle for bTB in the UK has not been deployed.
 
Test and slaughter is a barbaric, wasteful and archaic approach to the problem even though it has reduced bTB to a minimum in some countries. Successive Governments and the Farming Industry seem reluctant to rigorously enforce, all necessary cattle measures needed to control bovine TB. This has been clearly evident for the last 30 years or so.
 
The obvious solution, neglected for decades, is the immunisation of newborn calves with BCG. The DIVA test, successfully developed before 6th November 2007, differentiates between infected and vaccinated animals, and further enhances the prospects for the control of bovine TB in the UK by vaccination.
 
Dr Jayne Hope, Dr Chris Howard and Dr Paul Stopp, carried out the research, and on receiving an Animal Health Award, Dr Jayne Hope stated:
 
“The ultimate benefit of accurate diagnosis of disease , in the light of vaccination would be a reduction of the incidence of bovine TB with associated improvements in animal health and welfare, and livelihood of farmers.”
 
 
Bovine TB is often described as the most serious threat to the cattle industry today and its reduction a priority for the farming industry.
However, it appears that there is a complete lack of urgency regarding cattle vaccination. If the work to enable deployment of the vaccine had been commenced at the same time as work began on the DIVA test it could have been deployed three years ago, four more years are expected to pass before its eventual deployment. In this time of economic hardship can the UK afford to through away literally hundreds of millions of pounds over the next four years in compensation payments to farmers?
 
Pet owners value their animals and are prepared to pay to have them immunised against various diseases. There is no Government compensation program for a lost pet. The following 1 is taken from a care of pets website:
 
“Infectious diseases used to kill thousands of pets each year. It’s worth remembering that many of the pet diseases we vaccinate against are killers. [And] “Only vaccination in these animals exposed to these diseases can prevent infection.”
 
A plethora of pet diseases controlled by vaccination are listed on the site.
 
A multitude of cattle diseases around the World are being controlled or eliminated by vaccination. This is having a profound effect in areas such as East Africa where people’s lives literally depend on the health of their cattle
 
We already protect UK cattle from numerous insidious diseases and of course what vaccination has done for humans cannot be overstated.
 
The Independent Scientific Group, (The ISG) who conducted on the Randomised Badger Culling Trials, commented in their final report page 180, paragraph 10.85:
 
The ISG considers that Defra has not devoted sufficient effort to analysis of cattle testing and movement data, and that this in turn, coupled with a reluctance within Defra to consider any radical changes in control policies, has impaired the development of new policies .
 
Professor Bourne commented in the Chairman’s overview page 15, paragraph 14:
 
14. We also hope that Defra will expand the role of scientists and other relevant experts in developing evidence-based policies. The strength and quality of scientific expertise already available to Defra through its Executive Agencies means that it is well placed to adopt this approach, but we have been aware of some considerable reluctance to accept
and embrace scientific findings. We have therefore recommended how structures could be changed to introduce a much needed vigour into policy development and implementation.
 
The economic crisis in full swing, and Government leaders are consistently reminding us of their need to reduce spending. Why should the majority of taxpayers accept painful cuts in crucial areas while literally hundreds of millions of pounds are thrown away in compensation payments to farmers for slaughtered cattle that could have been vaccinated against bovine TB? The time for the Government to act is now
 
Sally
GL in an email dated 15/01/11 reminded us of the following paragraph in the ISG final report, which explains the spread of TB in cattle can easily be reversed if only a small reduction in the prevelance is made. Vaccination of cattle will certainly impact this disease in a major way, even though its not 100% effective.
 
Page 175
 
10.60 Mathematical models have indicated that the basic reproduction number for between-herd infection in cattle in Great Britain is about 1.1 (Cox et al., 2005 and Chapter 7). This means that, for each new TB herd breakdown identified, on average a further 1.1 new herd breakdowns arise. Notwithstanding the contribution that badgers make to cattle TB, the value of 1.1 suggests that relatively modest changes aimed at more effective detection of infected cattle and prevention of their movement between herds would force the critical value below 1, leading to a reverse in the upward trend in incidence. The major epidemiological factor influencing this, in addition to transmission from wildlife, is the presence of undiagnosed cattle that can act as a source for amplifying infection within herds and for exacerbating spread of infection by movement of infected cattle between herds. Therefore, improved diagnosis and more rigorous cattle movement controls should be key to the success of any future control policy.
 
 
 
Sally
BBC's On Your Farm broadcast on 19th December 2010 was a visit to the Veterinary Laboratories Agency at Weybridge. Here they have been undertaking trials for some time into cattle vaccination and alternatives tests for bTB. A current trial, involving some 34 calves in three pens, is evaluating the BCG vaccine. Half had been vaccinated. The presenter reminded listeners that this is the same vaccine given to young teenagers to protect against the human form of TB before the programme was stopped some years ago. It has been used on more humans than any other vaccine. Professor Glyn Hewinson informed the listener that up until the 1950s it could be used on cattle. It was only made illegal for cattle when the skin test was made compulsory as any cow that had been vaccinated came up as a reactor following the skin test.
 
Hewinson explained that his department had been working on a vaccination for cattle since 1998 when the Krebbs report advised this was the best option for controlling bTB in cattle. Over £80 million pounds has been spent so far on vaccination and diagnostic tests, all funded by Defra (the taxpayer!). The scientific hurdles were almost complete and a BCG vaccine for cattle was expected to be licensed by 2012, together with a diagnostic test which would detect the difference between vaccinated and infected animals. . The vaccine had be be shown it was safe (BCG vaccine has long been considered to be one of the safest vaccines there is!), particularly as it would be used on food animals (it did not take long to bring in a vaccine for other diseases, such as blue tongue!).
 
The security levels at the Weybridge laboratories was very tight, particularly in the central area where they were actually infecting cattle with bTB. Protective clothing had to be worn, and masks (farmers and vets do not wear such protective clothing during testing!). The bacteria is introduced into the lungs. However, as it was stressed that the welfare of the animals was important, only low doses of the bacteria were used to limit suffering - so there were no clinical signs (clinical signs always rare these days!). Around 500 cattle had been infected in this way. Some had been vaccinated, others were used as control and not vaccinated. We were told that the vaccination ones don't always get infected but all the unvaccinated ones became infected. Immune response was used to see if an animal had TB. Every animal had then been slaughtered and lesions looked for on postmortem. Sufficient animals had now been evaluated and the team were ready to prepare its dossier for the official licensing process.. Important lessons had apparently been learnt on detecting infection and how the disease is spread. It was considered that the BCG vaccine was the most advanced and could be licensed quickly. It was expected that a vaccination programme for cattle would dampen down infection which would then hit a plateau.
 
Hewinson confirmed that the skin test does not always work. He said no test is perfect.
 
We were told that once the vaccine was licenced legislation would have to be changed (EU) to make vaccination legal once again. This would take over three years!
 
Hewison is also involved in the trials re cattle vaccination in Ethiopia. This is a country which cannot afford to needlessly cull its cattle! In such countries use of the BCG vaccination for cattle is legal.
 
 
 
Sally
Interesting DEFRA report, 'Project SE3120: Investigate the longer-term effects on farm businesses of a bTB breakdown'. (http://www.defra.gov.uk/foodfarm/farmanimal/diseases/atoz/tb/research/summary/se3120.htm). The project ended 30/09/08!
 
There was a section that deals with vaccination. There was apparently evidence of a substantial willingness to pay for a cattle TB vaccine amongst farmers. Farmers primarily valued the ability of a vaccine to reduce the probability of a breakdown. However, farmers also valued insurance backing that would pay compensation to farmers should vaccinated cattle test bTB positive. Farmers appeared to value the ability of a vaccine to reduce the severity of a breakdown somewhat less. Two different methods were used to estimate willingness to pay, and gave broadly comparable results. Farmers’ perception of the risk of their cattle having a TB breakdown was positively correlated with their willingness to pay for a TB vaccine. In general, cattle farmers did not think that the development of a cattle vaccine was, by itself, the answer to the TB problem; rather, its role was as part of a combined strategy with a number of elements, including wildlife control.
 
The findings were based on qualitative information from interviews with a stratified sample of farmers in England and Wales (selected using VetNet database), who had experienced a bTB breakdown. It was stressed that further examination of qualitative data would be necessary to explore the issues.
 
Sally
Email comments from Ruth (14/11/10)
 
I think to bear in mind always that protection from disease or reduction in lesions is not the same as protection from infection. It has been difficult in humans to look at the protection from infection the BCG vaccine might confer. It is thought this does occur, but it would vary in human populations and depend on age of vaccination (young) and lack of exposure to subverting environmental mycobacteria species, which is very variable in the world.
 
Even the most scrupulously careful PM examination would not be sufficient to reveal lack of infection with certainty (the infection might be latent and at least some latent foci do not yield culturable mycobacteria). Really the immune response and time are the best assessors of this. Lack or switching off of Th1 or cell mediated immunity, called anergy, is replaced by the formation of antibodies to mycobacterial proteins. Antibodies are a Th2 immune response so called, and are secreted by B cells primed by certain populations of helper T-cells- different to the populations of T-cells active in Th1 responses. In humans about 10% of actively infected persons are expected to be antibody positive and most of these will have a negative skin test called the mantoux in humans. The black hole in diagnosis in cattle is an antibody test. This is used in badgers as in the field vaccine study and this detects infections late in their course and widespread etc in badgers.
 
As I mentioned the new young cattle born each year would have to be vaccinated. I have not heard even in the cattle trials of a yearly vaccination of older cattle. They would have abcesses at the vaccination site and it would acheive no benefit. Not breeding cattle yourself you should remember that each farm where animals are bred will double their cattle population each year with the newborn calves (in the case of sheep triple it as most ewes have twins).
 
Just to emphasize again that BCG vaccination must be given to an uninfected animal or human to have any beneficial effect.
 
The equations for levels of vaccination for herd immunity are quite complicated and they are oversimplifying the question in the suggested example for comparison, FMD. For one thing infectivity, following infection, with TB once it occurs in an individual is likely to continue for that individuals life, therefore vaccination of all the contacts is necessary as they are exposed during the life of the infectious individual. I am sure there are estimates of human infection rates in households with an index case and they will be very high eventually over time. I have an old book I could probably find a figure for you.
 
If some of the vaccinees are infected, not being protected against infection, if and when they become infectious later in their lives they will also remain infectious for their life. This would surely entail vaccination of the genereations for at least several of them depending on the efficaciousness of the vaccine. But if the vaccine does not prevent infection but does prevent the individual becoming infectious this again would be more effective. (In actual fact the BCG may prevent some individuals from becoming infectious but not all.) In humans the removal of infectious possibly vaccinated cases, has been done by treating infectious individuals with chemotherapy so they no longer shed TB for the rest of their lives- screening for these has added to this benefit removing more of them by detecting more of them even those that are not ill.
 
BCG is a live vaccine so is processed differently to a dead one. It is irrelevant to compare it to viral vaccines- the mechanism of protection is very different as bacteria and viruses are different beasts and the immune system responds differently. Even using the DNA or pox vector vaccines to boost immunity to TB in conjunction with BCG, these are all designed to deliver mycobacterial proteins of importance in the protective effect of macrophage killing of mycobacteria, into the appropriate immune cells the same as those stimulated by BCG. Dead vaccines are scavenged by different immune cells so the pathways evoked are different. The latter are more likely to evoke just the antibody response. Antibody immunity in TB is useless.
 
Yes the experimental assessment of vaccine protection is not the same as natural exposure. It is thought that in natural TB infections very few viable organisms need be inhaled to initiate an infection in the respiratory tract. Many more need to be swallowed to initiate infection in the GI tract. It is also possible that the pathogenicity of the natural organisms may be different to laboratory cultured organisms.
 
The DIVA test for BCG vaccinated cattle is likely to be the gamma interferon test with all its faults and difficulties, but using peptides or recombinant proteins making it much more specific but less sensitive thatn the Bovigam test the currently used gamma interferon test in cattle. It would in fact be similar to that used for humans that detects both latency and infection without distinguishing between them (the Quantiferon Gold test so called).
 
Though M bovis or M tuberculosis infect for life- whether or not they can be cultured from the site of latency- the BCG vaccine is not thought to give rise to a latent infection nor an active local infection at or near the site of injection of exposure for more than weeks or perhaps a few months. This is part of the attenuation acheived in the 1920s not that they would have been able to assess this or aim for this at the time. They were looking for clinical attenuation of M bvois in calves. I looked in some cattle papers and there is no evidence that I know of in cattle, or humans for that matter, that BCG gives rise to a persistent or latent infection.
 
 
 
Sally
DEFRA's consultation papers: Bovine tuberculosis: the Government's approach to tackling the disease .... Sept 2010. The full text of the extracts from the documents below can be found at:
https://www.defraconnect.defra.gov.uk/assets/a/0/5/3/d2226304add8830b222ac2157ddb4c9080781742d150783400/Consultation%20Document....
https://www.defraconnect.defra.gov.uk/assets/0/3/1/1/8149f28c5d296378fbae09a687b24c9080a851e4d147892380/Annex%20C%20Scientific%2...
https://www.defraconnect.defra.gov.uk/assets/9/3/5/b/59d4f228d1f73b0a2dba52eff7b04c9080c5e829b740656819/Annex%20D%20Veterinary%2...
https://www.defraconnect.defra.gov.uk/assets/9/3/5/b/59d4f228d1f73b0a2dba52eff7b04c9080c5e829b740656819/Annex%20D%20Veterinary%2...
ONCE AGAIN THE PAPERS CONCENTRATE MAINLY ON BADGERS AND NOT CATTLE! HERE WE PULL OUT THE USEFUL INFORMATION REGARDING CATTLE VACCINATION. WE BELIEVE THAT THE VACCINATION OF CATTLE AGAINST BTB WILL GIVE AS GOOD A CONTROL AS THE EXISTING TESTING PROGRAMME, BE EASIER FOR FARMERS AND SAVE MONEY TOO.
Section 2: A package of measures to tackle bovine TB, page 12, para 28, tells us that the Government is committed to putting in place a package of measures to tackle bovine TB which adds up to a balanced programme, with measures deployed in a flexible way to address TB risks at the local level. ARE THE PROPOSALS OUTLINED USING A SLEDGEHAMMER TO CRACK A NUT?
Para 28 goes on to say that many of the measures are already in place, one of these is focused research and development (including development of a cattle vaccine).
Page 21 sets out 'Research and Development Costs'. Between 1991/92 and 2009/10 DEFRA has funded over 90 individual research projects and invested a massive £86 million, much of this directed towards developing vaccines and associated diagnostic tests YET WE STILL HAVE THE SAME UNRELIABLE, TIME CONSUMING, SKIN TEST WITH THE ASSOCIATED HEALTH AND SAFETY RISKS FROM SO MUCH CATTLE HANDLING.
On the same page under 'Cattle vaccines research' we are told there is currently no cattle vaccine available. In the same sentence we are told that cattle vaccination could have potential benefits in reducing prevalence, incident and spread of bovine TB in the cattle population and could also reduce the severity of a herd breakdown, regardless of infection being ion produced by wildlife or cattle. THE BCG VACCINE IS ALREADY AVAILABLE, IT HAS BEEN USED SUCCESSFULLY IN FIELD TRIALS ON CATTLE AND IS USED TO CONTROL TB IN OTHER SPECIES. It goes on to say that cattle vaccine will not guarantee that all cattle vaccinated are fully protected - BUT THE EXISTING TESTING PROGRAMME FAILS IN THIS RESPECT!
Page 23
62. Defra had invested £18 million by the end of the last financial year on the development of cattle vaccines and associated diagnostic tools (AND £11 MILLION ON DEVELOPING A BADGER VACCINE!). We aim to have a licensed cattle vaccine by 2012. This vaccine is BCG (Bacille Calmette-Guérin, the human TB vaccine) which sensitizes cattle to the mandatory tuberculin skin test for some time after vaccination and can lead to a positive result when an animal is not infected with M. bovis (a ‘false positive’). Therefore Defra is also developing a diagnostic test to differentiate infected from vaccinated animals (known as a ‘DIVA’ test) that could be used alongside the tuberculin skin test, where necessary, to confirm whether the animal is indeed infected. Our aim is also to have the DIVA test approved by 2012. (SO, WITH THE POLITICAL WILL, A PROGRAMME FOR CATTLE COULD BE STARTED FROM THIS DATE).
Para 63. However, there is currently an EU ban on vaccinating cattle against M. bovis and only cattle which test negative to the tuberculin skin test can be traded in the EU. These restrictions also have consequences for trade in cattle products. Hygiene rules for food of animal origin stipulate that raw milk must come from cows belonging to a herd which is officially TB-free (OTF). Milk from non-OTF herds can still be used but must be pasteurised, and milk from cows that give a positive reaction to a bovine TB test cannot enter the food chain. Once a licensed cattle
vaccine and effective DIVA test are available, the basis for declaring herds tuberculosis-free will need to change. As part of the ongoing consultation on the new EU Animal Health Law, we will be using the strong scientific and technical evidence on the efficacy and safety of the cattle vaccine and the role of a DIVA test to request the necessary changes to EU legislation to lift the requirement for the skin test to be the only test to confer OTF herd status. Due to the need to change EU legislation, which is a lengthy process, we anticipate that a cattle vaccine and DIVA test could not be used in the field before 2015 at the earliest (THIS IS NOT GOOD ENOUGH - WITH THE POLITICAL WILL THIS COULD BE BROUGHT FORWARD, IF NECESSARY USING DEROGATION).
In parallel with discussions at EU level we will be working with the food industry and regulators to provide the necessary reassurance about the safety of meat and other animal products entering the human food chain where they derive from animals which tested clear of bovine TB but which had been vaccinated. (THE BCG VACCINE HAS BEEN IN USE FOR YEARS AND CONSIDERED ONE OF THE SAFEST VACCINES AVAILABLE).
‘Scientific evidence of vaccination’, page 5 of the 'Badger TB vaccines' Annex C
Para 15. The vaccine Mycobacterium Bovis Bacille Calmette-Guérin (BCG) is a live attenuated (pathogen which has been 'weakened' and produces immunity but does not cause disease in the immunocompetent individuals) strain of Mycobacterium bovis (M. bovis), the bacterium that causes bovine tuberculosis. It is the most widely used human vaccine globally providing protection against tuberculosis caused by both M. bovis and Mycobacterium tuberculosis (the bacterium that causes most cases of human tuberculosis) and remains one of the safest vaccines available.
Para 16. BCG has also been widely used for vaccine studies in laboratory animals and is currently being developed for use in a variety of livestock and wild animals. In addition to badgers, vaccination with BCG has been shown to generate protective immunity in mice, guinea pigs, monkeys, rabbits, cattle, ferrets, brushtail possums, deer, white-tailed deer and elk (Corner et al., 2008; Griffin et al., 1999; Buddle et al., 1995; Aldwell et al., 1995a; Aldwell et al., 1995b; Abolhassani et al., 2000; Dannenberg et al., 2000; Cross et al., 2000; Lagranderie et al., 1993; Lyadova et al., 2001; Waters et al., 2003; Waters et al., 2004).
THIS WHOLE SECTION INDICATES THAT TRIALS HAVE SUGGESTED VACCINATION WILL BE SUCCESSFUL ENOUGH FOR BADGERS SO ONE WOULD ASSUME THE SAME CRITERIA CAN BE APPLIED FOR CATTLE.
Para 42 is particularly relevant.
The efficacy of BCG in laboratory infection studies may be underestimated as artificially high doses of M. bovis are commonly used to induce experimental infection. Although we don’t have evidence for badgers, there is some evidence in some other animal species, that in settings of natural transmission of M. bovis from infected animals to vaccinated individuals, BCG vaccination may confer complete protection from disease in some vaccinated individuals, in addition to reducing pathology in others. This is highlighted by a recent field experiment in cattle conducted in Ethiopia (SUCH COUNTRIES CANNOT AFFORD TO CULL CATTLE NEEDLESSLY) with Holstein cattle which demonstrated that BCG vaccination can prevent disease in a substantial proportion of cattle as well as significantly reduce pathology in others (Ameni et al., 2010). BCG vaccination has also been shown to reduce the incidence of tuberculosis in free-living brushtail possums following a recent field vaccination study of possums in New Zealand (Tompkins et al., 2009).
Para 44 warns that BCG vaccination is not 100% effective. BUT THEN NEITHER IS THE SKIN OR BLOOD TESTS). IT GOES ON TO SAY THAT (REFERRING TO BADGERS). .. In addition, as far as we know, BCG vaccination does not benefit already infected animals. Disease control benefits would be expected to accrue incrementally during a vaccination campaign as the number of successfully immunised badgers (COULD ALSO READ CATTLE) increased and as previously infected animals died off. The main benefits of vaccination may take some time to develop, especially where the weight of infection is greatest, and are likely to be through the longer-term build up of herd immunity in the badger (OR CATTLE) population.
Extracts from Annex D ‘Introduction and background’
What is a vaccine?
7. A vaccine is “a preparation of antigenic material [that is] used to induce immunity against pathogenic organisms”1. Vaccines stimulate antibody production and/or prime the body’s white blood cells to respond to a pathogen. The exact mechanism depends on which type of immune response is protective against a particular pathogen.
8. However, not all vaccines target pathogens: some immuno-contraceptives for instance target reproductive hormones. They “fool” the body into thinking these hormones are foreign and therefore stimulate antibody production to these hormones, decreasing the reproductive ability of the individual.
Basic immunity
9. The immune response is divided into two components: innate immunity and adaptive immunity. The innate immunity is the first defence mechanism animals use against infection. It includes physical barriers to infection such as the skin and stomach acid. It also includes some of the inflammatory cells that digest bacteria, such as macrophages. Many pathogens have evolved to overcome innate immunity and so the more complex, adaptive system is required. Adaptive immunity encompasses antibody production and cell-mediated immunity (CMI) comprising several cell subsets of white blood cells called T cells. Some of these T cells, the so-called T helper cells (Th) can stimulate the rest of the immune system to help fight infection. One example of such a Th cell sub-population is the Th1 cells: these stimulate macrophages to kill ingested mycobacteria).
10. Different pathogens will invade different compartments and cells in the body, and each immune response is therefore unique and tailored to that pathogen and body system. The types of pathogen will also affect the exact immune response stimulated.
11. Pathogens in the TB family, including Mycobacterium bovis (M. bovis), are intracellular organisms that grow inside macrophages (the cells that digest bacteria as part of innate immunity). This enables them to evade many of the host’s natural defenses. The immune response that results is therefore complex and the details of what constitutes a protective immune response are not fully known, although it is accepted that CMI and, in particular, Th1 cells play a major role in protective immunity against mycobacteria (Delogu and Fadda 2009). This can make producing an effective vaccine more challenging than producing vaccines against viral infections where antibody is often the main component of immunity.
Vaccine efficacy
12. The ultimate success of a vaccine (its efficacy) in an individual will depend on its ability to stimulate the appropriate immune response to infection. Genetic and environmental factors can influence the immune response an individual mounts to a particular pathogen (and a vaccine).
13. The efficacy of a vaccine in a control programme will depend on what the policy-maker aims to achieve with vaccination. Vaccines can –
a.prevent infection and colonisation;
b. prevent clinical disease;
c. decrease excretion of an organism and thus pathogen transmission; and
d. decrease prevalence of a pathogen in a population.
16. TB vaccination can achieve this by increasing the proportion of non-susceptibale badgers (OR CATTLE?) and so ultimately decreasing the proportion of infected badgers (OR CATTLE?).
Vaccination strategies
17. Vaccination for animal disease control can be used –
a. around an infected area to “contain” infection (so called ring vaccination); b. across an area to act as a “fire break” to stop the spread of disease;
c. across a population to disrupt transmission from small pockets of infection;
and
d. in animals before exposure (i.e. in young animals) to protect them before they enter an environment posing a high risk of exposure.
 
TB vaccination
18. The bacille Calmette-Guerin (BCG) vaccine was developed early in the 20th century by attenuating (making less virulent) an M. bovis isolate from a cow. Early use in children in Europe showed that it was effective, particularly at protecting childhood forms of TB (referenced in Delogu and Fadda, 2009). This vaccine is still the only licensed human TB vaccine in the world, indicating its beneficial use and the difficulties in developing another more effective TB vaccine.
19. Vaccination of animals against TB has been suggested as a useful tool “wherever animals of high economic, social or conservation value are involved and test and slaughter or culling programs are not applicable” (Corner and others 2002).
 
20. A review of the effectiveness of BCG vaccine in animals was conducted by Suazo et al. (2003). They state that, in cattle, “vaccination decreased infectiousness of infected animals (rather than by preventing infection) by reducing the size of lesions and the burden of mycobacteria.” However, the efficacy of BCG in laboratory infection studies may be underestimated as artificially high doses of M. bovis are commonly used to induce experimental infection. In settings of natural transmission from infected animals to vaccinated individuals, BCG vaccination may confer complete protection from disease in some vaccinated individuals. This is highlighted by a recent field experiment in cattle conducted in Ethiopia with Holstein cattle which demonstrated that BCG vaccination can prevent disease in a substantial proportion of cattle as well as significantly reduce pathology in others (Ameni and others 2010). BCG vaccination has also been shown to reduce the incidence of TB in free-living brushtail possums following a recent field vaccination study in New Zealand (Tompkins and others 2009). Another recent field experiment in cattle demonstrated that BCG vaccination significantly prevented nasal shedding of bacteria in vaccinated calves (Lopez-Valencia and others 2010) thereby demonstrating that BCG vaccination decreases the infectivity of vaccinated animals.
Herd immunity
26. Vaccination of enough individuals in a population can have a protective effect for the remaining unvaccinated animals: this effect is called herd immunity and is the basis for the efficacy of many large-scale population vaccination programmes (in humans and animals). Vaccination needs to be continued to maintain herd immunity.
27. Herd immunity works because there are enough protected individuals in a population to prevent or decrease transmission of disease, therefore protecting the remaining unvaccinated animals.
28. A good example of the importance of herd immunity is the combined MMR (Measles Mumps Rubella) human vaccine that has been used for many years in the UK and has been very successful at controlling these childhood diseases. However, the “MMR scare”, where the vaccination was linked to autism, resulted in decreased vaccine uptake. As the numbers of vaccinated children decreased, the number of cases of these diseases increased.
29. The benefit of herd immunity is that there is no need to vaccinate 100 % of susceptible animals in a population to get the protective benefit from vaccination; only enough to break transmission is needed (i.e. get “in front” of the disease).
30. The minimum level of vaccine coverage needed for herd immunity can be calculated from a mathematical value called R0, or the net reproduction number. R0 is an estimate of the number of animals one infected animal will, in turn, infect. An early estimate of R0 for TB in badgers was low, at around 1.2 (Anderson and Trewhella 1985). Although this assumed a simple density dependence which has been subsequently questioned, such a low R0 indicates relatively few animals need to be protected to get herd immunity against TB, i.e. to reduce R0 below 1 (compare this with fast-moving, highly infectious diseases such as FMD, where the R0 number is relatively high, and so a greater proportion of the herd needs to be immunised to get herd immunity).
40. Research has shown that BCG vaccine in humans can be overwhelmed in certain situations, particularly in some developing countries. It has been proposed that this is due to exposure to environmental mycobacteria (Andersen and Doherty 2005). The same authors suggest a large pool of latent TB might also act in the same way to “overwhelm” vaccination programmes in humans. There is concern that the same might be true for BCG in badgers, in which case vaccination will not be able to reduce cattle TB in high incidence areas.
41. However, BCG in animals seems to provide much more consistent protection (Andersen and Doherty 2005) and the recent results from the BVS agree with this. Unlike culling however, large-scale field trials of the efficacy of BCG in badgers at reducing cattle TB incidence have not been conducted.
 
 
 
Sally
Email discussions regarding vaccination between Ruth and Sally 11th and 12th November 2010
 
Dear Ruth, I know you are skeptical about cattle vaccination but what do you think about the recently published info for badger vaccine which claims a '74 per cent reduction in the proportion of wild badgers testing positive to the antibody blood test for TB in badgers'. Notwithstanding the added bit re the blood test not being an absolute indicator of protection from disease, so the field results cannot tell us the degree of vaccine efficacy, this seems a very positive result and presumably figures could be similar for cattle. bearing in mind, too, that beef cattle are generally slaughtered at only 3 years and dairy on average 5 years, surely this does make cattle vaccine a good option and far better than wretched skin test.
 
Dear Sally, the antibody test (as done in the Badger statpak) would only become positive late in the course of infection when there is a heavy load of M bovis and it is widespread in the body, this could be before becoming ill or of course the badger could already be ill- it is likely to be shedding mycobacteria at this stage. The 74% protection is against this late stage of disease when the animal is likely to be infectious. This is the disseminated infection stage when shedding occurs from urine etc. This is of course what the vaccine is successful in doing in human neonates, preventing disseminated infection and overwhelming disease.
 
Very useful (in humans) in badgers and perhaps would save cattle from exposure to M bovis deposited in badger urine for instance. Note the caveat that BCG vaccination has never eliminated TB from a human population where it has been applied. I am not sure whether it could be expected to eliminate M bovis from badgers, unless the vaccine gave some protection against infection in the first place. If oral vaccination of neonate badgers took place and given they don't live long and their intense exposure to individuals shedding large amounts of mycobacteria in the urine etc. had been removed maybe......
 
It is said this type of widespread TB infection in the body is something to which badgers are particularly prone (perhaps like camelids and goats too)- unlike cattle above the age of young calves and humans above the age of neonate or young child.
 
The vaccine would have to be given to uninfected badgers to be effective (I would think they can't know this in the fields trials). This is why they think the best use of vaccination would be in a ring around the culling area where the badger population is not so likely to be infected. Culling to remove at least some of the infected badgers in the culling area presumably sited in a TB hot spot in cattle where M bovis was also known to be present in badgers would be logical in attaining the greatest effect on reduction of transmission from badgers to cattle combined with ring vaccination.
 
Unfortunately there is not a test for antibodies in cattle developed yet. I think this is a significant hole in the armoury of the fight against TB in cattle.
 
I do not know how protective the vaccine is for calves. NZ has tried it in cattle and found their best option still remains herd screening and removal of the possum. But they are in a different place to us.
 
If we vaccinate cattle we are looking at the gamma interferon test for cattle but using peptides. This is a relatively difficult test but would be much more specific than the current Bovigam test using whole protein from M bovis and avian mycobacteria species, it may also be less sensitive. If we had an antibody test for cattle this would help to detect widespread or advanced infection in cattle and be able to deliver removal of infected cattle in a screening programme in vaccinated herds.
 
I think it is a disgrace that the vaccination trials are only now beginning on badgers. Is this the effect of the Badger lobby and the Krebbs trials?
 
Thanks Ruth, very useful. I wondered if the fact that this trial seemed to give 74% protection in badgers, could it therefore be assumed it would give similar protection in cattle along the same lines as you say? As TB takes so long to develop, surely the relatively short life-spans of cattle will aid vaccine effectiveness or am I missing the point somewhere?!
 
Dear Sally, the protection offered to badgers by the vaccine is not necessarily freedom from infection, merely from disseminated infection and widespread disease and shedding in high titre.
 
The number of infected cattle that would go on to get disseminated infection and widespread disease is probably much smaller proportionately. Anyway I don't believe that cattle often get renal and urinary infection and so shed in the urine like badgers (neither do humans)- they may if infected go on to shed from the lungs on the breathe, or in their milk. If the vaccine had offered a good level of protection against infection in cattle rather than merely protection against disease NZ would still be using it widely in their at risk cattle.
 
As you know the vaccine does not affect the pulmonary infection in humans nor therefore shedding in the sputum and on the breathe.
 
As the present goal is infection free cattle not merely disease free cattle then I am not sure what the policy of vaccinating cattle could acheive unless the vaccine can be shown to be protective against infection.
 
I think there should be a new interim strategy for cattle aiming for control short of the present wholesale slaughter of any bovine that may have latent or active infection and any that are unfortunate enough to give a false positive on the tests.
 
Thanks Ruth, very interested in your last paragraph - how would that work?
 
Dear Sally, I am not sure either. First of all if we vaccinated all neonatal calves then any being finished as meat are going to be short lived and should not be expected to develop advanced disease such as shedding from the lungs and of course they will not be breeding and spreading infection by milk for instance (calves don't have pasteurised milk). On the farms which only finish cattle and there are quite a few of these, many with outside or extensive grazing for at least some of their lives, should not have skin test positive animals culled for instance indeed they could buy untested but vaccinated calves. They need have no tests unless there is an ill calf, this could have an antibody test done for instance for M bovis infection
 
That then leaves the problem of any cattle on the move who are not going to a finishing farm and will be used fo breeding.
 
If they don't move then if they don't develop progressive disease that is heading for widespread infection and ultimately disease and shedding, then is there a need to cull them? It could be a latent or well contained disease when antibody negative. If the farm was screened annually with a blood test for antibodies and antibody positive animals culled then late infections would be removed and opportunity for spread by cattle shedders eliminated more or less. All positive anitbody tests should be verified by array and the animal have a post mortem and culture.
 
If the cattle move of ffarm then there should be a health history relevant to the farm of origin on the passport. The vets could be paid to do this rather than so much TB testing, and the passport electronically updated. Actually this should not be confined to just TB but a whole number of infections such as Johne's, BVD, IBR, leptospirosis, husk, vaccination history and so on. The cattle to be moved off the farm should all have a standard skin test. If there has been a history of TB on the farm they should have a gamma interferon test (using peptides and not the Bovigam test in its current format) and an antibody test in addition. The option for the farmer should be to keep the skin test or and gamma interferon test positive animals on his farm provided they are healthy, & provided they are antibody test negative.
 
If one's farm has had TB in the past or has some skin test or and gamma interferon positive animals then buying a 3 test negative animal from another farm which has had or has TB is not a great risk.
 
If one's farm is and has always been negative for TB tests then whilst having the assurance the animal one is buying is skin test negative one can avoid animals from an infected farm, past or present, to avoid any recently infected animal.
 
Confidentiality of TB and other infections would not be possible and is misguided in my opinion. Actually there are diseases in sheep such as CLA, Jaagsticke's disease, tick borne infections and scrapie which should also register on a farm's 'general sheep passport'.
 
I am interested in the development of sensitive tests for infection such as detection of specified proteins in blood for instance, differentiation of antibody response to specified proteins; these might be good indicators of advancing infection in the face of poor or ineffectual immune control by the infected animal. Whilst gamma interferon testing will remain challenging and expensive these latter could be very cheap, automated and reliably applicable. Another test in the future which could also be cheap is a microarray to detect RNAs in the blood associated with active TB infection or the immune reponse to it.
 
In my opinion the positive standard skin test is probably the best of the current bunch of tests. I am far from convinced the Bovigam test has anything near the specificity claimed for it in widescale practice in the UK. The antibody test in cattle has not been developed- it has been for humans, badgers and elephants and is very useful. No test will of course be 100% accurate, but a strategy of this kind should avoid killing large numbers of animals with inconclusive, severe reading skin tests, the low or NK cell false positives on the Bovigam test and loads of cattle with well controlled infections who are not infectious and most probably will never be. It also does not suggest immediate killing of cattle except when there is a verified antibody positive animal and this is monitored by PM and culture. Many infected animals will live and can be retested and observed all their lives and picked out when infection is advanced.
 
If there is the attempt through culling and ring vaccination to control M bovis in badgers (oral vaccine will be cheaper than capture and injection) with a closer monitoring of infection in badgers (I believe they should bite the bullet and do PCR testing of badger latrines despite the pussy footing DEFRA are doing on the issue now, as the important point is to monitor for high level shedding) Farmers can stop being terrified, the project will not cost the 100 million it does now so savings will be possible. Control of TB will take a long time, there will be no solution like vaccination against BTV8 that was effective in one season. It is a process of attrition- to gradually reduce the number of infected animals transmitting M bovis and the number of animals that any one infectious animal can infect, so R0 falls below 1 so the disease will be on a course to die out over time.
 
Thank you Ruth, some very interesting suggestions and I wonder how we can get all this explored further? Presumably vaccinating calves (annually?) and implementing the other suggestions, will bring a reduction in a fairly short time and be far more cost effective but not necessarily much easier for farmers in short term? Would annual vaccination then be necessary?
 
So even though DEFRA have said a vaccine for cattle (with DIVA test) will be licensed in 2012 you don't think vaccination of older cattle will be viable?
 
Dear Sally, BCG vaccination is only done once. It is a live vaccine.
 
There would have to be development of better testing, particularly the antibody testing for cattle. Education of vets and farmers would be another big hurdle.
 
I doubt very much that vaccination of older cattle will make any difference because they will already have been exposed to environmental mycobacteria. It will have to rely on the vaccination of young calves I would think, the younger the better. I am not sure if this is being looked at for cattle by any research groups, it is quite clear in humans that this is the case.
 
I have just looked at the summary on Warmwell of the efficacy of intramuscular BCG vaccination studied on badgers submitted by GLyn Hewinson et al to DEFRA. The badgers were only kept alive for 12 weeks after vaccination and the vaccinated animals were protected in so far that they had a significantly smaller number of lesions PM and significantly less shedding. There is no mention that the vaccine protected them from getting infected from the deliberate exposure dose of 1000 organisms into the bronchi. Interestingly there is not a sinble mention of oral vaccination even in the introduction to that report.
 
In the case of orally vaccinating badgers one might have to put out vaccine bait annually because one does not know how many badgers and which have eaten the vaccine bait, and there are new cubs annually, new susceptibles and they will need to be vaccinated. In the case of farmers vaccinating calves as long as there was some kind of proof of BCG vaccination then I do not see why it should be repeated. There have been efforts to develop DNA vaccines that would allow one or other of the M bovis proteins to be expressed to boost or redirect the response to a protective one usually after an initial priming BCG.
 
I am rather appalled at the abdication of a strategy in England as the proposal is to allow farmers to apply to cull or vaccinate badgers at their own expense. I have just had a letter from the CLA. Each landowners name would be secret and the persons licensed to cull or capture and vaccinate will also be secret. It does not sound as though there will be culling areas and ring vaccination just a random application by landowners selecting to do either. No appreciation of the fact that vaccination of an already infected badger will make no difference. The assumption would be that badgers on a farm with a TB problem would be infected. In the uninfected ring zones of TB areas no one will bother to vaccinate badgers at what I am sure will be a considerable expense.
 

 
Sally
Email from DS 10/11/10 Is the badger vaccine the same for cattle? And is the vaccine, if injected into live cattle, safe with regards to subsequent meat for human consumption.?
 
Email (10/11/10) from KB (New Zealand microbiologist replied; 'I am sorry, I do not know what the badger vaccine consists of, but if it really protects badgers then it should do the same for cattle. With regard to the meat of vaccinated cattle, there should be no problem. In New Zealand, cattle are vaccinated against brucellosis, without the meat being affected. The only problem with vaccinating animals against a pathogen like Brucella or TB is that this invalidates any immunologically based test for infection. One cannot then tell whether the antibodies identified in the test are due to vaccination or infection'.
 
According to several books on the subject, BCG vaccine is one of the safest vaccinations available.
 
Sally
http://www.environmental-expert.com/resultEachPressRelease.aspx?cid=11227&codi=207057&lr=1&word=bovine+tb
 
On the 9/11/10 Defra made public supporting data behind the successful licensing of the first tuberculosis vaccine for badgers (Badger BCG), which was licensed by the Veterinary Medicines Directorate in March this year. The studies were carried out by the Veterinary Laboratories Agency (VLA) and the Food and Environment Research Agency (Fera). The laboratory studies with captive badgers demonstrated that the vaccination of badgers by injection with BCG significantly reduces the progression, severity and excretion of Mycobacterium bovis infection. A key finding of the field study, conducted over four years in a naturally infected population of more than 800 wild badgers in Gloucestershire, was that vaccination resulted in a 74 per cent reduction in the proportion of wild badgers testing positive to the antibody blood test for TB in badgers. The blood test is not an absolute indicator of protection from disease, so the field results cannot tell us the degree of vaccine efficacy. While the findings indicate a clear effect of vaccination on badger disease, data from the laboratory and field studies do not lend themselves to giving a definitive figure for BadgerBCG vaccine efficacy. Nor do they provide information on the effect of badger vaccination in reducing TB incidence in cattle.
 
A scientific paper summarising the results of the injectable BCG badger vaccine research has been accepted for publication by the scientific journal Proceedings of the Royal Society B (Biological Sciences) and will be published shortly.
 
 
 
 
 
Sally
We asked the alpaca experts (/www.alpacatb.org) the following questions (email 14/10/10)
 
1. Has there been any progress for a BCG vaccination for alpacas yet?
2. The individual the subject of the video (alpaca shown with symptoms of coughing and higher than expected breathing rate), what would have been the likely scenario if it had been left to live? Would it have died? Would it have recovered? Could it have been treated successfully at that stage?
 
Response email from Gina (vet) 14/10/10
The BCG vaccine has been found to be effective in cattle and badgers as well as humans, so may well work in camelids BUT it's not legal to use it at present. This is partly because it is not known what effect vaccination would have on TB tests and we don't yet have a test which can distinguish between infected and vaccinated animals.
 
The animal suffering side effects may well have apparently recovered (most did, a few died) but all of them turned out to have rampant TB, so showing side effects was a better predictor of TB infection than the result of the skin test.
 
Treatment is strongly discouraged by Defra because it's not possible to say whether the animal is cured, infected, infectious or what.
 
 
 
Sally
On 17th September 2010 the 'Field evaluation of the efficacy of Mycobacterium bovis bacillus Calmette-Guerin against bovine tuberculosis in neonatal calves in Ethiopia' (http://www.ncbi.nlm.nih.gov/pubmed/20719984), was published.
 
Whilst I realise that the conditions in Ethiopia are very different to the UK (and they have a lot more cattle!), if this shows success for a country where there is currently no control (and presumably therefore significant TB levels), then the efficacy would be even better in the UK where even in the so called 'hot spot' areas levels, in comparison, are far lower.
 
Comment from Ruth (email 29/10/10) ' I did look at one reference published in 2010 by Ameni in which he evaluated the response to BCG of crossbred neonatal calves vaccinated under the age of one month and Zebu calves who seemed not to have such a marked gamma interferon response to the BCG vaccine as the crossbred calves. In the abstract you sent me I notice they are holstein calves (I wonder how appropriate these are for Africa and high maintenance!). We must assume that at least some of the adult skin test positive cattle were infectious (I am not sure if they were naturally infected or experimentally infected) but at least they were kept in field conditions with the calves. I wonder what this means in Ethiopia- grazing outside or in corrals outside eating harvested forage?
 
Anyway I am glad to see the vaccine was apparently effective for just over half the animals. This makes it a viable option in Ethiopia. I don't think the efficacy could be assumed to be better in the UK. I am not sure what effect environmental mycobacteria might have in the UK compared with Ethiopia; the human BCG vaccine trial results were varied in different parts of the world. And it may be that breed of cattle influence the outcome, as of course would age of vaccination. Under one month of age is really a human definition of neonatal, I am not sure what this should properly be for cattle, one month of life outside in the field is quite a long time during which exposure to environmental mycobacteria before vaccination can take place.
 
I would also be pleased if they used the ESAT-6 and CFP-10 genetically engineered peptides in the gamma interferon test, as it would be more specific than the Bovigam test as it would not trigger a non-specific response from the natural killer cells which we and cattle possess. M kansasii infection would cross react in this test but that is uncommon in cattle Dr Vordermeier has said to me.'
 
 
 
Sally
Information under Access to Information
 
QUESTION: I see that DEFRA has indicated (see extract below - from Bovine Tuberculosis: the Government's approach to tackling the disease and consultation on a badger control policy, September 2010) that the cattle vaccination will be licensed by 2012 and the DIVA test alongside it. Is DEFRA intending to take any action to seek a derogation from the EU so a vaccination programme can be implemented from 2012? If not, please explain why not?
 
http://www.defra.gov.uk/corporate/consult/tb-control-measures/100915-tb-control-measures-condoc.pdf
 
'62. Defra had invested £18 million by the end of the last financial year on the development of cattle vaccines and associated diagnostic tools. We aim to have a licensed cattle vaccine by 2012. This vaccine is BCG (Bacille Calmette-Guérin, the human TB vaccine) which sensitizes cattle to the mandatory tuberculin skin test for some time after vaccination and can lead to a positive result when an animal is not infected with M. bovis (a „false positive‟). Therefore Defra is also developing a diagnostic test to differentiate infected from vaccinated animals (known as a „DIVA‟ test) that could be used alongside the tuberculin skin test, where necessary, to confirm whether the animal is indeed infected. Our aim is also to have the DIVA test approved by 2012.'
 
Sally
Information under Access to Information Request DWO0000192539 made 27/08/10
 
QUESTION: Are you able to confirm that the cattle vaccination and DIVA test selected will be available / introduced as an alternative approach to the existing testing programme in 2015 as has been mentioned in several government reports.
 
RESPONSE (email 30/9/10) : We can advise that the earliest projected date for the use of a BCG cattle vaccine with a differential diagnostic test to Differentiate Infected from Vaccinated Animals (a so-called 'DIVA test') is 2015. This is because cattle vaccines are currently prohibited under EU legislation as they are based on BCG, which interferes with the statutory primary diagnostic test, the tuberculin skin test. Vaccinated cattle would therefore react as if infected and herds could not be declared Officially TB Free (OTF). Therefore, as part of the UK research programme we are developing a diagnostic test, a so-called 'DIVA test'. Changes will be required to the EU legislation to allow this test to be used in place of, or alongside the tuberculin skin test to confer OTF status.
 
The possible future use of cattle vaccines has been discussed with the European Commission and the Commission has indicated that an accredited DIVA test will be critical for a cattle vaccination policy. We will continue to work closely with the Commission and other Member States on this.
Regards,
 
Nadeem Raja
 
TB Communications Unit
Bovine TB Programme
Food and Farming Group
Department for Environment, Food and Rural Affairs
Area 6E, 9 Millbank, c/o Nobel House, 17 Smith Square, London SW1P 3JR
 

 
Sally
http://www.defra.gov.uk/corporate/consult/tb-control-measures/100915-tb-control-measures-condoc.pdf
Extract from DEFRA's report is set out below:
62. Defra had invested £18 million by the end of the last financial year on the development of cattle vaccines and associated diagnostic tools. We aim to have a licensed cattle vaccine by 2012. This vaccine is BCG (Bacille Calmette-Guérin, the human TB vaccine) which sensitizes cattle to the mandatory tuberculin skin test for some time after vaccination and can lead to a positive result when an animal is not infected with M. bovis (a „false positive‟). Therefore Defra is also developing a diagnostic test to differentiate infected from vaccinated animals (known as a „DIVA‟ test) that could be used alongside the tuberculin skin test, where necessary, to confirm whether the animal is indeed infected. Our aim is also to have the DIVA test approved by 2012.
 
Comment:
Para 63. is about changing the EU laws, which says it will take until 2015 to get EU approval. However, a derogation could be applied for, as has been done with many other issues. This would mean that a cattle vaccination could start the year after next!
 
A % figure for effectiveness is not given, but I seem to remember that it was expected to be more than adequate to break the cycle of the disease. Vaccinated cattle that may still become infected will only have it mildly and may not become infectious. Today's cattle have short life spans ( especially beef cattle) so all this will be irrelevant.
 
 
 
 

 
Sally
There was an interesting news item published on the Telegraph website on 12/09/10 regarding badger vaccine. http://www.telegraph.co.uk/earth/wildlife/7996663/Oral-TB-vaccine-may-prevent-need-for-badger-cull.html
 
Researchers have apparently found a way of protecting the BCG vaccine, which offers immunity against TB, from being destroyed by powerful acids in badgers' stomachs, meaning it can be fed to badgers in bait left outside their sets rather them needing to be caught and injected.
 
Ruth commented in an email dated 12/09/10
The Irish have been working on the BCG vaccine for years, including a trial of oral vaccine, and I am so glad we are going to use a product they have developed instead of time wasting by DEFRA and excuses for money and jobs to reinvent the wheel as DEFRA is in the habit of, especially anything they could make money from viz the rapid PCR testing for FMD. I do not know how near the Irish are to obtaining a license for its use.
 
Usually an acid stomach is associated with eating meat and is necessary for the action of peptidases and the digestion of protein. I do not know if the stomach PH of badgers is much more acid than the human: initially the BCG vaccine was given orally to humans in the 1920s and it worked as well as giving it intradermally as at present, one of the advantages of non-oral vaccination is that much lower doses of vaccine can be used. BCG vaccine is also instilled into the bladder to prevent or treat recurrence of bladder cancer, and urine is pretty acid. So I suspect the oil may be for environmental stabilisation in the bait rather than resistance to acid.
 
I don't know how well the oral vaccine will work- 1. badgers need to be vaccinated before being exposed and possibly infected with M bovis, 2. the way the M bovis infection appears to spread in badgers, widespread leading to infection of many organs and shedding in urine for example, may make the vaccine more successful in them than in cattle or humans, in both of which pulmonary infection and spread is said to be the most important and against which the BCG vaccine seems fairly ineffectual.
 
Sally
Full paper at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC101541/pdf/ii005809.pdf
 
Vaccination of Cattle with Mycobacterium bovis Culture Filtrate
Proteins and Interleukin-2 for Protection
against Bovine Tuberculosis
D. NEIL WEDLOCK,1* BRIDGET VESOSKY,2 MARGOT A. SKINNER,1 GEOFFREY W. DE LISLE,1
IAN M. ORME,2 AND BRYCE M. BUDDLE1
Received 10 April 2000/Returned for modification 15 May 2000/Accepted 3 July 2000
 
In this study vaccines prepared from culture filtrate proteins (CFP) of Mycobacterium bovis and interleukin-2
(IL-2) were tested in cattle for their capacity to stimulate immune responses and to protect against an
intratracheal challenge with virulent M. bovis. Nine groups of cattle were vaccinated with combinations of
different doses of CFP and bovine IL-2 mixed with a monophosphoryl lipid A (MPL) adjuvant. An additional
group was vaccinated with M. bovis BCG. Immune responses in CFP–IL-2-vaccinated animals differed from
those seen in BCG-vaccinated animals by inducing high antigen-specific antibody responses and low levels of
gamma interferon and IL-2 released from purified protein derivative-stimulated whole-blood cultures. In a
concurrent experiment, additional animals were added to the high-dose CFP–IL-2, MPL control, and BCG
groups and these expanded groups of animals were challenged intratracheally with virulent M. bovis. Although
the lung lesion scores were significantly lower for both the CFP–IL-2-and BCG-vaccinated groups compared to
the MPL control group, the overall level of protection was greatest for the BCG-vaccinated animals. There were
more animals with extrathoracic spread of disease in the CFP–IL-2 group than in the other groups. While
vaccination of cattle with M. bovis CFP gave an encouraging reduction in tuberculous lesions and did not
induce a delayed-type hypersensitivity response to PPD, future CFP vaccines must prevent any extrathoracic
spread of disease.
Copyright © 2000, American Society for Microbiology. All Rights Reserved.
 
 
Sally
http://www.radionz.co.nz/news/rural/2952/new-tb-vaccines-being-developed New Zealand
AgResearch scientists developing vaccines to protect cattle and deer from bovine tuberculosis are expecting to have the answers on their effectiveness in the next three years. The research programme, which includes the development of improved TB testing methods, has received a grant from the Government science funding body, FORST, of $750,000 per year for five years.
Although the current level of infection in farmed animals is low, bovine Tb is still endemic in possums and other wild animals in 40% of New Zealand. And it's costing the country more than $100 million a year to control the disease.
Dr Bryce Buddle, who leads AgResearch's TB Immunology and Animal Health team, says having cost-effective vaccines and tests would give farmers another way of controlling and reducing bovine TB levels. Dr Buddle says scientists are also investigating a new protein-based vaccine that would not induce a skin-test reaction.
 
Sally
In the Bovine TB special Bovine TB issue of Gwlad Summer 2010, it states that the Welsh Assembly Government is actively involved in discussions regarding BCG vaccine for badgers. We are told that the vaccine is granted Limited Marketing Authorisation, so can only be used as a preventative measure and will not protect animals that are already infected. However Chief Vet, Christianne Glossop, tells us, "We have always recognised that vaccination must form part of our thinking as we look to eradicate TB from the Welsh cattle herd. There are all kinds of complications however which mean that we are not even close to vaccinating cattle, but we are keeping an active interest in the development of a cattle vaccine.' She does not tell us what these complications are.
 
Sally
Subject: RE: Information under Access to Information Request DWO0000192539 email response dated 27 August 2010.
 
Sorry for my delay in responding to you.
 
The piece of work IAH published in the paper was actually a small part of our overall vaccines and DIVA research program. IAH did not actually approach Defra for further funding to develop this test and I believe they sought private funding to develop the test. Incidentally we are still funding this group as part of a different project as they are a good research team.
 
Their press release may have given the impression that this was a major breakthrough but we believe this approach has some drawbacks. Their finding that a vaccinated animal takes longer than an infected animal to respond to the normal gamma interferon test is interesting but we think the other type of gamma interferon test I mentioned in my response (using antigens found in M.bovis but not BCG ) is a better approach.
 
In short it is better to have a test that gives a clear yes/no answer rather than one that is based on when cells respond to the antigen. Using the IAH approach there would always be the risk that some infected animals could respond more slowly than expected (and be incorrectly classed as vaccinated). This should not happen using M.bovis specific antigens as sufficient time is allowed for the cells to respond to the antigen and so we believe this test is more likely to be accepted as a DIVA test.
 
As the cattle BCG vaccine is not yet licensed as a veterinary product for use in the UK and has not received approval for use by the EU we feel we should focus on developing a DIVA test that will have the best chance of acceptance.
 
Regards
James
 
We have now asked if he is able to confirm that the cattle vaccination and DIVA test selected will be available / introduced as an alternative approach to the existing testing programme in 2015 as has been mentioned in several government reports.
 
Sally
Email from Ruth 21/7/10
I do wonder if aerosol vaccination might be a possibility for badgers, ie blowing BCG laden aerosol down badgers setts known to have newborn cubs, so vaccinating all animals within the sett including the newborns!    I will investigate whether aerosol vaccination with BCG has ever been done- I am pretty certain it has not, though BCG in aerosol was studied at Porton Down in the 2nd world war or soon after to test it for germ warfare!  Aerosol vaccination with live measles vaccine strains on human children has been done and exposed everyone in the vaccinating area and they developed enormous immune responses the safety of which was questioned.  So it ceased though I believe it has recently been proposed again, and there may be more sophisticated methods now of administration. 
 
Sally
Email from Ruth 19/7/10
I am reading the chapter on TB vaccination in Plotkin (the largest tome and bible on vaccination for humans).  It is comprehensive and a balanced view (over 400 references on TB vaccination) and the sort of standard I should like to see in veterinary medicine.  Plotkin worked on cytomagalovirus vaccine and has written one of the shortest chapters in the book.  The authors of the TB vaccination chapter are all US professors; the general standard of infectious diseases and research & opinioin in the US is the highest including MMWR a report that one can read completely free on the web.
 
Already there are some interesting points.  1stly that BCG vaccination may promote the reactivation of latent TB and progressive disease.  Thus there may be more TB disease in vaccinated groups than unvaccinated groups.
 
2ndly that though many trials on the effects of BCG vaccination have been done their ability to answer quiestions such as whether BCG vaccintion is protective preventing infection for example, are limited by the diagnostic tests there are.  In the undeveloped countries the lack of any scientific diagnostic facilities except perhaps acid fast staining of sputum, and the ganeral difficulty of diagnosis of TB in children compared to adults.  The endpoint of these trials may be unclear and not strictly comparable.  Whilst it is clear that BCG vaccination in newborns and infants does prevent disseminated disease and TB meningitis, the results on other effects are varied.  Near the equator, saprophytic and pathogenic species of mycobacteria are more prevalent in the environment so this adds further difficulty to assessing BCG vaccination as it is clear that infection or exposure to these mycobacteria and even their proteins in water, soil and food, alters the immune response, specifically from TH1 to TH2, away from the protective response to the ineffectual or harmful response (provoking excessive tissue damage around sites of infection mediated by TNF, tumour necrosis factor).
 
3rdly that the vaccination of newborns and infants is successful in preventing disease and death at that time in life because at that age they are unlikely to be exposed to mycobacteria in the environment and not yet infected with TB so that BCG vaccination can be effective. 
 
I am not at all sure about doing nothing about TB infection in either cattle, or badgers or deer.  We would then have an environment where M bovis would become widespread all over the UK.  How much unpasteurised milk is drunk or used to make cheese?  Similarly for goats or sheep. There are other pathogens in the environment for humans, brucella, salmonella and E coli 0157 for example.  Some countries control salmonella in their dairy cattle for instance and we have got rid of brucella by slaughtering infected cattle.   These pathogens are killed by pasteurisation of milk, but can contaminate meat and by poor hygiene pass to cooked food with outbreaks- 1 000s of salmonella cases a year though not many associated with cattle, but contamination of chicken meat, and in the USA, E coli 0157 from salad crops contaminated by wild boar faeces!  There has recently been an outbreak of campylobacter and E coli 0157 from a dairy licensed to sell unpasteurised milk in the US. 
 
Export of live cattle would probably be impossible from England and Wales.
 
Perhaps we should have a holding operation until better tests and vaccines came along.  If we were then, in the future, to slaughter every infected cow accurately tested this would be an awful lot, 25%? (the infection rate within a family is about 25 to 50% on exposure to an infectious case) Preferrable perhaps to wait for really good vaccines that could protect cattle so that all would be vaccinated and boosted from birth- with no attempt to kill infected animals unless diseased, relying upon the vaccine to do its work and probably in about 15 years bovine TB would then very nearly be eliminated (15 years because the cohorts of vaccinated cattle from birth would accumulate in the national herd so that in about 15 years time all cattle would have commenced their vaccination at birth so either be protected fully from infection or from active progression of the early latent infection state).
 
Sally
Email from Ruth 13/7/10
Vaccination will not control TB in cattle as it has never done so in humans though it may, along with other measures, help to reduce the deaths from TB and perhaps spread of TB and the number of cases over a period of time.
 
Firstly it will allow TB to spread all over the country as infected cattle are moved about, this would also spill over into all badger populations and perhaps deer as well especially where there are large numbers as in Norfolk.  Vaccination could only be used if there was to be a test or tests that could distinguish infected, whether or not vaccinatied, individuals from vaccinated uninfected individuals, and infected indiciduals culled. 
 
Secondly, without testing for TB infection in cattle and removing infected cattle we could not take part in export trade of cattle.  As part of Europe and close to other countries I don't see how this is to be denied indefinitely and such a situation be acceptable to farmers.  Perhaps the second of these might be accepted as in the BSE epidemic we were not allowed to export live cattle.  Scotland would want to close its border not only to cattle but to English badgers and deer!
 
I am interested to learn more of how to detect the following individuals, 1 with active infection, 2 with latent infection, 3 never infected nor vaccinated, 4 never infected and vaccinated (vaccination does not alter the course of TB so vaccinated infected individuals are irrelevant).  We should cull cattle and badgers (and deer) with 1 active infection.  We should treat individuals with 2 latent infection (work is proceeding on this in human medicine and may need one drug for a short time or a long acting depot of the drug perhaps) , this would prevent reactivation and progress to the active infection state.  Those individuals 3 never infected and never vaccinated should be vaccinated (improved vaccines are needed especially for older individuals) .  Finally 4 vaccinated and never infected individuals may need to have some kind of boost to ensure their immunity is protective.  Whilst active infection is about measures to prevent contact between such individuals in group 1 and others especially those in group 3 should be taken. 
 
In human medicine individuals in group 1 are treated with a combination of anti-microbials for 6 months, 9 months may be necessary in the case of M bovis.  But otherwise research is going on to identify accurately these different groups by diagnostic tests, to research treatment of latent infection, to improve the vaccination most especially to prevent TB infection altogether particularly lung infection acquired by inspriation of TB bacteria.  Animal medicine follows on the coat tails of human medicine. We are nowhere near carrying out a plan such as that in the preceding paragraph.
 
 
 
 
Sally
In New Zealand a grant of $750,000 per annum for five years has been give to AgResearch’s TB Immunology and Animal Health team, Foundation for Research, Science and Technology. The team are working on developing a vaccine for TB in cattle that is effective, economical and compatible with current TB testing methods. Apparently a commercial spin off from the team’s research will be the potential for novel vaccines and diagnostic tests to be manufactured and sold to overseas markets, although this is a few years away. This new funding will enable the team to build on the breakthroughs that have been made to date and create biotechnological tools to protect cattle and deer against TB infection.
Source: www.scoop.co.nz/stories/SC1008/S00024/funding-boosts-tb-research.htm
 
Sally
CATTLE VACCINATION
“The best prospect for control of TB in the British herd is to develop a cattle vaccine” – Krebs Report (1997).
 
Defra produced a report 'Options for vaccinating cattle against bovine tuberculosis' which is available at http://www.defra.gov.uk/foodfarm/farmanimal/diseases/atoz/tb/documents/vaccine_cattle.pdf
 
 
The following information on cattle (and badger) vaccination and the progress being made in this area, has been published by Defra at http://www.defra.gov.uk/foodfarm/farmanimal/diseases/atoz/tb/research/vaccine.htm
 
Defra has confirmed that developing a TB vaccine for badgers and cattle is a long-term goal and a substantial part of the Defra research programme focuses on this. Total investment (since 1998) in vaccine development reached more than £17.8 million by the end of March 2008. Over £5.5 million was invested in cattle and badger vaccine research in 2007/2008. Defra says real progress has been made. Testing candidate vaccines in naturally infected cattle and badgers, and developing novel vaccine delivery systems, is underway and work on developing potential vaccination policy options has begun.
 
On 7 July 2008, the Secretary of State announced a commitment to additional funding over the next 3 years. During this time period, £20 million will be spent on vaccine development to strengthen the prospects of successfully developing a usable vaccine.
 
This additional funding will help to further develop oral badger vaccines and investigate ways in which they could most effectively be deployed. It will also enable work to continue that is necessary to apply for a licence for a cattle BCG vaccine and boost work looking at non-sensitising vaccines for cattle.
 
Increased funding will not result in a vaccine being available sooner. While the programme of research has been designed to minimise the time required to deliver licensed vaccines, research by its nature takes time and a significant proportion of the work can only be addressed sequentially. For example, the majority of safety and efficacy studies required for licensing an oral badger vaccine must use the final formulation and therefore cannot start until this is available. Additional effort has been focussed on addressing areas of scientific and policy uncertainty in an attempt to prevent the timeline from slipping.
 
Badger vaccines are likely to be available sooner than cattle vaccines. The earliest projected date for the widespread use of badger vaccine is 2014 for BCG oral badger vaccine. The first product available for use from the research programme is an injectable BCG badger, which was licensed in March 2010 and will be used in a Badger Vaccine Deployment Project.
 
The earliest projected date for the widespread use of a BCG cattle vaccine with a differential diagnostic test (DIVA) is mid to late-2015.
 
Cattle
Defra is funding research, in collaboration with New Zealand workers, to vaccinate cattle experimentally with Bacille Calmette Guerin (BCG) and other vaccine candidates, which includes a range of live attenuated and sub-unit vaccines. The research programme has successfully identified lead candidate vaccines for bTB and although this work is still ongoing, delivery protocols for some of the candidates are now being looked at.
 
Interesting websites with information on trials undertaken regarding cattle vaccination in the UK and abroad.
 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC95651/ Differentiation between Mycobacterium bovis BCG-Vaccinated and M. bovis-Infected Cattle by Using Recombinant Mycobacterial Antigens (1999)
 
http://cvi.asm.org/cgi/content/full/6/1/1 Differentiation between Mycobacterium bovis BCG-Vaccinated and M. bovis-Infected Cattle by Using Recombinant Mycobacterial Antigens (1999)
 
http://iai.asm.org/cgi/content/full/71/9/4901 A DNA Prime-Mycobacterium bovis BCG Boost Vaccination Strategy for Cattle Induces Protection against Bovine Tuberculosis (2003)
 
http://upetd.up.ac.za/thesis/available/etd-03082005-105106/unrestricted/00dissertation.pdf 'The Evaluation of a BCG Vaccine Against Bovine Tuberculosis in African Buffalo' (2004)
 
http://www.tuberculosisjournal.com/article/S1472-9792(04)00071-X/abstract Cattle as a model for development of vaccines against human tuberculosis (2004)
 
http://www.iah.bbsrc.ac.uk/research/BovCelImm/BovCelImm_jh.shtml Development of a Simple, Sensitive, Rapid Test which Accurately Discriminates BCG Vaccinated from Mycobacterium bovis Infected Cattle (funded by DEFRA) (2007)
 
http://www.tuberculosisjournal.com/article/S1472-9792(08)00008-5/abstract Vaccination of cattle with Mycobacterium bovis BCG by a combination of systemic and oral routes (2008)
 
www.ncbi.nlm.nih.gov/pubmed/18439875 Vaccination of cattle with Mycobacterium bovis BCG by a combination of systemic and oral routes. (2008)
 
http://ukpmc.ac.uk/articles/PMC2715681?accid=PMC2715681 Viral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosis. (2009)
 
Comment from Ruth re above links:
The most recent, 2009, of boosting the BCG priming by a vaccinia virus carrying an TB antigen is a more effective way of giving this same antigen than a DNA vaccine, already assayed and though an improvement not the answer.  The idea of using cattle for research on human vaccine development is nothing new as this was done by Calmette and Guerin in France in the 1920s.
 

 
Sally
The following Access to Information enquiry was made to DEFRA by email on 7/6/10.
 
Dear Tom, could you please advise what progress is being made for a vaccination porgramme for cattle. It would appear from the links below that significant progress has already been made and the BCG vaccine could be used immediately.
 
http://www.iah.bbsrc.ac.uk/research/BovCelImm/BovCelImm_jh.shtml
 
http://www.iah.ac.uk/press_release/2007/JHope_Nov07.htm
 
It would appear that the main reason for the reluctance to start a vaccination programme for cattle means that the existing skin test would have to be phased out, as vaccinated cattle would show up as positive reactors. HOWEVER it must be remembered that the skin test is not a perfect test, and yet the overall TB status off an area is based solely on the results of this test, ie the test defines the TB status of an area. The test indicates that the animal has mounted an immune response capable of recognising M. bovis and does not conclude actual infection. It means that animals may have been exposed to a bacterium that can cause TB at some point in their life (or have been vaccinated!).  
 
Current EU regulations mean that vaccinated cattle could not be exported to the rest of the EU, as current tests cannot distinguish between infected and vaccinated animals. In reality this does not matter for meat and dairy products as pasteurisaion and cooking kills the  bacteria that causes bTB.The only products at risk would be those used in their raw state.   Indeed many countries, where bTB is endemic or only controlled, export products to the UK.
 
We must therefore conclude that real reason for the existing eradication policy to to protect the market for live exports of cattle, and to comply with existing EU regulations which insist on its countries achieving TB-free status. Obviously countries which do not have bTB are unlikely to want to risk importing any infected cattle, how ever small the risk.  However, if one looks at the export figures for Great Britain (ref 1)) over the last few years it is difficult how such a decision can be justified in cost terms for the UK. 
 
In 2006 89,567 cattle were exported with a value of £3,332,000
In 2007 85,487 cattle were exported with a value of £2,548,1457
In 2008 51.809 cattle were exported with a value of £31,457,000
 
The numbers and value is falling year-on-year and, even more surprising, is the fact that the value of this market is considerably less than the annual costs of the existing eradication policy for bTB. Surely this makes a vaccination programme for cattle viable and an appropriate case should be made to the EU in this respect?
 
Ref 1  Access to Information request - email response from DEFRA dated 12/10/2009
 
Regards
Sally
 
Reply received 28/07/10 by email
 
Subject: Re: Information under Access to Information Request DWO0000192539
 
Thank you for enquiry about bovine TB tests that can Differentiate between Infected and Vaccinated Animals (so called DIVA tests). Defra are continuing to fund the development of cattle vaccines (most notably BCG) and therefore a DIVA test is also required.
 
Our current lead candidate in this area is a version of the gamma interferon test somewhat different from the one described in the paper mentioned in the IAH press release you provided us with (test developed by Dr Jayne Hope and colleagues at the Institute for Animal Health’s Compton Laboratory).
 
This test, currently being developed by the VLA, uses a group of proteins found in M. bovis but not BCG to look for an immune response in cattle indicating the animal is currently infected with bTB. (See  “Screening of Highly Expressed Mycobacterial Genes Identifies Rv3615c as a Useful Differential Diagnostic Antigen for the Mycobacterium tuberculosis Complex” by Sidders et al. Infect Immun. 2008 September; 76(9): 3932–3939 for more information http://www.iah.bbsrc.ac.uk/research/BovCelImm/BovCelImm_jh.shtml and http://www.iah.ac.uk/press_release/2007/JHope_Nov07.htm).
 
This test has been shown to discriminate between small numbers of experimentally infected or experimentally vaccinated cattle and is currently undergoing evaluation to see how good it is at detecting bTB compared with non-DIVA tests in a large number (>10,000)  of unvaccinated animals. Results from this evaluation are expected later this year.
 
The validation of a DIVA test is a long process, a scientific publication showing that a test can work in principle is the first step but the testing of a large numbers of samples from different types of animals is then required for full acceptance. As the introduction of a bTB vaccine and a DIVA test requires the agreement of other EU countries we will need a large body of evidence to show that vaccination and DIVA testing is a potentially effective method to control bTB.
Yours Sincerely
 
Dr.James McCormack
Bovine TB Research
Veterinary Research Unit
Food and Farming Group
Defra
 
Also an interesting extract below from http://www.southwestbusiness.co.uk/somerset/Minister-Jim-plenty-things/article-2462184-detail/article.html - particularly about Dutch tuberculin, with comments after from Ruth (email dated 28/710)
 
'In the meantime, the number of new outbreaks of TB has shown a very welcome, but slightly mysterious, decline. According to Defra figures for the first quarter of this year, the incidence of disease has fallen by just under 12 per cent for GB as a whole.
 
But within that figure are all sorts of variations. In the South West for example, the incidence of disease is much the same as last year in Devon, Dorset and Somerset, but in Cornwall, the percentage of herds failing a TB test has fallen by almost 40 per cent. What is the secret of the Cornish success, I wonder? Is it just cyclical, or is there some other factor?
 
But it does give the lie to suggestions that it may be evidence of some overall change in policy, like tighter cattle controls or a switch to Dutch tuberculin in the testing process, because that would produce a similar effect across all areas'.
 
Comments from Ruth (email dated 28/7/10)
This particular product manufactured in Holland is more likely to pick up infected cattle or evoke a response than the previous PPD used for skin testing in Britain, from that article by Anthony Gibson a retired and emminent vet.  However PPD or tuberculin is a poorly defined complex mixture of antigens from whatever mycobacterium it is made, quote from Wikipedia.  Indeed even BCG is an unsatisfactorily variable vaccine- there are a number of strains, the components and biological state of the bacilli in the vaccine and the number of bacilli in the vaccine seem rather loose and difficult to control and replicate.  It seems the only strain of BCG licensed for use in Europe, a mild strain, is the one being used for badger vaccine when it might be more appropriate to use a stronger and perhaps more efficaceous strain.
 
The DIVA test to look at differentiating the BCG vaccinated cattle from infected cattle, whether or not vaccinated by BCG (in fact perhaps in the future very likely to have been vaccinated), is of course being developed.  It rests upon the fact that BCG has lost a chumk of the genome encoding ESAT-6 and CFP-10 amongst other proteins but these are strongly immunogenic.  However, in cattle only about 70% of infected cattle make an immune response to them of their activated T-cells secreting interferon gamma.  If the RV3615c recombinant protein (or carefully chosen peptides representing the immunogenic parts of this protein) are added to the mix of ESAT-6 and CFP-10 this improves to 91%.  The uninfected but vaccinated animals don't make a response.
 
The puzzling thing about this protein is that it is encoded in BCG, it is not part of the lost genes.  However, as it has a function associated with the production and function of ESAT-6 and CFP-10 in M bovis, which are not expressed by BCG.  RV3615c is also highly immunogenic but not being expressed functionally and secreted it appears not to be available to the immune system.  This was not a result they were expecting to find in their screening for additional peptides to include in the DIVA test.
 
The type of testing using pepetides is of the type used for humans and is much more specific than the BOVIGAM test using PPD which, particularly in young animals stimulates innate immunity and interferon gamma release even when the animal has never been infected with M bovis.  These new tests using peptides are therefore more specific.
 
The number of animals used in the paper are of course quite small and comprise several cattle breeds.  Obviously the work should be scaled up and it may depend very much on the strain of BCG used as well, this European strain is the only one licensed for use in Europe.  I am sure that other antigens will have to be looked for as well, and perhaps another independant back-up method- we would never rely on just one test like this in humans.
 
 
 
 

 

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