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?
Sally
25 Aug 2010, 4:38 PM
CATTLE VACCINATION “The best prospect for control of TB in the British herd is to develop a cattle vaccine” – Krebs Report (1997).
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://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://www.tuberculosisjournal.com/article/S1472-9792(04)00071-X/abstract Cattle as a model for development of vaccines against human tuberculosis (2004)
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)
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
22 Aug 2010, 7:32 PM
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.
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
'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.
Sally
21 Aug 2010, 7:28 PM
Ruth responds in an email of 21 August 2010
This is very interesting and is part of the research into what features of the immune system make individuals likely to develop disease with pathogens (that do not cause disease in every infected person unlike rabies for example). This research concerns the human organism and M tuberculosis. What of cattle and M bovis? The TB research team at Weybridge used to believe that cattle did not really have latent M bovis infection in the way that humans do, ie quiescent for decades. Indeed there was a study in Australia where 10 skin test positive cattle were kept indefinitely in isolation, I presume as a group, until each went down with TB. However Dr Vordermeier admittted a few years ago when I visited Luddington with the Saunders that they were rethinking the issue of latency in cattle. It also sounds as though the badger may resemble the goat and alpaca in getting a more widespread and progressive disease, but I don't know that latency may not also occur in some individuals of these species. I would think that not nearly enough is known of the immune systems of these animals as compared to the human, i.e. the monoclonal anitbodies to identify different subsets of immune cells would not have been developed. M bovis also lacks some genes in M tuberculosis and this may alter the immune response and the pathogenicity of M bovis.
I don't know what original work is being done in NZ as the article gives no hint really as to what this is but I expect it is based on other work making such developments possible. For instance a chimera virus with a M bovis protein or two inserted into it, diagnostic tests based on proteins excreted from M bovis and revealed by the sequencing of the bacterium. Perhaps the mysterious 'nose' smelling a diagnosis based upon an associated protein or molecule appearing in an infected individual, we have heard very little of this.
Sadly with the thoughtless slaughter of cattle on any test result deemed positive or suspicious of M bovis infection and little work done on the incidence and spread of M bovis in badgers we know very little of what I call the natural history of the infection as it exists on farms and in the countryside. Laboratory infections are different as laboratory strains are used and large doses are introduced by what are probably unnatural means (not the inhalation of aerosol).
Sally
21 Aug 2010, 7:27 PM
I was surprised to see it report that only 1 in 10 people who have been infected with TB get the full-blown disease. Would this be a similar percentage for cattle? If this is so then the majority of those cattle slaughtered are killed needlessly - and as cattle have such short life spans maybe the percentage would be even less for cattle? This would then surely make vaccination viable as a more humane, cost effective and easier option?
Email from Ruth dated 17/7/10 Vaccination against TB of cattle is fraught with problems with the current testing they have available. I am not sure if there is any real move to make a programme to put this into action as an option in a project though we could vaccinate uninfected neonatal cattle. Vaccination of cattle in NZ has not solved the problem of M bovis infection by itself and as you have reported control of possums (in NZs case exermination is desirable) is proving essential.
The lifespan question is interesting. Considering that badgers do not live long on average they do succeed in transmitting the infection to each other even so. With many suckler cattle and dairy cattle living 10 years or more one can see this could happen ie infection and disease gradually advancing so that lung disease and shedding occurs especially in older and long infected animals, though these are of course not the only infectious cases amongst cattle.
Exactly what happens in the badger I am not sure though there are a number of routes of infection previously discussed.
In the case of goats and camelids their infection with M bovis seems to be disastrous- the infection commonly spreads rapidly and makes them sick and they die within months or about a year. They shed the infection infecting others. Skin testing on camelids is of limited value apparently and I am not sure how useful it will be in goats- rapidly progressing infection and widespread disease is likely to lead to negative skin tests, in humans and cattle too, as the cell mediated immune response to M bovis is suppressed.
Sally
15 Jul 2010, 3:21 PM
A Science Search for Testing TB Vaccines in Cattle - SE3212 on the DEFRA website reveals (http://randd.defra.gov.uk/Default.aspx?Menu=Menu&Module=More&Location=None&ProjectID=8648) that the Krebs report has recommended the development of cattle vaccines as the most promising strategy to control bovine tuberculosis in the UK. Specifically, it addresses sections A to D, and F, as listed under Developing improved strategies to reduce herd breakdown: A by the development of an M. bovis cattle challenge model and the use of BCG as prototype vaccine. B by testing a prototype M. bovis BCG auxotroph vaccine in cattle. C by conducting a MPB83 DNA vaccine-based vaccination trial. D by identifying new M. bovis antigens through the screening of a cosmid library, by looking at cytokine responses and bacterial killing in vitro by vaccinated and infected cattle, and finally by assessing the role of CD8+ T cells. F by assessing defined M. bovis antigens and peptides as reagents for differential diagnosis, by testing if these antigens are compromised after M. bovis challenge of vaccinated cattle
On 13/01/10 questions were asked in parliament on the subject of 'Bovine Tuberculosis: Vaccination'. (http://www.publications.parliament.uk/pa/cm200910/cmhansrd/cm100113/text/100113w0002.htm)
Mr. Sanders: To ask the Secretary of State for Environment, Food and Rural Affairs when he expects a diagnostic test to differentiate between infected and vaccinated animals to become available for use in vaccinating cattle against tuberculosis. [310716]
Jim Fitzpatrick: The earliest projected date for the use of a BCG cattle vaccine with a DIVA test to Differentiate Infected from Vaccinated Animals is 2015.
It should be noted that in addition to the science, there are a number of key policy, legal, commercial, regulatory and manufacturing issues surrounding the implementation of a vaccine against bovine TB.
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. DEFRA will continue to work closely with the Commission and other member states to minimise the time required to make the required legislative changes once the necessary scientific information is available.
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
5 Jul 2010, 6:07 PM
The BCG (bacillius Clamette Guerin) vaccine provides immunisation against TB. In humans TB is a serious, but curable, infectious disease that usually affects the lungs but can affect any part of the body. According to NHS literature in the UK as a whole, TB has increased by 27% since the 1980s, from 5745 to 7400 cases per year. It is of greater risk to humans than bovine TB yet, surprisingly, it does not attract the same kind of attention or resources as bovine TB.
The following information is from the Breakspear Medical Group Ltd and relates to the most common form of TB that affects humans. For over fifty years there was a TB vaccination programme for teenagers in schools. However, a few years ago this was discontinued. Apparently the Dept of Health said the pattern of TB in Britain had completely changed since the post-war years when the disease was mostly seen in young adults, hence the porgramme in schools. However, nowadays it is babies up to one year old who are most likely to develop the human form of TB, with the added risk of contracting meningitis. In order to catch TB you usually have to be in close and lengthy contact with someone who has TB in their lungs or throat. Clinical symptoms include a persistent cough that gets worse over several weeks; loss of weight for no apparent reason; fever and heavy night sweats; feeling of tiredness and; coughing up blood. Around eighteen areas across Britain currently have high rates of TB. Thirteen of these are in London and have higher than 40 cases per 100,000 population. Babies in these areas are offered the BCG vaccination in the first month of life, as are babies whose parents or grandparents come from countries where rates exceed 40 cases per 100,000. These recommendations aim to reflect the shift of TB infection in this country.
Interestingly many European countries have either dropped, or never offered, school TB immunisation porgammes.
TB is curable and, as with cattle, it may be latent with no symptoms. A blood test can help diagnosis of latent TB. The Mantoux test (which replaced the Heaf test) can be performed to determine if a person has a degree of natural immunity. It is considered to be 70% effective. 0-4mm swelling indicates no antibodies (natural immunity) so vaccination can be offered; 5-14mm means the person has immunity and so does not need vaccination; and above 14mm the person probably has TB and will need further tests, xrays and treatment. TB can be cured through a course of special antibiotics and once treatment is started patients will feel better after 2 - 4 weeks although treatment must continue for over six months, Left untreated it can lead to death.
Sally
2 Jul 2010, 2:17 PM
Email from Ruth dated 21/6/10.
If you didn't react to the Heaf test you had NOT been exposed to TB therefore were given the BCG to give you immunity and protection at least against fatal infection, meningo-encephalitis for example.
Response to a skin test does not differentiate between exposure to M tuberculosis or M bovis and the immunity from the BCG is equally effective as far as is known (or ineffective) against either organism. To differentiate between the 2 organisms as a rule they must be cultured- molecular biology methods are I am sure being honed but they are usually only positive in animals or humans in which culture is also positive so offer no real advantage of sensitivity.
Your correspondent could have acquired M bovis from a farm or drinking unpasteurised milk as she remembers, or it could have been from a school teacher or even a family member and might be M tuberculosis. Now and for several decades follow up of significant contacts of cases of infectious TB have been tested and screened for infection (one of the ways that TB infection in developed societies has been controlled) and treated of course. Also the treatment of latent TB is also being investigated as another way to bring down the burden of infection in the human population.
There are both false positives and false negatives with skin testing, but not as many as one might suppose or the usefulness of the skin test would be much poorer than it is (it has been effective in eradication of cattle TB in countries with no significant wildlife reservoir). 4mm is a very small response to measure accurately on a cow. One is looking for thickening of the skin by 'induration', a hard lump with an abrupt edge, because the thickening is due to cellular infiltration and not due to fluid leaking from blood vessels as happens in a lot of skin lumps like bites etc. It is a subjective test and when one gets down to 4mm on a hairy cow I really wonder whether another person would make the same finding. I am glad she was spared and is now fine and fluked.
Immunity to TB or other infections is not passed on to children, only antibody before or just after birth that lasts only a few months in the neonate before it is completely degraded. The sort of immunity to TB, cellular, would not be passed on.
There is little mileage for funding to research into the prevalence of latent TB infection in research. I can find no big statistical surveys on people in developed or undeveloped countries. In India in urban areas the prevalence is thought to be 80% in adults in one small study and less than 2% in the UK, this was using a gamma interferon test rather than the skin test looking for past infection (ESAT-6 antigen not in BCG but in M bovis and M tuberculosis). One of the confounding factors for a cheap wideranging study is the prevalence of BCG vaccination, which is more likely to be detected on a skin test if given within the last few years. Selective antigens are used in gamma interferon tests on humans and these little studies have used this new test. But any clear idea of the changing prevalence of infection with TB and its link to age, place of origin, social class etc would require large studies and I am sure these will not be motivated unless treatment of latent infection proves worthwhile, very effective at ablating the organisms carried, and the chance of reinfection is low or there is a really good protective vaccine.
Sally
18 Jun 2010, 6:58 PM
Ruth responds (email dated 17/6/10) Rowena had the Heaf test. This was tuberculin in tiny amount pricked into the skin (the intradermal layer) by a circle with points on it on the forearm and there would be a ring of raised hard red spots in 2 days. It was in fact a skin test. It was not the BCG that was administered but tuberculin, the purified protein derivative - NO LIVE ORGANISMS.
The correspondent and one other in her class at school gave a positive skin test therefore had been infected. If there had been active disease (the CXR was one of the important tests done to exclude this) she would have been treated for 6 months with multiple drug therapy. However, the infection was latent in her and her classmate.
There was no point in giving her BCG as it would make no difference to her outcome and in fact her immune reaction to it would have given a deep and painful ulcer that would have taken a long time to heal.
She has not yet reactivated to TB. She may do so yet as an old woman or when she becomes ill, perhaps with renal failure, for example, or has cancer treatment etc. She may never reactivate the TB infection and it may remain latent all her life. If she reactivates it she may or may not be infectious to others, but when diagnosed she will be treated.
She is right that if she were a cow she would be culled immediately.
I don't know the average figures for exposure to TB and latency or active infection in the UK, different populations and ages would have very different figures. I expect that overall it is less than half, and in some places and age groups it would be only a few percent.
Sally
17 Jun 2010, 6:33 PM
In an email on 17th June 2010 Rowena said.
'Of course all 'genuine country dwellers' share the concern of farmers forced to kill their stock, particularly when those animals show no outward signs of disease. I don't fully understand the intricacies of testing method sensitivity and selectivity, but I do know that if I was a cow, I would have been 'put down' when I was 13, after the BCG skin prick test revealed that I had been exposed to the TB bacterium, probably from drinking raw milk. I am still alive and generally healthy and productive 38 years later, unlike the many healthy cows that have been compulsorily slaughtered, with their owners compensated at taxpayers expense. The majority of my classmates were vaccinated, with only I and one other child out of about 100 having immunity. Chest X Rays revealed that we were perfectly heathy and we did not need to have the BCG jab. Surely, vaccination of cattle would be the most practical long-term solution to the problem and the only potential loss would be the already diminishing live export market.'
Sally
15 Jun 2010, 7:19 PM
In an email on 13th Match 2010 Ruth says, As I have said nowhere does the BCG vaccine do a good job in controlling TB disease in humans. In humans all possible measures have been used and in developed countries these have had effect. But as I explained previously there may be unquantified factors, such as own bedroom, good housing when compared to 150 years ago, and better nutrition and so on.
I think it is essential that all possible measures are used for cattle TB until we have a revolutionary vaccine that is excellent at preventing infection upon exposure, rather than merely certain kinds of disease but not the commonest of all, pulmonary infection and disease.'
Sally
15 Jun 2010, 7:17 PM
1. How likely is it that other mammal species (which have not had the attention given to badgers) turn out to be reservoirs too (eg rats, cats - both far more abundant and in closer proximity to cattle than badgers? I realise that many species are considered spillover hosts but what changes this status, ie how did the badger become a reservoir for the disease and not simply a spillover host?
2. It would seem that the bacteria that causes TB is so endemic that it would be virtually impossible to eliminate at the current time? Does the existing BCG vaccination do a good job of controlling the disease?
Sally
15 Jun 2010, 7:16 PM
In an email from Ruth on 11 June 2010 she said 'Here are a couple of truths
1. Where there is no wild animal reservoir, M bovis has been eliminated from the cattle herd by skin testing viz Austratlia (the Australian possum was not infected in Australia but is in NZ!!) even though the skin test is not perfect it is good enough. It very nearly was here too. The essence of control is ensuring that each infected animal on average infects less than one other animal. It must be that in TB infection and disease the infectious cases infect many more than one, when perhaps most other cases never become infectious and don't infect any others but that is enough when there are no constraints and suitable conditions to maintain the epidemic - each infection lasts the individuals' lifetime from the point in time of infection.
2. Vaccination in the human population has not eliminated TB anywhere it has been used and that is in practically every country in the world.
Ideally I would like to test the latrines of every sett / badger social group of M bovis by PCR. If it is present then that sett should be culled, in a culling area. The assumption is that almost every individual in the sett will be infected, even if it is latent in some, as badgers live in a conducive environment at very close quarters and spread M bovis by a number of routes between each other. If the sett latrines were negative for M bovis I would place oral vaccine especially at the time of young cubs present, the mother may vaccinate them by reguritation of vaccine, or they may get it on eating laced peanuts scttered about the sett.'
Sally
15 Jun 2010, 7:11 PM
It is all so complex and one can see why it is taking so long to resolve. I can understand what you say but bearing in mind that pasteurisation/cooking kills off bacteria, so there is little risk to human health, will it matter if it takes a while? We know the existing skin test is not likely to be picking up all infected cattle anyway.
This is interesting but again, probably clutching at straws! http://news.bbc.co.uk/1/hi/sci/tech/4783368.stm Writing in the UK scientific journal Biology Letters, researchers say herds on farms with hedges and ungrazed land are less likely to become infected. They suspect hedges keep cattle away from badgers, which carry TB.
Sally
15 Jun 2010, 7:09 PM
In an email from Ruth on 9 June 2010 she said: 'What effect would vaccination have on newborn cattle in terms of protection against infection? They don't know and are guessing. How long will it take for the cohorts of vaccinated and newborn cattle to come to form the whole breeding herd- 10 years I should think. They will still be testing and culling infected cattle of which they expect to continue.
The infection rate in badger setts that are infected in the hyperendemic areas is very high, I would think the majority of badgers killed will have been infected. I continue with my point that I think that you are not being practical to think that vaccination alone will control M bovis in cattle. I think culling of badgers as infected cattle are culled now, and then vaccination of badgers and cattle should help greatly to reduce the infection but I couldn't say by how much. Actually I think we need better tests to detect infected cattle but that would be in order to cull them'.
Sally
10 Jun 2010, 3:29 PM
An interesting link in connection with the above post:
www.iah.bbsrc.ac.uk/research/BovCelImm/BovCelImm_jh.shtml The bovine immune mechanisms research group is funded by both BBSRC and DEFRA. The overarching aim of the work of the group is to further understand immune responses in cattle. This knowledge can be applied to understanding infection and immunity processes; this is central to the development of improved vaccination or control strategies for economically important diseases of cattle, including bovine tuberculosis (bTB).
A major area of research, being carried out in collaboration with the Veterinary Laboratories Agency, is to assess the protective efficacy of bTB vaccines and to define correlates of protective immunity in cattle that might be targeted by effective vaccination strategies. t is recognized that elimination of the disease in both cattle and humans will depend on effective vaccines and sensitive, specific diagnostic tests. The development of new vaccines for TB has been the subject of intense research since the development of the attenuated Bacille Calmette Guerin (BCG) vaccine strain of Mycobacterium bovis almost 100 years ago. Despite the development and testing of subunit vaccines, DNA vaccines, attenuated and modified mycobacteria strains and more, BCG remains the gold standard and is still most effective vaccine particularly against TB in children. It would appear that neonatal calves gain similar protection following BCG vaccination and this is a major area of research by the Bovine Immune Mechanisms group.
Sally
10 Jun 2010, 3:21 PM
Back in November 2007 a Dr Jayne Hope and colleagues at the Institute for Animal Health’s Compton Laboratory developed a test that could distinguish cattle that have been vaccinated against bovine tuberculosis (TB) from those that had been infected by the causative agent, the bacterium Mycobacterium bovis. In recognition of the research (funded by Defra) that led to this development, Dr Hope and her team won an Animal Health Award in the 'Outstanding Contribution by an Academic or Scientific Institution' category. In 2007 vaccination of cattle against TB using the BCG vaccine is under active consideration. BCG is the vaccine used to immunise people against TB. BCG-vaccinated cattle test positive using the tuberculin skin test. Therefore, an essential part of any bovine TB vaccination strategy is being able to distinguish vaccinated cattle from infected ones. Research* by Dr Hope and her colleagues Dr Chris Howard and Paul Sopp showed that immune system cells (circulating effector T cells) of cattle that had previously been infected by M. bovis had far more of a protein called gamma interferon than did TB-vaccinated ones. This discovery has led Dr Hope and colleagues to develop a rapid diagnostic test that could allow same day, on farm, diagnosis of TB. Commercialisation of this test is being investigated.
Dr Hope said: “The ultimate benefit of accurate diagnosis of disease, in the light of vaccination, would be a reduction in the incidence of bovine TB with associated improvements in animal health and welfare, and livelihood of farmers. By reducing the incidence of TB in the UK there would be improved economic competitiveness in the farming industry.” *The research that led to this development is described in the paper ‘Flow Cytometric Detection of Gamma Interferon Can Effectively Discriminate Mycobaterium bovis BCG-Vaccinated Cattle from M. bovis-Infected Cattle’ by P. Sopp, C.J. Howard and J.C. Hope, published in the journal Clincial and Vaccine Immunology ( 2006, Volume 13, issue 12, pages 1343-1348).
We have written to Dr Hope and Defra to see what has become of this research and test.
Sally
9 Jun 2010, 2:57 PM
“The best prospect for control of TB in the British herd is to develop a cattle vaccine” – Krebs Report (1997).
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.
Sally
9 Jun 2010, 2:49 PM
In an email from Ruth on 8th June she wrote:
'I support the use of BCG vaccine in cattle, but I think it is misguided to think it can be the one solution. There is no mention of how well the BCG vaccine works in neonatal calves (my own thought is that they could be vaccinated when one puts in the first ear tag). As I have mentioned before the benefit of vaccinating neonatal humans of which about 1 billion have been vaccinated, is to save the babies from death due to severe disease, either a generalised bacteraemia and many foci of infection throughout the body or a more focused version of this, a tuberculous meningo-encephalitis. Both of these are fatal. The vaccine has not proven effective against pulmonary infection, and the vaccinated babies may be infected but mount a containing response. It has been difficult to prove the BCG vaccine protects against infection, but it has been concluded recently that it does at least to some extent.
Vaccination alone cannot be expected to control bovine TB.
The vaccinated cattle are not likely to give a standard positive skin test response after about one year post-vaccine, if they are similar to humans. The skin response to tuberculin in the BCG vaccinated humans is weak and usually transient after vaccination.
The gamma interferon test in infected animals is not as clear cut as suggested as the amount of gamma interferon made in response to infection varies, whilst being high at first when the skin test response is positive, as the bacterial infection progresses and the cell mediated responses weaken so the level of gamma interferon falls in late infection. The test using cell sorting as specified in the articicle enclosed may be more specific than the Bovi-gam test, and as they say, in calves there is a high count of natural killer cells and gamma-delta cells that both release gamma interferon so the cell sorter is doubtless programmed to count only T4-cells that produce gamma interferon, hence its specificity.
I am sure the detection of infected cattle and the reduction of infection in badgers and other endemic hosts of M bovis in this country will remain necessary.
As I keep on emphasizing no one simple strategy will do against bovine TB and the problem of M bovis in our environment.
I don't see why we have to export live animals for breeding etc, when semen or embryos can be exported. This affects many policies, not least the medieval FMD policy of stamping out by slaughter when we have vaccines for FMD that work every bit as well as BTV vaccines. Both of these vaccines work in a different way to BCG and have an efficacy not far below 100% of protection against infection when the vaccine is a good match for the infecting virus. TB is a different ball game.'
Sally
8 Jun 2010, 10:58 AM
On the 7/6/10 we wrote to the TB Team, Office of the Chief Veterinary Officer.
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.
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 the real reason for the existing eradication policy is 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 £1,457,000 In 2009 11,050 cattle were exported with a value of £152,000
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 requests - email responses from DEFRA dated 12/10/2009 and 14/6/10
The response received on 8/6/10 was as follows:
'Thank you for your e-mail of 7 June 2010. You comments have been noted. The Welsh Assembly Government is committed to supporting the development of effective badger and cattle vaccines for use in the control of bovine TB and is working closely with Defra on research into vaccines. The importance that is attached to vaccine development is clearly demonstrated by the fact that, in July 2008, Defra announced they would be committing a further £20 million to the TB Vaccines Programme, over the next three years, to the development of usable Bacillus Calmette-Guérin (BCG) vaccines.
This additional funding will help to further develop vaccines and investigate ways in which they could most effectively be deployed. It will also enable the necessary work to continue in the application for a license for a cattle BCG vaccine and boost work looking at non-sensitising vaccines for cattle. Non-sensitising vaccines can be used without a differential diagnostic test to Differentiate Infected from Vaccinated Animals (DIVA).
You have correctly identified in your e-mail that, in its current form, EU legislation prohibits the use of a TB vaccine for cattle. EU legislation would have to be amended to allow cattle vaccination, particularly with a vaccine which sensitises cattle to the tuberculin skin test, without trade restrictions being imposed on live animals. A DIVA test would have to be used alongside the skin test to confirm the ‘status’ of the animal. This represents a significant obstacle which would need to be overcome prior to any widespread use of a cattle vaccine. Work has begun to identify and address this issue.
Research on the efficacy of a vaccine for cattle is ongoing. The earliest projected date for the widespread use of a BCG cattle vaccine with a DIVA test is mid to late 2015.
The development of a vaccine for cattle will be monitored closely with a view to introducing it into Welsh policy as and when it is available and appropriate.'
Ruth (Guest)
21 Apr 2010, 4:13 PM
Yes any person or animal shedding TB on the breathe can infect another. The commonest form of TB in humans is Mycobacteria tuberculosis infection of the lungs. Rarely there are outbreaks in cattle which are M tuberculosis which has been transmitted from humans to cattle. That is why they check at least one animal in a herd breakdown by isolating the mycobacteria so it can be typed into bovis or tuberculosis. All human isolates are also typed into bovis or tuberculosis.
It is thought that M bovis infection of the human lung, though possible, is rarely infectious by that route to other humans, though it certainly can be, let alone to cattle. The assumption is that M bovis isolated in cattle is the cattle / badger infection. Indeed the genotyping and spoligotyping which is also done on any cattle isolate would pick out something unusual. Apparently older humans have genetic types of M bovis not currently circulating in the British cattle herds. Cattle and badgers have the same genotypes and spoligotypes prevalent in the populations in an area like sandwiches, one peice of bread being the cattle the other the badgers and each sandwich made with matching genotypes.
I would be pretty sure that the M bovis in cattle in Australia and in New Zealend were brought over by cattle imported from the UK. It is not endemic in wildlife there except the possum in NZ but not in Australia where that possum originates (however in NZ it would be best if they could exterminate the possum a non-native and very damaging to the flora and fauna of NZ). I would not be so sure about M bovis in the USA or in Asia or Africa. Detailed sequencing may elucidate the spread of M bovis round the world. It evolved from M tuberculosis perhaps as long as 150,000 yrs ago but I am not sure how much agreement there is on the time scale yet.
Sally (Guest)
21 Apr 2010, 4:11 PM
Can the human form of TB pass from a human to cattle? We are seeing an increase of the human form in the UK and we have a lot of workers from countries such as Poland (where I understand TB is rife) and many of these are working on farms. With increased globalisation perhaps we should bear in mind that around 85% of cattle and 82% of the human population are in areas where bovine TB is either only partially controlled or not controlled at all.
Ruth (Guest)
21 Apr 2010, 4:04 PM
Some are sadly misinformed on the value of BCG vaccination in the human population of Britain in eliminating TB infection. In my vaccination bible,Vaccines by Plotkin et al 2008 5th edition 1725 pages, I quote "all of these issues make it impossible to estimate the effects of BCG vaccination programs on the epidemiology of tuberculosis (in humans) 1.Divergent results of BCG vaccination trials make it difficult to estimate vaccine efficacy. 2.Reported epidemiology of TB in the developing world is incomplete. 3.The vaccine is primarily administered to infants and children whereas the worldwide burden of TB is mainly seen as pulmonary disease in adults. 4.TB increased in many countries in the 1980s and 1990s as a result of HIV as well as other factors unrelated to BCG vaccination." .
Sally (Guest)
21 Apr 2010, 3:48 PM
If the BCG didn't do much to contribute to the decline of TB among humans what did cause its decline? I realise it is actually increasing again now (even in this country) and is associated with Aids but was the decrease in TB attributed to better living condition?
Ruth (Guest)
21 Apr 2010, 3:47 PM
With regards to protection of humans using the BCG vaccine. in my vaccination bible, 'Vaccines' by Plotkin et al 2008, 5th edition 1725 pages, I quote "all of these issues make it impossible to estimate the effects of BCG vaccination programs on the epidemiology of tuberculosis (in humans) 1.Divergent results of BCG vaccination trials make it difficult to estimate vaccine efficacy. 2. Reported epidemiology of TB in the developing world is incomplete. 3.The vaccine is primarily administered to infants and children, whereas the worldwide burden of TB is mainly seen as pulmonary disease in adults. 4. TB increased in many countries in the 1980s and 1990s as a result of HIV, as well as other factors unrelated to BCG vaccination."
