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1 Badgers are the most significant wildlife reservoir of bovine TB in the UK, followed by Red Deer in some areas such as Exmoor, and when the Wild Boar population increases they may also be a reservoir in the Forest of Dean for instance. The significant reservoir is one in which the infection circulates and is maintained 'endemic'. If Hedgehogs, or perhaps more relevantly farm cats are infected these are largely one off and dead end incidents- M bovis infection may be found occasionally in cats and dogs (and humans) but they are not a self-maintained reservoir with circulation of the M bovis from cat to cat, or dog to dog etc. There may be little self -limited clusters. Hedgehogs are killed by badgers, hunted down as they walk about by night, and if they roll up they have no defence against the badger- in fact the badger may be playing a role in their huge population fall over 90% so that they are only found in gardens and in parts of the country where badgers are scarce. The badger is now very numerous, ever more so and probably at historically high numbers. The proposed cull of badgers in Wales is in the Intensive Action Area, a part of North Pembrokeshire where cattle TB has been very problematic, the cull was not proposed to occur everywhere and in the area to be culled the goal was reduction of the population of badgers by 70% not extermination. In the IAA area the incidence of farm breakdowns has been reduced by about 37% so far, with many, in fact every measure, that might help, and much investment on the farmers part to keep badgers out of cattle housing for instance, and other restrictions on them with regard to cattle movement and purchasing of cattle fodder etc. The vaccine BCG that is used for humans and proposed for use in cattle does not prevent infection, and in humans has not prevented disease at the site of infection, the lungs, reuslting from the most common access of the bacteria - inhaled in the breathe in very small particles that go down into the air sacs. Indeed vaccinees can develop lung disease and shed bacteria on the breathe to infect others. If M bovis infects it needs to gain entry to immune cells, the macrophages that ingest bacteria. It controls its environment in those cells and survives and multiplies, unlike most other bacteria such as staphylococci that are killed after ingestion by macrophages. The BCG vaccine upon infection of the vaccinee with M bovis makes the immune system secrete gamma interferon that activates the macrophages to kill at least some but perhaps not all M bovis bacteria they harbour. This prevents dissemination of M bovis in the body and widespread disease and infection of other sites and shedding from these sites ie the kidney and shedding in the urine. Thus the vaccine has saved countless babies and childrens lives but not been shown to protect against infection. Indeed infected humans are diagnosed by many means and if infected treated. Thus BCG works in a completely different way to virus vaccines such as BTV8 which stimulate the protective neutralising antibody in the vaccinated individuals. This type of immune response does not occur against bacteria. At present any cattle infected with M bovis are destroyed. There is no test for cattle to distinguish a latent from active progressing M bovis infection. There have been efforts to improve the BCG vaccine to little avail as yet. BCG may be quite ineffective if the vaccinated individual is exposed to some of the many species of environmental mycobacteria, which are very common except in deserts. As yet there is no significant improvement in the vaccine to prevent infection. 1. The vaccination of badgers with BCG may help to reduce exposure of cattle to M bovis shed into the environment by badgers, in their urine for example by decreasong the number of badgers with widespread infection such as of their kidneys and urinary tract. This has not been scientifically

2 trialled to show reduction in cattle infection though vaccination of badgers has been shown to reduce the number of badgers with heavy widespread infection. At the moment badgers are vaccinated intramuscularly after trapping, there is not an oral vaccine licensed for badgers. (BCG when first developed was used as an oral vaccine for human neonates of tuberculous mothers with great succes to prevent serious disease in the 1920s.) The Krebs trials showed there was an overall reduction of new herd breakdowns by 16%, this effect lasted for at least 2 years after culling ceased, and the initial perturbation effect from disturbing the badger population when culling was first commenced was shown to vanish after the first year or two. I cannot understand the hysterical protective impulse of those determined that badgers should not be culled under any circumstances, they are a species protected under the law anyway. They never mention hedgehogs. I think it is completely irrational and most of the people at the local Wildlife Trust of which I am a Trustee are oversensitive about it to the point of foolishness I think. For instance they understand the need to kill grey squirrels in areas where red squirrels might survive, and are trained to kill them, also to kill mink where they are destructive of the ever rarer water voles, to take eggs from most of the Black-backed gulls on Skomer Island to reduce their predation on the Shearwaters etc etc. They do not of course keep cattle and have never had to destroy them or suffer the consequences- there is no reimbursement for the expenses for quarantining a herd (which usually lasts for a year at least) such as buying in fodder for cattle that should have moved off the farm. The skin testing for cattle is by no means perfect, neither is the cattle BoviGam test, and a fair proportion of herd breakdowns as it is called here, have no culled animal that prooves to be infected with TB at the abattoir post mortem, that is isolation of M bovis either from lesions or from collected lymph nodes- in some of the herds the cases may have been latent or early infections and the wrong lymph nodes collected explaining the negative isolation results, and in others where small numbers of animals are involved, perhaps one positive, the cattle may not be infected at all. Killing badgers will not solve the problem, but the problem in cattle cannot be solved without solving the problem in badgers. Eradication in cattle will not be possible because of continued reinfections from infected badgers. The balance of nature here is a pretty human managed one: there is no really wild area in Britain, it has all been altered and changed profoundly by man, much more than one might think. My own opinion is that in the IAA area either culling the badgers and vaccination of surviving ones or vaccination of badgers (though vaccination alone has not been scientifically proven to reduce cattle infeciton) should be done to support the effort made by the farmers, who have acheived a 37% reduction in cattle herd infections so far, and see if it is possible to eradicate cattle TB in that area. M bovis is a very difficult problem in cattle- whilst being of minimal risk to humans provided pastuerisation of milk for human consumption is carried out. I hope I can answer some more questions. Firstly there is no need to give oral vaccine to 2. calves- best to vaccinate them by injection within hours of birth when one tags them. On the whole the vaccine works the best when given within hours of birth, this has been shown for calves and of course for humans- before any environmental mycobacteria have had a chance to modify the immune response to BCG which I think would be the most likley reason for this. The number of live BCG bacilli in the injected vaccine can be very much less than the oral vaccine, and essentially that is why it was changed for human babies from oral to injectable. Work on vaccines and research on TB is driven very largely by research on human TB, the veterinary effort is very minor by comparison. Whilst a goal for human vaccine can be prevention

3 of disease, for instance of the lungs and thus prevent spread, which together with treatment could abolish, more or less, TB in a generation or two, that for cattle needs to be prevention against infection. 3. If better testing came about so that active infection could be distinguished from latent or inactive infection (this can re-emerge later into an active infection or re-infection can occur) then the vaccine preventing disease could be used for cattle with culling only of active disease, vaccine failures. Exposure in cattle will continue from wildlife. I believe it may not be possible to make a vaccine against TB that prevents infection altogether (unlike viral vaccines). This is because the specific immunity generated by vaccination can only come into effect once the TB bacteria have entered a macrophage, the only mechanism of killing or inactivating TB bacteria. The entry into a macrophage sets in motion the generation of a specific immune response to TB so that tests which check for immunity to TB as distinguished from that to BCG alone will pick up the infected vaccinated animal as an infected animal. One would have to trust the efficacy of the TB vaccine and have the appropriate test to check for vaccine failures that are active infections. I can't say whether one bacteria in one macrophage would be sufficient to evoke the specific immune response (recognising bacterial proteins that are present in M bovis as opposed to BCG from which some genetic information has been lost including several proteins in its modification to a less pathogenic oraganism than M bovis or M tuberculosis, but it has also lost the ability to persist in the vaccinee even as a latent infection). There certainly is the possibility immediately for better more comprehensive and specific testing for cattle, and the understanding of the complex molecular biology of TB will certainly give rise to new possibilities. There are 100s of proteins made by M bovis. I am not sure to what extent selenium or other trace elements such as iodine make a difference to 1) the susceptibility to infection and 2) its progression. This would come back to the hypothesis that those with healthy immune systems are less vulnerable. This may be the case, for sure HIV infection and AIDS or immune suppression from transplantation of organs does make a big difference to both of these. These severe immune defects are not found in animals who would die quickly from other causes, simple pneumonia for instance. There are some genetic markers of natural relative resistance but neither trace elements nor breeding would eliminate TB infection even if they reduced it. It is said that a fierce cell-mediated response from the healthy immune system can destroy the lungs from over an exhuberant immunity causing destructive cavitation. Yet the immune response can halt TB in humans so that they survive at least for some years with lesions but inactive TB infection- this is what was hoped for in the sanatoria before the advent af antituberculous therapy. TB is a uniquely interesting bacterial infection because it is one that is for life with the possiblity of changes in course and outcome and an evolving immune response- an effective response can change to an ineffective immune response. The gradually increasing load of mycobacterial antigen at some point switches off the cell-meditaed response and gamma interferon, which gives at least some control, to that of an antibody response which is hopeless- the end will come. The bacteria multiply in the macrophages unchecked by any gamma interferon induced killing.

4 Possible steps to be taken: reducing the badger population to normal levels. Scientifi trail (see point 1) vaccinating calves (see point 2) better tests (see point 3)

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