Originally from: Farmtalking
                        
From: ...

Originally from – Ruth Watkins

Bovine TB – compassion for the health of cattle and badgers
Vaccination strategies for health

I find the strategies for health of humans in our society, modern Britain, have been neglected or disregarded by the veterinary establishment for farm animals – BSE was the start of the consequences of so doing. DEFRA and the veterinary establishment have failed to recognise that humans are animals too. The farm animals must be as remarkably similar on genetic analysis to humans as mice have proven to be. The immune system must be very similar to our own. The control of disease by killing farm animals is promoted unashamedly and no apology made for failing to apply methods in human medicine to the care of farm animals as in the FMD epidemic of 2001.

Vaccination of wild animals against rabies and classical swine fever
For FMD the veterinary establishment and DEFRA have not agreed that vaccination to live should be the primary response to an outbreak. The advice of the Royal Society and EU inquiries have fallen on deaf ears blocked by the cotton wool of defensive self-justification. In Germany and other European countries the success of the vaccination of wild foxes with bait containing live attenuated rabies virus as oral vaccine has proven successful in eliminating rabies from the fox population. But here we are still focussing on killing foxes with poison if rabies were introduced into British foxes hence the experiments on poisoning foxes in Scotland. There are two distinct populations of wild animals infected by rabies in Europe; the virus that circulates amongst bats is a different strain from that circulating amongst foxes. As far as I know there is no strategy for vaccinating wild bats. The same strategy for vaccination of foxes against rabies is to be applied to classical swine fever. Bait containing live attenuated classical swine fever virus is being put out for wild boar in Germany. Within the space of about 3 months they have already 60% vaccine induced immunity in the target population. The plan is to prevent outbreaks of classical swine fever in farm pigs by eliminating the circulation of virus in wild boar on the other side of the fence.

Vaccination against bovine TB
Could we use BCG vaccine, the live attenuated mycobacterium vaccine first developed by Camille Guirin, called "Bacille Camille Guirin", BCG? This was derived originally from Mycobacterium bovis the cause of TB in cattle. I believe we could – at the very least we could embark on a usefully large field trial in badgers and cattle in a TB hot spot. Farmers with cattle, even closed herds are finding infection in their herd when brought in cattle or cattle contacts are excluded which can only come from local infected badgers. Infected badgers die a miserable death from Mycobacterium bovis. Thus cattle and badgers should be considered in any attempt to control and eliminate bovine TB.

I have been to a lecture (Pathogenesis of infectious diseases: emerging aspects held 14th Nov 2002 Royal College of Pathologists) given by Dr Mark Doherty from the Statens Serum Institute in Denmark that manufactures BCG and PPD, a purified protein derivative. He has worked on human and animal infection with Mycobacterium bovis. Badgers can be immunised orally with BCG, they love chocolate so Dr Doherty suggested they could be given chocolate containing BCG, "badger chocolates". Cattle can also be immunised, more practically by subcutaneous inoculation as in humans – it will cause an ulcer at the inoculation site in them as it does in us. The immunity is at least partially protective in both species.

PPD is used as a specific skin test for immunity, the TB-test in cattle, the Heaf test in humans. A vaccinated bovine, human or badger will make a small lump in the skin as response to PPD (this is due to the helper T-cell specific response to TB signifying the immune system has seen this particular protein before) as will one who has been infected in the past whether the infection be dormant or active. The solution in distinguishing vaccinated from infected animals is similar to that in FMD.

Just as the killed (inactivated) FMD vaccine is in effect a marker vaccine as it has been purified excluding the non-structural viral proteins so it turns out that BCG is also a marker vaccine. In the steps now lost in the mists of time which led to the isolation of an attenuated live bacteria called BCG (one able to elicit immunity but not cause disease) proteins were lost that are present in Mycobacterium bovis. These proteins can be used in an in-vitro test for T-cell response specifically to the lost proteins. Gamma interferon is secreted by T-cells that have been previously exposed to these particular proteins and can be accurately measured. The presence of gamma interferon in the test indicates the animal has been infected with Mycobacterium bovis at some point in the past. Such a test has been licensed by the FDA for use in humans for Mycobacterium tuberculosis and has been developed for cattle for Mycobacterium bovis I understand from Dr Doherty. Infection can be distinguished from vaccination. The tools of modern medicine are there to be used to combat the spread of Mycobacterium bovis and ultimately to eliminate the infection.

Using imperfect vaccines – rabies vaccine with specific immunoglobulin No vaccine works perfectly. Whilst scientists on the Royal Society Inquiry may believe that such a one could be developed there has been surprising success using imperfect vaccines, such as small pox. There is only one vaccine in human medicine that can be made to work perfectly in preventing disease in all instances, and it is thought also to prevent replicative cellular virus infection. This can only be achieved by the simultaneous administration of specific anti-virus immunoglobulin. This is immunisation against rabies. The rabies human diploid-cell derived vaccine killed or inactivated by beta-propriolactone is safe and potent. It is a simple vaccination IM or intradermal, and after exposure to rabies a course is given in conjunction with anti-rabies antibodies contained in human immunoglobulin derived from a vaccinee. (This is an opportunity to make sure my readers understand this and discard out of date notions of a painful and dangerous series of injections they would fear to undergo) All human cases of rabies will die (there are 3 attested recoveries published in the literature but it is not beyond doubt that these 3 persons had rabies). There has never been a death from rabies when the correct prophylaxis is given promptly after exposure with vaccine and immunoglobulin of attested quality and the course completed. This is a tremendous achievement in medicine but not applied to the thousands of persons who die of rabies each year in India or Africa.

Surely we should not wait for perfect vaccines before applying them to animals when we have taken such favourable advantage for our human selves. Doctors of human medicine are pragmatic, and humbled by the success of the imperfect vaccines they have had the good fortune to be able to use and receive. The single area in the health of Britain that has shown a very significant improvement in morbidity and mortality since the inception of the NHS in 1948 (when I was born and my employer throughout my working life) is in that of infection. Vaccination and the control and elimination of infection that it has afforded are not the least part of this improvement in health and life expectancy. Doctors have been dependent on scientists for these advances and remain so. Indeed in human medicine in Britain the scientists working on infectious disease continue to make significant international contribution to progress more so in this than in any other area.

Badgers, cattle and the reality of a control and elimination programme for bovine TB Whilst human medicine tries to put these benefits into practice in Britain it is clear to me that their veterinary colleagues do not. Can we be a civilised society whilst there is this discrepancy? It is not easy to take those steps that put it into practice, even a pilot study, and learn how it can most successfully be applied and then to carry it through. This includes educating and persuading the population, in this instance the farmers and persons with an interest in badger welfare.

Motivation for a study of BCG vaccination in a bovine TB hot spot
 
There is an epidemic of bovine and badger TB that is increasing yet nothing is done other than to find increasing numbers of cattle herds infected and eliminate bovine TB in the infected herd by slaughter of infected animals as they are identified. This can be a slow and costly business to the farmer and does little apparently to stem the infection spreading to new herds in previously uninfected areas, nor does it address infection in badgers. This may result from contact with infected bovines but it may also be responsible for spreading the infection to previously uninfected herds in the locality.

A pilot study to control the spread of Mycobacterium bovis in a TB hot-spot area will require a careful strategy backed up by appropriate sampling and testing of both badgers and cattle. Commonsense measures such as TB-testing any cattle sold out of or into the area would be an essential component of any plan.

Reasons for culling infected animals
 
Infected cattle and if possible infected badgers would have to be weeded out by culling because treatment takes 6 months with multiple drug therapy throughout, in isolation whilst still shedding Mycobacterium bovis, not possible for cattle or badgers. Vaccination doesn't treat TB nor in all instances does it prevent infection so if possible the burden of infected animals should be removed, easier for cattle than for badgers (trapped animals are anaesthetized for sampling, kept for several days, and only culled if they are positive for TB on testing otherwise returned to their own set). Close contact with an animal shedding mycobacteria such as living in the same house, the same shed or the same set is a highly effective way of spreading infection, much more so than casual contact when a much smaller dose at a single time-point is given to the exposed animal. Vaccine is more likely to be effective in the latter case.

Unlike virus infection such as FMD mycobacteria infection is not necessarily always infectious from one individual to another. Mycobacterium bovis is only spread when it is shed into the environment, most frequently as an aerosol from foci of infection in the lungs which discharge into the bronchi. Many infected individuals do not shed the bacterium into the environment.

Testing for the presence of Mycobacterium bovis
 
The presence of infection in cattle herds or trapped badgers in the area would be sought as it is now, by skin testing and by gamma interferon testing. Such testing would be systematic rather than piece meal as now, when the neighbouring herds of cattle to an infected herd may not be tested for another year or so. Any culled animal with a positive test result would have a PM, as now, and the organism would be isolated from lesions and subjected to PCR directly from the lesions to confirm infection.

The immunity and disease status of badgers should be determined if possible, returning tested but uninfected badgers to their own sets. The gamma interferon test should be verified for them so that it can be used in conjunction with the skin test. Their lungs could be x-rayed and faecal and sputum samples taken for bacterial isolation and PCR whilst they are anaesthetized and held at a special veterinary centre.

Molecular epidemiology
 
As well as testing individuals for infection genetic sequencing of strains of Mycobacterium bovis can be used as in human medicine to track the relationship of infection in an outbreak, to a common source, multiple sources or the reactivation of infection acquired years ago. A variable part of the genome could be used to assign a strain to examine how closely related the isolates are on an infected farm, an infected set and between the farms and sets. This information can be examined in the light of the field epidemiology. The study would take place over several years and it is possible that there could already be useful samples stored in TB hot spots and from the Krebs study.

Infected herds of cattle
 
The first response to an infected herd of cattle would be BCG vaccination of the remaining uninfected members of the herd, each electronically tagged. The incubation of bovine TB in cattle negative at the first screen would be sought by gamma interferon testing at three months and perhaps six months later as well as at the end of the study to find out if there was any further spread or reintroduction. It would be interesting to know whether this speeded up the time to elimination of TB from the herd compared to the present strategy of testing and killing and waiting until the herd is clear on two tests at least 3 months apart.

Whether uninfected herds of cattle in the area should also be vaccinated is debatable. Uninfected and unvaccinated herds act as sentinels for local spread amongst cattle and by badgers or other animals, including humans. There is no reason why humans should not eat BCG vaccinated cattle so vaccinating cattle is an option for farmers who might like to do so as they are next to an infected herd or badger set. Modelling would be useful to suggest which uninfected herds could benefit from immunisation particularly once the spread of bovine TB is better understood.

Reasons for vaccination of badgers in their wild undisturbed state
 
Has the use of BCG been assayed in an infected herd of cattle outside laboratory experiments? How effective the vaccine is or is not in cattle cannot be assumed to apply to badgers without testing BCG vaccination in them also. The vaccine could be successful in badgers if it curtails infection so that the infected badger is not infectious to others (the mycobacteria are entombed in a calcified inflammatory lesion) even though it may allow infection (be an imperfect vaccine). Thus bovine TB could be eliminated from the badger population if not reintroduced from cattle.

Badger chocolates would be widely spread in the area to cover all badger sets, at a time to ensure young badgers were immunised, perhaps twice a year. The dose of oral vaccine would be larger than that given by inoculation. The oral dose is likely to give rise to an inflammatory response in the gut associated lymphoid tissue – this is not desirable in cattle.

The Irish proposal to kill all badgers over wide areas and repopulate with BCG vaccinated badgers may not be as effective nor as desirable as blanket vaccination of the whole local population. It may not be possible to kill all badgers in a large area. Unvaccinated badgers may repopulate more quickly than vaccinated badgers can be released into the area. Equally it is not possible to selectively cull all infected badgers. Perhaps proven infected sets may have to be culled. However mycobacteria are environmentally hardy organisms and will be in the environment of the set especially where infected badgers have died underground gassed or poisoned. The most elegant and ultimately cheapest way of eliminating bovine TB from badgers would be by mass immunisation of the population in-situ, in their wild undisturbed state, if this strategy should work. It is this strategy that should be tested.

The control and elimination of bovine TB
 
The ultimate goal of the pilot study would be to control and eliminate Mycobacterium bovis from all potentially infectable species: cattle, badgers and humans in the area under study. If this could be achieved then it could be widely applied.

No programme of this nature is possible through individual funding by farmers even supposing they could afford it- the majority of livestock farmers could not. As in medicine good public health policies need public funding and conscientious application by persons with appropriate training in infection.