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Tuberculosis vaccination: the long road to a better BCG
The Veterinary Journal The Veterinary Journal 166 (2003) 1–2 www.elsevier.com/locate/tvjl
Guest editorial
Tuberculosis vaccination: the long road to a better BCG The Holy Grail of a human tuberculosis (TB) vaccine offering significantly greater and more predictable protection than BCG continues to be elusive, despite the massive incentives to find it. Human infection with Mycobacterium tuberculosis is a global experience, with estimates that a third of the worldÕs population is infected, resulting in upwards of eight million active cases and more than two million deaths each year (Ginsberg, 2002). Given these figures one may forget that M. bovis, the infective agent of bovine tuberculosis, also results in human infection and additionally is a major cause of economic loss to farming industries world-wide through production losses and damage to international trade. Most developed countries have implemented eradication programmes for bovine tuberculosis. Some have been highly successful, for example in several Western European countries and more recently in Australia. These programmes have invariably depended on a test-andslaughter strategy using the tuberculin-based intradermal diagnostic test in one form or another as the herdscreening test (Clifton-Hadley and Wilesmith, 1995). Programmes in other countries, such as the United Kingdom and New Zealand, have met with success initially but to date eradication has proved impossible. This has been ascribed to the existence of widespread infection in one or more wildlife reservoirs, for example the brushtail possum in New Zealand and the European badger in Great Britain (GB) and Ireland. As a result, there have been active control programmes implemented against these species in areas of high cattle TB incidence but with varying degrees of success. In GB, TB incidence in cattle has increased inexorably since the mid-1980s, with an average number of confirmed new incidents exceeding 1000 over the last three years. Failure to control cattle TB in GB through badger culling for over a quarter of a century culminated in the third independent review of the problem (Krebs, 1997). Accepting that badgers were a cause of herd breakdowns, the report recommended a national trial to assess the extent of badger involvement in cattle TB. A further recommendation was that the development of a cattle TB vaccine should be actively pursued while maintaining the option of a badger vaccine. On casual consideration of the two approaches, a cattle vaccine appears the more attractive since one
would have control over the target population and could apply a vaccine through injection, so reaching the coverage required in the geographical areas at risk. Assuming that EU legislation could be changed to accommodate vaccine use, the problem here is that the vaccine would have to be particularly effective, preventing not only transmission between animals in a herd but also the establishment of persistent infection from whatever source. Additionally, easy differentiation between vaccinated and infected animals would be a requirement so that monitoring for infection could continue without raising the number of false positive reactors. This might not be straightforward as successfully vaccinated animals subsequently challenged with M. bovis might react positively to any immunological test used to screen for infected animals. These difficulties argue for the wildlife vaccine option, although to make such an approach worthwhile assumes an almost uni-directional spread of disease from wildlife to cattle and a limited amount of between-herd transmission. Results from the randomised badger culling trial will be crucial for any future decision to undertake badger vaccination. Moreover, following the foot and mouth disease epidemic and subsequent increased movement of cattle during restocking, it is possible that cattle are now playing a greater role in spreading TB than was the case previously. The requirements of a wildlife vaccine are somewhat different from those of a cattle vaccine. The primary goal of a badger vaccine would be to reduce the rate of TB transmission to cattle. Therefore, it need not prevent establishment of persistent infection providing it reduces the likelihood of transmission of TB to cattle by limiting the rate of M. bovis excretion. Producing a vaccine for and applying it to a wildlife species presents considerable developmental and logistical challenges. Before using a badger vaccine in the field, the efficacy of the vaccine must be established in badgers and evidence must be obtained that the vaccine does not exacerbate the disease in animals that are already infected with M. bovis. Data must also be obtained to define optimal dose and duration of immunity induced by the vaccine and to establish the safety of the vaccine in badgers, man and other species that might become exposed to the vaccine in the field. One other
1090-0233/03/$ - see front matter Crown Copyright Ó 2003 Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S1090-0233(03)00081-9
2
Guest editorial / The Veterinary Journal 166 (2003) 1–2
important property of any vaccine currently is that it must not sensitise cattle to the tuberculin test. Once these requirements have been satisfied the logistics of vaccinating badgers in the field could be considered. It is timely that in this edition of The Veterinary Journal, Delahay and co-workers outline some of the ecological considerations that must be taken into account in developing an effective badger vaccine and for its successful delivery in the field (Delahay et al., 2003). These include determining a suitable means of delivery, achieving adequate coverage and avoiding application to non-target species, including cattle. The Independent Scientific Group, responsible for implementing the recommendations of the Krebs Report (1997) are currently producing a scoping study, examining the practicalities, including resource implications, of developing, testing and applying an effective TB vaccine for either cattle or badgers. It is likely that the list of requirements will be long. However, the success with rabies vaccination in foxes provides some basis for hoping that they will not be insurmountable.
R.S. Clifton-Hadley R.G. Hewinson Veterinary Laboratories Agency Weybridge, Woodham Lane New Haw, Addlestone Surrey KT15 3NB, UK E-mail address: [email protected]
References Clifton-Hadley, R., Wilesmith, J., 1995. An epidemiological outlook on bovine tuberculosis in the developed world. In: Griffin, F., de Lisle, G. (Eds.), Tuberculosis in Wildlife and Domestic Animals. University of Otago Press, Otago, pp. 178–182. Delahay, R.J., Wilson, G.J., Smith, G.C., Cheeseman, C.L., 2003. Vaccinating badgers (Meles meles) against Mycobacterium bovis: the ecological considerations. The Veterinary Journal 166, 43–51. Ginsberg, A.M., 2002. WhatÕs new in tuberculosis vaccines? Bulletin of the World Health Organization 80, 483–488. Krebs, J.R., 1997. In: Bovine Tuberculosis in Cattle and Badgers. MAFF Publications, London, p. 191.
Guest editorial
Tuberculosis vaccination: the long road to a better BCG The Holy Grail of a human tuberculosis (TB) vaccine offering significantly greater and more predictable protection than BCG continues to be elusive, despite the massive incentives to find it. Human infection with Mycobacterium tuberculosis is a global experience, with estimates that a third of the worldÕs population is infected, resulting in upwards of eight million active cases and more than two million deaths each year (Ginsberg, 2002). Given these figures one may forget that M. bovis, the infective agent of bovine tuberculosis, also results in human infection and additionally is a major cause of economic loss to farming industries world-wide through production losses and damage to international trade. Most developed countries have implemented eradication programmes for bovine tuberculosis. Some have been highly successful, for example in several Western European countries and more recently in Australia. These programmes have invariably depended on a test-andslaughter strategy using the tuberculin-based intradermal diagnostic test in one form or another as the herdscreening test (Clifton-Hadley and Wilesmith, 1995). Programmes in other countries, such as the United Kingdom and New Zealand, have met with success initially but to date eradication has proved impossible. This has been ascribed to the existence of widespread infection in one or more wildlife reservoirs, for example the brushtail possum in New Zealand and the European badger in Great Britain (GB) and Ireland. As a result, there have been active control programmes implemented against these species in areas of high cattle TB incidence but with varying degrees of success. In GB, TB incidence in cattle has increased inexorably since the mid-1980s, with an average number of confirmed new incidents exceeding 1000 over the last three years. Failure to control cattle TB in GB through badger culling for over a quarter of a century culminated in the third independent review of the problem (Krebs, 1997). Accepting that badgers were a cause of herd breakdowns, the report recommended a national trial to assess the extent of badger involvement in cattle TB. A further recommendation was that the development of a cattle TB vaccine should be actively pursued while maintaining the option of a badger vaccine. On casual consideration of the two approaches, a cattle vaccine appears the more attractive since one
would have control over the target population and could apply a vaccine through injection, so reaching the coverage required in the geographical areas at risk. Assuming that EU legislation could be changed to accommodate vaccine use, the problem here is that the vaccine would have to be particularly effective, preventing not only transmission between animals in a herd but also the establishment of persistent infection from whatever source. Additionally, easy differentiation between vaccinated and infected animals would be a requirement so that monitoring for infection could continue without raising the number of false positive reactors. This might not be straightforward as successfully vaccinated animals subsequently challenged with M. bovis might react positively to any immunological test used to screen for infected animals. These difficulties argue for the wildlife vaccine option, although to make such an approach worthwhile assumes an almost uni-directional spread of disease from wildlife to cattle and a limited amount of between-herd transmission. Results from the randomised badger culling trial will be crucial for any future decision to undertake badger vaccination. Moreover, following the foot and mouth disease epidemic and subsequent increased movement of cattle during restocking, it is possible that cattle are now playing a greater role in spreading TB than was the case previously. The requirements of a wildlife vaccine are somewhat different from those of a cattle vaccine. The primary goal of a badger vaccine would be to reduce the rate of TB transmission to cattle. Therefore, it need not prevent establishment of persistent infection providing it reduces the likelihood of transmission of TB to cattle by limiting the rate of M. bovis excretion. Producing a vaccine for and applying it to a wildlife species presents considerable developmental and logistical challenges. Before using a badger vaccine in the field, the efficacy of the vaccine must be established in badgers and evidence must be obtained that the vaccine does not exacerbate the disease in animals that are already infected with M. bovis. Data must also be obtained to define optimal dose and duration of immunity induced by the vaccine and to establish the safety of the vaccine in badgers, man and other species that might become exposed to the vaccine in the field. One other
1090-0233/03/$ - see front matter Crown Copyright Ó 2003 Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S1090-0233(03)00081-9
2
Guest editorial / The Veterinary Journal 166 (2003) 1–2
important property of any vaccine currently is that it must not sensitise cattle to the tuberculin test. Once these requirements have been satisfied the logistics of vaccinating badgers in the field could be considered. It is timely that in this edition of The Veterinary Journal, Delahay and co-workers outline some of the ecological considerations that must be taken into account in developing an effective badger vaccine and for its successful delivery in the field (Delahay et al., 2003). These include determining a suitable means of delivery, achieving adequate coverage and avoiding application to non-target species, including cattle. The Independent Scientific Group, responsible for implementing the recommendations of the Krebs Report (1997) are currently producing a scoping study, examining the practicalities, including resource implications, of developing, testing and applying an effective TB vaccine for either cattle or badgers. It is likely that the list of requirements will be long. However, the success with rabies vaccination in foxes provides some basis for hoping that they will not be insurmountable.
R.S. Clifton-Hadley R.G. Hewinson Veterinary Laboratories Agency Weybridge, Woodham Lane New Haw, Addlestone Surrey KT15 3NB, UK E-mail address: [email protected]
References Clifton-Hadley, R., Wilesmith, J., 1995. An epidemiological outlook on bovine tuberculosis in the developed world. In: Griffin, F., de Lisle, G. (Eds.), Tuberculosis in Wildlife and Domestic Animals. University of Otago Press, Otago, pp. 178–182. Delahay, R.J., Wilson, G.J., Smith, G.C., Cheeseman, C.L., 2003. Vaccinating badgers (Meles meles) against Mycobacterium bovis: the ecological considerations. The Veterinary Journal 166, 43–51. Ginsberg, A.M., 2002. WhatÕs new in tuberculosis vaccines? Bulletin of the World Health Organization 80, 483–488. Krebs, J.R., 1997. In: Bovine Tuberculosis in Cattle and Badgers. MAFF Publications, London, p. 191.