Bovine TB and the development of new vaccines

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Abstract

Bovine tuberculosis (bTB) is caused by Mycobacterium bovis. The incidence of bTB is increasing in cattle herds of developed countries that have a wild life reservoir of M. bovis, such as the UK, New Zealand and the USA. The increase in the incidence of bTB is thought to be due, at least in part, to a wildlife reservoir of M. bovis. M. bovis is also capable of infecting humans and on a worldwide basis, M. bovis is thought to account for up to 10% of cases of human TB [Cosivi O, Grange JM, Daborn CJ et al. Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerg Infect Dis 1998;4(1):59–70]. Thus, the increased incidence of bTB, besides being a major economic problem, poses an increased risk to human health. In the UK, the incidence of bTB continues to rise despite the use of the tuberculin test and slaughter control policy, highlighting the need for improved control strategies. Vaccination of cattle, in combination with more specific and sensitive diagnostic tests, is suggested as the most effective strategy for bovine TB control. The only vaccine currently available for human and bovine TB is the live attenuated Bacille Calmette Guerin (BCG). BCG is thought to confer protection through the induction of Th1 responses against mycobacteria. However, protection against TB conferred by BCG is variable and to this date the reasons for the successes and failures of BCG are not clear. Therefore, there is a need to develop vaccines that confer greater and more consistent protection against bTB than that afforded by BCG. Given that BCG is currently the only licensed vaccine against human TB, it is likely that any new vaccine or vaccination strategy will be based around BCG. In this review we discuss immune responses elicited by mycobacteria in cattle and the novel approaches emerging for the control of bovine TB based on our increasing knowledge of protective immune responses.

Résumé

La tuberculose bovine (bTB) est provoquée par Mycobacterium bovis. Son incidence est en augmentation dans les troupeaux de certains pays industrialisés comme le Royaume Uni, la Nouvelle Zélande ou les Etats-Unis, du fait de l’infection d’animaux sauvages qui jouent le rôle de réservoir. M. bovis est aussi capable d’infecter l’homme : on estime que près de 10% des cas de tuberculose humaine dans le monde lui sont imputables [Cosivi O, Grange JM, Daborn CJ et al. Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerg Infect Dis 1998;4(1):59–70]. L’augmentation de l’incidence de la bTB, outre ses conséquences économiques, représente donc aussi un risque pour la santé publique. Au Royaume Uni, la bTB progresse malgré la mise en œuvre d’une politique de contrôle par tests tuberculiniques et abattage systématique des animaux, suggérant qu’il est nécessaire de renforcer ce contrôle par la mise en œuvre d’une vaccination du bétail et le développement de tests de dépistage spécifiques et plus sensibles. Le seul vaccin dont on dispose à l’heure actuelle contre les tuberculoses humaine et bovine est le BCG (Bacille Calmette Guérin), prototype de vaccin vivant atténué. La protection due au BCG est liée à l’induction d’une réponse immunitaire Th1 mais elle parait variable, sans qu’on soit en mesure d’expliquer le pourquoi de ses succès ou de ses échecs. Il serait donc important de pouvoir disposer de vaccins susceptibles d’induire une protection meilleure et de manière plus consistante que le BCG. Vu que ce dernier est le seul vaccin autorisé à ce jour contre la tuberculose humaine, il est vraisemblable que tout nouveau vaccin ou toute nouvelle stratégie vaccinale devra être basé sur le BCG. Cet article passe en revue les réponses du système immunitaire à l’infection à mycobactéries chez le bétail et illustre les nouvelles approches vaccinales du contrôle de la bTB qu’on peut envisager à la lumière du progrès de nos connaissances en matière de réponses immunitaires protectrices.

Section snippets

Introduction: Bovine tuberculosis—an overview

Mycobacterium bovis is the causative agent of bovine tuberculosis (bTB) and is also capable of infecting humans. In the 1930s, it was estimated that 15–20% of the UK cattle herd were infected with M. bovis. Around the same time, before the introduction of milk pasteurisation, it is reported that up to 6% of human TB deaths were due to M. bovis infection. The introduction of the skin test and slaughter policy to high incidence areas in the UK in the 1950s, followed by nationwide application of

Immune responses to Mycobacteria

Stimulation of the adaptive immune response of vertebrates by an antigen will induce the development of immunological memory in most cases. Upon re-exposure to the same antigen, the immune response will be faster and may also be of greater intensity, which may be crucial in the face of relatively fast replicating organisms, such as viruses or bacteria. Vaccination is based on the induction of immunological memory and successful vaccines induce appropriately biased, long-lived immune responses.

Requirements for a cattle TB vaccine

From a practical perspective, vaccinating cattle via injection would be easy and allow wide population coverage. Ideally a bTB vaccine would not only help to prevent transmission to other cattle but also prevent establishment of infection, which may be difficult to attain in all animals under a wide range of conditions. In addition, diagnostic tests that will allow the discrimination between vaccinated/protected and vaccinated/un-protected animals (differential diagnosis) are essential, with

Mycobacterium bovis Bacille Calmette Guerin (BCG)

The only potential vaccine currently available for bovine and human TB, M. bovis BCG, is unlikely to fulfil all of the criteria defined above for an ideal cattle vaccine. However, BCG remains the standard against which to judge the efficacy of any novel vaccines or strategies.

BCG was derived through serial passage of M. bovis on glycerol-soaked potato slices by Calmette and Guerin in 1921. Challenge experiments and field trials in cattle—as in human trials [79]—have demonstrated a high degree

Progress in developing cattle TB vaccines and vaccination strategies

Interestingly, the results obtained and conclusions reached in both the human and bovine TB vaccine research areas are very similar [78]. TB vaccine development programmes have largely been directed at replacing BCG. However, despite testing large numbers of vaccine candidates in small animal models most conferred significantly less protection than BCG and the degree of protection observed with some of these vaccines in cattle has been so far considerably lower than that observed with BCG (see

The future of TB vaccines

Early immune events are likely to be pivotal in determining the outcome of infectious challenge, and vaccination must stimulate appropriate immune responses. It is now well established that the major host cells for mycobacteria: MO and DC, display divergent responses to infection with mycobacteria. This response is likely dependent upon unique expression patterns of PRR by MO and DC. Early responses of DC dictate the nature of the subsequent adaptive immune response and as such, vaccines

Conclusions

Significant progress has been made in the development of TB vaccines for cattle. Most significantly, in parallel with developments in the human TB vaccine development field, vaccine strategies are now being considered for supplementing rather than replacing BCG vaccination. In particular, subunit vaccines based on DNA or proteins in adjuvant used in combination with BCG have resulted in better protection against experimental challenge with M. bovis than BCG vaccination on its own. BCG

Acknowledgement

The authors were funded by the Department for Environment, Food and Rural Affairs, United Kingdom and Biotechnology and Biological Sciences Research Council, UK.

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