Potential benefits of cattle vaccination as a supplementary control for bovine tuberculosis

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tVaccination for the control of bovine tuberculosis (bTB) in cattle is not currently used within any international control program, and is illegal within the EU. Candidate vaccines, based upon Mycobacterium bovis bacillus Calmette-Guérin (BCG) all interfere with the action of the tuberculin skin test, which is used to determine if animals, herds and countries are officially bTB-free. New diagnostic tests that Differentiate Infected from Vaccinated Animals (DIVA) offer the potential to introduce vaccination within existing eradication programs. We use within-herd transmission models estimated from historical data from Great Britain (GB) to explore the feasibility of such supplemental use of vaccination. The economic impact of bovine Tuberculosis for farmers is dominated by the costs associated with testing, and associated restrictions on animal movements. Farmers' willingness to adopt vaccination will require vaccination to not only reduce the burden of infection, but also the risk of restrictions being imposed. We find that, under the intensive sequence of testing in GB, it is the specificity of the DIVA test, rather than the sensitivity, that is the greatest barrier to see a herd level benefit of vaccination. The potential negative effects of vaccination could be mitigated through relaxation of testing. However, this could potentially increase the hidden burden of infection within Officially TB Free herds. Using our models, we explore the range of the DIVA test characteristics necessary to see a protective herd level benefit of vaccination. We estimate that a DIVA specificity of at least 99.85% and sensitivity of >40% is required to see a protective benefit of vaccination with no increase in the risk of missed infection. Data from experimentally infected animals suggest that this target specificity could be achieved in vaccinates using a cocktail of three DIVA antigens while maintaining a sensitivity of 73.3% (95%CI: 61.9, 82.9%) relative to post-mortem detection.This study was funded by Defra project SE3127 and uses nationally collected incidence and cattle-movement data sets held by Defra

Display of antigens on polyester inclusions lowers the antigen concentration required for a bovine tuberculosis skin test

The tuberculin skin test is the primary screening test for the diagnosis of bovine tuberculosis (TB), and use of this test has been very valuable in the control of this disease in many countries. However, the test lacks specificity when cattle have been exposed to environmental mycobacteria or vaccinated with Mycobacterium bovis bacille Calmette-Guérin (BCG). Recent studies showed that the use of three or four recombinant mycobacterial proteins, including 6-kDa early secretory antigenic target (ESAT6), 10-kDa culture filtrate protein (CFP10), Rv3615c, and Rv3020c, or a peptide cocktail derived from those proteins, in the skin test greatly enhanced test specificity, with minimal loss of test sensitivity. The proteins are present in members of the pathogenic Mycobacterium tuberculosis complex but are absent in or not expressed by the majority of environmental mycobacteria and the BCG vaccine strain. To produce a low-cost skin test reagent, the proteins were displayed at high density on polyester beads through translational fusion to a polyhydroxyalkanoate synthase that mediates the formation of antigen-displaying inclusions in recombinant Escherichia coli. Display of the proteins on the polyester beads greatly increased their immunogenicity, allowing for the use of very low concentrations of proteins (0.1 to 3 μg of mycobacterial protein/inoculum) in the skin test. Polyester beads simultaneously displaying all four proteins were produced in a single fermentation process. The polyester beads displaying three or four mycobacterial proteins were shown to have high sensitivity for detection of M. bovis-infected cattle and induced minimal responses in animals exposed to environmental mycobacteria or vaccinated with BCG.Full Tex

Development of cattle TB vaccines based on heterologous prime-boosting strategies

AbstractDevelopment of a TB vaccine for cattle is a research priority in Great Britain. Two challenges need to be addressed. Firstly, vaccine strategies enhancing the efficacy of M. bovis bacille Calmette Guérin (BCG), currently the only potentially available TB vaccine, and secondly the development of a diagnostic test to be used alongside vaccination to differentiate vaccinated and infected animals (DIVA test). Significant progress in developing TB vaccines for cattle has been made over the last 7 years. Specifically: (i) DNA, protein, or viral subunit subunit vaccines used in combination with BCG have been shown to give superior protection against experimental challenge in cattle than BCG (heterologous prime-boost), (ii) neonatal BCG vaccination provides protection, (iii) prototype reagents that allow discrimination between vaccinated and infected animals have been developed; and (iv) and correlates of disease severity have been identified that can predict the success or failure of vaccination. The present overview provides details of some of these advances. [Ethiop.J.Health Dev. 2008;22(Special Issue):100-104

T-Cell and Antibody Responses to Mycobacterial Antigens in Tuberculin Skin-Test-Positive Bos indicus and Bos taurus Cattle in Ethiopia

Higher IFN-γ responses to mycobacterial antigens were observed in Bos taurus (Holsteins) than in Bos indicus (Zebu) cattle which could due to differences in antigen recognition profiles between the two breeds. The present study was conducted to evaluate mycobacterial antigen recognition profiles of the two breeds. Twenty-three mycobacterial antigens were tested on 46 skin test positive (24 Zebu and 22 Holstein) using enzyme-linked immunospot assay (ELISPOT) and multiple antigen print immunoassay (MAPIA). Herds from which the study cattle obtained were tested for Fasciola antibody. The T cells from both breeds recognized most of the mycobacterial antigens at lower and comparable frequencies. However, antigens such as CFP-10, ESAT-6, Rv0287, Rv0288, MPB87, Acr-2, Rv3616c, and Rv3879c were recognized at higher frequencies in zebu while higher frequencies of T cell responses were observed to Hsp65 in both breeds. Furthermore, comparable antibody responses were observed in both breeds; MPB83 being the sero-dominant antigen in both breeds. The prevalence of Fasciola antibody was 81% and similar in both breeds. This piece of work could not lead to a definitive conclusion if there are differences in mycobacterial recognition profiles between the two breeds warranting for further similar studies using sound sample size from the two breeds

A mycobacterial growth inhibition assay (MGIA) for bovine TB vaccine development

Human tuberculosis remains a significant cause of mortality and morbidity throughout the world. The global economic impact of bovine TB is considerable. An effective vaccine would be the most cost-effective way to control both epidemics, particularly in emerging economies. TB vaccine research would benefit from the identification of an immune correlate of protection with which vaccines could be gated at both preclinical and clinical levels. In-vitro mycobacterial growth inhibition assays (MGIA) are functional assays that include most aspects of the complex host immune response to mycobacteria, and they may serve as functional immune correlates for vaccine development. We applied to cattle an MGIA that was developed for use with human and murine samples. Several technical difficulties were encountered while transferring it to the cattle model. However, our data demonstrate that the assay was not discriminatory in cattle and further work is needed before using it for bovine TB vaccine development

The intractable challenge of evaluating cattle vaccination as a control for bovine tuberculosis

Vaccination of cattle against bovine Tuberculosis (bTB) has been a long-term policy objective for countries where disease continues to persist despite costly test-and-slaughter programs. The potential use of vaccination within the European Union has been linked to a need for field evaluation of any prospective vaccine and the impact of vaccination on the rate of transmission of bTB. We calculate that estimation of the direct protection of BCG could be achieved with 100 herds, but over 500 herds would be necessary to demonstrate an economic benefit for farmers whose costs are dominated by testing and associated herd restrictions. However, the low and variable attack rate in GB herds means field trials are unlikely to be able to discern any impact of vaccination on transmission. In contrast, experimental natural transmission studies could provide robust evaluation of both the efficacy and mode of action of vaccination using as few as 200 animals

A comparative study on the epidemiology and immuno-pathology of bovine tuberculosis in Bos indicus and Bos taurus cattle in Ethiopia

AbstractBovine tuberculosis is a disease of dual effect, having public health and economic implications. The present study was conducted on its epidemiology and immuno-pathology in Holstein and Zebu breeds of cattle. Skin test, post mortem examination and pathology scoring, bacteriology, whole blood gamma interferon assay, ELISPOT assay, and lateral flow assay were used. An overall prevalence of 13.5% (n=5,424) was recorded; both prevalence (2 =61.8; P<0.001) and severity of pathology (mean pathology scores + SEM: 6.84±0.79 vs. 5.21±0.30; P=0.018, Mann-Whitney test) were significantly higher in Holstein than in Zebu. Similarly, IFN- responses to avian PPD (0.490.10 vs. 0.390.07), bovine PPD (0.630.11 vs. 0.430.07), or the ESAT6-CFP10 protein cocktail (0.430.01 vs. 0.300.05) were significantly higher (for all antigens: p<0.02) in Holstein than in Zebu cattle. However, both Holstein and Zebu exhibited similar T cell and antibody responses to different mycobacterial antigens i.e. no repertoire difference was observed between the two breeds. Thus, the present study showed increased susceptibility of Holsteins to bovine TB as compared to Zebu, similarity between Holsteins and Zebus in their antigen responses, and a positive correlation between IFN- responses and severity of pathology of bovine TB. [Ethiop.J.Health Dev. 2008;22(Special Issue):132-134