Development of a diagnostic compatible BCG vaccine against Bovine tuberculosis

Abstract

Bovine tuberculosis (BTB) caused by Mycobacterium bovis remains a major problem in both the developed and developing countries. Control of BTB in the UK is carried out by test and slaughter of infected animals, based primarily on the tuberculin skin test (PPD). Vaccination with the attenuated strain of the M. bovis pathogen, BCG, is not used to control bovine tuberculosis in cattle at present, due to its variable efficacy and because it interferes with the PPD test. Diagnostic tests capable of Differentiating Infected from Vaccinated Animals (DIVA) have been developed that detect immune responses to M. bovis antigens absent in BCG; but these are too expensive and insufficiently sensitive to be used for BTB control worldwide. To address these problems we aimed to generate a synergistic vaccine and diagnostic approach that would permit the vaccination of cattle without interfering with the conventional PPD-based surveillance. The approach was to widen the pool of M. bovis antigens that could be used as DIVA targets, by identifying antigenic proteins that could be deleted from BCG without affecting the persistence and protective efficacy of the vaccine in cattle. Using transposon mutagenesis we identified genes that were essential and those that were non-essential for persistence in bovine lymph nodes. We then inactivated selected immunogenic, but non-essential genes in BCG Danish to create a diagnostic-compatible triple knock-out ΔBCG TK strain. The protective efficacy of the ΔBCG TK was tested in guinea pigs experimentally infected with M. bovis by aerosol and found to be equivalent to wild-type BCG. A complementary diagnostic skin test was developed with the antigenic proteins encoded by the deleted genes which did not cross-react in vaccinated or in uninfected guinea pigs. This study demonstrates the functionality of a new and improved BCG strain which retains its protective efficacy but is diagnostically compatible with a novel DIVA skin test that could be implemented in control programmes.

Evaluation of the Control Options of Bovine Tuberculosis in Ethiopia Using a Multi-Criteria Decision Analysis

“…This is likely influenced by the role of BCG in sensitizing cattle to respond to the conventional BTB diagnostic test, combined with the low level of protection of BCG vaccine in cattle compared to its relative effectiveness in humans (22). To overcome the diagnostic limitations of PPD skin test, an alternative skin test that can differentiate infected from vaccinated animals (DIVA) was developed (24). Thus, in the presence of the alternative test with DIVA role BCG vaccination would be the preferred control option for control of BTB, particularly in low and middle income countries like Ethiopia (24).…”

“…To overcome the diagnostic limitations of PPD skin test, an alternative skin test that can differentiate infected from vaccinated animals (DIVA) was developed (24). Thus, in the presence of the alternative test with DIVA role BCG vaccination would be the preferred control option for control of BTB, particularly in low and middle income countries like Ethiopia (24).…”

Zoonotic Tuberculosis – The Changing Landscape

“…A major constraint of using BCG vaccination in cattle is the fact that trading blocs like the European Union prohibit the use of TB vaccines in cattle, since vaccination compromises the interpretation of traditional TB diagnostic tests. However, these concerns have been addressed with the development of more specific tests that differentiate infected from vaccinated animals (DIVA®) ( Vordermeier et al, 2011 ) and of a diagnostic compatible BCG vaccine strain not eliciting an immune response in the compatible skin test ( Chandran et al, 2019 ). Although BCG should offer some protection against multiple MTBC species, including M. orygis , it should be recognized that protection will not be complete and should be used to complement, rather than replace, more traditional control measures.…”

Prime Vaccination with Chitosan-Coated Phipps BCG and Boosting with CFP-PLGA against Tuberculosis in a Goat Model

“…Bovine Tuberculosis (bTB) remains a serious problem for livestock worldwide, especially in developing countries, where the strategy of “test-and-slaughter” is not economically viable [ 1 , 2 , 3 , 4 ]. The prevalence of bTB in dairy cattle in not developed countries is especially high; therefore, the testing and disposing of cattle would represent high costs to the dairy industry, rendering this practice unfeasible.…”