A Defined Antigen Skin Test That Enables Implementation of BCG Vaccination for Control of Bovine Tuberculosis: Proof of Concept

Srinivasan, Sreenidhi; Subramanian, Saraswathi; Balakrishnan, S; Selvaraju, Kathiravan Ramaiyan; Manomohan, Vandana; Selladurai, Suganya; Jothivelu, Monika; Kandasamy, Srinivasan; Raj, Gopal Dhinakar; Kumanan, K.; Conlan, Andrew J. K.; Veerasami, Maroudam; Bakker, Douwe; Vordermeier, Martin; Kapur, Vivek

doi:10.3389/fvets.2020.00391

Cited by 17 publications

(17 citation statements)

References 23 publications

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“…However, it is noteworthy that these studies provided key foundational evidence that highlighted both the variable protection afforded by BCG in experimental and natural challenge, as well as showed that BCG vaccination sensitizes animals to tuberculins and hence would confound ongoing test and slaughter tuberculosis eradication programs. However, recent attempts to develop BCG-compatible diagnostic tests have shown great promise and paved the way for implementation of BCG-based control programs in LMICs and other endemic regions ( 7 – 9 ). Thus, there is renewed interest in exploring the use of BCG vaccination as a component of national control programs, particularly where test and slaughter is unfeasible ( 58 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

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A Meta-Analysis of the Effect of Bacillus Calmette-Guérin Vaccination Against Bovine Tuberculosis: Is Perfect the Enemy of Good?

et al. 2021

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More than 50 million cattle are likely exposed to bovine tuberculosis (bTB) worldwide, highlighting an urgent need for bTB control strategies in low- and middle-income countries (LMICs) and other regions where the disease remains endemic and test-and-slaughter approaches are unfeasible. While Bacillus Calmette-Guérin (BCG) was first developed as a vaccine for use in cattle even before its widespread use in humans, its efficacy against bTB remains poorly understood. To address this important knowledge gap, we conducted a systematic review and meta-analysis to determine the direct efficacy of BCG against bTB challenge in cattle, and performed scenario analyses with transmission dynamic models incorporating direct and indirect vaccinal effects (“herd-immunity”) to assess potential impact on herd level disease control. The analysis shows a relative risk of infection of 0.75 (95% CI: 0.68, 0.82) in 1,902 vaccinates as compared with 1,667 controls, corresponding to a direct vaccine efficacy of 25% (95% CI: 18, 32). Importantly, scenario analyses considering both direct and indirect effects suggest that disease prevalence could be driven down close to Officially TB-Free (OTF) status (<0.1%), if BCG were introduced in the next 10-year time period in low to moderate (<15%) prevalence settings, and that 50–95% of cumulative cases may be averted over the next 50 years even in high (20–40%) disease burden settings with immediate implementation of BCG vaccination. Taken together, the analyses suggest that BCG vaccination may help accelerate control of bTB in endemic settings, particularly with early implementation in the face of dairy intensification in regions that currently lack effective bTB control programs.

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Section: Discussionmentioning

confidence: 99%

“…In particular, the antigens ESAT-6, CFP10 and Rv3615c have shown promise for differential diagnosis of bTB ( 4 , 6 , 7 ). The DIVA capability of these antigens has been demonstrated in both experimental and naturally infected animals, hence enabling the use of BCG vaccination as part of future bTB control programs ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

A Meta-Analysis of the Effect of Bacillus Calmette-Guérin Vaccination Against Bovine Tuberculosis: Is Perfect the Enemy of Good?

et al. 2021

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“…Other tests include the single cervical tuberculin test (SCT, also referred to as single intradermal test, SIT) that relies on the injection of PPD-B only and is often used as the prescribed test for international trade. Recent developments in tuberculin skin testing for cattle include the use of defined skin test antigen preparations to increase test sensitivity, for example, DIVA tests compatible with BCG vaccination 1 , 4 – 6 .…”

Section: Introductionmentioning

confidence: 99%

Temporal dynamics of intradermal cytokine response to tuberculin in Mycobacterium bovis BCG-vaccinated cattle using sampling microneedles

Steinbach

Jalili‐Firoozinezhad

Srinivasan

et al. 2021

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Bovine tuberculosis (bTB) is a disease of livestock with severe and worldwide economic, animal welfare and zoonotic consequences. Application of test-and-slaughter-based control polices reliant on tuberculin skin testing has been the mainstay of bTB control in cattle. However, little is known about the temporal development of the bovine tuberculin skin test response at the dermal sites of antigen injection. To fill this knowledge gap, we applied minimally-invasive sampling microneedles (SMNs) for intradermal sampling of interstitial fluid at the tuberculin skin test sites in Mycobacterium bovis BCG-vaccinated calves and determined the temporal dynamics of a panel of 15 cytokines and chemokines in situ and in the peripheral blood. The results reveal an orchestrated and coordinated cytokine and local chemokine response, identified IL-1RA as a potential soluble biomarker of a positive tuberculin skin response, and confirmed the utility of IFN-γ and IP-10 for bTB detection in blood-based assays. Together, the results highlight the utility of SMNs to identify novel biomarkers and provide mechanistic insights on the intradermal cytokine and chemokine responses associated with the tuberculin skin test in BCG-sensitized cattle.

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“…However, there are several major limitations to the OIE-recommended tuberculin-based skin tests, including the fact that the active components in the reagent are undefined and their interference with BCG-based vaccination. In contrast, the peptide-based DST offers superior quality control and potential for DIVA has previously been demonstrated in cattle (10), and the current study indicates that the DST antigens are promising candidates for differentiating between reactor and uninfected buffaloes. Limitations of the study include the relatively small number of animals and their origin from a single dairy farm.…”

Section: Discussionmentioning

confidence: 54%

A Defined Antigen Skin Test for Diagnosis of Bovine Tuberculosis in Domestic Water Buffaloes (Bubalus bubalis)

et al. 2021

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Bovine tuberculosis (bTB) remains endemic in domestic water buffaloes (Bubalus bubalis) in India and elsewhere, with limited options for control other than testing and slaughter. The prescribed tuberculin skin tests with purified protein derivative (PPD) for diagnosis of bTB preclude the use of Bacille Calmette-Guérin (BCG)-based vaccination because of the antigenic cross-reactivity of vaccine strains with Mycobacterium bovis and related pathogenic members of the M. tuberculosis complex (MTBC). For the diagnosis of bTB in domestic water buffaloes, we here assessed a recently described defined-antigen skin test (DST) that comprises overlapping peptides representing the ESAT-6, CFP-10 and Rv3615c antigens, present in disease-causing members of the MTBC but missing in BCG strains. The performance characteristics of three doses (5, 10 or 20 μg/peptide) of the DST were assessed in natural tuberculin skin test reactor (n = 11) and non-reactor (n = 35) water buffaloes at an organized dairy farm in Hisar, India, and results were compared with the single intradermal skin test (SIT) using standard bovine tuberculin (PPD-B). The results showed a dose-dependent response of DST in natural reactor water buffaloes, although the SIT induced a significantly greater (P < 0.001) skin test response than the highest dose of DST used. However, using a cut-off of 2 mm or greater, the 5, 10, and 20 μg DST cocktail correctly classified eight, 10 and all 11 of the SIT-positive reactors, respectively, suggesting that the 20 μg DST cocktail has a diagnostic sensitivity (Se) of 1.0 (95% CI: 0.72–1.0) identical to that of the SIT. Importantly, none of the tested DST doses induced any measurable skin induration responses in the 35 SIT-negative animals, suggesting a specificity point estimate of 1.0 (95% CI: 0.9–1.0), also identical to that of the SIT and compares favorably with that of the comparative cervical test (Se = 0.85; 95% CI: 0.55–0.98). Overall, the results suggest that similar to tuberculin, the DST enables sensitive and specific diagnosis of bTB in water buffaloes. Future field trials to explore the utility of DST as a defined antigen replacement for tuberculin in routine surveillance programs and to enable BCG vaccination of water buffaloes are warranted.

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A Defined Antigen Skin Test That Enables Implementation of BCG Vaccination for Control of Bovine Tuberculosis: Proof of Concept

Cited by 17 publications

References 23 publications

A Meta-Analysis of the Effect of Bacillus Calmette-Guérin Vaccination Against Bovine Tuberculosis: Is Perfect the Enemy of Good?

A Meta-Analysis of the Effect of Bacillus Calmette-Guérin Vaccination Against Bovine Tuberculosis: Is Perfect the Enemy of Good?

Temporal dynamics of intradermal cytokine response to tuberculin in Mycobacterium bovis BCG-vaccinated cattle using sampling microneedles

A Defined Antigen Skin Test for Diagnosis of Bovine Tuberculosis in Domestic Water Buffaloes (Bubalus bubalis)

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