Tuberculosis vaccination: Microbiological and immunological summary of a series of experimental challenge studies

Background : Bovine tuberculosis (TB) caused by Mycobacterium bovis remains a persistent zoonotic and agricultural challenge, despite advances in eradication programs targeting cattle. The complexity of TB epidemiology, especially in extensive livestock systems and wildlife reservoirs, necessitates novel control strategies. Vaccination has re-emerged as a promising tool, with growing interest in inactivated vaccines for both efficacy and diagnostic compatibility. Objectives : This study evaluates the comparative efficacy of homologous and heterologous inactivated vaccines against the standard live Bacille Calmette–Guérin (BCG) vaccine in calves, focusing on M. bovis isolation, gross TB lesions, immune responses, and compatibility with Differentiating Infected from Vaccinated Animals (DIVA) strategies. Methods : Data from four controlled vaccination and challenge trials involving 41 calves were analyzed. Animals were vaccinated with live BCG or heat-inactivated M. bovis via the oral or parenteral routes, with immunologic assays, skin tests, and post-mortem analyses conducted to evaluate vaccine performance. Results : All vaccination strategies significantly reduced M. bovis bacterial loads in the lungs compared to non-vaccinated controls, achieving up to 99% reductions. However, bacterial loads in lymphoid tissues increased, underscoring tuberculosis as a primarily lymphatic disease. Diagnostic interference varied by vaccine type and administration route, with oral administration showing lower interference. Gross lesion scores were inconsistent across groups, suggesting limited utility as a measure of vaccine efficacy. Immune responses revealed enhanced detection of infection post-vaccination, particularly with inactivated vaccines, which showed promising compatibility with DIVA strategies. Lung bacterial load appeared to be decoupled from cellular immune responses and lymph node lesions and bacterial load which were negatively correlated among themselves. Conclusions : This study demonstrates that inactivated vaccines offer a safe and effective means of reducing TB transmission by confining bacterial presence to lymphoid tissues and minimizing diagnostic interference. Vaccination programs should shift from eradication goals to transmission control, prioritizing reductions in reproductive rate (R₀) over total bacterial clearance. These findings highlight the need for revised evaluation criteria and support the integration of inactivated vaccines into TB control strategies.