Aerosol BCG Boosts Lung Immunity Against Tuberculosis

Tuberculosis remains a major global health threat because the currently licensed vaccine, Mycobacterium bovis BCG, gives limited protection against pulmonary TB in adolescents and adults — the age groups that drive transmission and most deaths. Roland Brosch and his team set out to improve on this by using a genetically modified form of BCG that more strongly stimulates the immune system while keeping low virulence. They previously made a recombinant strain called BCG::ESX-1 Mmar that heterologously expresses ESX-1 functions from Mycobacterium marinum. That modification changes how the host innate immune system senses the bacteria, through phagosomal rupture-associated induction of type I interferon and enhanced inflammasome activity, and in earlier mouse models produced better protection against TB disease. In the study summarized here the researchers asked whether changing how the vaccine is given — by aerosol inhalation rather than the standard subcutaneous route — would further improve protection. They compared the new BCG::ESX-1 Mmar with parental BCG Pasteur in a C57BL/6J mouse model to see how route and strain interact to shape immune responses in the lung and overall protection against M. tuberculosis.

Using C57BL/6J mice, the researchers compared aerosol vaccination with subcutaneous vaccination for both BCG Pasteur and BCG::ESX-1 Mmar. They measured multiple immune readouts in lungs and spleen and then challenged the mice with M. tuberculosis. Aerosol vaccination with either BCG Pasteur or BCG::ESX-1 Mmar produced higher frequencies of CD4+ and CD8+ T effector memory (TEM) cells in the lungs than subcutaneous vaccination. In the spleen, all vaccinated groups showed comparable poly-functional Th1 (IL-2, TNF-α and IFN-γ) cytokine-producing subsets. Importantly, aerosol vaccination triggered significantly higher IL-17 responses in the lung without causing severe lung pathology; these responses were linked to local and transient inflammatory cytokine production and immune cell infiltration. Aerosol delivery also led to high levels of humoral IgG and IgM in bronchoalveolar lavage fluid and induced substantial lung CD69+ CD103+ T resident memory (TRM) cells, covering both CD4+ and CD8+ subsets in the airways — effects not seen with subcutaneous vaccination. These combined immune changes translated into significantly improved protection against M. tuberculosis and reduced lung pathology in aerosol-vaccinated mice. Across both vaccination routes, BCG::ESX-1 Mmar induced stronger T-cell immunity and better protection than parental BCG Pasteur.

The findings point to two actionable lessons for TB vaccine development. First, how a vaccine is delivered matters: aerosol (mucosal) vaccination produced stronger local lung immunity — including TEM and TRM cells, higher IL-17 responses, and airway antibodies — and better controlled M. tuberculosis in this mouse model than standard subcutaneous shots. Second, the recombinant live-attenuated candidate BCG::ESX-1 Mmar, which brings ESX-1 functions from Mycobacterium marinum into BCG, further enhances T-cell responses and protection compared with BCG Pasteur regardless of route. Together these observations suggest that combining a more immunogenic BCG backbone with mucosal delivery could be a promising strategy to improve protection against pulmonary TB. The authors note that vaccine efficacy depends on vaccine strain, host model and route of vaccination, and propose that aerosol vaccination with BCG::ESX-1 Mmar is a strong candidate for testing in other animal models and, eventually, in human clinical trials to see whether the same improvements translate beyond mice.