Therapeutic efficacy of pulmonary live tuberculosis vaccines against established asthma by subverting local immune environment

Abstract

Background: Substantial recent advances in the comprehension of the molecular and cellular mechanisms behind asthma have evidenced the importance of the lung immune environment for disease outcome, making modulation of local immune responses an attractive therapeutic target against this pathology. Live attenuated mycobacteria, such as the tuberculosis vaccine BCG, have been classically linked with a type 1 response, and proposed as possible modulators of the type 2 response usually associated with asthma. Methods: In this study we used different acute and chronic murine models of asthma to investigate the therapeutic efficacy of intranasal delivery of the live tuberculosis vaccines BCG and MTBVAC by regulating the lung immune environment associated with airway hyperresponsiveness (AHR). Findings: Intranasal administration of BCG, or the novel tuberculosis vaccine candidate MTBVAC, abrogated AHR-associated hallmarks, including eosinophilia and lung remodeling. This correlated with the re-polarization of allergen-induced M2 macrophages towards an M1 phenotype, as well as with the induction of a strong allergen-specific Th1 response. Importantly, vaccine treatment was effective in a scenario of established chronic asthma where a strong eosinophil infiltration was already present prior to immunization. We finally compared the nebulization efficiency of clinical formulations of MTBVAC and BCG using a standard commercial nebulizer for potential aerosol application. Interpretation: Our results demonstrate that pulmonary live tuberculosis vaccines efficiently revert established asthma in mice. These data support the further exploration of this approach as potential therapy against asthma.

TIPICO XI: report of the first series and podcast on infectious diseases and vaccines (aTIPICO)

“…Instead of using the usual bronchoscope to administer intratracheally the exact dose in macaques, the study of Dr Martín is based on the use of nebulizers suitable for clinical use. 96 Even, if the inhalation route will show better protection results than intradermal route, it will have to be submitted to the whole regulatory process and it will take another 10–20 y. Therefore, for now, the main goal is the authorization of the use of intradermal MTBVAC as a vaccine with great possibilities of protecting against the respiratory form of the TB and save millions of lives as soon as possible, while new alternative and potentially more effective routes are under research.…”

Repurposing mucosal delivery devices for live attenuated tuberculosis vaccines

“…Therefore, we believe that research efforts should be directed toward developing and evaluating a simple, cost-effective, user-friendly, and easily available single-use device with the ability to deliver the vaccine deep into human lungs. Both BCG ( 41 ) and MTBVAC (a promising TB vaccine in clinical trials) delivery via the intranasal route has successfully been tested in animal models, including those with co-morbidities ( 42 ). However, there is no published information on what kind of delivery device could deliver a live attenuated TB vaccine intranasally or intratracheally into human lungs.…”