A new tool for accelerating tuberculosis vaccine development
Authors: Mangalakumari Jeyanathan, Zhou Xing
Journal: The Lancet Infectious Diseases (2024)

Tuberculosis remains a formidable global health challenge, causing substantial morbidity and mortality due to the limited protection in the lungs provided by the current BCG vaccine.1WHOGlobal tuberculosis report 2023.https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023Date: Nov 7, 2023Date accessed: March 5, 2024Google Scholar The urgent need for an effective tuberculosis vaccine has prompted innovative approaches to accelerate vaccine development. One such approach is the use of controlled human infection models, which offer a unique opportunity to evaluate candidate tuberculosis vaccines in a cost-effective manner.2Jackson S McShane H Challenges in developing a controlled human tuberculosis challenge model.Curr Top Microbiol Immunol. 2022; (published online March 25.)https://doi.org/10.1007/82_2022_252Google Scholar Although the concept is not new,3Choy RKM Bourgeois AL Ockenhouse CF Walker RI Sheets RL Flores J Controlled human infection models to accelerate vaccine development.Clin Microbiol Rev. 2022; 35e0000821Crossref PubMed Scopus (1) Google Scholar developing such models for tuberculosis research presents unique challenges because the use of Mycobacterium tuberculosis, the causative agent of tuberculosis, as a challenge agent is not ethical. As a safer alternative, a skin challenge model—using the live attenuated Mycobacterium bovis BCG vaccine as a surrogate for M tuberculosis—has been studied with commendable results.4Minassian AM Satti I Poulton ID Meyer J Hill AVS McShane H A human challenge model for Mycobacterium tuberculosis using Mycobacterium bovis Bacille Calmette-Guérin.J Infect Dis. 2012; 205: 1035-1042Crossref PubMed Scopus (0) Google Scholar, 5Harris SA Meyer J Satti I et al.Evaluation of a human BCG challenge model to assess antimycobacterial immunity induced by BCG and a candidate tuberculosis vaccine, MVA85A, alone and in combination.J Infect Dis. 2014; 209: 1259-1268Crossref PubMed Scopus (59) Google Scholar However, because tuberculosis is primarily an airborne infectious disease that affects the lungs, the skin model does not capture the complexities of pulmonary tuberculosis infection. In The Lancet Infectious Diseases, Iman Satti and colleagues6Satti I Marshall JL Harris SA et al.Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial.Lancet Infect Dis. 2024; (published online April 12.)https://doi.org/10.1016/S1473-3099(24)00143-9Google Scholar showed the biological plausibility of administering BCG via aerosol inhalation, the natural route of M tuberculosis infection, in a controlled human infection model. Inhaled aerosol BCG was well tolerated by healthy adults who had no previous exposure to either M tuberculosis or BCG. Moreover, the successful recovery of BCG from the lungs after aerosol inhalation considerably strengthens the feasibility of using this approach to evaluate the effectiveness of potential vaccines. In their first-in-human study, Satti and colleagues6Satti I Marshall JL Harris SA et al.Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial.Lancet Infect Dis. 2024; (published online April 12.)https://doi.org/10.1016/S1473-3099(24)00143-9Google Scholar took a systematic approach. They conducted a meticulous dose-escalation study, with doses ranging from 1 × 104 to 1 × 107 colony-forming units of aerosolised BCG, to establish a safe and well tolerated dose. They then conducted a single-blinded, randomised controlled trial, administering the selected dose of 1 × 107 BCG either through aerosol inhalation or intradermal injection as a reference point to evaluate safety and tolerance levels. No significant differences were found in the overall frequency of adverse events between the two groups, including respiratory adverse events. The occurrence of systemic adverse events in the aerosol group indicates the possibility of the inhaled BCG spreading throughout the body. However, all adverse events after aerosol BCG resolved over time. Using a sensitive detection method, Satti and colleagues reported recovery of live BCG at 14 days post-infection from all study participants in the aerosol group when both bronchoalveolar fluids and cells were analysed. However, the recovery rate decreased to 42% when only bronchoalveolar fluid was analysed. This finding underscores the importance of airway sampling. The authors also analysed host immune responses using bronchoalveolar fluid-derived cells and blood samples. They showed that aerosol BCG induced a higher frequency of mucosal immune responses specific to BCG than intradermal BCG, despite similar total cell counts in the bronchoalveolar fluid. Aerosol BCG also elicited a greater frequency of CD4+ T cells expressing IFNγ, TNFα, IL-2, and IL-17 specific for purified protein derivative (PPD), whereas bronchoalveolar antibody responses to PPD did not differ between the two groups. Notably, both groups showed systemic CD4+ and CD8+ T-cell responses specific to PPD above baseline levels. This finding suggests the possibility of BCG dissemination, the egress of PPD-specific cells from the lungs, or both in the aerosol group.7Carbone FR Unique properties of tissue-resident memory T cells in the lungs: implications for COVID-19 and other respiratory diseases.Nat Rev Immunol. 2023; 23: 329-335Crossref PubMed Scopus (4) Google Scholar The findings from this proof-of-concept study mark a considerable advancement in tuberculosis research, affirming the potential of using BCG aerosol human challenge models. Moreover, the study suggests the feasibility of administering a BCG vaccine via inhaled aerosol to humans—a vaccination strategy that is gaining attention given its potency for inducing robust respiratory mucosal immunity, which cannot be achieved with injectable vaccines.8Jeyanathan M Fritz DK Afkhami S et al.Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.JCI Insight. 2022; 7e155655Crossref Scopus (47) Google Scholar, 9Satti I Meyer J Harris SA et al.Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial.Lancet Infect Dis. 2014; 14: 939-946Summary Full Text Full Text PDF PubMed Google Scholar However, ensuring the safety of delivering BCG through inhaled aerosols requires comprehensive evaluation across various scenarios. How individuals immunised with candidate tuberculosis vaccines will react to BCG aerosol challenges is still unclear, especially candidate vaccines that are also administered via the aerosol route. Although a previous study deemed mucosal BCG administration safe for people with varying levels of tuberculosis exposure,10Davids M Pooran A Hermann C et al.A human lung challenge model to evaluate the safety and immunogenicity of PPD and live Bacillus Calmette-Guérin.Am J Respir Crit Care Med. 2020; 201: 1277-1291Crossref PubMed Google Scholar the study used targeted lung instillation rather than aerosol delivery. Unlike the compartmentalised immune responses observed with lung instillation,10Davids M Pooran A Hermann C et al.A human lung challenge model to evaluate the safety and immunogenicity of PPD and live Bacillus Calmette-Guérin.Am J Respir Crit Care Med. 2020; 201: 1277-1291Crossref PubMed Google Scholar the study by Satti and colleagues showed systemic responses with aerosolised BCG. Nevertheless, the immunological data derived from the inhaled aerosol BCG approach in the study by Satti and colleagues are invaluable. The data will aid in identifying protection correlates and offer opportunities to pinpoint biomarkers in circulation that can predict the successful induction of mucosal immunity after respiratory mucosal vaccination. We note that the assessment of mucosal immunity was limited to a single timepoint on day 14 after aerosol BCG inhalation, and understanding the nature of mucosal immune responses at later timepoints will be important. The study also underscores the importance of addressing key variables in the BCG aerosol human challenge model, including ensuring the accuracy of the aerosol delivery device, adjusting the dose of BCG owing to potential viability changes during long-term storage, and refining bronchoalveolar lavage techniques for consistent BCG recovery. Future research should explore less invasive sampling methods—such as sputum and nasal washing—to improve participant engagement, along with molecular techniques for optimal BCG detection. We declare no competing interests. Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trialThis first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection. Full-Text PDF Open Access