Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG

Julia L. Marshall, Iman Satti, Mirvat Surakhy, Stephanie A. Harris, Hazel Morrison, Rachel E. Wittenberg, Marco Polo Peralta Alvarez, Shuailin Li, Raquel Lopez Ramon, Emily Hoogkamer, Francsico Javier Salguero, Fernando Ramos Lopez, Celia Mitton, Ingrid Cabrera Puig, Rebecca Powell Doherty, Rachel Tanner, Timothy S. C. Hinks, Henry Bettinson and Helen McShane ()
Additional contact information
Julia L. Marshall: University of Oxford
Iman Satti: University of Oxford
Mirvat Surakhy: University of Oxford
Stephanie A. Harris: University of Oxford
Hazel Morrison: University of Oxford
Rachel E. Wittenberg: University of Oxford
Marco Polo Peralta Alvarez: University of Oxford
Shuailin Li: University of Oxford
Raquel Lopez Ramon: University of Oxford
Emily Hoogkamer: University of Oxford
Francsico Javier Salguero: Porton Down
Fernando Ramos Lopez: University of Oxford
Celia Mitton: University of Oxford
Ingrid Cabrera Puig: University of Oxford
Rebecca Powell Doherty: University of Oxford
Rachel Tanner: University of Oxford
Timothy S. C. Hinks: The University of Oxford
Henry Bettinson: The University of Oxford
Helen McShane: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG’s lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens.

Date: 2025
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DOI: 10.1038/s41467-025-60285-4

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