title: Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques.
abstract: Nine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, the Mycobacterium bovis BCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4β1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom andrew.white@phe.gov.uk.
authors.forename: A D
authors.initials: AD
authors.lastname: White
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Sarfas
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: West
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: L S
authors.initials: LS
authors.lastname: Sibley
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: A S
authors.initials: AS
authors.lastname: Wareham
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Clark
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: M J
authors.initials: MJ
authors.lastname: Dennis
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Williams
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: P D
authors.initials: PD
authors.lastname: Marsh
authors.affiliation: Public Health England, Microbiological Services Division, Porton Down, Salisbury, United Kingdom.
authors.forename: S A
authors.initials: SA
authors.lastname: Sharpe
mesh_terms: D000336:Aerosols; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology; D039041:Integrin alpha4beta1; D007371:Interferon-gamma / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000382:microbiology*; D008253:Macaca mulatta; D023421:Models, Animal; D009163:Mycobacterium bovis / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D000336:Aerosols; D001500:BCG Vaccine; D016207:Cytokines; D039041:Integrin alpha4beta1; D007371:Interferon-gamma