title: Ultra low dose aerosol challenge with Mycobacterium tuberculosis leads to divergent outcomes in rhesus and cynomolgus macaques.
abstract: Well characterised animal models that can accurately predict efficacy are critical to the development of an improved TB vaccine. The use of high dose challenge for measurement of efficacy in Non-human primate models brings the risk that vaccines with the potential to be efficacious against natural challenge could appear ineffective and thus disregarded. Therefore, there is a need to develop a challenge regimen that is more relevant to natural human infection. This study has established that ultra-low dose infection of macaques via the aerosol route can be reproducibly achieved and provides the first description of the development of TB disease in both rhesus and cynomolgus macaques following exposure to estimated retained doses in the lung of less than 10 CFU of Mycobacterium tuberculosis. CT scanning in vivo and histopathology revealed differences in the progression and burden of disease between the two species. Rhesus macaques exhibited a more progressive disease and cynomolgus macaques showed a reduced disease burden. The ability to deliver reproducible ultra-low dose aerosols to macaques will enable the development of refined models of M. tuberculosis infection for evaluation of the efficacy of novel tuberculosis vaccines that offers increased clinical relevance and improved animal welfare.
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK. Electronic address: sally.sharpe@phe.gov.uk.
authors.forename: Sally
authors.initials: S
authors.lastname: Sharpe
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: White
authors.affiliation: The Churchill Hospital, Headington, Oxford, UK.
authors.forename: Fergus
authors.initials: F
authors.lastname: Gleeson
authors.affiliation: The Churchill Hospital, Headington, Oxford, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: McIntyre
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Donna
authors.initials: D
authors.lastname: Smyth
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clark
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sarfas
authors.affiliation: Aeras, Rockville, MD 20850, USA.
authors.forename: Dominick
authors.initials: D
authors.lastname: Laddy
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Rayner
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Hall
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Williams
authors.affiliation: Public Health England, Porton Down, Wiltshire, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Dennis
mesh_terms: D000336:Aerosols; D000818:Animals; D058491:Bacterial Load; D001706:Biopsy; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D018450:Disease Progression; D054884:Host-Pathogen Interactions; D019570:Inhalation Exposure; D008168:Lung / Q000000981:diagnostic imaging / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000276:immunology; D013045:Species Specificity; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014397:Tuberculosis, Pulmonary / Q000000981:diagnostic imaging / Q000276:immunology / Q000382:microbiology* / Q000473:pathology
chemical_list: D000336:Aerosols
keywords: Aerosol challenge; Low dose; Non-human primate; Tuberculosis