title: Using Data from Macaques To Predict Gamma Interferon Responses after Mycobacterium bovis BCG Vaccination in Humans: a Proof-of-Concept Study of Immunostimulation/Immunodynamic Modeling Methods.
abstract: Macaques play a central role in the development of human tuberculosis (TB) vaccines. Immune and challenge responses differ across macaque and human subpopulations. We used novel immunostimulation/immunodynamic modeling methods in a proof-of-concept study to determine which macaque subpopulations best predicted immune responses in different human subpopulations. Data on gamma interferon (IFN-γ)-secreting CD4+T cells over time after recentMycobacterium bovisBCG vaccination were available for 55 humans and 81 macaques. Human population covariates were baseline BCG vaccination status, time since BCG vaccination, gender, and the monocyte/lymphocyte cell count ratio. The macaque population covariate was the colony of origin. A two-compartment mathematical model describing the dynamics of the IFN-γ T cell response after BCG vaccination was calibrated to these data using nonlinear mixed-effects methods. The model was calibrated to macaque and human data separately. The association between subpopulations and the BCG immune response in each species was assessed. The macaque subpopulations that best predicted immune responses in different human subpopulations were identified using Bayesian information criteria. We found that the macaque colony and the human baseline BCG status were significantly (P< 0.05) associated with the BCG-induced immune response. For humans who were BCG naïve at baseline, Indonesian cynomolgus macaques and Indian rhesus macaques best predicted the immune response. For humans who had already been BCG vaccinated at baseline, Mauritian cynomolgus macaques best predicted the immune response. This work suggests that the immune responses of different human populations may be best modeled by different macaque colonies, and it demonstrates the potential utility of immunostimulation/immunodynamic modeling to accelerate TB vaccine development.
authors.affiliation: TB Modelling Group, CMMID, TB Centre, London School of Hygiene and Tropical Medicine, London, United Kingdom Sophie.rhodes@lshtm.ac.uk.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Rhodes
authors.affiliation: Public Health England, Porton Down, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sarfas
authors.affiliation: TB Modelling Group, CMMID, TB Centre, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Imperial College, London, United Kingdom.
authors.forename: Gwenan M
authors.initials: GM
authors.lastname: Knight
authors.affiliation: Public Health England, Porton Down, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: White
authors.affiliation: College of Health and Life Sciences, Department of Life Sciences, Brunel University, London, United Kingdom.
authors.forename: Ansar A
authors.initials: AA
authors.lastname: Pathan
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
authors.affiliation: TomegaVax, Portland, Oregon, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Evans
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Helen
authors.identifier: http://orcid.org/0000-0002-0435-1006
authors.initials: H
authors.lastname: Fletcher
authors.affiliation: Public Health England, Porton Down, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Sharpe
authors.affiliation: TB Modelling Group, CMMID, TB Centre, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Richard G
authors.initials: RG
authors.lastname: White
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism*; D008251:Macaca; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009163:Mycobacterium bovis / Q000276:immunology*; D055815:Young Adult
chemical_list: D001500:BCG Vaccine; D007371:Interferon-gamma
keywords: T-cell immunity; bacillus Calmette-Guérin; interferons; mathematical modeling; nonhuman primates; tuberculosis; tuberculosis vaccines