Predicting IFN-γ responses after BCG vaccination in humans from macaques: A proof-of-concept study of Immunostimulation/Immunodynamic modelling methods

Abstract

Introduction: Macaques play a central role in human tuberculosis(TB) vaccine development. Immune and challenge responses differ across macaque and human subpopulations. We determined which macaque subpopulations best predicted immune responses in different human subpopulations, using novel immunostimulation/immunodynamic modelling methods in a proof of concept study. Methods: Data on IFN-γ secreting CD4+ T cells over time after recent BCG vaccination were available for 55 humans and 81 macaques. Human population covariates were: baseline BCG vaccination status, time since BCG vaccination, gender and monocyte/lymphocyte cell count ratio. The macaque population covariate was colony of origin. A two-compartment mathematical model describing the dynamics of the post-BCG IFN-γ T cell response 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 BCG immune response in each species was assessed. Which macaque subpopulations best predicted immune responses in different human subpopulations was identified using Bayesian Information Criteria. Results: Macaque colony and human baseline-BCG status were significantly (p<0.05) associated with BCG-induced immune response. For baseline-BCG-naïve humans, Indonesian cynomolgus macaques and Indian rhesus macaques best predicted immune response. For baseline-BCG-vaccinated humans, Mauritian cynomolgus macaques best predicted immune response. Conclusion: The work suggests that the immune responses of different human populations may be best modelled by different macaque colonies, and demonstrates the potential utility of immunostimulation/immunodynamic modelling to accelerate TB vaccine development.