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.

Sophie J Rhodes,Sally Sharpe,Ansar A Pathan,Andrew White,Helen Mcshane,Helen Fletcher,Gwenan M Knight,Charlotte Sarfas,Richard G White,Thomas G Evans,Helene F Rosenberg

doi:10.1128/cvi.00525-16

Sophie J Rhodes, Sally Sharpe + Show 9 more

Open Access

https://doi.org/10.1128/cvi.00525-16

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Abstract

ABSTRACTMacaques 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 recent Mycobacterium bovis BCG 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.

Highlights

Macaques play a central role in the development of human tuberculosis (TB) vaccines
Both species have been shown to respond to bacillus Calmette-Guérin (BCG) vaccination, which affords them partial protection from TB [15,16,17,18,19]; it has been shown that the same experimental conditions may lead to divergent outcomes for the two species [7, 20,21,22]
These differences suggest that the immune responses of different human populations may be best modeled by different macaque colonies

Summary

Introduction

Macaques play a central role in the development of human tuberculosis (TB) vaccines. Immune and challenge responses differ across macaque and human subpopulations. Differing levels of protection have been observed for Chinese and Mauritian cynomolgus macaques: Mauritian cynomolgus macaques developed end-stage progressive TB in 7 weeks, while Chinese cynomolgus macaques remained healthy past the end of the study (12 weeks) [23] These differences suggest that the immune responses of different human populations (e.g., those with previous BCG vaccination or those who are BCG naïve) may be best modeled by different macaque colonies. In order to increase the likelihood of developing an effective vaccine, it is critical to identify and understand differences between macaque populations

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