LAUSR

Unlike drug dose optimisation, mathematical modelling has not been applied to vaccine dose finding. We applied a novel Immunostimulation/Immunodynamic mathematical modelling framework to translate multi-dose TB vaccine immune responses from mice, to predict most immunogenic dose in humans. Data were previously collected on IFN-γ secreting CD4+ T cells over time for novel TB vaccines H56 and H1 adjuvanted with IC31 in mice (1 dose groups (0.1–1.5 and 15 μg H56 + IC31), 45 mice) and humans (1 dose (50 μg H56/H1 + IC31), 18 humans). A two-compartment mathematical model, describing the dynamics of the post-vaccination IFN-γ T cell response, was fitted to mouse and human data, separately, using nonlinear mixed effects methods. We used these fitted models and a vaccine dose allometric scaling assumption, to predict the most immunogenic human dose. Based on the changes in model parameters by mouse H56 + IC31 dose and by varying the H56 dose allometric scaling factor between mouse and humans, we established that, at a late time point (224 days) doses of 0.8–8 μg H56 + IC31 in humans may be the most immunogenic. A 0.8–8 μg of H-series TB vaccines in humans, may be as, or more, immunogenic, as larger doses. The Immunostimulation/Immunodynamic mathematical modelling framework is a novel, and potentially revolutionary tool, to predict most immunogenic vaccine doses, and accelerate vaccine development.Mathematical modelling: TB vaccine responsesPharmacodynamic mathematical modelling has long-been successfully applied to optimise drug dosing but has not been widely leveraged for vaccine regimens. Richard G. White and colleagues fit a novel mathematical model to mouse vaccine responses elicited by the experimental TB subunit vaccine H56 adjuvanted with IC31. The authors use interferon-γ frequency in CD4+ T cells as arguably the most relevant single parameter in TB responses. Responses were peaked not saturating, suggesting that optimal responses might occur at lower doses of vaccine. Indeed, the analysis suggests that relatively low doses (0.8–8 μg) of H-series vaccines (H1 and H56) in IC31 might in fact be the most immunogenic at least at late time points. Although the conclusions await clinical validation, the novel modelling approach used here could in principle be applied to optimise dosing of almost any vaccine.