Section: New Results

Mecanistic modeling

Methodology

Estimation methods in mechanistic models can be seen as an inverse problem, in which we want to recover the individual parameters that have produced some observations. In collaboration with the Inria MONC & M3DISIM team, we propose a method for estimation in ODE with mixed effects on parameters based on Kalman based filter (also known as linear quadratic estimation (LQE)) that consist in correcting the original dynamic at each time by a feedback control.

Applications

Applied to IL-7 therapy

We have developed two approaches to optimize the injection of IL-7 in HIV-infected patients: one based on a statistical model and one based on Piecewise Deterministic Markov Processes (PDMP).

Villain L, Commenges D, Pasin C, Prague M, Thiébaut R. Adaptive protocols based on predictions from a mechanistic model of the effect of IL7 on CD4 counts. Statistics in Medicine. 2018;38:221-235.

Pasin C, Dufour F, Villain L, Zhang H, Thiébaut R. Controlling IL-7 Injections in HIV-Infected Patients. Bulletin of Mathematical Biology. 2018;80:2349-2377.

Applied to development of new HIV immunotherapies and vaccines

HIV infection can be treated but not cured with combination antiretroviral therapy, and new therapies that instead target the host immune response to infection are now being developed. Two recent studies of such immunotherapies, conducted in an animal model (SIV-infected rhesus macaques), have shown that agents which target the innate immune receptor TLR7 along with recombining viral-vector vaccines can prevent or control the rebound in viremia that usually accompanies the discontinuation of antiretroviral drugs. However, the mechanism of action of these therapies remains unknown. In collaboration with Harvard School of public health and Harvard program for evolutionary dynamics, we delineate the best model and the best procedure for treatment effect selection in order to delineate the each of each immunotherapies and design subsequent trials.

Applied to development of Ebola vaccines

We have analysed data from three clinical trials conducted under the EBOVAC1 consortium in 4 different countries (UK, Kenya and Uganda/Tanzania) and assessing the safety and immunogenicity of prime-boost vaccine regimens combining one adenovirus-based vector and one modified vaccine Ankara. In particular, we have modeled the dynamics of the humoral immune response following the boost immunization and fitted both linear mixed models and ODEs-based mechanistic models to the antibody concentrations data. This analysis allowed the estimation of the durability of the antibody response, as well as the identification of factors of variability of the response.

Pasin C, Balelli I, Van Effelterre T, Bockstal V, Soloforosi L, Prague M, Douoguih M, Thiébaut R. Dynamics of the humoral immune response to a prime-boost Ebola vaccine: quantification and sources of variation. Under revision in Journal of Virology.