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Analysis of the determinants and modelisation of the post- vaccination immune response in experimental vaccine strategies

Abstract : Specific methodological challenges exist in vaccine clinical trials, due principally to specificities of vaccine development, clinical trial design, absence of validate correlate of protection, and complexities of new immunological assays for evaluating immunogenicity of vaccine candidates. These require methodological research to define the most appropriate methods. This thesis focuses on methodological research to optimize methods used in the clinical development of vaccines, especially to propose and develop statistical methods to model immunogenicity, using HIV and Ebola vaccine clinical trials as an example. We first investigated the dynamics of the immune responses post-vaccination and showed that early sampling time points should be considered in future clinical trials to better understand the role of the early CD4 helper T cells and to evaluate their predictive role in the immune response to vaccines. Then, we developed a new bivariate modelling approach for the analysis of the cellular immune response (assessed by intracellular cytokine staining, ICS) that showed good statistical performances and should become the new statistical standard method for ICS analyses in vaccine trials. This work will have a direct impact on the assessment on the ICS response in vaccine clinical trials. Regarding the humoral response, we showed that there are still significant uncertainties in the determinants of the antibody response after preventive vaccination against Ebola virus disease. This emphasizes the interest of harmonizing measurement methods and study designs. Furthermore, it indicates the need of randomized multi arm Ebola vaccine trials for accurate comparison of immunogenicity between different vaccine strategies. Finally, we presented the methodology of an international randomized phase 2 trial against Ebola, and in particular a methodological and ethical reflection related to the enrollment of study personnel in Ebola vaccine trial in a nonepidemic context. Methods developed in this thesis will contribute to improve the design and analysis of future vaccine trials, and also could be transposable more widely to other research domains.
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https://hal.inria.fr/tel-02430642
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Submitted on : Tuesday, January 7, 2020 - 5:44:31 PM
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Edouard Lhomme. Analysis of the determinants and modelisation of the post- vaccination immune response in experimental vaccine strategies. Santé publique et épidémiologie. Université de bordeaux, 2019. English. ⟨tel-02430642⟩

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