Application of Modeling Approaches to Explore Vaccine Adjuvant Mode-of-Action

Abstract

Novel adjuvant technologies have a key role in the development of next-generationvaccines, due to their capacity to modulate the duration, strength and quality of theimmune response. The AS01 adjuvant is used in the malaria vaccine RTS,S/AS01 andin the licensed herpes-zoster vaccine (Shingrix) where thevaccine has proven its abilityto generate protective responses with both robust humoral and T-cell responses. Formany years, animal models have provided insights into adjuvant mode-of-action (MoA),generally through investigating individual genes or proteins. Furthermore, modeling andsimulation techniques can be utilized to integrate a variety of different data types;ranging from serum biomarkers to large scale “omics” datasets. In this perspectivewe present a framework to create a holistic integration of pre-clinical datasets andimmunological literature in order to develop an evidence-based hypothesis of AS01adjuvant MoA, creating a unified view of multiple experiments. Furthermore, we highlighthow holistic systems-knowledge can serve as a basis for the construction of models andsimulations supporting exploration of key questions surrounding adjuvant MoA. Usingthe Systems-Biology-Graphical-Notation, a tool for graphical representation of biologicalprocesses, we have captured high-level cellular behaviorsand interactions, and cytokinedynamics during the early immune response, which are substantiated by a series ofdiagrams detailing cellular dynamics. Through explicitlydescribing AS01 MoA we havebuilt a consensus of understanding across multiple experiments, and so we present aframework to integrate modeling approaches into exploringadjuvant MoA, in order toguide experimental design, interpret results and inform rational design of vaccines