Data_Sheet_2_Application of Modeling Approaches to Explore Vaccine Adjuvant Mode-of-Action.PDF

Novel adjuvant technologies have a key role in the development of next-generation vaccines, due to their capacity to modulate the duration, strength and quality of the immune response. The AS01 adjuvant is used in the malaria vaccine RTS,S/AS01 and in the licensed herpes-zoster vaccine (Shingrix) where the vaccine has proven its ability to generate protective responses with both robust humoral and T-cell responses. For many years, animal models have provided insights into adjuvant mode-of-action (MoA), generally through investigating individual genes or proteins. Furthermore, modeling and simulation techniques can be utilized to integrate a variety of different data types; ranging from serum biomarkers to large scale “omics” datasets. In this perspective we present a framework to create a holistic integration of pre-clinical datasets and immunological literature in order to develop an evidence-based hypothesis of AS01 adjuvant MoA, creating a unified view of multiple experiments. Furthermore, we highlight how holistic systems-knowledge can serve as a basis for the construction of models and simulations supporting exploration of key questions surrounding adjuvant MoA. Using the Systems-Biology-Graphical-Notation, a tool for graphical representation of biological processes, we have captured high-level cellular behaviors and interactions, and cytokine dynamics during the early immune response, which are substantiated by a series of diagrams detailing cellular dynamics. Through explicitly describing AS01 MoA we have built a consensus of understanding across multiple experiments, and so we present a framework to integrate modeling approaches into exploring adjuvant MoA, in order to guide experimental design, interpret results and inform rational design of vaccines.

新型佐剂技术在下一代疫苗研发中发挥关键作用，因其能够调节免疫应答的持续时间、强度与质量。AS01佐剂（AS01 adjuvant）已应用于疟疾疫苗RTS,S/AS01以及获批上市的带状疱疹疫苗（Shingrix），该类疫苗已被证实可诱导兼具强体液免疫与T细胞免疫的保护性应答。长期以来，动物模型通常通过探究单个基因或蛋白质，为佐剂作用模式（mode-of-action, MoA）提供了研究视角。此外，建模与仿真技术可用于整合多种不同类型的数据，从血清生物标志物到大规模“组学（omics）”数据集均涵盖在内。本综述中，我们提出了一套框架，可实现临床前数据集与免疫学文献的全方位整合，以此构建基于证据的AS01佐剂作用模式假说，形成多实验的统一视图。此外，我们还阐述了全方位系统知识可作为构建模型与仿真的基础，助力探索佐剂作用模式相关的核心问题。我们借助系统生物学图形符号（Systems-Biology-Graphical-Notation）——一种用于生物过程图形化展示的工具——捕捉到了早期免疫应答过程中的高层次细胞行为、细胞相互作用以及细胞因子动态变化，且该结果通过一系列详述细胞动态变化的图表得到了验证。通过明确阐释AS01佐剂的作用模式，我们已达成多实验间的认知共识；据此我们提出了一套将建模方法整合至佐剂作用模式探索的框架，用以指导实验设计、结果解读，并为疫苗的理性研发提供依据。