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

Abstract

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.

Proteomic as an Exploratory Approach to Develop Vaccines Against Tick-Borne Diseases Using Lyme Borreliosis as a Test Case

“…The identification of good vaccine candidates is key to the development of a vaccine, and so is the choice of the adjuvants and antigen delivery system in order to induce protective immunity. Besides aluminum hydroxide, which is largely used in vaccines, new adjuvants are being developed to improve the strength and quality of the immune response such as AS01 adjuvant [ 63 ]. Innovative techniques have also been developed lately to better deliver antigens in the outermost layer of the skin by microneedles [ 64 ].…”

Army Liposome Formulation (ALF) family of vaccine adjuvants

“…The precise mechanisms of action of innate immunity induced by the liposomal AS01 formulation containing MPLA and QS21 are still not completely understood; however, complex modeling algorithms are being devised to address those issues [63]. The mechanisms of action of AS01 and ALFQ may differ in certain ways because of the structural differences and compositions of the liposomes: AS01 liposomes have unsaturated phospholipids, and 33.7 mol% cholesterol compared to phospholipid, while ALFQ has saturated phospholipids and 55% cholesterol (Table 1).…”

Failure of BCG Necessitates to the Development of New Novel Vaccine

“…Adjuvants may role as delivery organizations that can efficiently transport the antigen into the Antigen-Presenting-Cells (APCs) to fuel the elicitation of antigen-specific immune reactions [13] but choosing the optimal adjuvant is of fundamental importance in vaccine formulations to develop of an effective cell-mediated immune reaction. Adjuvants may exert their effects through diverse (vi) supporting Ag transportation to draining lymphatic-nodes; (vii) stimulation of inflammasomes, adjuvants trigger innate-immuneoutcome to generate a local immuno-competent milieu at shot spot [14,15] (Figure 2).…”

“…Neutrophil cells are one of the highest in numbers and recruited first at the site of adjuvant injection. Particulate adjuvants generate a local pro-inflammatory milieu to appoint more immune cells [17,13]. Alum generally activates the complement cascade and recruits cells from blood to generate an inflammatory atmosphere at spot location [13,18].…”

“…Particulate adjuvants generate a local pro-inflammatory milieu to appoint more immune cells [17,13]. Alum generally activates the complement cascade and recruits cells from blood to generate an inflammatory atmosphere at spot location [13,18]. There are few adjuvants which are also capable of guiding antigen presentation by the Major-Histocompatibility-Complexes (MHCs).…”