Abstract
Modern subunit vaccines based on homogeneous antigens offer more precise targeting and improved safety compared with traditional whole-pathogen vaccines. However, they are also less immunogenic and require an adjuvant to increase the immunogenicity of the antigen and potentiate the immune response. Unfortunately, few adjuvants have sufficient potency and low enough toxicity for clinical use, highlighting the urgent need for new, potent and safe adjuvants. Notably, a number of natural and synthetic carbohydrate structures have been used as adjuvants in clinical trials, and two have recently been approved in human vaccines. However, naturally derived carbohydrate adjuvants are heterogeneous, difficult to obtain and, in some cases, unstable. In addition, their molecular mechanisms of action are generally not fully understood, partly owing to the lack of tools to elucidate their immune-potentiating effects, thus hampering the rational development of optimized adjuvants. To address these challenges, modification of the natural product structure using synthetic chemistry emerges as an attractive approach to develop well-defined, improved carbohydrate-containing adjuvants and chemical probes for mechanistic investigation. This Review describes selected examples of natural and synthetic carbohydrate-based adjuvants and their application in synthetic self-adjuvanting vaccines, while also discussing current understanding of their molecular mechanisms of action.
Highlights
Abstract | Modern subunit vaccines based on homogeneous antigens offer more precise targeting and improved safety compared with traditional whole-pathogen vaccines
Despite their history and key role, adjuvants have long been used without a real insight into how exactly they potentiate the immune response, and only a few adjuvants have demonstrated sufficient potency and low toxicity to be licensed for human vaccines
Chemical synthesis is emerging as a powerful approach on this front, providing practical access to homogeneous carbo hydrate compounds for adjuvant development, as well as enabling further structure–activity relationships (SARs) studies towards improved synthetic analogues
Summary
The mechanisms of action of QS-21 are poorly understood, hindering rational development of improved analogues and selection of optimal adjuvant–antigen combinations in future vaccines. A depot effect by which the adjuvant increases the lifetime of the antigen and its presentation to the immune system may not be operative, as prolonged persistence and sustained released of the antigen at the injection site could not be a QS-21Api/Xyl QS-18Api/Xyl QS-17Api/Xyl
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