Current subunit vaccines based on well-defined molecular antigens offer improved safety and more precise targeting than whole-pathogen vaccines. However, they are inherently less immunogenic and require coadministration with an adjuvant to increase antigen immunogenicity and potentiate the immune response. QS-21 is a saponin natural product adjuvant extracted from the Quillaja saponaria (QS) tree that has been recently approved as part of a combination system within the malaria and shingles vaccines. However, natural QS-21 suffers from scarcity, heterogeneity, hydrolytic instability, and dose-limiting toxicity, which has hindered its further widespread clinical use as a stand-alone adjuvant. In addressing these challenges, we have identified critical structure-activity relationships of the QS saponin class that have led to optimized synthetic saponin adjuvants. In this presentation, I will first provide an overview of our latest studies on the development of new streamlined saponin variants with minimal and optimal structural elements for adjuvant activity, which elicited potent antibody responses in mice without appreciable toxicity. Leveraging our privileged synthetic saponin scaffold, we have developed a novel, molecularly defined tri-component vaccine platform involving chemical conjugation of tumor-associated glycopeptide antigens. The resulting saponin conjugates induced high levels of antibodies recognizing the native antigen on cancer cells and self-assembled into stably organized micelle-like aggregates as assessed by NMR spectroscopy. The modularity of the synthetic strategy, as well as the increased immunogenicity and structural stability of this new class of saponin-based, self-adjuvanting vaccine constructs makes them promising candidates for further development.

Development of saponin-based synthetic adjuvants and molecular vaccines

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