Advisor(s)

Pengfei Wang

Committee Member(s)

Hui-Ting Lee
Jianmei Leavenworth
Sadanandan Velu
Wenfang Sun

Document Type

Dissertation

Date of Award

6-18-2026

Degree Name

Doctor of Philosophy (PhD)

School

College of Arts and Sciences

Department

Chemistry

Abstract

ABSTRACT Saponin-based vaccine adjuvants have attracted considerable attention owing to the clinical success of QS-21, a potent immunostimulant capable of inducing balanced humoral and cellular immune responses, yet its widespread application is limited by supply constraints, chemical instability, and dose-dependent toxicity. To address these challenges, we previously developed two semisynthetic saponin adjuvants, VSA-1 and VSA-2, derived from abundant Momordica saponins through a single-step modification, which exhibit QS-21–comparable immunopotentiating activity with improved accessibility and stability. Here, we first performed a systematic structure–activity relationship (SAR) study of the VSA series using MS I as the lead scaffold. Modulation of the side-chain length revealed an optimal C12 geometry for maximal adjuvant activity, whereas further elongation or increased steric bulk reduced immunostimulatory potency. In addition, reduction of the C23 carbonyl group completely abolished activity, demonstrating its essential role in immune activation. We then established a modular design strategy in which the adjuvant core and functional side chain are independently tunable. Using soybean saponins as representative natural scaffolds, a structurally diverse library was generated to delineate the interplay between intrinsic aglycone features and side-chain architecture. This approach provides generalizable SAR principles and enables the rational fine-tuning of immunological profiles while greatly enhancing synthetic flexibility. Finally, the VSA platform was applied to the construction of a fully synthetic three-component self-adjuvanting cancer vaccine by integrating a tumor-associated MUC-1 antigen, the saponin adjuvant, and a linker into a single molecular entity. This built-in adjuvant design significantly improved antigen uptake and elicited robust antigen-specific humoral and cellular immune responses. Collectively, this work establishes a versatile and sustainable saponin adjuvant platform, elucidates key structural determinants governing adjuvanticity, and provides a modular strategy for the development of next-generation synthetic vaccines for infectious diseases and cancer immunotherapy. Keywords: Saponin-based adjuvants; Structure–activity relationship study; Self-adjuvanting vaccines; MUC1 cancer vaccine

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