QS-21: Structural insights, immunological mechanisms, and prospects for rational design of safer vaccine adjuvants

QS-21, a refined adjuvant based on saponins, is isolated from the bark of the soap-bark tree (Quillaja saponaria). It has garnered significant interest in the creation of next-generation vaccine adjuvants due to its robust ability to elicit Th1-type and Th2-type immunological responses. Despite its successful incorporation into licensed vaccines such as Shingrix® (herpes zoster) and Mosquirix® (malaria), the widespread application of QS-21 remains constrained by several limitations, including limited natural availability, chemical instability, dose-dependent toxicity, and an incompletely elucidated mechanism of action. This review provides a comprehensive overview of the natural sources, molecular structure, clinical applications, and immunological mechanisms of QS-21, based on research conducted both in vivo and in vitro. It also presents new developments in QS-21's structure-activity relationship (SAR), highlighting the possibility of creating less hazardous and more stable analogs through chemical synthesis and biosynthetic engineering. These strategies offer promising avenues for the rational design of novel adjuvants to support the development of more effective and safer vaccines.