Seminar

Discovery of Better Saponin Vaccine Adjuvants at the Chemistry-Immunology Interface

Alberto Fernández-Tejada, PhD

The saponin natural product QS-21 is one of the most potent and promising investigational adjuvants – substances added to vaccines to enhance the immunogenicity of the antigen and potentiate the immune response. Although QS-21 has been co-administered with vaccines against cancers and infectious diseases in many clinical trials, its inherent liabilities – scarcity, heterogeneity, instability, and toxicity – have limited its widespread clinical use. Moreover, its molecular mechanisms of action are poorly understood. This talk will cover my research efforts in the group of the late Professor David Y. Gin at Memorial Sloan Kettering Cancer Center (USA) on the development of improved synthetic saponin adjuvants based on QS-21. A number of QS 21 variants incorporating stable acyl chain amide linkages, truncated carbohydrate domains, and targeted modifications at the triterpene and central glycosyl ester linkage were designed, chemically synthesized, and immunologically evaluated. These multidisciplinary studies defined key minimal structural requirements for adjuvant activity, established correlations between saponin conformation and activity, and provided synthetically accessible saponin adjuvants with better therapeutic profiles. Moreover, leveraging these structure–activity relationships, novel saponin probes with high potency and reduced toxicity were developed and employed in in vivo biodistribution and fluorescence imaging studies, providing early insights into the enigmatic mechanisms of saponin immunopotentiation.