Weak antigens used in antitumor and antiviral vaccines often require an adjuvant, a substance that helps stimulate enough of an immune response to make the vaccine effective. But few such adjuvants are currently available. David Y. Gin and colleagues at Memorial Sloan-Kettering Cancer Center, in New York City, are reporting some new compounds that could extend the family of vaccine adjuvants (J. Am. Chem. Soc., DOI: 10.1021/ja9082842). The team was inspired by QS-21, a saponin natural product obtained from bark extracts of the South American tree Quillaja saponaria. QS-21, which consists of a triterpene, a branched trisaccharide, and a glycosylated acyl chain, is a potent adjuvant but hasn’t been commercialized because it’s unstable, scarce, difficult to purify, and toxic in large doses. Gin and coworkers overcame these problems by designing QS-21 analogs in which they replaced unstable ester linkages in the acyl chain with stable amide linkages. The three new compounds, which are prepared by a semisynthetic route, are potent adjuvants—and two of them are less toxic than QS-21. The researchers conclude that QS-21 analogs don’t need to be as complex as the original saponin to be effective and that the toxicity can be separated from efficacy.