The development of therapeutic vaccines often includes the use of synthetic small molecule antigen constructs to elicit immune response. However, many subunit antigen vaccines are less immunogenic than those employing attenuated microorganisms. As a result, they often require co-administration with an adjuvant or immunostimulating complex, a substance that is itself not necessarily immunogenic but functions in concert with the antigen to enhance/prolong immune response. Purified extracts from the bark of the South American tree, Quillaja saponaria Molina, exhibit remarkable adjuvant activity. Among the more active components of these extracts are several complex triterpene saponins, including QS-21Aapi, which has emerged as one of the most promising adjuvants for immune response potentiation and dose-sparing in vaccine therapy. Melanoma, breast cancer, small cell lung cancer, prostate cancer, HIV, and malaria are among the numerous maladies targeted in several recent and ongoing vaccine clinical trials using QS-21Aapi as a critical adjuvant component for immune response augmentation.
Whereas the design of subunit antigen constructs has played an influential role in the development of clinically viable vaccine therapies, efficacy modulation of vaccines through the design and chemical synthesis of distinct molecular adjuvants has been comparatively less common given the structural complexity of these substances. With the aid of several chemical glycosylation methodologies developed in our laboratories, we have achieved the first synthesis and structure verification of QS-21Aapi. Additionally, the synthesis and structure verification of other potent immunostimulatory constituents of Quillaja saponaria, such as QS-7, are underway. Through collaborations with immunologists and clinicians, current efforts are also devoted to the generation of designed structural analogs for the development of more powerful and stable adjuvants for both anti-cancer and anti-viral therapeutic vaccines. As a consequence, we are in a unique position to conduct systematic structure-activity investigations on this class of natural product with the goal of unraveling its as yet unknown mechanism of immunostimulatory activity.