- Adjuvants are natural or chemical substances added to vaccines that enhance the immune response to a co-administered antigen to levels significantly higher than those induced by the antigen alone, resulting in more robust immune responses and longer-term vaccine protection. Moreover, they also enable to reduce the amount of antigen and number of immunizations needed, facilitating dose-sparing, and making vaccination more cost-effective and accessible worldwide. The saponin natural product QS-21 isolated from the bark of Quillaja saponaria (QS), has risen some significant interest as an adjuvant for vaccines, as it showed an unparalleled ability to enhance immunological responses against a variety of different antigens. However, the mechanism by which QS-21 potentiates the immune response is not fully elucidated. Despite its great potential as a vaccine adjuvant, QS-21 suffers from dose-limiting toxicity, hydrolytic instability, and an unknown mechanism of action, which greatly hampered its licensing for human vaccines. Nonetheless, it has been used as an investigational adjuvant in over 100 clinical trials, including Phase III, and has recently been approved for use in two vaccines against malaria, shingles, Covid-19 vaccine. Despite of this, the unknown mechanism of action for QS-21 is a long-standing question in immunology and a concern for its further clinical applications.
- This novel research represents a unique opportunity to address long-standing mechanistic questions concerning saponin immunopotentiation that have not been resolved so far. The unprecedented identification of the involved receptor proposed herein will allow us to determine for the first time the mechanism of action of QS21. This combined knowledge will, in turn, give us the opportunity to rationally design saponin adjuvants with the highest potency for each individual antigen (depending on the different pathways the antigen is being processed by the immune system), resulting in new and more effective subunit vaccine for the benefit of the society.
- The overall objective of this original proposal is to elucidate the mechanism of action by which the saponin adjuvant QS-21 potentiates the immune response. To achieve this ambitious but feasible goal, three main objectives have been proposed:
1: Synthesis of a variety of novel saponin photoaffinity probes (SPAPs), consisting of QS-21 derivatives as bioactive ligands, linked to a photoreactive group (benzophenones, and diazirines) and biotin as a reporter group.
2: Identification of the saponin lead compound in terms of a) best adjuvant activity/immunological response in mice, and b) selective capture of the putative target by the SPAPs via the photoreactive group.
3: Identification of involved molecular target via in vitro studies with murine DCs, followed by chemical proteomic analysis.
