ORIGINAL RESEARCH article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
This article is part of the Research TopicImmunomodulation of the immune system by phytochemicals: Exploring the therapeutic potential of natural compoundsView all 9 articles
Structure and Immunological Activity of QS-21 Variant from Quillaja saponaria Aerial Biomass
Provisionally accepted
Ricardo San Martín1*
Yuzhong Liu2Yihan Yang2Christopher B. Fox3,4L. Ravi Iyer3Raodoh Mohamath3Gabi Ramer-Denisoff3Robert Kinsey3Jeffrey A. Guderian3
Jessica Schwabach1
Siwen Deng1Natalia de Andrade Teixeira Fernandes1*Clayton Radke5- 1Sutardja Center for Entrepreneurship and Technology, College of Engineering, University of California, Berkeley, Berkeley, United States
- 2Department of Chemistry, The Scripps Research Institute, La Jolla, United States
- 3Access to Advanced Health Institute, Seattle, United States
- 4Department of Biological Engineering, College of Engineering, Utah State University, Logan, United States
- 5Department of Chemical and Biomolecular Engineering, College of Chemistry, University of California, Berkeley, Berkeley, United States
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QS-21 is a triterpenoid saponin adjuvant component widely used in human vaccines, but its commercial supply is limited because it is sourced almost exclusively from the bark of mature Quillaja saponaria trees in Chile. In this study, we report the identification, isolation, as well as structural and immunological characterization of QS-21-Rhamnose (QS-21-Rha), a naturally occurring structural variant that predominates in the leaves and twigs of young Q. saponaria shrubs cultivated in California. Analytical profiling showed that QS-21-Rha represents more than 95% of QS-21 variants in the aerial biomass. High-resolution MS/MS and NMR spectroscopy confirmed that QS-21-Rha differs from QS-21 by the C3 terminal rhamnose substitution of xylose. Both in vitro and in vivo studies demonstrated that QS-21-Rha elicits strong adaptive immune responses, notably robust CD4⁺ T cell activation with immunostimulatory potency comparable to, and exceeding, that of traditionally bark-derived QS-21. From a production standpoint, aerial tissues provide a renewable and higher-yielding source where 1 kg of QS-21 can be obtained from pruning 200 young shrubs, compared with ~1,700 kg of bark, which is equivalent to debarking 100–120 mature trees. These results establish QS-21-Rha as a chemically defined, immunologically active, and more sustainable vaccine adjuvant candidate to potentially address both supply-chain resilience and global vaccine access.
Keywords: Adaptive Immunity, CD4 T cell activation, QS-21, Saponin adjuvant, Structure-activity relationship (SAR), vaccine adjuvant
Received: 19 Dec 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 San Martín, Liu, Yang, Fox, Iyer, Mohamath, Ramer-Denisoff, Kinsey, Guderian, Schwabach, Deng, Fernandes and Radke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ricardo San Martín
Natalia de Andrade Teixeira Fernandes
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