QS-21
QS-21 is a purified plant extract used as a vaccine adjuvant. It is derived from the soap bark tree (Quillaja saponaria), which is native to the countries of Chile, Peru, and Bolivia.[1] The crude drug (Quillajae cortex, Quillaia) is imported from Peru and Chile.[2]
The extract contains water-soluble triterpene glycosides, which are members of a family of plant-based compounds called saponins. It has been tested as an adjuvant in various vaccines in attempts to improve their efficacy. It is believed to enhance both humoral and cell-mediated immunity.[1]
Use
[edit]QS-21 has been clinically evaluated as a vaccine adjuvant. As of 2002[update], it had been tested in more than 3000 patients in 60 clinical trials.
Direct, unencapsuled QS-21 is very liable to hydrolysis. It also causes immediate pain at injection site and in vitro causes hemolysis. All of these can be prevented by packaging QS-21 into lipid-based particles, which also have the added advantage of targeting its delivery to phagocytes. It is part of:[3]
- AS-01 (also known as AS01E), GSK's adjuvant used in the Shingrix vaccine,[4] the RTS,S vaccine, and the M72/AS01E vaccine. AS-01 consists of QS-21 and 3-O-desacyl-4’-monophosphoryl lipid A (MPL) sealed inside cholestrol-based liposomes.[3]
- Army Liposome Formulation Q (ALFQ), MPL and QS-21 sealed inside cholesterol-based liposomes produced by the US Army.[3] Designed to be unencumbered by AS-01 patents, it was created in 2019 by enhancing the existing, MPL-based Army Liposome Formulation (ALF) with QS-21.[5][6]
- Matrix-M, Novavax's adjuvant used in the Novavax COVID-19 vaccine. Matrix-M contains a mixture of soapbark saponins sealed in nanoparticles made of cholesterol and phospholipid; one of these saponins is QS-21.[3]
- Immune-stimulating complex (ISCOM) of 1984 and ISCOMATRIX (CSL Limited, 2012), two forerunners to Matrix-M[3]
Sources
[edit]Tree bark
[edit]Isolation of QS-21 destroys the soap bark tree, prompting governments to regulate industrial extraction.[1] The United States has invoked the 1950 Defense Production Act to preserve vaccine raw materials for its own companies.[7]
A semi-synthesis strategy from 2013 relies on purifying the prosapogenin (triterpene and branched trisaccharide) part of the molecule and adding the rest of QS-21 synthetically, doubling the yield over simple isolation (amount produced from a given amount of tree bark). This semi-synthetic approach has also facilitated experimentation with alternative acyl chain compositions.[8]
In 2017, FDA approved the Shingrix vaccine which makes use of the extracted form of QS-21 made by Agenus under the trade name Stimulon.[9] Agenus remains the sole US manufacturer of FDA-approved QS-21 as of 2021.[10]
Plant tissue culture
[edit]Several companies have succeeded in isolating the compound from plant tissue cultures of the soapbark plant.
The aforementioned Agenus created a spin-off company called SaponiQx to manage its QS-21 business. SaponiQx submitted the Master File for its cultured plant cell (cpc) version of QS-21 to the US FDA in 2023.[11] An animal study using this cpc-QS-21 was published in 2024.[12]
Transgenic tobacco
[edit]In 2024, a team at the John Innes Centre in Norwich, UK identified the complete 20-step biosynthetic pathway of QS-21 and cloned it into tobacco.[13]
Transgenic yeast
[edit]In 2024, an international team of collaborators succeed in engineering yeast to perform the complete biosynthesis of QS-21.[14] One of the scientists pointed out that the yeast process is around 1000 times faster than trees because only mature trees produce QS-21. "Even at the levels we're producing it, it's cheaper than producing it from the plant."[14]
Total synthesis
[edit]QS-21 has been made by total chemical synthesis, but required an inefficient 76-step process that is not commercially viable. This is not unlike the total chemical synthesis of many other complex biomolecules, which served mainly to confirm their structure rather than to produce an economically-viable source.[14]
References
[edit]- ^ a b c Ragupathi G, Gardner JR, Livingston PO, Gin DY (2013). "Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer". Expert Rev Vaccines. 10 (4): 463–70. doi:10.1586/erv.11.18. PMC 3658151. PMID 21506644.
- ^ Max Wichtl, ed. (2004). Herbal Drugs and Phytopharmaceuticals: A Handbook for Practice on a Scientific Basis. Medpharm Publishers. p. 492. ISBN 3-88763-100-5.
- ^ a b c d e Stertman, L; Palm, AE; Zarnegar, B; Carow, B; Lunderius Andersson, C; Magnusson, SE; Carnrot, C; Shinde, V; Smith, G; Glenn, G; Fries, L; Lövgren Bengtsson, K (31 December 2023). "The Matrix-M™ adjuvant: A critical component of vaccines for the 21(st) century". Human Vaccines & Immunotherapeutics. 19 (1): 2189885. doi:10.1080/21645515.2023.2189885. PMC 10158541. PMID 37113023.
The Matrix-M adjuvant consists of two different populations of physically stable nanoparticles mixed at a defined ratio (85% Matrix-A + 15% Matrix-C). Matrix-A and Matrix-C contain different Q. saponaria saponin fractions with complementary properties. Matrix-C particles contain Fraction-C saponins (mainly consisting of QS-21)...
- ^ "SHINGRIX package insert" (PDF). Food and Drug Administration. Retrieved 7 April 2019.
- ^ Alving, Carl R.; Peachman, Kristina K.; Matyas, Gary R.; Rao, Mangala; Beck, Zoltan (3 March 2020). "Army Liposome Formulation (ALF) family of vaccine adjuvants". Expert Review of Vaccines. 19 (3): 279–292. doi:10.1080/14760584.2020.1745636. PMC 7412170. PMID 32228108.
- ^ Alving, Carl R.; BECK, Zoltan (8 October 2019). "US10434167B2 Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin".
- ^ Wang P (March 2021). "Natural and Synthetic Saponins as Vaccine Adjuvants". Vaccines. 9 (3): 222. doi:10.3390/vaccines9030222. PMC 8001307. PMID 33807582.
- ^ Chea EK, Fernández-Tejada A, Damani P, Adams MM, Gardner JR, Livingston PO, Ragupathi G, Gin DY (2013). "Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes". J Am Chem Soc. 134 (32): 13448–57. doi:10.1021/ja305121q. PMC 3436428. PMID 22866694.
- ^ "FDA Approves GSK's Shingles Vaccine with Agenus' QS-21 Stimulon® Adjuvant" (Press release).
- ^ Agenus Inc. "First QS-21 Royalty Payment Due to Agenus is Triggered". www.prnewswire.com (Press release).
- ^ "SaponiQx Announces Breakthrough in Scaling Up of STIMULON™ Cultured Plant Cell Adjuvant".
- ^ Swart, Maarten; Allen, Jessica; Reed, Brendan; Izquierdo Gil, Ana; Verspuij, Johan; Schmit-Tillemans, Sonja; Chakkumkal, Anish; Findeis, Mark; Hafner, Angela V.; Harjivan, Chandresh; Kurnat, Rebecca; Kuipers, Harmjan; Zahn, Roland; Brandenburg, Boerries (20 December 2024). "Plant Cell Culture-Derived Saponin Adjuvant Enhances Immune Response Against a Stabilized Human Metapneumovirus Pre-Fusion Vaccine Candidate". Vaccines. 12 (12): 1435. doi:10.3390/vaccines12121435. PMID 39772095.
- ^ Martin LB, Kikuchi S, Rejzek M, Owen C, Reed J, Orme A, Misra RC, El-Demerdash A, Hill L, Hodgson H, Liu Y, Keasling JD, Field RA, Truman AW, Osbourn A (April 2024). "Complete biosynthesis of the potent vaccine adjuvant QS-21". Nat Chem Biol. 20 (4): 493–502. doi:10.1038/s41589-023-01538-5. PMC 10972754. PMID 38278997.
- ^ a b c Liu Y, Zhao X, Gan F, Chen X, Deng K, Crowe SA, Hudson GA, Belcher MS, Schmidt M, Astolfi MC, Kosina SM, Pang B, Shao M, Yin J, Sirirungruang S, Iavarone AT, Reed J, Martin LB, El-Demerdash A, Kikuchi S, Misra RC, Liang X, Cronce MJ, Chen X, Zhan C, Kakumanu R, Baidoo EE, Chen Y, Petzold CJ, Northen TR, Osbourn A, Scheller H, Keasling JD (May 2024). "Complete biosynthesis of QS-21 in engineered yeast". Nature. 629 (8013): 937–944. Bibcode:2024Natur.629..937L. doi:10.1038/s41586-024-07345-9. PMC 11111400. PMID 38720067.