Abstract
Immunoadjuvants have major effects on the immune responses in vaccine formulations. Many specific adjuvants have been studied, including mineral salts, emulsions, cytokines, non-ionic block copolymers, carbohydrate polymers, muramyl dipeptides, and saponin-based adjuvants. Here, we focus on quillaic acid–containing saponin-based adjuvants and their mechanisms of action. Interestingly, when analyzing the adjuvants capable of forming immune-stimulating complexes, one of the characteristics shared by the majority of them is the presence of quillaic acid as the aglycone. This suggests that quillaic acid might be a strategic molecule for immunoadjuvant activity and a powerful candidate in the development of novel adjuvants.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aguilar JC, Rodríguez EG (2007) Vaccine adjuvants revisited. Vaccine 25:3752–3762. https://doi.org/10.1016/j.vaccine.2007.01.111
Apostólico JS, Lunardelli VAS, Coirada FC, Boscardin SB, Rosa DS (2016) Adjuvants: classification, modus operandi, and licensing. J Immunol Res 2016:1–16. https://doi.org/10.1155/2016/1459394
Arslan I (2014) Simenoside A, a new triterpenoid saponin from Gypsophila simonii Hub.-Mor. Chem Biodivers 11:445–450. https://doi.org/10.1002/cbdv.201300118
Arslan I (2017) A new acylated and oleanane-type triterpenoid saponin from Gypsophila arrostii roots. Int J Food Prop 20:507–513. https://doi.org/10.1080/10942912.2016.1168437
Arslan I, Cenzano AM (2020) N-triterpene saponins in cancer therapy: a review of the mode of action. Rev Bras Farmacogn 30:1–6. https://doi.org/10.1007/s43450-020-00033-5
Arslan I, Ili P (2015) Genotoxicological assessment of nebuloside-A a triterpenoid saponin compound on whole blood DNA. Int J Food Prop 18:2374–2379. https://doi.org/10.1080/10942912.2014.971185
Arslan I, Celik A, Chol JH (2012) A cytotoxic triterpenoid saponin from under-ground parts of Gypsophila pilulifera Boiss. & Heldr. Fitoterapia 83:699–703. https://doi.org/10.1016/j.fitote.2012.02.005
Arslan I, Celik A, Melzig MF (2013) Nebulosides A-B, novel triterpene saponins from under-ground parts of Gypsophila arrostii Guss. var. nebulosa. Bioorgan Med Chem 21:1279–1283. https://doi.org/10.1016/j.bmc.2012.12.036
Bigaeva E, Doorn EV, Liu H, Hak E (2016) Meta-analysis on randomized controlled trials of vaccines with QS-21 or ISCOMATRIX adjuvant: safety and tolerability. PLoS One 11:e0154757. https://doi.org/10.1371/journal.pone.0154757
Bomford R, Stapleton M, Winsor S, Beesley JE, Jessup EA, Price KR, Fenwick GR (1992) Adjuvanticity and ISCOM formation by structurally diverse saponins. Vaccine 10:572–577. https://doi.org/10.1016/0264-410x(92)90435-m
Buglione-Corbett R, Pouliot K, Marty-Roix R, Li W, West K, Wang S, Morelli AB, Lien E, Lu S (2014) Reduced MyD88 dependency of ISCOMATRIXTM adjuvant in a DNA prime-protein boost HIV vaccine. Hum Vaccin Immunother 10:1078–1090. https://doi.org/10.4161/hv.27907
Cibulski SP, Siveira F, Mourglia-Ettlin G, Teixeira TF, Santos HF, Yendo AC, Costa F, Fett-Neto AG, Gosmann G, Roehe PM (2016) Quillaja brasiliensis saponins induce robust humoral and cellular responses in a bovine viral diarrhea virus vaccine in mice. Comp Immunol Microbiol Infect Dis 45:1–8. https://doi.org/10.1016/j.cimid.2016.01.004
Cibulski S, Rivera-Patron M, Suarez N, Pirez M, Rossi S, Yendo AC, Costa F, Gosmann G, Fett-Neto A, Roehe PM, Silveira F (2017) Leaf saponins of Quillaja brasiliensis enhance long-term specific immune responses and promote dose-sparing effect in BVDV experimental vaccines. Vaccine 36:55–65. https://doi.org/10.1016/j.vaccine.2017.11.030
Dalsgaard K (1974) Saponin adjuvants. 3. Isolation of a substance from Quillaja saponaria Molina with adjuvant activity in food-and-mouth disease vaccines. Arch Gesamte Virusforsh 18:349–360
de Costa F, Yendo ACA, Cibulski SP, Fleck JD, Roehe PM, Spilki FR, Gosmann G, Fett-Neto AG (2014) Alternative inactivated poliovirus vaccines adjuvanted with Quillaja brasiliensis or Quil-A saponins are equally effective in inducing specific immune responses. PLoS One 9:1–7. https://doi.org/10.1371/journal.pone.0105374
de Oliveira CAC, Perez AC, Merino G, Prieto JG, Alvarez AI (2001) Protective effects of Panax ginseng on muscle injury and inflammation after eccentric exercise. Comp Biochem Physiol C Toxicol Pharmacol 130:369–377. https://doi.org/10.1016/s1532-0456(01)00262-9
Delmas F, Di Giorgio C, Elias R, Gasquet M, Azas N, Mshvildadze V, Dekanosidze G, Kemertelidze E, Timon-David P (2000) Antileishmanial activity of three saponins isolated from ivy, alpha-hederin, beta-hederin and hederacolchiside A(1), as compared with their action on mammalian cells cultured in vitro. Planta Med 66:343–347. https://doi.org/10.1055/s-2000-8541
den Brok M, Büll C, Wassink M, Graaf AM, Wagenaars JA, Minderman M, Thakur M, Amigorena S, Rijke EO, Schrier CC, Adema GJ (2016) Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation. Nat Commun 7:13324. https://doi.org/10.1038/ncomms13324
Didierlaurent AM, Laupeze B, Pasquale AD, Hergli N, Collignon C, Garçon N (2017) Adjuvant system AS01: helping to overcome the challenges of modern vaccines. Expert Rev Vaccines 16:55–63. https://doi.org/10.1080/14760584.2016.1213632
Fleck JD, Kauffmann C, Spilki F, Lencina CL, Roehe PM, Gosmann G (2006) Adjuvant activity of Quillaja brasiliensis saponins on the immune responses to bovine herpesvirus type 1 in mice. Vaccine 24:7129–7134. https://doi.org/10.1016/j.vaccine.2006.06.059
Galea M, Tzortzakis H (1932) Essai d’immunisation antiaphteuse du cobaye à l’aide d’un virus aphteux saponiné. C R Soc Biol 109:21–23
Gevrenova R, Voutquenne-Nazabadioko L, Harakat D, Prost E, Henry M (2006) Complete 1H and 13C NMR assignments of saponins from roots of Gypsophila trichotoma Wend. Magn Res Chem 44:686–691. https://doi.org/10.1002/mrc.1827
Haridas V, Arntzen CJ, Gutterman JU (2001) Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), inhibit activation of nuclear factor-kappa B by inhibiting both its nuclear localization and ability to bind DNA. Proc Natl Acad Sci U S A 98:11557–11562. https://doi.org/10.1073/pnas.191363498
Kauffmann C, Machado AM, Fleck JD, Provensi G, Pires VS, Guillaume D, Sonnet P, Reginatto FH, Schenkel P, Gosmann G (2004) Constituents from leaves of Quillaja brasiliensis. Nat Prod Res 18:153–157. https://doi.org/10.1080/14786410310001608055
Kensil CR (1996) Saponins as vaccine adjuvants. Crit Rev Ther Drug Carrier Syst 13:1–55
Krasteva I, Yotova M, Yosifov D, Benbassat N, Jenett-Siems K, Konstantinov S (2014) Cytotoxicity of gypsogenic acid isolated from Gypsophila trichotoma. Pharmacogn Mag 10:430–433. https://doi.org/10.4103/0973-1296.133299
Lacaille-Dubois MA, Wagner H (2001) Saponins, in: Atta-Ur-Rahman (Ed.), Studies in natural products chemistry series, vol. 21, Elsevier Science, pp. 633–687
Leroux-Roels G, Marchant A, Levy J, Van Damme P, Schwarz TF, Horsmans Y, Jilg W, Kremsner PG, Haelterman R, Clément F, Gabor JJ, Esen M, Hens A, Carletti I, Fissette L, Da Silva FT, Burny W, Janssens M, Moris P, Didierlaurent AM, Van Der Most R, Garçon N, Van Belle P, Van Mechelen M (2016) Impact of adjuvants on CD4+ T cell and B cell responses to a protein antigen vaccine: results from a phase II, randomized, multicenter trial. Clin Immunol 169:16–27. https://doi.org/10.1016/j.clim.2016.05.007
Livingston PO, Adluri S, Helling F, Yao TJ, Kensil CR, Newman MJ, Marciani D (1994) Phase I trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 14:1275–1280. https://doi.org/10.1016/s0264-410x(94)80052-2
Marty-Roix R, Vladimer GI, Pouliot K, Weng D, Buglione-Corbett R, West K, JD MM, Chee JD, Wang S, Lu S, Lien E (2016) Identification of QS-21 as an inflammasome-activating molecular component of saponin adjuvants. J Biol Chem 291:1123–1136. https://doi.org/10.1074/jbc.M115.683011
Mastrolorenzo A, Tiradritti L, Salimbeni L, Zuccati G (1995) Multicentre clinical trial with herpes simplex virus vaccine in recurrent herpes infection. Int J STD AIDS 6:431–435. https://doi.org/10.1177/095646249500600611
McCluskie MJ, Weeratna RD (2001) Novel adjuvant systems. Curr Drug Targets Infect Disord 1:263–271. https://doi.org/10.2174/1568005014605991
McNeela EA, Mills KHG (2001) Manipulating the immune system: humoral versus cell-mediated immunity. Adv Drug Deliv Rev 51:43–54. https://doi.org/10.1016/S0169-409X(01)00169-7
Mohamed SM, Backheet EY, Bayoumi SA, Jain S, Cutler SJ, Tekwani BL, Ross SA (2015) Potent antitrypanosomal triterpenoid saponins from Mussaenda luteola. Fitoterapia 107:114–121. https://doi.org/10.1016/j.fitote.2015.10.011
Nazir M, Harms H, Loef I, Kehraus S, El-Maddah F, Arslan I, Rempel V, Müller CE, König GM (2015) GPR18 inhibiting amauromine and the novel triterpene glycoside auxarthonoside from the sponge-derived fungus Auxarthron reticulatum. Planta Med 81:1141–1145. https://doi.org/10.1055/s-0035-1545979
Oda K, Matsuda H, Murakami T, Katayama S, Ohgitani T, Yoshikawa M (2000) Adjuvant and haemolytic activities of 47 saponins derived from medicinal and food plants. Biol Chem 381:67–74. https://doi.org/10.1515/BC.2000.009
Oleszycka E, Lavelle EC (2014) Immunomodulatory properties of the vaccine adjuvant alum. Curr Opin Immunol 28:1–5. https://doi.org/10.1016/j.coi.2013.12.007
Petrovsky N (2015) Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf 38:1059–1074. https://doi.org/10.1007/s40264-015-0350-4
Ragupathi G, Gardner JR, Livingston PO, Gin DY (2011) Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer. Expert Rev Vaccines 10:463–470. https://doi.org/10.1586/erv.11.18
Silveira F, Cibulski SP, Varela AP, Marqués JM, Chabalgoity A, de Costa F, Yendo ACA, Gosmann G, Roehe PM, Fernández C, Ferreira F (2011) Quillaja brasiliensis saponins are less toxic than Quil A and have similar properties when used as an adjuvant for a viral antigen preparation. Vaccine 29:9177–9182. https://doi.org/10.1016/j.vaccine.2011.09.137
Sivakumar SM, Safhi MM, Kannadasan M, Sukumaran N (2011) Vaccine adjuvants- current status and prospects on controlled release adjuvancity. Saudi Pharm J 19:197–206. https://doi.org/10.1016/j.jsps.2011.06.003
Sjölander A, Drane D, Maraskovsky E, Scheerlinck JP, Suhrbier A, Tennent J, Pearse M (2001) Immune responses to ISCOM formulations in animal and primate models. Vaccine 19:2661–2665. https://doi.org/10.1016/s0264-410x(00)00497-7
Sparg SG, Light ME, van Staden J (2004) Biological activities and distribution of plant saponins. J Ethnopharmacol 94:219–243. https://doi.org/10.1016/j.jep.2004.05.016
Sun HX, Xie Y, Ye YP (2009) Advances in saponin-based adjuvants. Vaccine 27:1787–1796. https://doi.org/10.1016/j.vaccine.2009.01.091
Waite DC, Jacobson EW, Ennis FA, Edelman R, White G, Kammer R, Anderson C, Kensil CR (2001) Three double blind, randomized trials evaluating the safety and tolerance of different formulations of the saponin adjuvant QS-21. Vaccine 19:3957–3967. https://doi.org/10.1016/s0264-410x(01)00142-6
Wallace F, Bennadji Z, Ferreira F, Olivaro C (2017) Analysis of an immunoadjuvant saponin fraction from Quillaja brasiliensis leaves by electrospray ionization ion trap multiple-stage mass spectrometry. Phytochem Lett 20:228–233. https://doi.org/10.1016/j.phytol.2017.04.020
Weng A, Bachran C, Fuchs H, Melzig MF (2008) Soapwort saponins trigger clathrin-mediated endocytosis of saporin, a type I ribosome-inactivating protein. Chem Biol Interact 176:204–211. https://doi.org/10.1016/j.cbi.2008.08.004
Yendo ACA, de Costa F, Cibulski SP, Teixeira TF, Colling LC, Mastrogiovanni M, Soulé S, Roehe PM, Gosmann G, Ferreira FA, Fett-Neto AG (2016) A rabies vaccine adjuvanted with saponins from leaves of the soap tree (Quillaja brasiliensis) induces specific immune responses and protects against lethal challenge. Vaccine 34:2305–2311. https://doi.org/10.1016/j.vaccine.2016.03.070
Yui S, Ubukata K, Hodono K, Kitahara M, Mimaki Y, Kuroda M, Sashida Y, Yamazaki M (2001) Macrophage-oriented cytotoxic activity of novel triterpene saponins extracted from roots of Securidaca inappendiculata. Int Immunopharmacol 1:1989–2000. https://doi.org/10.1016/s1567-5769(01)00126-6
Funding
This article was financially supported by Zonguldak Bulent Ecevit University, Scientific Research Unit (2019-3997-1044-01).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The author declares that there is no conflict of interest.
Rights and permissions
About this article
Cite this article
Arslan, I. Quillaic Acid–Containing Saponin-Based Immunoadjuvants Trigger Early Immune Responses. Rev. Bras. Farmacogn. 30, 467–473 (2020). https://doi.org/10.1007/s43450-020-00080-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43450-020-00080-y