Elucidating the Mechanisms of Action of Saponin-Derived Adjuvants

Marciani, Dante J.

doi:10.1016/j.tips.2018.03.005

Cited by 84 publications

(89 citation statements)

References 52 publications

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“…LQ and LMQ adjuvants are neutral liposome-based formulations containing cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and QS21, a proinflammatory saponin adjuvant that activates dendritic cells (DCs) and promotes the secretion of Th1 cytokines (25). LMQ also contains the synthetic Toll-like receptor 4 (TLR4) agonist 3-0-desacyl-4-monophosphoryl lipid A (3D-MPL).…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies

Rivera-Hernandez

Rhyme

Cork

et al. 2020

mBio

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Recent global advocacy efforts have highlighted the importance of development of a vaccine against group A Streptococcus (GAS). Combo5 is a non-M protein-based vaccine that provides protection against GAS skin infection in mice and reduces the severity of pharyngitis in nonhuman primates. However, Combo5 with the addition of aluminum hydroxide (alum) as an adjuvant failed to protect against invasive GAS infection of mice. Here, we show that formulation of Combo5 with adjuvants containing saponin QS21 significantly improves protective efficacy, even though all 7 adjuvants tested generated high antigen-specific IgG antibody titers, including alum. Detailed characterization of Combo5 formulated with SMQ adjuvant, a squalene-in-water emulsion containing a TLR4 agonist and QS21, showed significant differences from the results obtained with alum in IgG subclasses generated following immunization, with an absence of GAS opsonizing antibodies. SMQ, but not alum, generated strong interleukin-6 (IL-6), gamma interferon (IFN-␥), and tumor necrosis alpha (TNF-␣) responses. This work highlights the importance of adjuvant selection for non-M protein-based GAS vaccines to optimize immune responses and protective efficacy. Citation Rivera-Hernandez T, Rhyme MS, Cork AJ, Jones S, Segui-Perez C, Brunner L, Richter J, Petrovsky N, Lawrenz M, Goldblatt D, Collin N, Walker MJ. 2020. Vaccine-induced Th1-type response protects against invasive group A Streptococcus infection in the absence of opsonizing antibodies. mBio 11:e00122-20.

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Section: Discussionmentioning

confidence: 99%

Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies

Rivera-Hernandez

Rhyme

Cork

et al. 2020

mBio

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“…Some hypotheses advanced that QS-21 may facilitate Ag uptake into APCs by binding to cell surface lectins through its carbohydrate domains, leading to specific cytokine profiles that enhance the T and/or B cells' response (Marciani, 2003). An effective mechanism of action in which QS-21 apparently acts on both DCs and T cells was proposed (Marciani, 2018) (Fig. 3).…”

Section: Structure Of Qs-21 and Proposed Immunoadjuvant Mechanism Of mentioning

confidence: 99%

“…The role of aldehyde in QS-21 was highlighted in the T cell by forming an imine with the amino group of the T cell surface receptor such as CD2, providing a costimulatory signal to the T cell. This signal together with the mitogen-activated protein kinase (MAPK) ERK2 resulting from the activation of the TCR-MHC interaction, and the changes of the ionic balance Na + /K + , stimulates T cell activation resulting in the secretion of Th1 cytokines (Marciani, 2018) (Fig. 3).…”

Section: Structure Of Qs-21 and Proposed Immunoadjuvant Mechanism Of mentioning

confidence: 99%

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

2019

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Background: Vaccine adjuvants are compounds that significantly enhance/prolong the immune response to a coadministered antigen. The limitations of the use of aluminium salts that are unable to elicite cell responses against intracellular pathogens such as those causing malaria, tuberculosis, or AIDS, have driven the development of new alternative adjuvants such as QS-21, a triterpene saponin purified from Quillaja saponaria. Purpose: The aim of this review is to attempt to clarify the mechanism of action of QS-21 through either receptors or signaling pathways in vitro and in vivo with special emphasis on the co-administration with other immunostimulants in new adjuvant formulations, called adjuvant systems (AS). Furthermore, the most relevant clinical applications will be presented. Methods: A literature search covering the period 2014-2018 was performed using electronic databases from Sci finder, Science direct, Medline/Pubmed, Scopus, Google scholar. Results: Insights into the mechanism of action of QS-21 can be summarized as follows: 1) in vivo stimulation of Th2 humoral and Th1 cell-mediated immune responses through action on antigen presenting cells (APCs) and T cells, leading to release of Th1 cytokines participating in the elimination of intracellular pathogens. 2) activation of the NLRP3 inflammasome in mouse APCs with subsequent release of caspase-1 dependent cytokines, Il-1β and Il-18, important for Th1 responses. 3) synthesis of nearly 50 QS-21 analogs, allowing structure/activity relationships and mechanistic studies. 4) unique synergy mechanism between monophosphoryl lipid A (MPL A) and QS-21, formulated in a liposome (AS01) in the early IFN-γ response, promoting vaccine immunogenicity. The second part of the review is related to phase I-III clinical trials of QS-21, mostly formulated in ASs, to evaluate efficacy, immunogenicity and safety of adjuvanted prophylactic vaccines against infectious diseases, e.g. malaria, herpes zoster, tuberculosis, AIDS and therapeutic vaccines against cancer and Alzheimer's disease. Conclusion: The most advanced phase III clinical applications led to the development of two vaccines containing QS-21 as part of the AS, the Herpes Zoster vaccine (HZ/su) (Shingrix™) which received a license in 2017 from the FDA and a marketing authorization in the EU in 2018 and the RTS,S/AS01 vaccine (Mosquirix™) against malaria, which was approved by the EMA in 2015 for further implementation in Sub-Saharan countries for routine use.2014 have made the research on vaccines very attractive in the last decades (Lee and Nguyen, 2015). Modern subunit vaccines comprising homogeneous molecular antigens have been developed to prevent and treat many human diseases, but they are weakly immunogenic and must be administered with an adjuvant to elicit a potent immune response. Adjuvants whose name originates from the Latin word adjuvare https://doi.

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“…Chickpea, soybean, lentils, peanut, garden pea, broad bean, and alfalfa are rich in saponins (Oakenfull, 1981). The antibacterial and foaming properties of saponins led to the use of saponins as vaccine adjuvants (Marciani, 2018). In the human body, saponins can bind to bile salts to reduce cholesterol absorption (Marrelli et al, 2016).…”

Section: Saponinsmentioning

confidence: 99%

The Effects of Domestication on Secondary Metabolite Composition in Legumes

Contador

et al. 2020

Front. Genet.

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Legumes are rich in secondary metabolites, such as polyphenols, alkaloids, and saponins, which are important defense compounds to protect the plant against herbivores and pathogens, and act as signaling molecules between the plant and its biotic environment. Legume-sourced secondary metabolites are well known for their potential benefits to human health as pharmaceuticals and nutraceuticals. During domestication, the color, smell, and taste of crop plants have been the focus of artificial selection by breeders. Since these agronomic traits are regulated by secondary metabolites, the basis behind the genomic evolution was the selection of the secondary metabolite composition. In this review, we will discuss the classification, occurrence, and health benefits of secondary metabolites in legumes. The differences in their profiles between wild legumes and their cultivated counterparts will be investigated to trace the possible effects of domestication on secondary metabolite compositions, and the advantages and drawbacks of such modifications. The changes in secondary metabolite contents will also be discussed at the genetic level to examine the genes responsible for determining the secondary metabolite composition that might have been lost due to domestication. Understanding these genes would enable breeding programs and metabolic engineering to produce legume varieties with favorable secondary metabolite profiles for facilitating adaptations to a changing climate, promoting beneficial interactions with biotic factors, and enhancing health-beneficial secondary metabolite contents for human consumption.

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Elucidating the Mechanisms of Action of Saponin-Derived Adjuvants

Cited by 84 publications

References 52 publications

Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies

Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

The Effects of Domestication on Secondary Metabolite Composition in Legumes

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