Design and Synthesis of Potent <i>Quillaja</i> Saponin Vaccine Adjuvants

Adams, Michelle M.; Damani, Payal; Perl, Nicholas R.; Won, Annie; Hong, Feng; Livingston, Philip O.; Ragupathi, Govind; Gin, David Y.

doi:10.1021/ja9082842

Cited by 77 publications

(70 citation statements)

References 40 publications

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“…Previous, conservative modifications in the acyl chain domain of QS-21 have successfully decoupled adjuvant activity from toxicity 16 . Synthetically more-tractable variants have also been developed, albeit without reduction in toxicity 17 .…”

Section: Discussionmentioning

confidence: 99%

Development of a minimal saponin vaccine adjuvant based on QS-21

et al. 2014

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Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability, and an enigmatic molecular mechanism of action. Herein, we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained at the injection site and nearest draining lymph nodes preferentially compared to attenuated variants. Overall, these studies have yielded critical insights into saponin structure–function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.

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Section: Discussionmentioning

confidence: 99%

Development of a minimal saponin vaccine adjuvant based on QS-21

et al. 2014

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“…It is worth noting that the mechanism by which saponin potentiates an immune response remains unclear. Hypotheses have been raised about whether saponin, through lectin-mediated cell membrane interactions, could facilitate the uptake of the antigen into antigen-presenting cells, leading to specific cytokine profiles that enhance T and/or B-cell responses (Kensil 1996, Marciani 2003, Adams et al 2010.…”

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confidence: 99%

Antigenic extracts of Leishmania braziliensis and Leishmania amazonensis associated with saponin partially protects BALB/c mice against Leishmania chagasi infection by suppressing IL-10 and IL-4 production

Grenfell

Silva

Testasicca

et al. 2010

Mem. Inst. Oswaldo Cruz

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This study evaluated two vaccine candidates for their effectiveness in protecting BALB/c mice against Leishmania chagasiinfection. These immunogenic preparations were composed of Leishmania amazonensisor Leishmania braziliensisantigenic extracts in association with saponin adjuvant. Mice were given three subcutaneous doses of one of these vaccine candidates weekly for three weeks and four weeks later challenged with promastigotes of L. chagasiby intravenous injection. We observed that both vaccine candidates induced a significant reduction in the parasite load of the liver, while the L. amazonensisantigenic extract also stimulated a reduction in spleen parasite load. This protection was associated with a suppression of both interleukin (IL)-10 and IL-4 cytokines by spleen cells in response to L. chagasiantigen. No change was detected in the production of IFN-γ. Our data show that these immunogenic preparations reduce the type 2 immune response leading to the control of parasite replication

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“…Arabinosyl aliphatic amide 28 (SQS-0102) and dodecanoic amide 29 (SQS-0103) also elicited similar antibody responses but the former was associated with marked weight loss while the latter was nontoxic (Figure 3d). 29 Subtyping of anti-GD3 IgG antibodies for the IgG1 and IgG2 subtypes, indicative of T-helper type 2 (Th2) humoral and T-helper type 1 (Th1) cell-mediated immune responses, respectively, revealed predominance of IgG2b for all three saponin variants, similar to natural QS-21. These antibodies were also able to effect binding and lysis of a GD3-positive melanoma cell line, again consistent with the activity of natural QS-21.…”

Section: Development Of Improved Synthetic Saponin Adjuvantsmentioning

confidence: 96%

“…29 This required replacement of the bridging fucose residue in the linear tetrasaccharide domain with 4-amino-4-deoxygalactose. Thus, protected 4-azido-4-deoxygalactose 10 was synthesized from d -glucal (Scheme 2a), then coupled with trisaccharide hemiacetal 17 by dehydrative glycosylation 30 (Scheme 2b).…”

Section: Development Of Improved Synthetic Saponin Adjuvantsmentioning

confidence: 99%

Development of Improved Vaccine Adjuvants Based on the Saponin Natural Product QS-21 through Chemical Synthesis

2016

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ConspectusVaccines based on molecular subunit antigens are increasingly being investigated due to their improved safety and more precise targeting compared to classical whole-pathogen vaccines. However, subunit vaccines are inherently less immunogenic; thus, coadministration of an adjuvant to increase the immunogenicity of the antigen is often necessary to elicit a potent immune response. QS-21, an immunostimulatory saponin natural product, has been used as an adjuvant in conjunction with various vaccines in numerous clinical trials, but suffers from several inherent liabilities, including scarcity, chemical instability, and dose-limiting toxicity. Moreover, little is known about its mechanism of action. Over a decade-long effort, beginning at the University of Illinois at Urbana-Champaign and continuing at the Memorial Sloan Kettering Cancer Center (MSKCC), the group of Prof. David Y. Gin accomplished the total synthesis of QS-21 and developed a practical semisynthetic approach to novel variants that overcome the liabilities of the natural product. First, semisynthetic QS-21 variants were designed with stable amide linkages in the acyl chain domain that exhibited comparable in vivo adjuvant activity and lower toxicity than the natural product. Further modifications in the acyl chain domain and truncation of the linear tetrasaccharide domain led to identification of a trisaccharide variant with a simple carboxylic acid side chain that retained potent adjuvant activity, albeit with reemergence of toxicity. Conversely, an acyl chain analogue terminating in a free amine was inactive but enabled chemoselective functionalization with radiolabeled and fluorescent tags, yielding adjuvant-active saponin probes that, unlike inactive congeners, accumulated in the lymph nodes in vaccinated mice and internalized into dendritic cells. Subtle variations in length, stereochemistry, and conformational flexibility around the central glycosidic linkage provided QS-21 variants with adjuvant activities that correlated with specific conformations found in molecular dynamics simulations. Notably, deletion of the entire branched trisaccharide domain afforded potent, truncated saponin variants with negligible toxicity and improved synthetic access, facilitating subsequent investigation of the triterpene core. The triterpene C4-aldehyde substituent, previously proposed to be important for QS-21 adjuvant activity, proved to be dispensable in these truncated saponin variants, while the presence of the C16 hydroxyl group enhanced activity. Novel adjuvant conjugates incorporating the small-molecule immunopotentiator tucaresol at the acyl chain terminus afforded adjuvant-active variants but without significant synergistic enhancement of activity. Finally, a new divergent synthetic approach was developed to provide versatile and streamlined access to additional linear oligosaccharide domain variants with modified sugars and regiochemistries, opening the door to the rapid generation of diverse, synthetically accessible analogues. In this Accoun...

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Design and Synthesis of Potent Quillaja Saponin Vaccine Adjuvants

Cited by 77 publications

References 40 publications

Development of a minimal saponin vaccine adjuvant based on QS-21

Development of a minimal saponin vaccine adjuvant based on QS-21

Antigenic extracts of Leishmania braziliensis and Leishmania amazonensis associated with saponin partially protects BALB/c mice against Leishmania chagasi infection by suppressing IL-10 and IL-4 production

Development of Improved Vaccine Adjuvants Based on the Saponin Natural Product QS-21 through Chemical Synthesis

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