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Vaccine Adjuvants in Immunotoxicology
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
The saponin type obtained from Chilean soapbark tree (Quillaja saponaria Molina) shows strong adjuvant properties such as Quil A and its derivatives QS-21 (Sun, Xie, and Ye 2009; Ragupathi et al. 2010). They usually lead to immune cell proliferation and increased antibody production. There are studies showing that Quillaja saponins have mitogenic effects and cause T and B cell proliferation in this way. Although they have been used successfully in animal vaccines for a long time, they are highly toxic for humans. Besides forming severe local reactions and granulomas, they affect cholesterol in erythrocyte membrane and cause severe hemolysis. All Quillaja saponins are not still suitable for use in humans due to their high toxicity, hemolytic effects, and instable chemical structure (Yurdakök and İnce 2008; Ivanov et al. 2020).
Interleukin 12: A Potent Vaccine Adjuvant for Promoting Cellular Immunity and Modulating Humoral Immunity
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
In studies perhaps more directly relevant to clinical practice, several investigators have demonstrated the efficacy of IL-12 as an adjuvant in therapeutic antitumor vaccination. The Meth A sarcoma is heterozygous for three missense point mutations in the tumor suppressor gene p53. The peptide encoding one of these is capable of eliciting peptide-specific CD4+ and CD8+ T cell responses [12]. Vaccination with this peptide in combination with QS21 given subcutaneously and IL-12 given i.p. elicited a T cell response and cured mice of established tumor [13]. Immunization with any combination other than all three was not effective. The importance of both CD4+ and CD8+ cells was demonstrated by depletion with antibodies. Depletion of CD4+ cells at the primary but not the boost immunization abrogated the response. Depletion of CD8+ cells at either the primary immunization or the boost abrogated the therapeutic response.
Lung Cancer Vaccines
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Cheryl Ho, Oliver Gautschi, Primo N. Lara, David R. Gandara, Angela M. Davies
In a small pilot study, 17 patients with MAGE-3-expressing resected stage I or II NSCLC were enrolled (42). The first nine patients were vaccinated with 300 μg of MAGE-3 protein intradermally, every three weeks for four injections. The remaining eight patients received four injections intramuscularly every three weeks with MAGE-3 and AS02B adjuvant, containing monophosphoryl lipid A and QS21, a saponin extracted from the Quillaja saponaria Molina tree, to stimulate immune response. The investigators evaluated immune response to vaccination by antibody titres, CD4+ and CD8+ T-cell response. Modest MAGE-3 antibody titres were seen in three of nine patients treated with MAGE-3 alone compared to marked increases in seven of eight patients who were vaccinated with MAGE-3 plus the AS02B adjuvant. One patient in the MAGE-3 alone vaccinated group and four of the MAGE-3 with AS02B treated patients demonstrated a strong CD4+ T-cell response to the MAGE-3 DP4 peptide (amino acid 243–258). Measurement of associated cytokines indicated an increase in TNF-α, IFN-γ, and IL-2 following exposure to activated T-cell APCs, consistent with a Th1 predominant response. MAGE-3 alone was able to elicit an immune response in vaccinated NSCLC patients however; the addition of the AS02B adjuvant clearly enhanced the immunogenicity of the tumor antigen.
Preclinical developments in the delivery of protein antigens for vaccination
Published in Expert Opinion on Drug Delivery, 2023
Dylan A. Hendy, Alex Haven, Eric M. Bachelder, Kristy M. Ainslie
Another adjuvant that has been examined that produces a more balanced Th1/Th2 response is QS-21. QS-21 is a compound extracted from Chilean soapbark tree (Quillaja saponaria) that has been shown to promote Th1 responses [33–35]. QS-21 is included within AS01 which is an adjuvant system that is comprised of the TLR4 ligand MPL in addition to QS-21 [36]. AS01 is used in the shingles vaccine Shingrix (GSK) that was FDA approved in 2017. Shingrix is a recombinant subunit vaccine that uses the varicella zoster virus glycoprotein E as the antigen. Initial comparator studies of Shingrix to the previously used shingles vaccine Zostavax (a live attenuated shingles vaccine) showed that Shingrix produced elevated cellular and humoral immune responses compared to Zostavax [37]. The improved efficacy led to Zostavax being discontinued in the U.S. in 2020 [38]. However, QS-21 still has room for improvement, since when it is extracted from Chilean soap bark trees the tree is destroyed and it is not synthetically produced, so the supply is limited [39]. Further, QS-21 still requires co-delivery with another adjuvant for maximal efficacy, and injection site reactions remain a common side effect of QS-21 adjuvanted vaccines [40].
Saturated phospholipids are required for nano- to micron-size transformation of cholesterol-containing liposomes upon QS21 addition
Published in Journal of Liposome Research, 2019
Pushpendra Singh, Zoltan Beck, Gary R. Matyas, Carl R. Alving
In the course of construction of liposomes that might be utilized as adjuvants (i.e. as immunostimulants) for human vaccines, we have developed a novel type of liposome composition, referred to as Army Liposome Formulation with QS21 (ALFQ), that exhibits a high level of adjuvant potency (Beck et al.2015a). The ALFQ liposomes contain dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), cholesterol (Chol), synthetic monophosphoryl lipid A (MPLA), and QS21 (Beck et al.2015b). DMPC and DMPG are zwitterionic and anionic phospholipids, respectively, that contain saturated fatty acyl chains, and constitute the bulk lipid composition of the liposomes. MPLA is a glycophospholipid that anchors Gram-negative bacterial lipopolysaccharide (LPS) into the outer surface of the bacterial cells (Raetz et al.2007). QS21 is a saponin which is purified from a mixture of triterpene glycosides obtained from the bark of Quillaja saponaria Molina tree (Kensil et al.1991). During the manufacture of ALFQ, we discovered that after addition of QS21 to nano-size small unilamellar liposome vesicles (SUVs) lacking QS21, the SUVs suddenly became giant vesicles (up to ∼30-µm diameter) that appeared to be unilamellar (Beck et al.2015a). The precise mechanism of this remarkable structural transformation of ALFQ from nano-size to micron-size liposomes after QS21 addition is unknown. Here, we describe a chemical basis that enables this phenomenon.
Development of adjuvanted recombinant zoster vaccine and its implications for shingles prevention
Published in Expert Review of Vaccines, 2018
Nicolas Lecrenier, Pierre Beukelaers, Romulo Colindres, Desmond Curran, Carine De Kesel, Jean-Philippe De Saegher, Arnaud M Didierlaurent, Edouard Y Ledent, Johann F Mols, Tomas Mrkvan, Marie Normand-Bayle, Lidia Oostvogels, Fernanda Tavares Da Silva, Ventzislav Vassilev, Carlota Vinals, Alain Brecx
AS01 is a liposome-based adjuvant that contains two immunostimulants: 3-O-desacyl–monophosphoryl lipid A (MPL) and Quillaja saponaria Molina, fraction 21 (QS-21). MPL is the detoxified derivative of lipopolysaccharide from Salmonella minnesota and stimulates innate immunity via Toll-like receptor 4 [55]. QS-21 [56] is a saponin molecule extracted and purified from the bark of the Quillaja saponaria Molina tree. Recent work has shown that QS-21 formulated in liposomes activates the caspase-1 pathway via a cholesterol-dependent mechanism and that its adjuvant effect is mediated by the activation of lymph node macrophages [57,58].