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Christopher J Genito, Zoltan Beck, Timothy W Phares, Fanta Kalle, Keith J Limbach, Maureen E Stefaniak, Noelle B Patterson, Elke S Bergmann-Leitner, Norman C Waters, Gary R Matyas, Carl R Alving, Sheetij Dutta
Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P...
June 5, 2017: Vaccine
Doris Lambracht-Washington, Min Fu, Pat Frost, Roger N Rosenberg
BACKGROUND: Aggregated amyloid-β peptide 1-42 (Aβ42), derived from the cellular amyloid precursor protein, is one of the pathological hallmarks of Alzheimer's disease (AD). Although active immunization against Aβ42 peptide was successful in AD mouse models and led to removal of plaques and improved memory, a similar clinical trial in humans (Aβ42 peptide immunization with QS-21 adjuvant) was stopped in phase II, when 6% of the treated patients developed encephalitis. Currently ongoing passive immunizations with the injection of preformed monoclonal antibodies against different epitopes within the Aβ1-42 peptide, which do not lead to activation of the immune system, have shown some effects in slowing AD pathology...
April 26, 2017: Alzheimer's Research & Therapy
Michael Hüll, Carl Sadowsky, Heii Arai, Ghislaine Le Prince Leterme, Ann Holstein, Kevin Booth, Yahong Peng, Tamotsu Yoshiyama, Hideo Suzuki, Nzeera Ketter, Enchi Liu, J Michael Ryan
OBJECTIVES: Long-term safety and tolerability of ACC-001 (vanutide cridificar), an anti-amyloid-beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer's disease. DESIGN: Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan. METHODS: Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 µg) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant...
January 16, 2017: Current Alzheimer Research
Sophie Detienne, Iain Welsby, Catherine Collignon, Sandrine Wouters, Margherita Coccia, Sophie Delhaye, Laurye Van Maele, Séverine Thomas, Maëlle Swertvaegher, Aurélie Detavernier, Abdelatif Elouahabi, Stanislas Goriely, Arnaud M Didierlaurent
Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169(+) resident macrophages of the draining lymph node where it elicited a local innate immune response...
December 20, 2016: Scientific Reports
Livia Brunner, Christophe Barnier-Quer, Nicolas Collin
QS-21, a saponin extracted from the tree Quillaja saponaria Molina, is a vaccine adjuvant which has been shown to elicit robust antibody and cell-mediated immune responses in a variety of preclinical and clinical studies [1]. Its purification from the natural source is a lengthy and difficult process. The commercially available saponin mixture Quil-A(®) is a fraction of the bark extract containing a variety of saponins, including QS-21. In order to facilitate access to QS-21 at laboratory-scale amounts, we propose here a method of purification of QS-21 starting from Quil-A(®)...
2017: Methods in Molecular Biology
Alberto Fernández-Tejada, William E Walkowicz, Derek S Tan, David Y Gin
Saponins are triterpene glycoside natural products that exhibit many different biological properties, including activation and modulation of the immune system, and have therefore attracted significant interest as immunological adjuvants for use in vaccines. QS-21 is the most widely used and promising saponin adjuvant but suffers from several liabilities, such as scarcity, dose-limiting toxicity, and hydrolytic instability. Chemical synthesis has emerged as a powerful approach to obtain homogeneous, pure samples of QS-21 and to improve its properties and therapeutic profile by providing access to optimized, synthetic saponin variants...
2017: Methods in Molecular Biology
Pengfei Wang, Dattatray A Devalankar, Qipu Dai, Ping Zhang, Suzanne M Michalek
Three QS-21-based vaccine adjuvant candidates with a terminal-functionalized side chain incorporated in the west wing trisaccharide have been synthesized. The terminal polar functional group serves to increase the solubility of these analogues in water. Two of the synthetic analogues have been shown to have adjuvant activity comparable to that of GPI-0100. The stand-alone adjuvant activity of the new synthetic analogues again confirmed that it is a feasible way to develop new saponin-based vaccine adjuvants through derivatizing at the west wing branched trisaccharide domain...
October 21, 2016: Journal of Organic Chemistry
Krishnamurthy Konduru, Amy C Shurtleff, Steven B Bradfute, Siham Nakamura, Sina Bavari, Gerardo Kaplan
Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health. Currently, there are no licensed vaccines or therapeutics to prevent and treat EBOV infection. Several vaccines based on the EBOV glycoprotein (GP) are under development, including vectored, virus-like particles, and protein-based subunit vaccines. We previously demonstrated that a subunit vaccine containing the extracellular domain of the Ebola ebolavirus (EBOV) GP fused to the Fc fragment of human IgG1 (EBOVgp-Fc) protected mice against EBOV lethal challenge...
2016: PloS One
Alberto Fernández-Tejada, Derek S Tan, David Y Gin
Vaccines 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...
September 20, 2016: Accounts of Chemical Research
Melanie R Neeland, Wei Shi, Catherine Collignon, Nadine Taubenheim, Els N T Meeusen, Arnaud M Didierlaurent, Michael J de Veer
The liposome-based adjuvant AS01 incorporates two immune stimulants, 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 is under investigation for use in several vaccines in clinical development. i.m. injection of AS01 enhances immune cell activation and dendritic cell (DC) Ag presentation in the local muscle-draining lymph node. However, cellular and Ag trafficking in the lymphatic vessels that connect an i.m. injection site with the local lymph node has not been investigated. The objectives of this study were: 1) to quantify the in vivo cellular immune response induced by AS01 in an outbred ovine model, 2) to develop a lymphatic cannulation model that directly collects lymphatic fluid draining the muscle, and 3) to investigate the function of immune cells entering and exiting the lymphatic compartments after s...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Can Çokçalışkan, Tunçer Türkoğlu, Beyhan Sareyyüpoğlu, Ergün Uzunlu, Ayca Babak, Banu B Özbilge, Veli Gülyaz
PURPOSE: One of the most important tools against foot-and-mouth disease, a highly contagious and variable viral disease of cloven-hoofed animals, is vaccination. However, the effectiveness of foot-and-mouth disease vaccines on slowing the spread of the disease is questionable. In contrast, high potency vaccines providing early protection may solve issues with the spread of the disease, escaping mutants, and persistency. To increase the potency of the vaccine, additives such as saponin and aluminium hydroxide are used...
July 2016: Clinical and Experimental Vaccine Research
Arnaud M Didierlaurent, Béatrice Laupèze, Alberta Di Pasquale, Nadia Hergli, Catherine Collignon, Nathalie Garçon
Adjuvants are used to improve vaccine immunogenicity and efficacy by enhancing antigen presentation to antigen-specific immune cells with the aim to confer long-term protection against targeted pathogens. Adjuvants have been used in vaccines for more than 90 years. Combinations of immunostimulatory molecules, such as in the Adjuvant System AS01, have opened the way to the development of new or improved vaccines. Areas covered: AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and the saponin QS-21...
January 2017: Expert Review of Vaccines
Hwee-Ing Ng, Germain J P Fernando, Alexandra C I Depelsenaire, Mark A F Kendall
Adjuvants play a key role in boosting immunogenicity of vaccines, particularly for subunit protein vaccines. In this study we investigated the induction of antibody response against trivalent influenza subunit protein antigen and a saponin adjuvant, QS-21. Clinical trials of QS-21 have demonstrated the safety but, also a need of high dose for optimal immunity, which could possibly reduce patient acceptability. Here, we proposed the use of a skin delivery technology - the Nanopatch - to reduce both adjuvant and antigen dose but also retain its immune stimulating effects when compared to the conventional needle and syringe intramuscular (IM) delivery...
2016: Scientific Reports
Ben W Greatrex, Alison M Daines, Sarah Hook, Dirk H Lenz, Warren McBurney, Thomas Rades, Phillip M Rendle
In an attempt to discover a new synthetic vaccine adjuvant, the glycosylation of hederagenin, gypsogenin, and oleanolic acid acceptors with di- and trisaccharide donors to generate a range of mimics of natural product QS-21 was carried out. The saponins were formulated with phosphatidylcholine and cholesterol, and the structures analyzed by transmission electron microscopy. 3-O-(Manp(1→3)Glcp)hederagenin was found to produce numerous ring-like micelles when formulated, while C-28 choline ester derivatives preferred self-assembly and did not interact with the liposomes...
December 2015: ChemistryOpen
Daming Zhu, Wenbin Tuo
No abstract text is available yet for this article.
April 2016: Natural Products Chemistry & Research
Emilia Bigaeva, Eva van Doorn, Heng Liu, Eelko Hak
BACKGROUND AND OBJECTIVES: QS-21 shows in vitro hemolytic effect and causes side effects in vivo. New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants (ISCOM, ISCOMATRIX and Matrix-M™) from vaccine trials. METHODS: A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™, which included a placebo control group and reported safety outcomes...
2016: PloS One
Roisin E O'Cearbhaill, Govind Ragupathi, Jianglong Zhu, Qian Wan, Svetlana Mironov, Guangbin Yang, Maria K Spassova, Alexia Iasonos, Sara Kravetz, Ouathek Ouerfelli, David R Spriggs, Samuel J Danishefsky, Paul J Sabbatini
We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011-Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD...
April 22, 2016: Cancers
John M Dye, Kelly L Warfield, Jay B Wells, Robert C Unfer, Sergey Shulenin, Hong Vu, Donald K Nichols, M Javad Aman, Sina Bavari
Marburg virus (MARV) was the first filovirus to be identified following an outbreak of viral hemorrhagic fever disease in Marburg, Germany in 1967. Due to several factors inherent to filoviruses, they are considered a potential bioweapon that could be disseminated via an aerosol route. Previous studies demonstrated that MARV virus-like particles (VLPs) containing the glycoprotein (GP), matrix protein VP40 and nucleoprotein (NP) generated using a baculovirus/insect cell expression system could protect macaques from subcutaneous (SQ) challenge with multiple species of marburgviruses...
April 8, 2016: Viruses
William E Walkowicz, Alberto Fernández-Tejada, Constantine George, Francisco Corzana, Jesús Jiménez-Barbero, Govind Ragupathi, Derek S Tan, David Y Gin
Immunological adjuvants such as the saponin natural product QS-21 help stimulate the immune response to co-administered antigens and have become increasingly important in the development of prophylactic and therapeutic vaccines. However, clinical use of QS21 is encumbered by chemical instability, dose-limiting toxicity, and low-yielding purification from the natural source. Previous studies of structure-activity relationships in the four structural domains of QS-21 have led to simplified, chemically stable variants that retain potent adjuvant activity and low toxicity in mouse vaccination models...
March 2016: Chemical Science
Florence Pasquier, Carl Sadowsky, Ann Holstein, Ghislaine Le Prince Leterme, Yahong Peng, Nicholas Jackson, Nick C Fox, Nzeera Ketter, Enchi Liu, J Michael Ryan
Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination...
2016: Journal of Alzheimer's Disease: JAD
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