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      Shaping Modern Vaccines: Adjuvant Systems Using MicroCrystalline Tyrosine (MCT ®)

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          Abstract

          The concept of adjuvants or adjuvant systems, used in vaccines, exploit evolutionary relationships associated with how the immune system may initially respond to a foreign antigen or pathogen, thus mimicking natural exposure. This is particularly relevant during the non-specific innate stage of the immune response; as such, the quality of this response may dictate specific adaptive responses and conferred memory/protection to that specific antigen or pathogen. Therefore, adjuvants may optimise this response in the most appropriate way for a specific disease. The most commonly used traditional adjuvants are aluminium salts; however, a biodegradable adjuvant, MCT ®, was developed for application in the niche area of allergy immunotherapy (AIT), also in combination with a TLR-4 adjuvant—Monophosphoryl Lipid A (MPL ®)—producing the first adjuvant system approach for AIT in the clinic. In the last decade, the use and effectiveness of MCT ® across a variety of disease models in the preclinical setting highlight it as a promising platform for adjuvant systems, to help overcome the challenges of modern vaccines. A consequence of bringing together, for the first time, a unified view of MCT ® mode-of-action from multiple experiments and adjuvant systems will help facilitate future rational design of vaccines while shaping their success.

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          Most cited references81

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          Pathogen recognition and innate immunity.

          Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
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            Pathogen recognition and inflammatory signaling in innate immune defenses.

            The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications.
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              Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns.

              Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens that can be mimicked by vaccine delivery systems are their size, shape and surface molecule organization. In addition, pathogen-associated molecular patterns can be used to induce innate immune responses that promote adaptive immunity. In this Review, we discuss the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                24 November 2020
                2020
                : 11
                : 594911
                Affiliations
                [1] 1 Allergy Therapeutics (UK) Ltd , Worthing, United Kingdom
                [2] 2 Bencard Adjuvant Systems [a Division of Allergy Therapeutics (UK) Ltd] , Worthing, United Kingdom
                [3] 3 Interim Translational Research Institute “iTRI”, National Center for Cancer Care and Research (NCCCR) , Doha, Qatar
                [4] 4 Department of BioMedical Research, Immunology RIA, University of Bern , Bern, Switzerland
                [5] 5 Bencard Allergie (GmbH) , München, Germany
                [6] 6 Dermatology, University Hospital Zurich , Zurich, Switzerland
                [7] 7 Jenner Institute, Nuffield Department of Medicine, University of Oxford , Oxford, United Kingdom
                Author notes

                Edited by: Christiane Hilger, Luxembourg Institute of Health, Luxembourg

                Reviewed by: Ulrich Matthias Zissler, Technical University of Munich, Germany; Dennis Russkamp, Medigene Immunotherapies GmbH, Germany

                *Correspondence: Matthew D. Heath, matthew.heath@ 123456allergytherapeutics.com

                This article was submitted to Immunological Tolerance and Regulation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.594911
                7721672
                33324411
                50fd1d33-525b-47fe-95e6-c6a39a2a5617
                Copyright © 2020 Heath, Mohsen, de Kam, Carreno Velazquez, Hewings, Kramer, Kündig, Bachmann and Skinner

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 August 2020
                : 19 October 2020
                Page count
                Figures: 4, Tables: 4, Equations: 0, References: 81, Pages: 12, Words: 5999
                Categories
                Immunology
                Review

                Immunology
                adjuvants,virus-like particles,microcrystalline tyrosine (mct®),allergy,disease,immunization,monophosphoryl lipid a (mpl®),vaccines

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