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      A systems approach to designing next generation vaccines: combining α-galactose modified antigens with nanoparticle platforms

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          Abstract

          Innovative vaccine platforms are needed to develop effective countermeasures against emerging and re-emerging diseases. These platforms should direct antigen internalization by antigen presenting cells and promote immunogenic responses. This work describes an innovative systems approach combining two novel platforms, αGalactose (αGal)-modification of antigens and amphiphilic polyanhydride nanoparticles as vaccine delivery vehicles, to rationally design vaccine formulations. Regimens comprising soluble αGal-modified antigen and nanoparticle-encapsulated unmodified antigen induced a high titer, high avidity antibody response with broader epitope recognition of antigenic peptides than other regimen. Proliferation of antigen-specific CD4 + T cells was also enhanced compared to a traditional adjuvant. Combining the technology platforms and augmenting immune response studies with peptide arrays and informatics analysis provides a new paradigm for rational, systems-based design of next generation vaccine platforms against emerging and re-emerging pathogens.

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          Most cited references38

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          Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity.

          Phenotypic and functional heterogeneity is the hallmark of effector and memory T cells. Upon antigenic stimulation, naïve CD4(+) T cells make choices to become effector Th1, Th2 or Th17 cells, or even Treg. In addition to differences in cytokine repertoire, effector CD4(+) T cells exhibit diversity in homing, such as migration to lymph node follicles to help B cells versus migration to inflamed tissues. Upon clearance of the antigen, two major types of memory T cells remain: central memory cells, which patrol lymphoid organs, and effector memory cells that act as sentinels in peripheral tissues such as the skin and the gut. Here, we review our current understanding of CD4(+) T-cell lineage heterogeneity and flexibility, with emphasis on the human system, and propose an organization of effector and memory T cells based on distinct functional modules.
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            Principles of vaccine design-Lessons from nature.

            Fred Zepp (2010)
            Microbial pathogens have developed complex and efficient ways of counteracting and evading innate and adaptive immune mechanisms. The strategies used by pathogens determine strongly the type of immune response a vaccine should elicit and how the vaccine should be formulated. Improved knowledge of immune response mechanisms has brought successes in the development of vaccines that protect against challenging pathogens as well as vaccines that can be used in immunocompromised and elderly populations. This includes the production of highly purified antigens that provide a better reactogenicity and safety profile than some of the early whole-pathogen vaccines. Successful attempts to improve antigen purity, however, can result in weakened immunogenicity. The search for approaches to overcome this has led to new technologies, such as live vector vaccines, DNA vaccines and novel adjuvant formulations, which have been based on growing knowledge of the interplay between innate and adaptive immune systems and the central role played by antigen-presenting cells. Of these technologies, one of the most promising to date is based on the use of innovative adjuvants combined with careful antigen selection. Vaccine design has therefore become more tailored, and in turn has opened up the potential of extending its application in immunotherapies to tackle diseases such as cancer, Alzheimer disease and immune-mediated disorders. 2010 Elsevier Ltd. All rights reserved.
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              Complement receptors CD21 and CD35 in humoral immunity.

              The complement system is a family of proteins that is involved in both innate and adaptive immunity. Complement receptors CD21 and CD35, which recognize activated products of C3 and C4, are predominantly expressed on B cells and follicular dendritic cells (FDCs) in the mouse. In this review, we focus on the role of FDC-expressed CD21 and CD35 in humoral immunity. They are the principle receptors for uptake and retention of immune complexes. In their absence, memory B-cell survival is markedly impaired. This is likely because of the lack of antigen but could also reflect a role for complement C3d ligand. How antigen is transported to FDCs remains an open question. In recent unpublished work using multiphoton intravital imaging, we found that small protein antigens presented in the lymph drain rapidly into B-cell follicles and are taken up by FDCs in a complement-dependent manner.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                20 January 2014
                2014
                : 4
                : 3775
                Affiliations
                [1 ]Department of Veterinary Microbiology and Preventive Medicine, Iowa State University , Ames, IA 50011
                [2 ]Department of Chemical and Biological Engineering, Iowa State University , Ames, IA 50011
                [3 ]Department of Materials Science and Engineering, Iowa State University , Ames, IA 50011
                [4 ]BioProtection Systems Corporation , a subsidiary of NewLink Genetics Corporation, Ames, IA 50010
                [5 ]Department of Food Science and Technology, University of Nebraska-Lincoln , Lincoln, NE 68583
                [6 ]These authors contributed equally to this work.
                [7 ]Current address: Boehringer Ingelheim, Ames, IA 50010.
                Author notes
                Article
                srep03775
                10.1038/srep03775
                3895907
                24441019
                6001f9d9-2e2f-4714-b186-66493a8959a5
                Copyright © 2014, Macmillan Publishers Limited. All rights reserved

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 09 July 2013
                : 20 December 2013
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