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      Vaccines: From Empirical Development to Rational Design

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      PLoS Pathogens
      Public Library of Science

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          Abstract

          Infectious diseases are responsible for an overwhelming number of deaths worldwide and their clinical management is often hampered by the emergence of multi-drug-resistant strains. Therefore, prevention through vaccination currently represents the best course of action to combat them. However, immune escape and evasion by pathogens often render vaccine development difficult. Furthermore, most currently available vaccines were empirically designed. In this review, we discuss why rational design of vaccines is not only desirable but also necessary. We introduce recent developments towards specifically tailored antigens, adjuvants, and delivery systems, and discuss the methodological gaps and lack of knowledge still hampering true rational vaccine design. Finally, we address the potential and limitations of different strategies and technologies for advancing vaccine development.

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          Most cited references81

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          Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

          A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
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            SYFPEITHI: database for MHC ligands and peptide motifs.

            The first version of the major histocompatibility complex (MHC) databank SYFPEITHI: database for MHC ligands and peptide motifs, is now available to the general public. It contains a collection of MHC class I and class II ligands and peptide motifs of humans and other species, such as apes, cattle, chicken, and mouse, for example, and is continuously updated. All motifs currently available are accessible as individual entries. Searches for MHC alleles, MHC motifs, natural ligands, T-cell epitopes, source proteins/organisms and references are possible. Hyperlinks to the EMBL and PubMed databases are included. In addition, ligand predictions are available for a number of MHC allelic products. The database content is restricted to published data only.
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              Systems Biology of Seasonal Influenza Vaccination in Humans

              We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV −/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                November 2012
                November 2012
                8 November 2012
                : 8
                : 11
                : e1003001
                Affiliations
                [1]Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
                University of Alberta, Canada
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PPATHOGENS-D-12-01184
                10.1371/journal.ppat.1003001
                3493475
                23144616
                a3a79567-2573-43ab-bc59-94f546462f15
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Pages: 7
                Funding
                This work was supported in part by grants from the EU (PANFLUVAC, TRANSVAC); BMBF in the context of the programs Gerontosys 2 (Gerontoshield), EuroNanoMed (HCVAX) and ERANetRUS (HCRUS), and the Helmholtz Association (IG-SCID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Review
                Biology
                Immunology
                Immunity
                Immunizations

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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