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      BoHV-4-based vector delivering Ebola virus surface glycoprotein

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          Abstract

          Background

          Ebola virus (EBOV) is a Category A pathogen that is a member of Filoviridae family that causes hemorrhagic fever in humans and non-human primates. Unpredictable and devastating outbreaks of disease have recently occurred in Africa and current immunoprophylaxis and therapies are limited. The main limitation of working with pathogens like EBOV is the need for costly containment. To potentiate further and wider opportunity for EBOV prophylactics and therapies development, innovative approaches are necessary.

          Methods

          In the present study, an antigen delivery platform based on a recombinant bovine herpesvirus 4 (BoHV-4), delivering a synthetic EBOV glycoprotein (GP) gene sequence, BoHV-4-syEBOVgD106ΔTK, was generated.

          Results

          EBOV GP was abundantly expressed by BoHV-4-syEBOVgD106ΔTK transduced cells without decreasing viral replication. BoHV-4-syEBOVgD106ΔTK immunized goats produced high titers of anti-EBOV GP antibodies and conferred a long lasting (up to 6 months), detectable antibody response. Furthermore, no evidence of BoHV-4-syEBOVgD106ΔTK viremia and secondary localization was detected in any of the immunized animals.

          Conclusions

          The BoHV-4-based vector approach described here, represents: an alternative antigen delivery system for vaccination and a proof of principle study for anti-EBOV antibodies generation in goats for potential immunotherapy applications.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-016-1084-5) contains supplementary material, which is available to authorized users.

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          Most cited references 29

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          Simple and highly efficient BAC recombineering using galK selection

          Recombineering allows DNA cloned in Escherichia coli to be modified via lambda (λ) Red-mediated homologous recombination, obviating the need for restriction enzymes and DNA ligases to modify DNA. Here, we describe the construction of three new recombineering strains (SW102, SW105 and SW106) that allow bacterial artificial chromosomes (BACs) to be modified using galK positive/negative selection. This two-step selection procedure allows DNA to be modified without introducing an unwanted selectable marker at the modification site. All three strains contain an otherwise complete galactose operon, except for a precise deletion of the galK gene, and a defective temperature-sensitive λ prophage that makes recombineering possible. SW105 and SW106 cells in addition carry l-arabinose-inducible Cre or Flp genes, respectively. The galK function can be selected both for and against. This feature greatly reduces the background seen in other negative-selection schemes, and galK selection is considerably more efficient than other related selection methods published. We also show how galK selection can be used to rapidly introduce point mutations, deletions and loxP sites into BAC DNA and thus facilitate functional studies of SNP and/or disease-causing point mutations, the identification of long-range regulatory elements and the construction of conditional targeting vectors.
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            Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial.

            A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa.
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              Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge.

              Ebolavirus disease causes high mortality, and the current outbreak has spread unabated through West Africa. Human adenovirus type 5 vectors (rAd5) encoding ebolavirus glycoprotein (GP) generate protective immunity against acute lethal Zaire ebolavirus (EBOV) challenge in macaques, but fail to protect animals immune to Ad5, suggesting natural Ad5 exposure may limit vaccine efficacy in humans. Here we show that a chimpanzee-derived replication-defective adenovirus (ChAd) vaccine also rapidly induced uniform protection against acute lethal EBOV challenge in macaques. Because protection waned over several months, we boosted ChAd3 with modified vaccinia Ankara (MVA) and generated, for the first time, durable protection against lethal EBOV challenge.
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                Author and article information

                Contributors
                alfonso.rosamilia@studenti.unipr.it
                sarah.jacca@studenti.unipr.it
                giulia.tebaldi1@studenti.unipr.it
                silvia.tiberti@studenti.unipr.it
                valentina.franceschi@unipr.it
                francesca.macchi@studenti.unipr.it
                sandro.cavirani@unipr.it
                gary.kobinger@phac-aspc.gc.ca
                don.knowles@ars.usda.gov
                00390521902677 , gaetano.donofrio@unipr.it
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                24 November 2016
                24 November 2016
                2016
                : 14
                Affiliations
                [1 ]Department of Medical-Veterinary Science, University of Parma, Via del Taglio 10, 43126 Parma, Italy
                [2 ]Special Pathogens Program, University of Manitoba and Public Health Agency of Canada, Winnipeg, MB Canada
                [3 ]Animal Disease Research Unit, Agricultural Research Service, United States Department of Agriculture, and Department of Veterinary Microbiology & Pathology, Washington State University, Pullman, WA USA
                Article
                1084
                10.1186/s12967-016-1084-5
                5122150
                27881138
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: Italian Ministry of University and Scientific Research (Italian National Grant MIUR, PRIN 2010-2011).
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Medicine

                recombineering, ebola virus, bovine herpesvirus 4, vaccine platform, viral vector

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