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      Development of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone

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          Abstract

          The global spread of Zika virus (ZIKV) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine. Here we report the development and characterization of a recombinant chimeric ZIKV vaccine candidate (termed ChinZIKV) that expresses the prM-E proteins of ZIKV using the licensed Japanese encephalitis live-attenuated vaccine SA14-14-2 as the genetic backbone. ChinZIKV retains its replication activity and genetic stability in vitro, while exhibiting an attenuation phenotype in multiple animal models. Remarkably, immunization of mice and rhesus macaques with a single dose of ChinZIKV elicits robust and long-lasting immune responses, and confers complete protection against ZIKV challenge. Significantly, female mice immunized with ChinZIKV are protected against placental and fetal damage upon ZIKV challenge during pregnancy. Overall, our study provides an alternative vaccine platform in response to the ZIKV emergency, and the safety, immunogenicity, and protection profiles of ChinZIKV warrant further clinical development.

          Abstract

          Given the recent Zika virus (ZIKV) epidemic, development of an effective vaccine is of high importance. Here, the authors use a licensed live-attenuated flavivirus vaccine backbone to develop a ZIKV vaccine and determine immunogenicity, safety and protection profiles in different animal models.

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          Most cited references 67

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          Zika Virus Associated with Microcephaly.

          A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.
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            Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.

            Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barré syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barré syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barré syndrome.
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              The Brazilian Zika virus strain causes birth defects in experimental models

              Summary Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (Family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys 1 . Until the 20th century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the island of Yap in Micronesia 2 . Patients experienced fever, skin rash, arthralgia and conjunctivitis 2 . From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America 3 . In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome 4,5 . Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKVBR) strain causes birth defects remains missing 6 . Here we demonstrate that the ZIKVBR infects fetuses, causing intra-uterine growth restriction (IUGR), including signs of microcephaly in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. Finally, we observed that the infection of human brain organoids resulted in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKVBR crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKVBR outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKVBR in human neurodevelopment.
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                Author and article information

                Affiliations
                [1 ]ISNI 0000 0004 1803 4911, GRID grid.410740.6, State Key Laboratory of Pathogen and Biosecurity, , Beijing Institute of Microbiology and Epidemiology, ; Beijing, 100071 China
                [2 ]ISNI 0000 0000 8653 1072, GRID grid.410737.6, Guangzhou Eighth People’s Hospital, , Guangzhou Medical University, ; Guangzhou, 510060 China
                [3 ]Department of Infection Control, The 306th Hospital of PLA, Beijing, 100101 China
                [4 ]ISNI 0000 0004 1803 4911, GRID grid.410740.6, Laboratory Animal Center, , Academy of Military Medical Science, ; Beijing, 100071 China
                [5 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Center for Systems Medicine, Institute of Basic Medical Sciences, , Chinese Academy of Medical Sciences and Peking Union Medical College, ; Beijing, 100005 China
                [6 ]ISNI 0000 0001 0662 3178, GRID grid.12527.33, Tsinghua-Peking Center for Life Sciences, School of Medicine, , Tsinghua University, ; Beijing, 100084 China
                [7 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Faculty of Biomedical Sciences, School of Cellular and Molecular Medicine, , University of Bristol, ; University Walk, Bristol, BS8 1TD UK
                [8 ]ISNI 0000 0001 1547 9964, GRID grid.176731.5, Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, , University of Texas Medical Branch, ; Galveston, Texas 77555 USA
                [9 ]ISNI 0000 0001 1547 9964, GRID grid.176731.5, Department of Pharmacology and Toxicology, , University of Texas Medical Branch, ; Galveston, Texas 77555 USA
                Contributors
                ORCID: http://orcid.org/0000-0002-0632-2807, qincf@bmi.ac.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                14 February 2018
                14 February 2018
                2018
                : 9
                2975
                10.1038/s41467-018-02975-w
                5813210
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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