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      Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus

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          ABSTRACT

          Zika virus (ZIKV) is a mosquito-borne flavivirus responsible for thousands of cases of severe fetal malformations and neurological disease since its introduction to Brazil in 2013. Antibodies to flaviviruses can be protective, resulting in lifelong immunity to reinfection by homologous virus. However, cross-reactive antibodies can complicate flavivirus diagnostics and promote more severe disease, as noted after serial dengue virus (DENV) infections. The endemic circulation of DENV in South America and elsewhere raises concerns that preexisting flavivirus immunity may modulate ZIKV disease and transmission potential. Here, we report on the ability of human monoclonal antibodies and immune sera derived from dengue patients to neutralize contemporary epidemic ZIKV strains. We demonstrate that a class of human monoclonal antibodies isolated from DENV patients neutralizes ZIKV in cell culture and is protective in a lethal murine model. We also tested a large panel of convalescent-phase immune sera from humans exposed to primary and repeat DENV infection. Although ZIKV is most closely related to DENV compared to other human-pathogenic flaviviruses, most DENV immune sera (73%) failed to neutralize ZIKV, while others had low (50% effective concentration [EC 50], <1:100 serum dilution; 18%) or moderate to high (EC 50, >1:100 serum dilution; 9%) levels of cross-neutralizing antibodies. Our results establish that ZIKV and DENV share epitopes that are targeted by neutralizing, protective human antibodies. The availability of potently neutralizing human monoclonal antibodies provides an immunotherapeutic approach to control life-threatening ZIKV infection and also points to the possibility of repurposing DENV vaccines to induce cross-protective immunity to ZIKV.

          IMPORTANCE

          ZIKV is an emerging arbovirus that has been associated with severe neurological birth defects and fetal loss in pregnant women and Guillain-Barré syndrome in adults. Currently, there is no vaccine or therapeutic for ZIKV. The identification of a class of antibodies (envelope dimer epitope 1 [EDE1]) that potently neutralizes ZIKV in addition to all four DENV serotypes points to a potential immunotherapeutic to combat ZIKV. This is especially salient given the precedent of antibody therapy to treat pregnant women infected with other viruses associated with microcephaly, such as cytomegalovirus and rubella virus. Furthermore, the identification of a functionally conserved epitope between ZIKV and DENV raises the possibility that a vaccine may be able to elicit neutralizing antibodies against both viruses.

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          Most cited references26

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          First report of autochthonous transmission of Zika virus in Brazil

          In the early 2015, several cases of patients presenting symptoms of mild fever, rash, conjunctivitis and arthralgia were reported in the northeastern Brazil. Although all patients lived in a dengue endemic area, molecular and serological diagnosis for dengue resulted negative. Chikungunya virus infection was also discarded. Subsequently, Zika virus (ZIKV) was detected by reverse transcription-polymerase chain reaction from the sera of eight patients and the result was confirmed by DNA sequencing. Phylogenetic analysis suggests that the ZIKV identified belongs to the Asian clade. This is the first report of ZIKV infection in Brazil.
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            A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus.

            Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.
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              Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions.

              Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Even though infected individuals develop potent and long-lasting serotype-specific neutralizing antibodies (Abs), the epitopes engaged by human neutralizing Abs have not been identified. Here, we demonstrate that the dengue virus (DENV)-specific serum Ab response in humans consists of a large fraction of cross-reactive, poorly neutralizing Abs and a small fraction of serotype-specific, potently inhibitory Abs. Although many mouse-generated, strongly neutralizing monoclonal antibodies (mAbs) recognize epitopes that are present on recombinant DENV envelope (E) proteins, unexpectedly, the majority of neutralizing Abs in human immune sera bound to intact virions but not to the ectodomain of purified soluble E proteins. These conclusions with polyclonal Abs were confirmed with newly generated human mAbs derived from DENV-immune individuals. Two of three strongly neutralizing human mAbs bound to E protein epitopes that were preserved on the virion but not on recombinant E (rE) protein. We propose that humans produce Abs that neutralize DENV infection by binding a complex, quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle. Mapping studies indicate that this epitope has a footprint that spans adjacent E protein dimers and includes residues at the hinge between domains I and II of E protein. These results have significant implications for the DENV Ab and vaccine field.
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                Author and article information

                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                19 July 2016
                Jul-Aug 2016
                : 7
                : 4
                : e01123-16
                Affiliations
                [a ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
                [b ]Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
                [c ]Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
                Author notes
                Address correspondence to R. S. Baric, rbaric@ 123456email.unc.edu .

                J.A.S. and J.A.P. contributed equally to this work.

                Editor W. Ian Lipkin, Columbia University

                This article is a direct contribution from a Fellow of the American Academy of Microbiology. External solicited reviewers: Shee Mei Lok, Duke-NUS GMS; Anna Durbin, Johns Hopkins Bloomberg School of Public Health.

                Article
                mBio01123-16
                10.1128/mBio.01123-16
                4958264
                27435464
                580ce10c-247b-49ce-920e-834622e145cb
                Copyright © 2016 Swanstrom et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 24 June 2016
                : 28 June 2016
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 45, Pages: 8, Words: 7163
                Funding
                Funded by: HHS | National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002
                Award ID: R01 AI 107731
                Award Recipient : Eileen McGowan Award Recipient : Jesica A. Swanstrom Award Recipient : Ellen F. Young Award Recipient : Emily N. Gallichotte Award Recipient : Aravinda de Silva Award Recipient : Ralph S. Baric
                Funded by: HHS | National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002
                Award ID: U19 AI 100625
                Award Recipient : Mark T. Heise Award Recipient : Ralph S. Baric Award Recipient : Kenneth S. Plante
                Funded by: HHS | National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002
                Award ID: T32 AI 007151-36A1
                Award Recipient : Kenneth S. Plante
                Funded by: Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) http://dx.doi.org/10.13039/100000865
                Award ID: Idea Grant
                Award Recipient : Jessica Plante Award Recipient : Eileen McGowan Award Recipient : Aravinda de Silva Award Recipient : Ralph S. Baric Award Recipient : Jesica A. Swanstrom Award Recipient : Ellen F. Young Award Recipient : Emily N. Gallichotte Award Recipient : Doug G. Widman
                Categories
                Research Article
                Custom metadata
                July/August 2016

                Life sciences
                Life sciences

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