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      Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques

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          Abstract

          Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.

          Author summary

          Chikungunya virus (CHIKV) causes fever, rash, and acute and chronic arthralgia. Currently there are no approved therapies to treat or vaccines to prevent CHIKV infection in humans. In this study, we engineered SVIR001, a recombinant fully human monoclonal antibody (mAb) that eliminated viremia, reduced viral load at the site of infection, and diminished spread to distant target tissues in rhesus macaques when administered after infection. SVIR001 treatment reduced joint inflammation and disease without impairing the induction of the adaptive immune response. These results demonstrate the efficacy of mAb therapy to reduce the severity of CHIKV disease.

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          Most cited references37

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          Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography.

          Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus that has caused widespread outbreaks of debilitating human disease in the past five years. CHIKV invasion of susceptible cells is mediated by two viral glycoproteins, E1 and E2, which carry the main antigenic determinants and form an icosahedral shell at the virion surface. Glycoprotein E2, derived from furin cleavage of the p62 precursor into E3 and E2, is responsible for receptor binding, and E1 for membrane fusion. In the context of a concerted multidisciplinary effort to understand the biology of CHIKV, here we report the crystal structures of the precursor p62-E1 heterodimer and of the mature E3-E2-E1 glycoprotein complexes. The resulting atomic models allow the synthesis of a wealth of genetic, biochemical, immunological and electron microscopy data accumulated over the years on alphaviruses in general. This combination yields a detailed picture of the functional architecture of the 25 MDa alphavirus surface glycoprotein shell. Together with the accompanying report on the structure of the Sindbis virus E2-E1 heterodimer at acidic pH (ref. 3), this work also provides new insight into the acid-triggered conformational change on the virus particle and its inbuilt inhibition mechanism in the immature complex.
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            Chikungunya in the Americas.

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              Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients.

              Chikungunya is a reemerging disease. In 2005-2006, a severe outbreak occurred on Reunion Island in the southwestern part of the Indian Ocean. Other islands in this area were affected during the same period. Adult patients with acute chikungunya (defined as onset of fever and/or polyarthralgia in the 5 days preceding consultation) and laboratory-confirmed chikungunya who were referred to Groupe Hospitalier Sud Reunion during the period from March 2005 through April 2006 were included in this retrospective study. Their clinical and laboratory features are reported. Laboratory-confirmed acute chikungunya was documented in 157 patients. The mean age of patients was 57.9 years, and the ratio of male to female patients was 1.24 : 1. Sixty percent of patients had at least 1 comorbidity. Ninety-seven patients (61.8%) were hospitalized, and 60 (38.2%) were treated as outpatients. Five fatalities were reported. One hundred fifty-one patients (96.1%) experienced polyarthralgia, and 129 (89%) experienced fever. Gastrointestinal symptoms were reported by 74 patients (47.1%), and skin rash was reported by 63 (40.1%). Hemorrhagic signs were rare. Lymphopenia and hypocalcemia were the prominent laboratory findings. Severe thrombocytopenia was rarely observed. Chikungunya virus can be responsible for explosive outbreaks of disease. Polyarthralgia and fever are the 2 main clinical features. In this era of travel and globalization, chikungunya should be considered in the differential diagnosis of febrile polyarthralgia with an abrupt onset.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                19 June 2017
                June 2017
                : 11
                : 6
                : e0005637
                Affiliations
                [1 ]Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, United States of America
                [2 ]Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, United States of America
                [3 ]Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, United States of America
                [4 ]Sanofi, Cambridge, United States of America
                [5 ]Pathology Services Unit, Division of Comparative Medicine, Oregon National Primate Research Center, Beaverton, United States of America
                [6 ]Sanofi, Marcy L’Etoile, France
                [7 ]Departments of Pediatrics and Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, United States of America
                Centers for Disease Control and Prevention, UNITED STATES
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: CC, SK, MM, PC, JR, ER, IF, and KC have ownership of stocks or shares in Sanofi. The rest of the authors have declared that no competing interests exist.

                • Conceptualization: MSD JEC KC DNS.

                • Funding acquisition: JEC MSD DNS.

                • Investigation: RB JMF NH CNK SSP AL PPS MD LMAC RMD ADL DNS.

                • Methodology: CC SK ADL MKA KC MM PC JR ER IF GS JEC MSD DNS.

                • Project administration: KC JEC MSD DNS.

                • Resources: KC MSD DNS.

                • Supervision: KC JEC MSD DNS.

                • Validation: KC JEC MSD DNS.

                • Visualization: RB JMF NH MSD DNS.

                • Writing – original draft: RB JMF NH ADL KC JEC MSD DNS.

                • Writing – review & editing: RB JMF NH CNK SSP AL PPS MD CC SK LMAC RMD ADL MKA KC MM PC JR ER IF GS JEC MSD DNS.

                Author information
                http://orcid.org/0000-0002-6828-2492
                Article
                PNTD-D-16-02246
                10.1371/journal.pntd.0005637
                5491320
                28628616
                c8682f21-74b8-4e14-a887-723f352506e1
                © 2017 Broeckel et al

                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
                : 30 December 2016
                : 11 May 2017
                Page count
                Figures: 7, Tables: 2, Pages: 25
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: AI109680
                Award Recipient :
                Funded by: Foundation for the National Institutes of Health (US)
                Award ID: AI114816
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: AI089591
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: U42 OD010426
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: P51-OD011092
                The work described in this manuscript was supported by NIH NIAID grants R01 AI089591 (MSD), R01 AI114816 (JEC and MSD), U19 AI109680 (DNS), and U42 OD010426 (MKA) and P51-OD011092 (ONPRC Core Grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Chikungunya Infection
                Medicine and Health Sciences
                Infectious Diseases
                Viral Diseases
                Chikungunya Infection
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Joints (Anatomy)
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Joints (Anatomy)
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Transmission and Infection
                Viral Load
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Togaviruses
                Alphaviruses
                Chikungunya Virus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
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                Togaviruses
                Alphaviruses
                Chikungunya Virus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
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                Togaviruses
                Alphaviruses
                Chikungunya Virus
                Biology and Life Sciences
                Organisms
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                Viral Pathogens
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                Alphaviruses
                Chikungunya Virus
                Biology and Life Sciences
                Physiology
                Immune Physiology
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                Medicine and Health Sciences
                Physiology
                Immune Physiology
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                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Antibodies
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
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                Biology and Life Sciences
                Biochemistry
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                Immune System Proteins
                Antibodies
                Biology and life sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Mammals
                Primates
                Monkeys
                Old World monkeys
                Macaque
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Enzyme-Linked Immunoassays
                Research and Analysis Methods
                Experimental Organism Systems
                Animal Models
                Rhesus Monkeys
                Biology and life sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Mammals
                Primates
                Monkeys
                Old World monkeys
                Macaque
                Rhesus Monkeys
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-06-29
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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