Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever
Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBO...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e36192-e36192 |
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| creator | Marzi, Andrea Yoshida, Reiko Miyamoto, Hiroko Ishijima, Mari Suzuki, Yasuhiko Higuchi, Megumi Matsuyama, Yukie Igarashi, Manabu Nakayama, Eri Kuroda, Makoto Saijo, Masayuki Feldmann, Friederike Brining, Douglas Feldmann, Heinz Takada, Ayato |
| description | Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF. |
| doi_str_mv | 10.1371/journal.pone.0036192 |
| format | Article |
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Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0036192</identifier><identifier>PMID: 22558378</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoviruses ; Amino acids ; Analysis ; Animal diseases ; Animal models ; Animals ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - immunology ; Antibodies, Neutralizing - chemistry ; Antibodies, Neutralizing - immunology ; Antibody Specificity ; Biology ; Blood circulation ; Cercopithecus aethiops ; CHO Cells ; Cricetinae ; Cricetulus ; Cytotoxicity ; Disease Models, Animal ; Ebola hemorrhagic fever ; Ebola virus ; Ebolavirus ; Ebolavirus - immunology ; Ebolavirus - pathogenicity ; Ebolavirus - physiology ; Encephalitis ; Enzymes ; Epidemics ; Epidemiology ; Epitopes - immunology ; Extremely high frequencies ; Fatalities ; Fever ; Glycoproteins ; Health aspects ; Hemorrhage ; Hemorrhagic fever ; Hemorrhagic Fever, Ebola - prevention & control ; Humans ; Immunization ; Immunization, Passive ; Immunoglobulin G ; Immunoglobulins ; Infectious diseases ; Laboratories ; Macaca mulatta ; Male ; Marburg virus disease ; Medical research ; Medicine ; Mice ; Models, Molecular ; Monoclonal antibodies ; Neutralizing ; Operations management ; Pathogenesis ; Primates ; Protection and preservation ; Protein Conformation ; Recombinant Fusion Proteins - chemistry ; Recombinant Fusion Proteins - immunology ; Swine flu ; Trends ; Vaccines ; Vero Cells ; Veterinary Science ; Viral diseases ; Viral Load - immunology ; Viremia ; Virology ; Virus diseases ; Viruses ; Wildlife conservation ; Zoonoses</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e36192-e36192</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c802t-60b44fa5482c3cfd7bde57e70dc0abda9fd69d9f9c76e2ddee5716c03c0e33553</citedby><cites>FETCH-LOGICAL-c802t-60b44fa5482c3cfd7bde57e70dc0abda9fd69d9f9c76e2ddee5716c03c0e33553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338609/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338609/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22558378$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Subbiah, Elankumaran</contributor><creatorcontrib>Marzi, Andrea</creatorcontrib><creatorcontrib>Yoshida, Reiko</creatorcontrib><creatorcontrib>Miyamoto, Hiroko</creatorcontrib><creatorcontrib>Ishijima, Mari</creatorcontrib><creatorcontrib>Suzuki, Yasuhiko</creatorcontrib><creatorcontrib>Higuchi, Megumi</creatorcontrib><creatorcontrib>Matsuyama, Yukie</creatorcontrib><creatorcontrib>Igarashi, Manabu</creatorcontrib><creatorcontrib>Nakayama, Eri</creatorcontrib><creatorcontrib>Kuroda, Makoto</creatorcontrib><creatorcontrib>Saijo, Masayuki</creatorcontrib><creatorcontrib>Feldmann, Friederike</creatorcontrib><creatorcontrib>Brining, Douglas</creatorcontrib><creatorcontrib>Feldmann, Heinz</creatorcontrib><creatorcontrib>Takada, Ayato</creatorcontrib><title>Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.</description><subject>Adenoviruses</subject><subject>Amino acids</subject><subject>Analysis</subject><subject>Animal diseases</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - chemistry</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Neutralizing - chemistry</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Antibody Specificity</subject><subject>Biology</subject><subject>Blood circulation</subject><subject>Cercopithecus aethiops</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cytotoxicity</subject><subject>Disease Models, Animal</subject><subject>Ebola hemorrhagic fever</subject><subject>Ebola virus</subject><subject>Ebolavirus</subject><subject>Ebolavirus - immunology</subject><subject>Ebolavirus - pathogenicity</subject><subject>Ebolavirus - physiology</subject><subject>Encephalitis</subject><subject>Enzymes</subject><subject>Epidemics</subject><subject>Epidemiology</subject><subject>Epitopes - immunology</subject><subject>Extremely high frequencies</subject><subject>Fatalities</subject><subject>Fever</subject><subject>Glycoproteins</subject><subject>Health aspects</subject><subject>Hemorrhage</subject><subject>Hemorrhagic fever</subject><subject>Hemorrhagic Fever, Ebola - prevention & control</subject><subject>Humans</subject><subject>Immunization</subject><subject>Immunization, Passive</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulins</subject><subject>Infectious diseases</subject><subject>Laboratories</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Marburg virus disease</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Monoclonal antibodies</subject><subject>Neutralizing</subject><subject>Operations management</subject><subject>Pathogenesis</subject><subject>Primates</subject><subject>Protection and preservation</subject><subject>Protein Conformation</subject><subject>Recombinant Fusion Proteins - chemistry</subject><subject>Recombinant Fusion Proteins - immunology</subject><subject>Swine flu</subject><subject>Trends</subject><subject>Vaccines</subject><subject>Vero Cells</subject><subject>Veterinary Science</subject><subject>Viral diseases</subject><subject>Viral Load - immunology</subject><subject>Viremia</subject><subject>Virology</subject><subject>Virus diseases</subject><subject>Viruses</subject><subject>Wildlife 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Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marzi, Andrea</au><au>Yoshida, Reiko</au><au>Miyamoto, Hiroko</au><au>Ishijima, Mari</au><au>Suzuki, Yasuhiko</au><au>Higuchi, Megumi</au><au>Matsuyama, Yukie</au><au>Igarashi, Manabu</au><au>Nakayama, Eri</au><au>Kuroda, Makoto</au><au>Saijo, Masayuki</au><au>Feldmann, Friederike</au><au>Brining, Douglas</au><au>Feldmann, Heinz</au><au>Takada, Ayato</au><au>Subbiah, Elankumaran</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-27</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e36192</spage><epage>e36192</epage><pages>e36192-e36192</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22558378</pmid><doi>10.1371/journal.pone.0036192</doi><tpages>e36192</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-04, Vol.7 (4), p.e36192-e36192 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1324600268 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Adenoviruses Amino acids Analysis Animal diseases Animal models Animals Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - immunology Antibodies, Neutralizing - chemistry Antibodies, Neutralizing - immunology Antibody Specificity Biology Blood circulation Cercopithecus aethiops CHO Cells Cricetinae Cricetulus Cytotoxicity Disease Models, Animal Ebola hemorrhagic fever Ebola virus Ebolavirus Ebolavirus - immunology Ebolavirus - pathogenicity Ebolavirus - physiology Encephalitis Enzymes Epidemics Epidemiology Epitopes - immunology Extremely high frequencies Fatalities Fever Glycoproteins Health aspects Hemorrhage Hemorrhagic fever Hemorrhagic Fever, Ebola - prevention & control Humans Immunization Immunization, Passive Immunoglobulin G Immunoglobulins Infectious diseases Laboratories Macaca mulatta Male Marburg virus disease Medical research Medicine Mice Models, Molecular Monoclonal antibodies Neutralizing Operations management Pathogenesis Primates Protection and preservation Protein Conformation Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - immunology Swine flu Trends Vaccines Vero Cells Veterinary Science Viral diseases Viral Load - immunology Viremia Virology Virus diseases Viruses Wildlife conservation Zoonoses |
| title | Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever |
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