Humoral Immune Responses of Dengue Fever Patients Using Epitope-Specific Serotype-2 Virus-Like Particle Antigens

Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated...

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Published in:	PloS one Vol. 4; no. 4; p. e4991
Main Authors:	Crill, Wayne D., Hughes, Holly R., Delorey, Mark J., Chang, Gwong-Jen J.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01.04.2009 Public Library of Science (PLoS)
Subjects:	Amino Acid Sequence Antibodies, Monoclonal - biosynthesis Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - immunology Antibodies, Viral - biosynthesis Antibodies, Viral - chemistry Antibodies, Viral - immunology Antibody response Antigenic determinants Antigens Antigens, Viral - chemistry Antigens, Viral - immunology Antiviral agents Aquatic insects Base Sequence Biosynthesis Dengue - immunology Dengue fever Dengue hemorrhagic fever Dengue virus Disease control Disease prevention DNA Primers Encephalitis Enzymes Epidemics Epitope Mapping Epitopes Epitopes - chemistry Epitopes - immunology Fever Health aspects Health risks Health services Hemorrhagic fevers Human behavior Humans Immune response Immune response (humoral) Immunoglobulin G Immunoglobulin M Immunoglobulins Immunology Immunology/Immune Response Infection Infections Infectious diseases Infectious Diseases/Viral Infections Medical research Microbiology/Medical Microbiology Models, Molecular Molecular Sequence Data Mosquitoes Neutralization Pathogenicity Pathogens Peptides Populations Protein Conformation Proteins Public health Sequence Homology, Amino Acid Vaccination Vaccine development Vaccines Vector-borne diseases Vectors Vectors (Biology) Viral diseases Viral envelope proteins Virology Virology/Emerging Viral Diseases Virology/Host Antiviral Responses Viruses West Nile virus United States > US Colorado
ISSN:	1932-6203, 1932-6203
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Abstract	Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing.
AbstractList	Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing. Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing.Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing.
Audience	Academic
Author	Crill, Wayne D. Delorey, Mark J. Hughes, Holly R. Chang, Gwong-Jen J.
AuthorAffiliation	Institute of Molecular and Cell Biology, Singapore Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U. S. Department of Health and Human Service, Fort Collins, Colorado, United States of America
AuthorAffiliation_xml	– name: Institute of Molecular and Cell Biology, Singapore – name: Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U. S. Department of Health and Human Service, Fort Collins, Colorado, United States of America
Author_xml	– sequence: 1 givenname: Wayne D. surname: Crill fullname: Crill, Wayne D. – sequence: 2 givenname: Holly R. surname: Hughes fullname: Hughes, Holly R. – sequence: 3 givenname: Mark J. surname: Delorey fullname: Delorey, Mark J. – sequence: 4 givenname: Gwong-Jen J. surname: Chang fullname: Chang, Gwong-Jen J.
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/19337372$$D View this record in MEDLINE/PubMed
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Copyright	COPYRIGHT 2009 Public Library of Science This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 2009
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: WDC GJJC. Performed the experiments: HRH. Analyzed the data: WDC HRH MD. Contributed reagents/materials/analysis tools: WDC GJJC. Wrote the paper: WDC.
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Snippet	Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe...
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SubjectTerms	Amino Acid Sequence Antibodies, Monoclonal - biosynthesis Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - immunology Antibodies, Viral - biosynthesis Antibodies, Viral - chemistry Antibodies, Viral - immunology Antibody response Antigenic determinants Antigens Antigens, Viral - chemistry Antigens, Viral - immunology Antiviral agents Aquatic insects Base Sequence Biosynthesis Dengue - immunology Dengue fever Dengue hemorrhagic fever Dengue virus Disease control Disease prevention DNA Primers Encephalitis Enzymes Epidemics Epitope Mapping Epitopes Epitopes - chemistry Epitopes - immunology Fever Health aspects Health risks Health services Hemorrhagic fevers Human behavior Humans Immune response Immune response (humoral) Immunoglobulin G Immunoglobulin M Immunoglobulins Immunology Immunology/Immune Response Infection Infections Infectious diseases Infectious Diseases/Viral Infections Medical research Microbiology/Medical Microbiology Models, Molecular Molecular Sequence Data Mosquitoes Neutralization Pathogenicity Pathogens Peptides Populations Protein Conformation Proteins Public health Sequence Homology, Amino Acid Vaccination Vaccine development Vaccines Vector-borne diseases Vectors Vectors (Biology) Viral diseases Viral envelope proteins Virology Virology/Emerging Viral Diseases Virology/Host Antiviral Responses Viruses West Nile virus
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Title	Humoral Immune Responses of Dengue Fever Patients Using Epitope-Specific Serotype-2 Virus-Like Particle Antigens
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