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Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections

Tomer Hertz, P. Robert Beatty, Zachary MacMillen, Sarah S. Killingbeck, Chunling Wang and Eva Harris
J Immunol May 15, 2017, 198 (10) 4025-4035; DOI: https://doi.org/10.4049/jimmunol.1700029
Tomer Hertz
Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and
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  • ORCID record for Tomer Hertz
P. Robert Beatty
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720
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Zachary MacMillen
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and
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Sarah S. Killingbeck
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720
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Chunling Wang
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720
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Eva Harris
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720
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Abstract

Dengue is a global public health problem and is caused by four dengue virus (DENV) serotypes (DENV1-4). A major challenge in dengue vaccine development is that cross-reactive anti-DENV Abs can be protective or potentially increase disease via Ab-dependent enhancement. DENV nonstructural protein 1 (NS1) has long been considered a vaccine candidate as it avoids Ab-dependent enhancement. In this study, we evaluated survival to challenge in a lethal DENV vascular leak model in mice immunized with NS1 combined with aluminum and magnesium hydroxide, monophosphoryl lipid A + AddaVax, or Sigma adjuvant system+CpG DNA, compared with mice infected with a sublethal dose of DENV2 and mice immunized with OVA (negative control). We characterized Ab responses to DENV1, 2, and 3 NS1 using an Ag microarray tiled with 20-mer peptides overlapping by 15 aa and identified five regions of DENV NS1 with significant levels of Ab reactivity in the NS1 + monophosphoryl lipid A + AddaVax group. Additionally, we profiled the Ab responses to NS1 of humans naturally infected with DENV2 or DENV3 in serum samples from Nicaragua collected at acute, convalescent, and 12-mo timepoints. One region in the wing domain of NS1 was immunodominant in both mouse vaccination and human infection studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against lethal DENV infection. Overall, we identified a small number of immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection.

Footnotes

  • This work was supported by Grants U54 AI65359 (E.H.), K25 AI087397 (T.H.) and U19 AI109761 Center for Research in Diagnostics and Discovery (E.H., Program Director I. Lipkin) from the National Institute of Allergy and Infectious Diseases.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    alum
    aluminum and magnesium hydroxide
    DENV
    dengue virus
    DF
    dengue fever
    DHF
    dengue hemorrhagic fever
    DSS
    dengue shock syndrome
    E
    envelope
    HA
    hemagglutinin A
    MA
    monophosphoryl lipid A + AddaVax
    MFI
    mean fluorescence intensity
    NS1
    nonstructural protein 1
    SAS
    Sigma adjuvant system
    SCpG
    Sigma adjuvant system+CpG DNA.

  • Received January 6, 2017.
  • Accepted March 6, 2017.
  • Copyright © 2017 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 198 (10)
The Journal of Immunology
Vol. 198, Issue 10
15 May 2017
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Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections
Tomer Hertz, P. Robert Beatty, Zachary MacMillen, Sarah S. Killingbeck, Chunling Wang, Eva Harris
The Journal of Immunology May 15, 2017, 198 (10) 4025-4035; DOI: 10.4049/jimmunol.1700029

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Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections
Tomer Hertz, P. Robert Beatty, Zachary MacMillen, Sarah S. Killingbeck, Chunling Wang, Eva Harris
The Journal of Immunology May 15, 2017, 198 (10) 4025-4035; DOI: 10.4049/jimmunol.1700029
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Print ISSN 0022-1767        Online ISSN 1550-6606