1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

  1. Natasha D Durham
  2. Aditi Agrawal
  3. Eric Waltari
  4. Derek Croote
  5. Fabio Zanini
  6. Mallorie Fouch
  7. Edgar Davidson
  8. Olivia Smith
  9. Esteban Carabajal
  10. John E Pak
  11. Benjamin J Doranz
  12. Makeda Robinson
  13. Ana M Sanz
  14. Ludwig L Albornoz
  15. Fernando Rosso
  16. Shirit Einav
  17. Stephen R Quake
  18. Krista M McCutcheon
  19. Leslie Goo  Is a corresponding author
  1. Chan Zuckerberg Biohub, United States
  2. Stanford University, United States
  3. Integral Molecular, Inc, United States
  4. Fundación Valle del Lili, Colombia
  5. Fred Hutchinson Cancer Research Center, United States
Research Article
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Cite this article as: eLife 2019;8:e52384 doi: 10.7554/eLife.52384

Abstract

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 4, and 6.

The following previously published data sets were used

Article and author information

Author details

  1. Natasha D Durham

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Aditi Agrawal

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Eric Waltari

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    Eric Waltari, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
  4. Derek Croote

    Department of Bioengineering, Stanford University, Stanford, United States
    Competing interests
    Derek Croote, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4907-1865
  5. Fabio Zanini

    Department of Bioengineering, Stanford University, Stanford, United States
    Competing interests
    Fabio Zanini, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7097-8539
  6. Mallorie Fouch

    Integral Molecular, Inc, Philadelphia, United States
    Competing interests
    No competing interests declared.
  7. Edgar Davidson

    Integral Molecular, Inc, Philadelphia, United States
    Competing interests
    No competing interests declared.
  8. Olivia Smith

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Esteban Carabajal

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  10. John E Pak

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  11. Benjamin J Doranz

    Integral Molecular, Inc, Philadelphia, United States
    Competing interests
    No competing interests declared.
  12. Makeda Robinson

    Department of Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  13. Ana M Sanz

    Clinical Research Center, Fundación Valle del Lili, Cali, Colombia
    Competing interests
    No competing interests declared.
  14. Ludwig L Albornoz

    Pathology and Laboratory Department, Fundación Valle del Lili, Cali, Colombia
    Competing interests
    No competing interests declared.
  15. Fernando Rosso

    Clinical Research Center, Fundación Valle del Lili, Cali, Colombia
    Competing interests
    No competing interests declared.
  16. Shirit Einav

    Department of Medicine, Stanford University, Stanford, United States
    Competing interests
    Shirit Einav, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6441-4171
  17. Stephen R Quake

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    Stephen R Quake, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1613-0809
  18. Krista M McCutcheon

    Infectious Disease Initiative, Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    Krista M McCutcheon, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
  19. Leslie Goo

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    lgoo@fredhutch.org
    Competing interests
    Leslie Goo, Inventor of the following patent application, which is co-owned by the Chan Zuckerberg Biohub and Stanford University: PCT patent application entitled ANTIBODIES AGAINST DENGUE VIRUS AND RELATED METHODS, Serial no. PCT/US2019/045427, filed August 7, 2019.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3866-6735

Funding

Chan Zuckerberg Biohub

  • Natasha D Durham
  • Aditi Agrawal
  • Eric Waltari
  • Fabio Zanini
  • Olivia Smith
  • Esteban Carabajal
  • John E Pak
  • Stephen R Quake
  • Krista M McCutcheon
  • Leslie Goo

Fred Hutchinson Cancer Research Center

  • Leslie Goo

National Institutes of Health (HHSN272201400058C)

  • Benjamin J Doranz

NSF Graduate Research Fellowship

  • Derek Croote

Kou-I Yeh Stanford Graduate Fellowship

  • Derek Croote

Catalyst Award from Dr Ralph and Marian Falk Medical Research Trust

  • Shirit Einav

Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program

  • Shirit Einav

Stanford Advanced Residency Training at Stanford Fellowship Program

  • Makeda Robinson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by the Stanford University Administrative Panel on Human Subjects in Medical Research (Protocol #35460) and the Fundación Valle del Lili Ethics committee in biomedical research (Cali, Colombia). All subjects, their parents, or legal guardians provided written informed consent, and subjects between 6 to 17 years of age and older provided assent.

Reviewing Editor

  1. Sara L Sawyer, University of Colorado Boulder, United States

Publication history

  1. Received: October 3, 2019
  2. Accepted: December 9, 2019
  3. Accepted Manuscript published: December 10, 2019 (version 1)
  4. Version of Record published: December 23, 2019 (version 2)

Copyright

© 2019, Durham et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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