Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes

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  • Gallichotte, Emily N.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Baric, Thomas J.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Yount, Jr., Boyd L.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Widman, Douglas G.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Durbin, Anna
    • Other Affiliation: Johns Hopkins Bloomberg School of Public Health
  • Whitehead, Steve
    • Other Affiliation: National Institutes of Health
  • Baric, Ralph S.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • de Silva, Aravinda M.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Dengue virus (DENV) infection causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome. It is estimated that a third of the world’s population is at risk for infection, with an estimated 390 million infections annually. Dengue virus serotype 2 (DENV2) causes severe epidemics, and the leading tetravalent dengue vaccine has lower efficacy against DENV2 compared to the other 3 serotypes. In natural DENV2 infections, strongly neutralizing type-specific antibodies provide protection against subsequent DENV2 infection. While the epitopes of some human DENV2 type-specific antibodies have been mapped, it is not known if these are representative of the polyclonal antibody response. Using structure-guided immunogen design and reverse genetics, we generated a panel of recombinant viruses containing amino acid alterations and epitope transplants between different serotypes. Using this panel of recombinant viruses in binding, competition, and neutralization assays, we have finely mapped the epitopes of three human DENV2 type-specific monoclonal antibodies, finding shared and distinct epitope regions. Additionally, we used these recombinant viruses and polyclonal sera to dissect the epitope-specific responses following primary DENV2 natural infection and monovalent vaccination. Our results demonstrate that antibodies raised following DENV2 infection or vaccination circulate as separate populations that neutralize by occupying domain III and domain I quaternary epitopes. The fraction of neutralizing antibodies directed to different epitopes differs between individuals. The identification of these epitopes could potentially be harnessed to evaluate epitope-specific antibody responses as correlates of protective immunity, potentially improving vaccine design.
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  • Article
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  • In Copyright
Journal title
  • PLoS Pathogens
Journal volume
  • 14
Journal issue
  • 2
Language
  • English
ISSN
  • 1553-7366

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