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

Emily N. Gallichotte, Thomas J. Baric, Boyd L. Yount, Douglas G. Widman, Anna P Durbin, Steve Whitehead, Ralph S. Baric, Aravinda M. de Silva

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1006934
JournalPLoS Pathogens
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2018

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Dengue Virus
Neutralizing Antibodies
Epitopes
Severe Dengue
Infection
Antibody Formation
Vaccination
Dengue Vaccines
Serogroup
Viruses
Virus Attachment
Reverse Genetics
Dengue
Antibodies
Virus Diseases
Immunity
Vaccines
Monoclonal Antibodies
Transplants
Amino Acids

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Gallichotte, E. N., Baric, T. J., Yount, B. L., Widman, D. G., Durbin, A. P., Whitehead, S., ... de Silva, A. M. (2018). Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. PLoS Pathogens, 14(2), [e1006934]. https://doi.org/10.1371/journal.ppat.1006934

Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. / Gallichotte, Emily N.; Baric, Thomas J.; Yount, Boyd L.; Widman, Douglas G.; Durbin, Anna P; Whitehead, Steve; Baric, Ralph S.; de Silva, Aravinda M.

In: PLoS Pathogens, Vol. 14, No. 2, e1006934, 01.02.2018.

Research output: Contribution to journalArticle

Gallichotte, EN, Baric, TJ, Yount, BL, Widman, DG, Durbin, AP, Whitehead, S, Baric, RS & de Silva, AM 2018, 'Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes', PLoS Pathogens, vol. 14, no. 2, e1006934. https://doi.org/10.1371/journal.ppat.1006934
Gallichotte, Emily N. ; Baric, Thomas J. ; Yount, Boyd L. ; Widman, Douglas G. ; Durbin, Anna P ; Whitehead, Steve ; Baric, Ralph S. ; de Silva, Aravinda M. / Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. In: PLoS Pathogens. 2018 ; Vol. 14, No. 2.
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