Dengue virus antibody database: Systematically linking serotype-specificity with epitope mapping in dengue virus

PLoS Negl Trop Dis. 2017 Feb 21;11(2):e0005395. doi: 10.1371/journal.pntd.0005395. eCollection 2017 Feb.

Abstract

Background: A majority infections caused by dengue virus (DENV) are asymptomatic, but a higher incidence of severe illness, such as dengue hemorrhagic fever, is associated with secondary infections, suggesting that pre-existing immunity plays a central role in dengue pathogenesis. Primary infections are typically associated with a largely serotype-specific antibody response, while secondary infections show a shift to a broadly cross-reactive antibody response.

Methods/principal findings: We hypothesized that the basis for the shift in serotype-specificity between primary and secondary infections can be found in a change in the antibody fine-specificity. To investigate the link between epitope- and serotype-specificity, we assembled the Dengue Virus Antibody Database, an online repository containing over 400 DENV-specific mAbs, each annotated with information on 1) its origin, including the immunogen, host immune history, and selection methods, 2) binding/neutralization data against all four DENV serotypes, and 3) epitope mapping at the domain or residue level to the DENV E protein. We combined epitope mapping and activity information to determine a residue-level index of epitope propensity and cross-reactivity and generated detailed composite epitope maps of primary and secondary antibody responses. We found differing patterns of epitope-specificity between primary and secondary infections, where secondary responses target a distinct subset of epitopes found in the primary response. We found that secondary infections were marked with an enhanced response to cross-reactive epitopes, such as the fusion-loop and E-dimer region, as well as increased cross-reactivity in what are typically more serotype-specific epitope regions, such as the domain I-II interface and domain III.

Conclusions/significance: Our results support the theory that pre-existing cross-reactive memory B cells form the basis for the secondary antibody response, resulting in a broadening of the response in terms of cross-reactivity, and a focusing of the response to a subset of epitopes, including some, such as the fusion-loop region, that are implicated in poor neutralization and antibody-dependent enhancement of infection.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology*
  • B-Lymphocytes / immunology
  • Cross Reactions*
  • Databases, Factual
  • Dengue Virus / classification
  • Dengue Virus / immunology*
  • Epitope Mapping*
  • Immunologic Memory
  • Protein Binding
  • Serogroup

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral

Grant support

The authors were supported by the U.S. Army Medical Research and Materiel Command (Ft. Detrick, MD) and the Military Infectious Disease Research Program (Grant# Z0010-TC-OC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.