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

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. © 2017 public library of science. all rights reserved.