The human B cell response to infection with dengue virus serotype 2 broadly engages the plasmablast repertoire and maintains a high degree of type-specificity in memory.

Abstract

Abstract The complexity of the serological response to the four serotypes of the dengue virus (DENV1-4) is a key factor confounding rational vaccine development for dengue. To refine our understanding of the basis of the humoral response to DENV, we used high-coverage approaches to unravel the early and late B cell response at the clonal level to a single controlled infection with DENV2 in humans. In peripheral blood specimens we identified the peak DENV2-induced early plasmablast response. By analyzing paired immunoglobulin heavy (IGH) and light (IGL) chains derived from peak plasmablasts we found broad evidence of lineage expansion, somatic hypermutation, and variable gene usage. We selected 92 IGH/IGL pairs from expanded lineages and found that 54 (59%) of these monoclonal antibodies (mAb) bound DENV2, five of which also neutralized virus. In these same subjects we assessed the memory B cell (MBC) repertoire at six months post infection by screening IgG from MBCs immortalized by genetic reprogramming to a germinal center-like state. Compared to the early plasmablast response, we found a drastic reduction in the DENV-specific population in the memory phase of the B cell response. There was a unexpectedly high degree of DENV2 type-specificity in the convalescent MBC pool, though heterotypic clones were also observed. MBC-derived mAbs mainly reacted to epitopes present on whole virions. Our results suggest that controlled DENV2 infection elicits a broad and complex early B cell response to DENV that contracts to yield a DENV-specific MBC compartment. These results provide insights into the basis for long-term serotype-specific humoral immunity and provide additional metrics by which to assess DENV vaccines.