Longitudinal antibody profiling after dengue reveals distinct dynamics by antibody specificity over 18 months

The four dengue virus serotypes (DENV1-4) co-circulate worldwide, posing major challenges for vaccine development. One key issue is that certain levels and subsets of cross-reactive antibodies have been associated with enhanced disease during subsequent infection with a different DENV serotype. To understand the heterogeneity of DENV antibody responses and delineate their distinct kinetics, we define the magnitude and kinetics of 84 antiviral antibody subsets (by isotype, subclass, antigen, and cross-reactivity) after primary versus secondary dengue, using longitudinal samples collected <1, 3, 6 and 18 months post-symptom onset from a pediatric hospital study in Nicaragua. Interestingly, we find that after primary infection, cross-reactive IgG antibody responses against the envelope protein rise, not wane, over time. Antibody kinetics vary by specificity as measured by homologous versus cross-reactive subsets, viral antigen, and subdomain of a single antigen. Further, a substantial fraction of subjects still have IgA, IgM, and IgG3 responses above the assay background at 18 months post-infection. Overall, we find that the cross-reactive subset of post-primary anti-DENV antibody responses demonstrates distinct kinetics from overall DENV-binding antibodies as well as from secondary immune responses, which has implications for the outcome of subsequent DENV infections.