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 can enhance disease during subsequent infection with a different DENV serotype. We defined 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 found that post-primary infection, cross-reactive IgG antibodies against the envelope protein rise, not wane, over time. Antibody kinetics varied by specificity as measured by infecting serotype versus cross-reactive subsets, viral antigen, and subdomain of a single antigen. Further, substantial seropositivity of IgA, IgM, and IgG3 at 18 months post-infection was observed. These findings highlight several novel conceptual insights into flavivirus immunity and disease risk and have implications for vaccine design and serodiagnosis.