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.

The authors have declared no competing interest.

This work was supported by grants U19AI118610 (EH, Ana Fernandez-Sesma) and P01AI106695 (EH) from the National Institute for Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH). T.S. was supported by the HHMI Hanna H. Gray Fellowship (Grant ID: GT16780). The PHDS was supported by NIAID/NIH grants R01AI099631 (AB) and U54 AI065359 (AB; Program Director Alan Barbour).

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