| Samenvatting: | <strong>Background</strong> The four dengue virus serotypes (DENV1-4) and Zika virus (ZIKV) are related mosquito-borne flaviviruses of major importance globally. While monoclonal antibodies and plasma from DENV-immune donors can neutralize or enhance ZIKV in vitro and in small animal models, and vice versa, the extent, duration, and significance of cross-reactivity remains unknown, particularly in flavivirus-endemic regions. <strong>Methods</strong> We studied neutralizing antibodies to ZIKV and DENV1-4 in longitudinal serologic specimens through 3 years post-infection from people in Latin America and Asia with laboratory-confirmed DENV infections. We also evaluated neutralizing antibodies to ZIKV and DENV1-4 in Zika patients through 6 months post-infection. <strong>Results</strong> In Zika patients, the highest neutralizing antibody titers were to ZIKV, with low-level cross-reactivity to DENV1-4 that was greater in DENV-immune individuals. We found in primary and secondary DENV infections, neutralizing antibody titers to ZIKV were markedly lower than to the infecting DENV and heterologous DENV serotypes. Cross-neutralization was greatest in early convalescence, then ZIKV neutralization decreased, remaining at low levels over time. <strong>Conclusions</strong> Patterns of antibody cross-neutralization suggest ZIKV lies outside the DENV serocomplex. Neutralizing antibody titers can distinguish ZIKV from DENV infections when all viruses are analyzed simultaneously. These findings have implications for understanding natural immunity and vaccines.
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