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Background: Zika virus has recently spread to South- and Central America, causing congenital birth defects and neurological complications. Many people at risk are flavivirus pre-immune due to prior infections with other flaviviruses (e.g. dengue virus) or flavivirus vaccinations. Since pre-existing cross-reactive immunity can potentially modulate antibody responses to Zika virus infection and may affect the outcome of disease, we analyzed fine-specificity as well as virus-neutralizing and infection-enhancing activities of antibodies induced by a primary Zika virus infection in flavivirus-naïve as well as yellow fever- and/or tick-borne encephalitis-vaccinated individuals. Methodology: Antibodies in sera from convalescent Zika patients with and without vaccine-induced immunity were assessed by ELISA with respect to Zika virus-specificity and flavivirus cross-reactivity. Functional analyses included virus neutralization and infection-enhancement. The contribution of IgM and cross-reactive antibodies to these properties was determined by depletion experiments. Principal findings: Pre-existing flavivirus immunity had a strong influence on the antibody response in primary Zika virus infections, resulting in higher titers of broadly flavivirus cross-reactive antibodies and slightly lower levels of Zika virus-specific IgM. Antibody-dependent enhancement (ADE) of Zika virus was mediated by sub-neutralizing concentrations of specific IgG but not by cross-reactive antibodies. This effect was potently counteracted by the presence of neutralizing IgM. Broadly cross-reactive antibodies were able to both neutralize and enhance infection of dengue virus but not Zika virus, indicating a different exposure of conserved sequence elements in the two viruses. Conclusions: Our data point to an important role of flavivirus-specific IgM during the transient early stages of infection, by contributing substantially to neutralization and by counteracting ADE. In addition, our results highlight structural differences between strains of Zika and dengue viruses that are used for analyzing infection-enhancement by cross-reactive antibodies. These findings underscore the possible impact of specific antibody patterns on flavivirus disease and vaccination efficacy. Author summary: The explosive spread of Zika virus, a flavivirus, to South- and Central America underscores the potential threat of newly emerging arthropod-borne viruses. Zika virus infection can cause congenital birth defects and neurological complications. Many people at risk are flavivirus pre-immune because of prior infections with other flaviviruses (e.g. dengue virus, which co-circulates in Zika outbreak regions) or vaccinations (e.g. against yellow fever or tick-borne encephalitis) and have non-protective cross-reactive antibodies at the time of infection. Since pre-existing immunity can modulate the specificity and functional activity of antibody responses, and cross-reactive antibodies have been implicated in disease enhancement, we compared the specificities of serum samples from flavivirus-naïve and vaccinated individuals after primary Zika virus infections. Prior immunity led to a strong booster of cross-reactive antibodies that did not neutralize Zika virus. Importantly, we could also show that newly formed IgM antibodies contributed significantly to virus neutralization and prevented infection enhancement by other antibodies. Our data thus show how pre-existing cross-reactive immunities can alter the specificities and functional activities of antibody responses in flavivirus infections, which may affect flavivirus-induced disease and the efficacy of vaccinations. [ABSTRACT FROM AUTHOR]