A Tale of Two Viruses: Does Heterologous Flavivirus Immunity Enhance Zika Disease?

The rise of Zika virus (ZIKV) and its unusual clinical manifestations provided ground for speculative debate. The clinical severity of secondary dengue virus (DENV) infections is associated with antibody-dependent enhancement (ADE), and it was recently suggested that previous exposure to DENV may worsen ZIKV clinical outcomes. In this Opinion article we analyze the relationship among different flaviviruses and ADE. We discuss new evidence obtained in non-human primates and human cohorts demonstrating that there is no correlation to ADE when ZIKV infection occurs in the presence of pre-existing DENV immunity. We propose a redefinition of ADE in the context of complex immunological flavivirus interactions to provide a more objective perspective when translating in vitro or in vivo observations into the clinical setting.