Cross-Reactivity of Non-Neutralizing Antibodies to Dengue and Zika Viruses: Implications for Vaccination

Dengue is the leading vector-borne viral disease of humans and poses a major international public health concern in tropical and subtropical regions in which it is endemic. Cross-reactivity among the different serotypes of dengue virus promotes antibody-dependent enhancement of secondary infection, an immunopathological response that is thought to amplify viral replication and thereby to increase disease severity. The previously relatively neglected fellow flavivirus Zika has now emerged strikingly in countries where dengue virus is endemic, notably across Latin America. Recent reports suggest that anti-dengue virus antibody can potentiate Zika virus replication. Conversely, it appears that anti-Zika virus antibody may exacerbate dengue infection. Such pre-existing immunity against one flavivirus may not only confuse the diagnosis of disease produced by infection with a heterologous flavivirus, but conceivably affect the clinical outcome. The existence of non-neutralizing antibodies to a prior dengue or Zika infection can result in worse disease manifestations upon infection with a secondary, heterologous flavivirus. This has important implications for the administration of vaccines currently in development, immunization with which will promote the generation of homotypic flavivirus antibodies but that may have an unintended adverse effect of raising susceptibility to heterologous infection of either dengue or Zika.