Enhancement of infection by pre-existing non-neutralizing antibodies to cross-reactive flaviviruses: Ramifications for vaccination against Dengue and Zika

Dengue is a prominent mosquito-transmitted viral disease of humans that is a significant public health consideration in tropical and subtropical regions of the world in which it is endemic. Cross-reactivity between different serotypes of dengue virus activates antibody-dependent enhancement of infections, an immunopathological response that it is thought to amplify viral replication and thereby to increase disease severity. The hitherto neglected closely related flavivirus Zika has now emerged strongly in areas where dengue virus is endemic, especially in South and Central America. Recent investigations indicate that anti-dengue virus immunoglobulin G may exacerbate Zika infection in an in vitro model. Conversely, it appears that anti-Zika virus IgG can enhance dengue virus replication in a target cell line. Such pre-existing immunity to one flavivirus may not only obscure the diagnosis of disease caused by infection with a heterologous flavivirus but potentially adversely affect the clinical outcome. The existence of non-neutralizing antibodies to a previous dengue or Zika infection can aggravate disease manifestations of a secondary, heterologous flavivirus infection. This has far-reaching ramifications for delivery of vaccines that are at present in development, immunization with which will stimulate production of homotypic flavivirus antibodies but which may have the inadvertent harmful effect of heightening susceptibility to heterologous infection of either dengue or Zika.