Antibody responses to Zika virus infections in flavivirus-endemic environments

ABSTRACT

Zika virus (ZIKV) infections occur in areas where dengue (DENV), West Nile (WNV), yellow fever (YFV), and other viruses of the genus Flavivirus co-circulate. The envelope protein (E) of these closely related flaviviruses induces specific long-term immunity, yet subsequent infections are associated with cross-reactive antibody responses that may enhance disease susceptibility and severity. To gain a better understanding of ZIKV infections against a background of similar viral diseases, we examined serological immune responses to ZIKV, WNV, DENV and YFV infections of humans and non-human primates (NHP). Using printed microarrays, we detected very specific antibody responses to primary infections with probes of recombinant E proteins from fifteen species and lineages of flaviviruses pathogenic to humans, while high cross-reactivity between ZIKV and DENV was observed with eleven printed native viruses. Notably, antibodies from human primary ZIKV or secondary DENV infections that occurred in flavivirus-endemic areas broadly recognized E proteins from many flaviviruses, especially DENV, indicating a strong influence of infection history on immune responses. A predictive algorithm was used to tentatively identify previous encounters with specific flaviviruses based on serum antibody interactions with the multi-species panel of E proteins. These results illustrate the potential impact of exposures to related viruses on the outcome of ZIKV infection, and offer considerations for development of vaccines and diagnostics.