Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCRconfirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations. (2-4). However, the more recent outbreaks have caused severe neurological complications including GuillainBarré Syndrome in adults and an increase in congenital microcephaly and other adverse birth outcomes in Brazil (5-7). The Pan American Health Organization has reported that as of May 2016, local transmission of ZIKV had spread to over 38 countries or territories in the Americas. In addition, a recent WHO report states that 44 new countries are experiencing their first ZIKV outbreak since 2015. Despite the improving surveillance of the virus, accurate diagnosis has been challenging given the similarities in the clinical presentation of ZIKV to other arboviral infections endemic in these regions, among other factors.During the viremic period, ZIKV can be found in patient blood, saliva, urine, and other bodily fluids early after symptom onset (8-10). During the Yap Islands epidemic in 2007, anti-ZIKV IgM ELISAs and ZIKV plaque reduction neutralization titer (PRNT) assays were performed to confirm infection in RT-PCR negative cases (2, 8). However, as these studies showed, the cross-reactivity between ZIKV and other flaviviruses makes confirmation of infection difficult, especially when patients may have had flavivirus exposures before their suspected ZIKV infection (2,8). Given the overlapping presence of DENV and other flaviviruses in a majority of ZIKV epidemic regions (11), there are great challenges in serology-based testing of flavivirus-immune patients (12).The DENV envelope (E) protein, considered a major imun...

Vulnerability of primitive human placental trophoblast to Zika virus

“…One factor that may have affected the data from Rio de Janeiro is that almost 90% of those women were serologically positive for Dengue (DENV), presumably due to past infections with one or more of the known DENV strains (DENV1-4). Sero-crossreactivity between DENV1-4 and ZIKV (18,19) may allow the latter to be piggybacked across the protective STB layer of the mature villous placenta. Such transcytosis of maternal IgG appears to be initiated around the beginning of the second trimester and continues to term (20).…”

Recent advances in human flavivirus vaccines

“…Preclinical studies have demonstrated a protective role of CD8 T cells and antibodies against ZIKV infection, the latter being sufficient for complete protection [67][68][69][70]. However, cocirculation of DENV, WNV and ZIKV has been reported in several countries and previous studies suggested an immunological cross-reactivity between viruses, which may drive immune-mediated enhancement [71][72][73]. This hypothesis was recently confirmed in mice demonstrating that DENV or WNV specific antibodies are cross-reactive to ZIKV and enhance disease severity in whole organisms [74].…”

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination?

“…Several reports have now explored this possibility 21,22,35,36 , showing that serum from dengue immune donors strongly binds to ZIKV by ELISA. While most of these sera are non-neutralizing of ZIKV some anti-dengue serum samples showed quite respectable neutralization of ZIKV (FRNT50 <1in200) 21,35 . However, although most anti-DENV serum samples fail to neutralize ZIKV they potently promote ADE of ZIKV in vitro.…”

“…Analysis of panels of monoclonal antibodies made from DENV or ZIKV infected donors have now been reported 12,18,22,35,37,38,39,40 . These mAb show substantial crossreaction between DENV and ZIKV suggesting that ZIKV could be considered as a fifth member of the DENV serocomplex.…”