Abstract
Zika virus (ZIKV) infections have been linked with neurological complications and congenital Zika syndrome. Given the high level of homology between ZIKV and the related flavivirus dengue virus (DENV), we investigated the level of cross-reactivity with ZIKV using a panel of DENV human mAbs. A majority of the mAbs showed binding to ZIKV virions, with several exhibiting neutralizing capacities against ZIKV in vitro. Three of the best ZIKV-neutralizing mAbs were found to recognize diverse epitopes on the envelope (E) glycoprotein: the highly conserved fusion-loop peptide, a conformation-specific epitope on the E monomer, and a quaternary epitope on the virion surface. The most potent ZIKV-neutralizing mAb (SIgN-3C) was assessed in 2 type I interferon receptor–deficient (IFNAR–/–) mouse models of ZIKV infection. Treatment of adult nonpregnant mice with SIgN-3C rescued mice from virus-induced weight loss and mortality. The SIgN-3C variant with Leu-to-Ala mutations in the Fc region (SIgN-3C-LALA) did not induce antibody-dependent enhancement (ADE) in vitro but provided similar levels of protection in vivo. In pregnant ZIKV-infected IFNAR–/– mice, treatment with SIgN-3C or SIgN-3C-LALA significantly reduced viral load in the fetal organs and placenta and abrogated virus-induced fetal growth retardation. Therefore, SIgN-3C-LALA holds promise as a ZIKV prophylactic and therapeutic agent.
Highlights
Zika virus (ZIKV) was first isolated in 1947 [1] and remained relatively neglected by the public health system for more than 50 years until its sudden reemergence in the Micronesian island of Yap in 2007 [2, 3]
Based on the estimated antibody dose required for 50% neutralization (IC50), SIgN-3C demonstrated higher neutralizing activity (IC50 = 0.93 μg/ml) against ZIKV than 1B-H1L1 (IC50 = 19.25 μg/ml) and 2F-H1L3 (IC50 > 30 μg/ml)
These 3 selected mAbs showed binding and neutralizing activity against the Brazilian ZIKV PE243 strain (Supplemental Figure 1). These human mAbs may be binding to different ZIKV epitopes that differ in accessibility or in their roles during infection
Summary
Zika virus (ZIKV) was first isolated in 1947 [1] and remained relatively neglected by the public health system for more than 50 years until its sudden reemergence in the Micronesian island of Yap in 2007 [2, 3]. While the symptoms of ZIKV infection are typically mild, there is strong evidence linking ZIKV with Guillain-Barré syndrome (GBS) and congenital Zika syndrome [10,11,12,13,14,15,16]. It continues to be a public health concern with severe social and economic impact. With no specific and licensed treatment available for ZIKV, there remains an urgent need to develop ZIKV prophylactic and therapeutic agents
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