Cross-reactive dengue human monoclonal antibody prevents severe pathologies and death from Zika virus infections
Yiu-Wing Kam, … , Lisa F.P. Ng, Laurent Rénia
Yiu-Wing Kam, … , Lisa F.P. Ng, Laurent Rénia
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e92428. https://doi.org/10.1172/jci.insight.92428.
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Research Article Infectious disease

Cross-reactive dengue human monoclonal antibody prevents severe pathologies and death from Zika virus infections

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.

Authors

Yiu-Wing Kam, Cheryl Yi-Pin Lee, Teck-Hui Teo, Shanshan W. Howland, Siti Naqiah Amrun, Fok-Moon Lum, Peter See, Nicholas Qing-Rong Kng, Roland G. Huber, Mei-Hui Xu, Heng-Liang Tan, Andre Choo, Sebastian Maurer-Stroh, Florent Ginhoux, Katja Fink, Cheng-I Wang, Lisa F.P. Ng, Laurent Rénia

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Figure 4

SIgN-3C and SIgN-3C-LALA treatments prevent ZIKV-induced congenital developmental deficiency in IFNAR–/– mice.

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SIgN-3C and SIgN-3C-LALA treatments prevent ZIKV-induced congenital deve...
(A) Representative images and (B) weight of fetuses isolated from mock-infected type I interferon receptor–deficient (IFNAR–/–) mice, Zika virus–infected (ZIKV-infected) isotype control, and ZIKV-infected mice with SIgN-3C or SIgN-3C-LALA treatments (all groups n ≥ 7). Each data point in dot plots was obtained from 1 fetus. Weights of fetuses are expressed relative to the mean of fetal weights from mock-infected IFNAR–/– mice. Viral load in the (C) amniotic fluid and (D) organs of fetuses from ZIKV-infected IFNAR–/– pregnant mice receiving isotype, SIgN-3C, and SIgN-3C-LALA antibodies (all groups n ≥ 7). Each data point in dot plots was obtained from 1 fetus. Mice were inoculated with 107 PFU ZIKV i.v. on E10.5 and treatments were given on days 0, 1, and 3 after infection. Mice were given 0.5 mg of isotype or treatment antibody per dose. All animals were harvested at E16.5. All data were analyzed using the Kruskal-Wallis test with Dunn’s multiple comparison. *P < 0.05, ***P < 0.001.