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 3

Treatment with SIgN-3C and its LALA variant prevent ZIKV-induced mortality in IFNAR–/– mice.

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Treatment with SIgN-3C and its LALA variant prevent ZIKV-induced mortali...
(A) Mortality, (B) weight change, and (C) viremia of Zika virus–infected (ZIKV-infected) type I interferon receptor–deficient (IFNAR–/–) mice receiving isotype (n = 10), SIgN-3C (n = 5), and SIgN-3C-LALA (n = 10) antibodies. Mice were inoculated with 104 PFU ZIKV s.c. at the ventral side of the footpad and treatments were given on days 1, 4, and 8 after infection. Mice were treated with 1 mg per dose of SIgN-3C and 0.5 mg per dose of SIgN-3C-LALA. Data shown are representative of 2 independent experiments. (D) Viral load in brain, spleen, liver, kidney, testes, and popliteal lymph node (pLN) of ZIKV-infected IFNAR–/– mice receiving isotype (n = 5), SIgN-3C (n = 5), and SIgN-3C-LALA (n = 4) antibodies at 6 days after infection. The mortality curve was analyzed using a log-rank (Mantel-Cox) test, while weight change, viremia, and viral load were analyzed using the Kruskal-Wallis test with Dunn’s multiple comparison. *P < 0.05; **P < 0.01; ***P < 0.001.