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. doi:10.1172/jci.insight.92428.
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Categories: 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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Modified SIgN-3C antibody (SIgN-3C-LALA) abrogated ADE in in vitro ZIKV ...

Figure 2

Modified SIgN-3C antibody (SIgN-3C-LALA) abrogated ADE in in vitro ZIKV infection.

(A) Antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection. ZIKV was preincubated with serial dilutions of 1B-H1L1, 2F-H1L3, SIgN-3C, and SIgN-3C-LALA (0.03 ng/ml to 30 μg/ml) before infecting K562 cells at MOI of 10. Noninfected cells and virus infection in the absence of mAb (control infection, gray dotted line) were used as controls. Results are presented as mean ± SEM of virus titer fold increase with the presence of different concentrations of mAbs, relative to control infection. Results are presented as average of 2 independent experiments. (B) Binding curves of SIgN-3C and SIgN03C-LALA mAbs by ZIKV virion ELISA. OD values were normalized to the result at 3 μg/ml. (C) SIgN-3C-LALA antibody preserves good neutralizing activity against ZIKV. Data are presented as mean ± SEM of 4 independent experiments, normalized to virus-only control. Nonlinear regression fitting was used to determine the IC50 values.