Convalescent patient-derived monoclonal antibodies targeting different epitopes of E protein confer protection against Zika virus in a neonatal mouse model

Jia Luo,Qihong Yan,Ling Chen,Fuchun Zhang,Hui Lei,Liqiang Feng,Shengnan Zhang,Long-Chuan Yu ,Edgar Davidson,Zhipeng Yao,Xinglong Liu,Xuefeng Niu,Changhua Yi,Yang Wang,Wei Xü ,Xiaoyan Zhang,Renshan Liang,Peihai Chen,Fan Zhang,Liang Zhao ,Lorraine Bryan ,Huibin Lv,j. Benjamin Doranz,Linbing Qu,Pingchao Li,Weiqi Pan,Qian Wang

doi:10.1080/22221751.2019.1614885

Abstract

ABSTRACT The Zika virus (ZIKV) outbreak and its link to microcephaly triggered a public health concern. To examine antibody response in a patient infected with ZIKV, we used single-cell PCR to clone 31 heavy and light chain-paired monoclonal antibodies (mAbs) that bind to ZIKV envelope (E) proteins isolated from memory B cells of a ZIKV-infected patient. Three mAbs (7B3, 1C11, and 6A6) that showed the most potent and broad neutralization activities against the African, Asian, and American strains were selected for further analysis. mAb 7B3 showed an IC50 value of 11.6 ng/mL against the circulating American strain GZ02. Epitope mapping revealed that mAbs 7B3 and 1C11 targeted residue K394 of the lateral ridge (LR) epitope of the EDIII domain, but 7B3 has a broader LR epitope footprint and recognizes residues T335, G337, E370, and N371 as well. mAb 6A6 recognized residues D67, K118, and K251 of the EDII domain. Interestingly, although the patient was seronegative for DENV infection, mAb 1C11, originating from the VH3-23 and VK1-5 germline pair, neutralized both ZIKV and DENV1. Administration of the mAbs 7B3, 1C11, and 6A6 protected neonatal SCID mice infected with a lethal dose of ZIKV. This study provides potential therapeutic antibody candidates and insights into the antibody response after ZIKV infection.

Highlights

Zika virus (ZIKV) is a member of the Flaviviridae family which includes dengue virus (DENV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV) [1,2]
To clone E-targeted monoclonal antibodies (mAbs) from a ZIKV-infected patient, we used recombinant ZIKV E protein as a probe to isolate E-specific memory B cells from a Chinese patient that had returned from Venezuela and was identified as infected with ZIKV during border entry
We tested the neutralizing activities of these three mAbs against two other ZIKV isolates, MR766 [5] and PRVABC59

Summary

Introduction

Zika virus (ZIKV) is a member of the Flaviviridae family which includes dengue virus (DENV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV) [1,2]. ZIKV is mainly transmitted by Aedes mosquitoes but can spread through sexual contact, blood transfusions, or via mother-to-child transmission during pregnancy [3,4]. ZIKV was first discovered in Africa in 1947 [5] and was confined within the equatorial zone of Africa and Asia until the 2007 outbreak in Yap Island, which was transmitted to French Polynesia and other Southern Pacific islands in 2013 [1,6]. It is believed that the adaptation and infectivity of ZIKV in mosquito-vectors contributed to the spread of the virus from Asia to the Americas [7]. It is known that ZIKV can cross the placental barrier, leading to fetal microcephaly, and can cause neurological complications in adults, such as Guillain-Barré syndrome [10,11,12]. There are no approved drugs or vaccines to mitigate the risk of ZIKV infection

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Results

Conclusion