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Molecular Determinants of Human Neutralizing Antibodies Isolated from a Zika Patient

Dec 16, 2016     Email"> PrintText Size

Zika virus (ZIKV) is a flavivirus that is currently causing global concern. Accumulating evidence suggests that infection is associated with microcephaly in newborns and neurological complications, such as Guillain-Barré syndrome, in adults, and there is currently no approved countermeasures against ZIKV infections. Parallel studies published by Dr. Michael Diamond from Washington University School of Medicine and Chinese Academy of Sciences showed that infection with ZIKV in mice results in acute and chronic testicular damage in these animals and eventually leads to infertility. These studies support sexual transmission of ZIKV, a previously-unknown aspect to flavivirus infections.

Research groups of Prof. YAN Jinghua from the Key Laboratory of Microbial Physiological and Metabolic Engineering and George Fu Gao from Key Laboratory of Pathogenic Microbiology and Immunology at the Institute of Microbiology of Chinese Academy of Sciences (IMCAS) described the isolation of Zika-specific human neutralizing antibodies with high potency from a convalescent Zika patient and characterization of these antibodies through in vitro neutralization assays, mechanism of binding through structural studies, and in vivo protection in a mouse model. Their study was published in Science Translational Medicine and demonstrated that the therapeutic potential of monoclonal antibodies against Zika fever and provide a structure-based rationale for the design of future specific antivirals.

The ZIKV envelope protein is known to facilitate virus entry and contains important epitopes for virus neutralization. In this study, researchers used a panel of memory B cell markers as well as soluble envelope (sE) to stain peripheral blood mononuclear cells isolated from a convalescent Zika patient. After cell sorting, 33 sE-specific memory B cells were obtained and 15 B cell receptors (BCRs) sequences were determined by RT-PCR. Through ELISA and SPR assay, 13 antibodies were confirmed to bind sE at variable affinities, targeting at least five different epitopes by competition test with Octet. Amongst these antibodies, three (Z20, Z23 and Z3L1) exerted potent neutralization activities against ZIKV. 

Additionally, Z23 and Z3L1 showed no cross-binding or cross-neutralization to dengue virus 1-4, the closest phylogenetic relative to ZIKV. Both Z23 and Z3L1 conferred complete post-exposure protection in vivo against ZIKV infection in mice, whereas Z20 conferred partial protection. Structural studies revealed that Z20, Z23 and Z3L1 bound to tertiary epitopes on domains I, II and/or III of the envelope protein, and inhibit virus entry through different mechanisms.

Outbreaks of infectious disease in recent years (MERS-CoV in 2012, H7N9 influenza virus in 2013, Ebola virus in 2014-16 and now Zika virus) have highlighted the shortage of therapeutics at hand to fight these infections. In addition to basic scientific interest, researchers have developed a platform that can isolate strongly neutralizing, specific monoclonal antibodies against any pathogen from the sera of convalescent patients within one month, providing a powerful tool to control and limit the number of infections from future outbreaks.

This study was supported by the State Key Research Development Program of China and the Zika Special Project of the Ministry of Science and Technology Reform and Development Project. WANG Qihui is supported by the Young Elite Scientist Sponsorship Program by China Association for Science and Technology. George Fu Gao is a leading principal investigator of the National Science Foundation of China (NSFC) Innovative Research Group. 

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(Editor: LIU Jia)

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YAN Jinghua

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