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Neutralization of Zika virus by germline-like human monoclonal antibodies targeting cryptic epitopes on envelope domain III.

Abstract

The Zika virus (ZIKV), a flavivirus transmitted by Aedes mosquitoes, has emerged as a global public health concern. Pre-existing cross-reactive antibodies against other flaviviruses could modulate immune responses to ZIKV infection by antibody-dependent enhancement, highlighting the importance of understanding the immunogenicity of the ZIKV envelope protein. In this study, we identified a panel of human monoclonal antibodies (mAbs) that target domain III (DIII) of the ZIKV envelope protein from a very large phage-display naive antibody library. These germline-like antibodies, sharing 98%-100% hoLogy with their corresponding germline IGHV genes, bound ZIKV DIII specifically with high affinities. One mAb, m301, broadly neutralized the currently circulating ZIKV strains and showed a synergistic effect with another mAb, m302, in neutralizing ZIKV in vitro and in a mouse model of ZIKV infection. Interestingly, epitope mapping and competitive binding studies suggest that m301 and m302 bind adjacent regions of the DIII C-C' loop, which represents a recently identified cryptic epitope that is intermittently exposed in an uncharacterized virus conformation. This study extended our understanding of antigenic epitopes of ZIKV antibodies and has direct implications for the design of ZIKV vaccines.

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    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

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    Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

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    Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.

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    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

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    Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

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    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

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    Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

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    Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

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    Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.

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    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

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    Biomissile Corporation, Shanghai 201203, China.

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    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

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    Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

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    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.

    Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

    Source

    Emerging microbes & infections 6:10 2017 Oct 11 pg e89

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29018252