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.

Longitudinal analysis of the antibody repertoire of a Zika virus-infected patient revealed dynamic changes in antibody response

“…Human antibodies with low SHM rates against ZIKV have been reported previously but lack of further investigation [9,11,12]. One group reported the cloning of a germline-like mAb using a phage display from a naïve human antibody library [37]. Another group reported that a panel of germline-like antibodies was cloned from circulating plasmablasts of a ZIKV-infected patient 12 days after symptom onset [38].…”

Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

“…Similar patterns have been reported in separate antibody studies. For monoclonal antibodies, germline-like human mAbs, m301 and m302, were reported that target ZIKV E DIII cryptic epitopes (C-C’ loop) and neutralize ZIKV potently both in vitro and in vivo [22]. Another human mAb, P1F12, originates from germline gene IGHV3-7 with an identity of 100% and neutralizes ZIKV potently as well [51].…”

Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human

“…Similar patterns have been described in previous studies. For monoclonal antibodies, germline-like human mAbs m301 and m302 were reported that target ZIKV E DIII cryptic epitopes (C-C' loop) and neutralize ZIKV potently both in vitro and in vivo (22). Another human mAb, P1F12, originates from germline gene IGHV3-7 with an identity of 100% and neutralizes ZIKV potently as well (53).…”

“…The surface envelope glycoprotein (E) of flaviviruses mediates entry and presents a potential target for neutralizing antibodies. Large numbers of E-targeting monoclonal antibodies (mAbs) have been identified with potent neutralizing activity and epitope specificity (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Previously, we isolated and characterized a panel of E-targeting mAbs from plasma and memory B cells from sequential blood samples of a DENV-naïve ZIKVinfected convalescent patient (Pt1) who acquired ZIKV infection in Venezuela during the 2016 outbreak and then returned to China (6,24).…”