A Novel Antigenic Site Spanning Domains I and III of the Zika Virus Envelope Glycoprotein Is the Target of Strongly Neutralizing Human Monoclonal Antibodies

Abstract

Zika virus (ZIKV), a mosquito-transmitted flavivirus, caused a large epidemic in Latin America between 2015 and 2017. Effective ZIKV vaccines and treatments are urgently needed to prevent future epidemics and severe disease sequelae. People infected with ZIKV develop strongly neutralizing antibodies linked to viral clearance and durable protective immunity. To understand the mechanisms of protective immunity and to support the development of ZIKV vaccines, we characterize here a strongly neutralizing antibody, B11F, isolated from a patient who recovered from ZIKV. Our results indicate that B11F targets a complex epitope on the virus that spans domains I and III of the envelope glycoprotein. While previous studies point to quaternary epitopes centered on domain II of the ZIKV E glycoprotein as targets of strongly neutralizing and protective human antibodies, we uncover a new site spanning domains I and III as a target of strongly neutralizing human antibodies. IMPORTANCE People infected with Zika virus develop durable neutralizing antibodies that prevent repeat infections. In the current study, we characterize a ZIKV-neutralizing human monoclonal antibody isolated from a patient after recovery. Our studies establish a novel site on the viral envelope that is targeted by human neutralizing antibodies. Our results are relevant to understanding how antibodies block infection and to guiding the design and evaluation of candidate vaccines.

Somatic Hypermutation and Framework Mutations of Variable Region Contribute to Anti-Zika Virus-Specific Monoclonal Antibody Binding and Function

“…Further studies will be required to determine the structure of MAb 289-3 complexed with ZIKV E protein. Three ZIKV-specific human MAbs have recently been described that also span an epitope in domains I and III ( 44 , 50 ). Alanine-scanning mutagenesis identified the critical residues recognized by two of these MAbs, B11F and A9E, as mapping within domain I alone.…”

“…Alanine-scanning mutagenesis identified the critical residues recognized by two of these MAbs, B11F and A9E, as mapping within domain I alone. Two critical domain I residues of MAb 289-3, E162 and G182, are described as escape mutation sites for MAb A9E ( 50 , 56 ). We also note that the critical residues K301 (domain III) and G182 (domain I) were also identified by shotgun mutagenesis analysis as critical for binding by the third MAb, protective anti-ZIKV MAb MZ4, which binds a site centered on the E protein domain I/III linker region ( 44 ).…”

“…Potently neutralizing ZIKV-specific human MAbs have been described that map to the domain III lateral ridge ( 43 , 45 – 47 ), domain II ( 47 , 48 ), or to complex epitopes spanning multiple domains ( 49 , 50 ), while fusion loop-specific MAbs are more likely to be cross-reactive with DENV ( 42 ). Three of the rabbit MAbs described here map to the domain III lateral ridge, a region that is also targeted by several mouse and human MAbs that have demonstrated ZIKV-neutralizing activity and protective immunity in mouse models, suggesting that this is an immunodominant region for ZIKV-specific neutralizing antibodies in multiple species ( 45 , 47 , 48 , 51 ).…”

Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes

“… 2 , 4 , 8 – 14 ZIKV co-circulates with dengue virus (DENV) in similar geographic locations, while most ZIKV infections that are detected in the United States occur in flavivirus-naive travelers returning from ZIKV-endemic areas. 15 , 16 The ZIKV and DENV envelope (E) glycoproteins elicit immunologic cross-reactivity due to genetic and structural similarity. 17 ZIKV vaccination strategies must avoid antibody-dependent enhancement (ADE) of DENV infection.…”