Structural Basis for Germline Antibody Binding to Zika Virus Envelope Domain III

Abstract

Infection with Zika virus (ZIKV), a flavivirus transmitted by mosquitoes, is usually asymptomatic or mild. However, newborns of infected mothers can display severe neurodevelopmental abnormalities and microcephaly. Given the recent epidemics, severity of symptoms, and lack of available treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. Vaccine design is complicated by concern that elicited antibodies may cross-react with other flaviviruses, such as dengue, West Nile, and yellow fever virus, which share a similar envelope protein. This cross-reactivity may cause antibody-dependent enhancement (ADE) of a subsequent infection and therefore worsen symptoms. To better understand the neutralizing antibody response and risk of ADE, further information on germline antibody binding to ZIKV and the affinity maturation process that gives rise to potently neutralizing antibodies is needed. Here, we compared mature and inferred-germline antibody binding to envelope protein domain III (EDIII) of ZIKV and other flaviviruses through binding assays, structural characterization, and neutralization and ADE studies. We showed that affinity maturation of the light chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing antibodies to ZIKV EDIII and identified interacting residues that contribute to weak, cross-reactive binding to other flaviviruses. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing antibodies, informing precautions for protein-based vaccines.

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