Broadly neutralizing antibodies against Zika virus from dengue patients with prior exposure to Japanese encephalitis virus

Abstract

Exposure to multiple mosquito-borne flaviviruses within a lifetime is not uncommon; however, how sequential exposures to different flaviviruses shape the cross-reactive (CR) humoral response against an antigen from a different serocomplex has yet to be explored. Here, we report that dengue-infected individuals initially primed with the Japanese encephalitis virus (JEV) showed broadly highly neutralizing potencies against the Zika virus (ZIKV). We also identified a rare class of ZIKV CR human monoclonal antibodies (huMAbs) with increased somatic hypermutation and broad neutralization against multiple flaviviruses. One huMAb, K8b, binds quaternary epitopes with heavy and light chains separately interacting with overlapping E dimer units spanning domains I, II, and III through cryo-electron microscopy and structure-based mutagenesis. Using JEV virus-like particle (VLP) immunization in mice further confirmed that such CR antibodies, mainly IgG3 isotype, can be induced and proliferate through heterologous DENV-2 VLP stimulation. Our findings provide novel insights for future vaccination strategies.