Zika virus-specific IgM elicited during pregnancy exhibits ultrapotent neutralization

Abstract

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM responses contribute to ZIKV immunity in pregnancy, mediating neutralization up to three months post symptoms. From a ZIKV-infected pregnant woman, we established a B cell line secreting a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets a novel envelope dimer epitope within Domain II. The arrangement of this epitope on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not achievable by IgG antibodies. DH1017.IgM protected against lethal ZIKV challenge in mice. Our findings identify a unique role of antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunoprophylactic, particularly during pregnancy. Key pointsO_LIPlasma IgM contributes to early ZIKV neutralization during pregnancy C_LIO_LIUltrapotent neutralization by pentameric DH1017.IgM mAb depends on isotype C_LIO_LIDH1017.IgM can engage all binding sites concurrently through different angles of approach C_LIO_LIDH1017.IgM protects mice against lethal ZIKV challenge C_LI