Summary
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 points
Plasma IgM contributes to early ZIKV neutralization during pregnancy
Ultrapotent neutralization by pentameric DH1017.IgM mAb depends on isotype
DH1017.IgM can engage all binding sites concurrently through different angles of approach
DH1017.IgM protects mice against lethal ZIKV challenge
Competing Interest Statement
M.B., S.R.P., T.S. and K.K.H. have filed a patent application directed to antibodies that are related to this work. S.R.P. is serving as a consultant for vaccine programs at Merck, Pfizer, Moderna, Dynavax and Hoopika. All other authors declare no conflict of interest.