A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization

• Published in: Cell Vol. 185; no. 25; pp. 4826 - 4840.e17
• Main Authors: Singh, Tulika, Hwang, Kwan-Ki, Miller, Andrew S., Jones, Rebecca L., Lopez, Cesar A., Dulson, Sarah J., Giuberti, Camila, Gladden, Morgan A., Miller, Itzayana, Webster, Helen S., Eudailey, Joshua A., Luo, Kan, Von Holle, Tarra, Edwards, Robert J., Valencia, Sarah, Burgomaster, Katherine E., Zhang, Summer, Mangold, Jesse F., Tu, Joshua J., Dennis, Maria, Alam, S. Munir, Premkumar, Lakshmanane, Dietze, Reynaldo, Pierson, Theodore C., Ooi, Eng Eong, Lazear, Helen M., Kuhn, Richard J., Permar, Sallie R., Bonsignori, Mattia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.12.2022
• Subjects: Animals; Antibodies, Neutralizing; Antibodies, Viral; cross-linking; Epitopes; Female; IgM; Immunoglobulin M - immunology; Immunoglobulin M - isolation & purification; immunotherapy; isotype; Mice; multivalent binding; neutralization; Neutralization Tests; pregnancy; Pregnancy - immunology; therapeutic antibodies; Zika; Zika Virus; Zika Virus Infection - immunology; multivalent binding; isotype; cross-linking; neutralization; pregnancy; immunotherapy; therapeutic antibodies; IgM; Zika
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.10.023

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 contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy. [Display omitted] •Plasma IgM contributes to early ZIKV neutralization during pregnancy•Ultrapotent neutralization by pentameric DH1017.IgM mAb depends on its isotype•DH1017.IgM can engage the ZIKV virion with multiple binding sites concurrently•DH1017.IgM protects mice more efficiently from ZIKV viremia than DH1017.IgG Singh et al. demonstrate that plasma IgM contributes to early Zika virus neutralization during pregnancy and isolate a pentameric IgM from a Zika virus-infected pregnant woman whose child was born without evidence of congenital Zika syndrome. This IgM’s ultrapotent neutralization in vitro and efficient protection from virus challenge in mice depends on its isotype, which enables modes of antigen recognition not available to IgG.