Zika virus-specific IgM elicited during pregnancy exhibits ultrapotent neutralization

Singh, T.; Hwang, K.-K.; Miller, A. S.; Jones, R. L.; Lopez, C. A.; Giuberti, C.; Gladden, M. A.; Miller, I.; Webster, H. S.; Eudailey, J. A.; Luo, K.; Von Holle, T.; Edwards, R. J.; Valencia, S.; Burgomaster, K. E.; Zhang, S.; Mangold, J. F.; Tu, J. J.; Dennis, M.; Alam, S. M.; Premkumar, L.; Dietze, R.; Pierson, T. C.; Ooi, E. E.; Lazear, H. M.; Kuhn, R. J.; Permar, S. R.; Bonsignori, M.

doi:10.1101/2021.11.23.469700

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bioRxiv · 10.1101/2021.11.23.469700

Zika virus-specific IgM elicited during pregnancy exhibits ultrapotent neutralization

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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

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Singh, T., Hwang, K.-K., Miller, A. S., Jones, R. L., Lopez, C. A., Giuberti, C., Gladden, M. A., Miller, I., Webster, H. S., Eudailey, J. A., Luo, K., Von Holle, T., Edwards, R. J., Valencia, S., Burgomaster, K. E., Zhang, S., Mangold, J. F., Tu, J. J., Dennis, M., Alam, S. M., Premkumar, L., Dietze, R., Pierson, T. C., Ooi, E. E., Lazear, H. M., Kuhn, R. J., Permar, S. R., Bonsignori, M.. 2021-11-23. Zika virus-specific IgM elicited during pregnancy exhibits ultrapotent neutralization. https://doi.org/10.1101/2021.11.23.469700

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