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

Tulika Singh, Kwan Ki Hwang, Andrew S. Miller, Rebecca L. Jones, Cesar A. Lopez, Sarah J. Dulson, Camila Giuberti, Morgan A. Gladden, Itzayana Miller, Helen S. Webster, Joshua A. Eudailey, Kan Luo, Tarra Von Holle, Robert J. Edwards, Sarah Valencia, Katherine E. Burgomaster, Summer Zhang, Jesse F. Mangold, Joshua J. Tu, Maria DennisS. Munir Alam, Lakshmanane Premkumar, Reynaldo Dietze, Theodore C. Pierson, Eng Eong Ooi, Helen M. Lazear, Richard J. Kuhn, Sallie R. Permar, Mattia Bonsignori

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)4826-4840.e17
JournalCell
Volume185
Issue number25
DOIs
Publication statusPublished - 8 Dec 2022

Keywords

  • cross-linking
  • IgM
  • immunotherapy
  • isotype
  • multivalent binding
  • neutralization
  • pregnancy
  • therapeutic antibodies
  • Zika

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