@article{ac8fafe913ec4d01b7c1c2fd011d0e9a,
title = "A Zika virus-specific IgM elicited in 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 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.",
keywords = "cross-linking, IgM, immunotherapy, isotype, multivalent binding, neutralization, pregnancy, therapeutic antibodies, Zika",
author = "Tulika Singh and Hwang, {Kwan Ki} and Miller, {Andrew S.} and Jones, {Rebecca L.} and Lopez, {Cesar A.} and Dulson, {Sarah J.} and Camila Giuberti and Gladden, {Morgan A.} and Itzayana Miller and Webster, {Helen S.} and Eudailey, {Joshua A.} and Kan Luo and {Von Holle}, Tarra and Edwards, {Robert J.} and Sarah Valencia and Burgomaster, {Katherine E.} and Summer Zhang and Mangold, {Jesse F.} and Tu, {Joshua J.} and Maria Dennis and Alam, {S. Munir} and Lakshmanane Premkumar and Reynaldo Dietze and Pierson, {Theodore C.} and Ooi, {Eng Eong} and Lazear, {Helen M.} and Kuhn, {Richard J.} and Permar, {Sallie R.} and Mattia Bonsignori",
note = "Funding Information: This work was supported by a Duke Global Health Institute Award to S.R.P., a Duke Incubation Fund Award to M.B. and by the Division of Intramural Research , NIAID, NIH (M.B.); by NIH grants R21-AI132677 (S.R.P.), R21-AI144631 (H.M.L.), F31-AI143237 (C.A.L.), K12-GM000678 (S.J.D.) and R01-AI073755 (R.J.K., PI: M.S. Diamond), by NIH/NIAID contract HHSN272201700060C (R.J.K; PI: K. Satchell), by the Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Esp{\'i}rito Santo (306/2016 to R.D.; Protocol Financial Support Number: 74910132/16), and by the Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior, Brazil (C.G.). Part of this work was done while M.B. and S.R.P were employed by the Duke Human Vaccine Institute (DHVI). We thank Drs. Aravinda de Silva (UNC Chapel Hill) and James Crowe (Vanderbilt University) for sharing reagents; Dr. M. Anthony Moody (DHVI), the DHVI Research Flow Cytometry Facility, and Brian Watts of the DHVI BIA Core Facility for helpful scientific discussions and/or logistical support; Dr. Geeta K. Swamy, Kristin E. Weaver, and Carolyn A. Weinbaum (Duke University) for clinical study and regulatory support; Juliana Carnielli, Solange Alves Vinhas, and Keyla Fonseca for establishing cohort enrollment and sample collections at Federal University of Esp{\'i}rito Santo; the Cassiano Antonio de Moraes Hospital maternity ward staff for supporting the participants{\textquoteright} deliveries and sample collections, and the mothers who participated in this study and made efforts to provide samples for research during pregnancy. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = dec,
day = "8",
doi = "10.1016/j.cell.2022.10.023",
language = "English",
volume = "185",
pages = "4826--4840.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier Science B.V., Amsterdam.",
number = "25",
}
