Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation
- PMID: 29396163
- PMCID: PMC6005179
- DOI: 10.1016/j.immuni.2018.01.005
Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation
Abstract
Respiratory syncytial virus (RSV) is a leading cause of infant mortality, and there are currently no licensed vaccines to protect this vulnerable population. A comprehensive understanding of infant antibody responses to natural RSV infection would facilitate vaccine development. Here, we isolated more than 450 RSV fusion glycoprotein (F)-specific antibodies from 7 RSV-infected infants and found that half of the antibodies recognized only two antigenic sites. Antibodies targeting both sites showed convergent sequence features, and structural studies revealed the molecular basis for their recognition of RSV F. A subset of antibodies targeting one of these sites displayed potent neutralizing activity despite lacking somatic mutations, and similar antibodies were detected in RSV-naive B cell repertoires, suggesting that expansion of these B cells in infants may be possible with suitably designed vaccine antigens. Collectively, our results provide fundamental insights into infant antibody responses and a framework for the rational design of age-specific RSV vaccines.
Keywords: IGHV3-11:IGLV1-40; IGHV3-21:IGLV1-40; crystal structures; germline; naive B cells; pneumoviridae.
Copyright © 2018 Elsevier Inc. All rights reserved.
Conflict of interest statement
L.M.W. is an inventor on pending patent applications describing the RSV antibodies (“Anti-respiratory syncytial virus antibodies, and methods of their generation and use,” USSN 62/411,500, USSN 62/411,508, and USSN 62/411,510). M.C., J.S.M., and B.S.G. are inventors on a patent entitled “Prefusion RSV F proteins and their use,” (US patent No. 9,738,689). L.M.W., A.S., and E.G. have an equity position in Adimab LLC.
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Comment in
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Infants Harness the Germline against RSV.Immunity. 2018 Feb 20;48(2):190-192. doi: 10.1016/j.immuni.2018.02.005. Immunity. 2018. PMID: 29466748
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References
-
- Adams PD, Grosse-Kunstleve RW, Hung LW, Ioerger TR, McCoy AJ, Moriarty NW, Read RJ, Sacchettini JC, Sauter NK, Terwilliger TC. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr D Biol Crystallogr. 2002;58:1948–1954. - PubMed
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