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A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus

View ORCID ProfileJennifer A. Jenks, Sharmi Amin, View ORCID ProfileAmit Kumar, View ORCID ProfileMadeline R. Sponholtz, View ORCID ProfileDaniel Wrapp, View ORCID ProfileSravani Venkatayogi, View ORCID ProfileJoshua Tu, View ORCID ProfileJason S. McLellan, View ORCID ProfileKevin Wiehe, View ORCID ProfileSallie R. Permar
doi: https://doi.org/10.1101/2022.01.19.476974
Jennifer A. Jenks
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
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Sharmi Amin
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
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Amit Kumar
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
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Madeline R. Sponholtz
2Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA 78712.
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Daniel Wrapp
2Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA 78712.
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Sravani Venkatayogi
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
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Joshua Tu
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
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Jason S. McLellan
2Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA 78712.
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Kevin Wiehe
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
3Department of Medicine, Duke University School of Medicine, Durham, NC 27710.
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Sallie R. Permar
1Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.
4Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065.
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  • For correspondence: sallie.permar@med.cornell.edu
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Abstract

Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but vaccine candidates have faced challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Remarkably, we found that the single amino acid heavy chain mutation A33N, an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution and a foundation for designing next-generation CMV vaccines.

One-sentence summary This manuscript identifies an early B cell lineage mutation that confers neutralizing function to antibodies targeting CMV fusogen gB.

Competing Interest Statement

J.A.J. has been a paid invited speaker by Moderna x Popsugar. S.R.P. serves as a consultant for Moderna, Merck, Dynavax, Pfizer, and Hookipa CMV vaccine programs and has a sponsored research program on CMV vaccine immunogenicity with Moderna and Merck.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 21, 2022.
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A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus
Jennifer A. Jenks, Sharmi Amin, Amit Kumar, Madeline R. Sponholtz, Daniel Wrapp, Sravani Venkatayogi, Joshua Tu, Jason S. McLellan, Kevin Wiehe, Sallie R. Permar
bioRxiv 2022.01.19.476974; doi: https://doi.org/10.1101/2022.01.19.476974
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A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus
Jennifer A. Jenks, Sharmi Amin, Amit Kumar, Madeline R. Sponholtz, Daniel Wrapp, Sravani Venkatayogi, Joshua Tu, Jason S. McLellan, Kevin Wiehe, Sallie R. Permar
bioRxiv 2022.01.19.476974; doi: https://doi.org/10.1101/2022.01.19.476974

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