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High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

Fabian Schmidt, Yiska Weisblum, Magdalena Rutkowska, Daniel Poston, Justin Da Silva, Fengwen Zhang, Eva Bednarski, Alice Cho, Dennis J. Schaefer-Babajew, Christian Gaebler, Marina Caskey, Michel C. Nussenzweig, Theodora Hatziioannou, Paul D. Bieniasz
doi: https://doi.org/10.1101/2021.08.06.455491
Fabian Schmidt
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Yiska Weisblum
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Magdalena Rutkowska
3Howard Hughes Medical Institute
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Daniel Poston
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Justin Da Silva
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Fengwen Zhang
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Eva Bednarski
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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Alice Cho
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
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Dennis J. Schaefer-Babajew
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
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Christian Gaebler
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
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Marina Caskey
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
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Michel C. Nussenzweig
2Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
3Howard Hughes Medical Institute
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Theodora Hatziioannou
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
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  • For correspondence: thatziio@rockefeller.edu pbieniasz@rockefeller.edu
Paul D. Bieniasz
1Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
3Howard Hughes Medical Institute
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  • For correspondence: thatziio@rockefeller.edu pbieniasz@rockefeller.edu
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Abstract

The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in SARS-CoV-2 convalescent and vaccinated individuals are key determinants of neutralization breadth and, consequently, the genetic barrier to viral escape. Using chimeric viruses and antibody-selected viral mutants, we show that multiple neutralizing epitopes, within and outside the viral receptor binding domain (RBD), are variably targeted by polyclonal plasma antibodies and coincide with sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic ‘polymutant’ spike proteins that resisted polyclonal antibody neutralization to a similar degree as currently circulating variants of concern (VOC). Importantly, by aggregating VOC-associated and plasma-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient to confer near-complete resistance to the polyclonal neutralizing antibodies generated by convalescents and mRNA vaccine recipients. Strikingly however, plasma from individuals who had been infected and subsequently received mRNA vaccination, neutralized this highly resistant SARS-CoV-2 polymutant, and also neutralized diverse sarbecoviruses. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation and may confer protection against future sarbecovirus pandemics.

Competing Interest Statement

PDB has received consulting fees from Pfizer Inc relating to mRNA vaccines

Copyright 
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 August 08, 2021.
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High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies
Fabian Schmidt, Yiska Weisblum, Magdalena Rutkowska, Daniel Poston, Justin Da Silva, Fengwen Zhang, Eva Bednarski, Alice Cho, Dennis J. Schaefer-Babajew, Christian Gaebler, Marina Caskey, Michel C. Nussenzweig, Theodora Hatziioannou, Paul D. Bieniasz
bioRxiv 2021.08.06.455491; doi: https://doi.org/10.1101/2021.08.06.455491
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High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies
Fabian Schmidt, Yiska Weisblum, Magdalena Rutkowska, Daniel Poston, Justin Da Silva, Fengwen Zhang, Eva Bednarski, Alice Cho, Dennis J. Schaefer-Babajew, Christian Gaebler, Marina Caskey, Michel C. Nussenzweig, Theodora Hatziioannou, Paul D. Bieniasz
bioRxiv 2021.08.06.455491; doi: https://doi.org/10.1101/2021.08.06.455491

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