High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape

Fabian Schmidt, Yiska Weisblum, Magdalena Rutkowska, Daniel Poston, Justin DaSilva, Fengwen Zhang, Eva Bednarski, Alice Cho, Dennis J. Schaefer-Babajew, Christian Gaebler, Marina Caskey, Michel C. Nussenzweig, Theodora Hatziioannou () and Paul D. Bieniasz ()
Additional contact information
Fabian Schmidt: The Rockefeller University
Yiska Weisblum: The Rockefeller University
Magdalena Rutkowska: The Rockefeller University
Daniel Poston: The Rockefeller University
Justin DaSilva: The Rockefeller University
Fengwen Zhang: The Rockefeller University
Eva Bednarski: The Rockefeller University
Alice Cho: The Rockefeller University
Dennis J. Schaefer-Babajew: The Rockefeller University
Christian Gaebler: The Rockefeller University
Marina Caskey: The Rockefeller University
Michel C. Nussenzweig: The Rockefeller University
Theodora Hatziioannou: The Rockefeller University
Paul D. Bieniasz: The Rockefeller University

Nature, 2021, vol. 600, issue 7889, 512-516

Abstract: Abstract The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in individuals who are SARS-CoV-2 convalescent and vaccinated are key determinants of neutralization breadth and the genetic barrier to viral escape1–4. Using HIV-1 pseudotypes and plasma selection experiments with vesicular stomatitis virus/SARS-CoV-2 chimaeras5, here we show that multiple neutralizing epitopes, within and outside the receptor-binding domain, are variably targeted by human polyclonal antibodies. Antibody targets coincide with spike sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic ‘polymutant’ spike protein pseudotypes that resisted polyclonal antibody neutralization to a similar degree as circulating variants of concern. By aggregating variant of concern-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in the SARS-CoV-2 spike protein are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by individuals who are convalescent or recipients who received an mRNA vaccine. However, plasma from individuals who had been infected and subsequently received mRNA vaccination neutralized pseudotypes bearing this highly resistant SARS-CoV-2 polymutant spike, or diverse sarbecovirus spike proteins. 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 potential future sarbecovirus pandemics.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (7)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-04005-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:600:y:2021:i:7889:d:10.1038_s41586-021-04005-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-04005-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().