https://www.nature.com/articles/s41586-021-04005-0?error=cookies_not_supported&code=fea21ae7-088a-4c14-ae48-45adad4ef0e9 Skip to main content Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Advertisement Advertisement Nature * View all journals * Search * My Account Login * Explore content * About the journal * Publish with us * Sign up for alerts * RSS feed 1. nature 2. articles 3. article High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape Download PDF * Article * Published: 20 September 2021 This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape * Fabian Schmidt^1^ na1, * Yiska Weisblum^1^ na1, * Magdalena Rutkowska^3, * Daniel Poston ORCID: orcid.org/0000-0001-9900-6717^1, * Justin Da Silva ORCID: orcid.org/0000-0001-6393-0000^1, * Fengwen Zhang^1, * Eva Bednarski^1, * Alice Cho^2, * Dennis J. Schaefer-Babajew ORCID: orcid.org/0000-0002-5380-2950^ 2, * Christian Gaebler ORCID: orcid.org/0000-0001-7295-8128^2, * Marina Caskey ORCID: orcid.org/0000-0003-1727-8693^2, * Michel C. Nussenzweig ORCID: orcid.org/0000-0003-0592-8564^2,3, * Theodora Hatziioannou ORCID: orcid.org/0000-0002-7889-0766^1 & * Paul D. Bieniasz ORCID: orcid.org/0000-0002-2368-3719^1,3 Nature (2021)Cite this article * 145 Altmetric * Metrics details Subjects * Immune evasion * SARS-CoV-2 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 the genetic barrier to viral escape^1-4. Using HIV-1 pseudotypes and plasma-selection experiments with vesicular stomatitis virus/ SARS-CoV-2 chimeras^5, we show that multiple neutralizing epitopes, within and outside the receptor binding domain (RBD), 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 (VOC). By aggregating VOC-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by convalescents or mRNA vaccine recipients. Strikingly, 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. Download PDF Author information Author notes 1. These authors contributed equally: Fabian Schmidt, Yiska Weisblum Affiliations 1. Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA Fabian Schmidt, Yiska Weisblum, Daniel Poston, Justin Da Silva, Fengwen Zhang, Eva Bednarski, Theodora Hatziioannou & Paul D. Bieniasz 2. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA Alice Cho, Dennis J. Schaefer-Babajew, Christian Gaebler, Marina Caskey & Michel C. Nussenzweig 3. Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA Magdalena Rutkowska, Michel C. Nussenzweig & Paul D. Bieniasz Authors 1. Fabian Schmidt View author publications You can also search for this author in PubMed Google Scholar 2. Yiska Weisblum View author publications You can also search for this author in PubMed Google Scholar 3. Magdalena Rutkowska View author publications You can also search for this author in PubMed Google Scholar 4. Daniel Poston View author publications You can also search for this author in PubMed Google Scholar 5. Justin Da Silva View author publications You can also search for this author in PubMed Google Scholar 6. Fengwen Zhang View author publications You can also search for this author in PubMed Google Scholar 7. Eva Bednarski View author publications You can also search for this author in PubMed Google Scholar 8. Alice Cho View author publications You can also search for this author in PubMed Google Scholar 9. Dennis J. Schaefer-Babajew View author publications You can also search for this author in PubMed Google Scholar 10. Christian Gaebler View author publications You can also search for this author in PubMed Google Scholar 11. Marina Caskey View author publications You can also search for this author in PubMed Google Scholar 12. Michel C. Nussenzweig View author publications You can also search for this author in PubMed Google Scholar 13. Theodora Hatziioannou View author publications You can also search for this author in PubMed Google Scholar 14. Paul D. Bieniasz View author publications You can also search for this author in PubMed Google Scholar Corresponding authors Correspondence to Theodora Hatziioannou or Paul D. Bieniasz. Supplementary information Supplementary Table 1 TSubstitutions enriched in rVSV/SARS-CoV-2 following selection in neutralizing plasma. Tabulated SARS-CoV-2 spike substitutions and their frequencies in rVSV/SARS-CoV-2 following passage in each of the RU27 plasma samples. Reporting Summary Rights and permissions Reprints and Permissions About this article Verify currency and authenticity via CrossMark Cite this article Schmidt, F., Weisblum, Y., Rutkowska, M. et al. High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape. Nature (2021). https://doi.org/10.1038/s41586-021-04005-0 Download citation * Received: 01 July 2021 * Accepted: 07 September 2021 * Published: 20 September 2021 * DOI: https://doi.org/10.1038/s41586-021-04005-0 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative Comments By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. 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