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

Author

Listed:
  • 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
    The Rockefeller University)

  • Theodora Hatziioannou

    (The Rockefeller University)

  • Paul D. Bieniasz

    (The Rockefeller University
    The Rockefeller University)

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.

Suggested Citation

  • Fabian Schmidt & Yiska Weisblum & Magdalena Rutkowska & Daniel Poston & Justin DaSilva & Fengwen Zhang & Eva Bednarski & Alice Cho & Dennis J. Schaefer-Babajew & Christian Gaebler & Marina Caskey & Mi, 2021. "High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape," Nature, Nature, vol. 600(7889), pages 512-516, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7889:d:10.1038_s41586-021-04005-0
    DOI: 10.1038/s41586-021-04005-0
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    Citations

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    Cited by:

    1. David J. Sullivan & Massimo Franchini & Michael J. Joyner & Arturo Casadevall & Daniele Focosi, 2022. "Analysis of anti-SARS-CoV-2 Omicron-neutralizing antibody titers in different vaccinated and unvaccinated convalescent plasma sources," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Milja Belik & Pinja Jalkanen & Rickard Lundberg & Arttu Reinholm & Larissa Laine & Elina Väisänen & Marika Skön & Paula A. Tähtinen & Lauri Ivaska & Sari H. Pakkanen & Hanni K. Häkkinen & Eeva Ortamo , 2022. "Comparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Kenneth Danh & Donna Grace Karp & Malvika Singhal & Akshaya Tankasala & David Gebhart & Felipe Jesus Cortez & Devangkumar Tandel & Peter V. Robinson & David Seftel & Mars Stone & Graham Simmons & Anil, 2022. "Detection of neutralizing antibodies against multiple SARS-CoV-2 strains in dried blood spots using cell-free PCR," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    4. Leander Witte & Viren A. Baharani & Fabian Schmidt & Zijun Wang & Alice Cho & Raphael Raspe & Camila Guzman-Cardozo & Frauke Muecksch & Marie Canis & Debby J. Park & Christian Gaebler & Marina Caskey , 2023. "Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Dapeng Li & David R. Martinez & Alexandra Schäfer & Haiyan Chen & Maggie Barr & Laura L. Sutherland & Esther Lee & Robert Parks & Dieter Mielke & Whitney Edwards & Amanda Newman & Kevin W. Bock & Mahn, 2022. "Breadth of SARS-CoV-2 neutralization and protection induced by a nanoparticle vaccine," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Noemia S. Lima & Maryam Musayev & Timothy S. Johnston & Danielle A. Wagner & Amy R. Henry & Lingshu Wang & Eun Sung Yang & Yi Zhang & Kevina Birungi & Walker P. Black & Sijy O’Dell & Stephen D. Schmid, 2022. "Primary exposure to SARS-CoV-2 variants elicits convergent epitope specificities, immunoglobulin V gene usage and public B cell clones," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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