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Self-assembling nanoparticles presenting receptor binding domain and stabilized spike as next-generation COVID-19 vaccines

Linling He, Xiaohe Lin, Ying Wang, Ciril Abraham, Cindy Sou, Timothy Ngo, Yi Zhang, Ian A. Wilson, Jiang Zhu
doi: https://doi.org/10.1101/2020.09.14.296715
Linling He
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA
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Xiaohe Lin
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA
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Ying Wang
4Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania 19140, USA.
5Department of Microbiology and Immunology, Temple University, Philadelphia, Pennsylvania 19140, USA.
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Ciril Abraham
4Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania 19140, USA.
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Cindy Sou
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA
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Timothy Ngo
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA
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Yi Zhang
4Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania 19140, USA.
5Department of Microbiology and Immunology, Temple University, Philadelphia, Pennsylvania 19140, USA.
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Ian A. Wilson
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA
3Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
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Jiang Zhu
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA
2Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California 92037, USA
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  • For correspondence: jiang@scripps.edu
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ABSTRACT

We present a comprehensive vaccine strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by combining antigen optimization and nanoparticle display. We first developed a receptor binding domain (RBD)-specific antibody column for purification and displayed the RBD on self-assembling protein nanoparticles (SApNPs) using the SpyTag/SpyCatcher system. We then identified the heptad repeat 2 (HR2) stalk as a major cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on three SApNPs with high yield, purity, and antigenicity. Compared to the RBD, the RBD-ferritin SApNP elicited a more potent murine neutralizing antibody (NAb) response on par with the spike. S2GΔHR2 elicited two-fold-higher NAb titers than the proline-capped spike (S2P), while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T-cell immunity, thereby providing a next-generation vaccine candidate to battle the COVID-19 pandemic.

ONE-SENTENCE SUMMARY The receptor binding domain and stabilized SARS-CoV-2 spike were displayed on nanoparticles as vaccine antigens and elicited potent immune responses.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 14, 2020.
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Self-assembling nanoparticles presenting receptor binding domain and stabilized spike as next-generation COVID-19 vaccines
Linling He, Xiaohe Lin, Ying Wang, Ciril Abraham, Cindy Sou, Timothy Ngo, Yi Zhang, Ian A. Wilson, Jiang Zhu
bioRxiv 2020.09.14.296715; doi: https://doi.org/10.1101/2020.09.14.296715
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Self-assembling nanoparticles presenting receptor binding domain and stabilized spike as next-generation COVID-19 vaccines
Linling He, Xiaohe Lin, Ying Wang, Ciril Abraham, Cindy Sou, Timothy Ngo, Yi Zhang, Ian A. Wilson, Jiang Zhu
bioRxiv 2020.09.14.296715; doi: https://doi.org/10.1101/2020.09.14.296715

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