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      A single immunization with spike-functionalized ferritin vaccines elicits neutralizing antibody responses against SARS-CoV-2 in mice

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          Abstract

          Development of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.

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          UCSF Chimera--a visualization system for exploratory research and analysis.

          Eric F. Pettersen, Thomas Goddard, Conrad Huang … (2004)
          The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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            Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

            Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett … (2020)
            Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260
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              Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

              Alexandra C Walls, Young-Jun Park, M. Alejandra Tortorici … (2020)
              Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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                Author and article information

                Journal
                Journal ID (nlm-ta): bioRxiv
                Journal ID (publisher-id): BIORXIV
                Title: bioRxiv
                Publisher: Cold Spring Harbor Laboratory
                Publication date (Electronic): 28 August 2020
                Electronic Location Identifier: 2020.08.28.272518
                Affiliations
                [1 ]Department of Biochemistry & Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA
                [2 ]Department of Bioengineering & James H. Clark Center, Stanford University, Stanford, CA 94305, USA
                [3 ]Department of Chemistry, Stanford University, Stanford, CA 94305, USA
                [4 ]Department of Pathology, Stanford University, Stanford, CA 94305, USA
                [5 ]Stanford Blood Center, Palo Alto, CA 94304, USA
                [6 ]Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
                [7 ]Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA
                Author notes

                Author contributions

                AEP, PAW, ST, MS, and PSK designed experiments. AEP and ST purified antigens for immunization. MS performed mouse work. PAW performed protein quantitation experiments and analysis. AEP performed antigen characterization, serum ELISAs and neutralizations, and data analysis. KZ performed cryo-EM sample preparation, data collection, and image processing. SL assisted with image processing. KZ, SL, and WC analyzed the cryo-EM data. TDP collected convalescent plasma samples. JEP assisted with protein characterization methods and optimization. AEP and PSK wrote the manuscript. All authors assisted with editing and approved the final version of the manuscript.

                [* ]Corresponding author: kimpeter@ 123456stanford.edu
                Article
                DOI: 10.1101/2020.08.28.272518
                PMC ID: 7457616
                PubMed ID: 32869030
                SO-VID: 07f47a9e-7820-42e7-8855-88a91b742e09
                License:

                It is made available under a CC-BY 4.0 International license.

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                Subject: Article

                Keywords: sars-cov-2,spike,ferritin nanoparticle,subunit vaccine
                Data availability:
                Keywords: sars-cov-2, spike, ferritin nanoparticle, subunit vaccine

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