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      Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with an endemic human CoV

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          Abstract

          A high-resolution understanding of the antibody response to SARS-CoV-2 is important for the design of effective diagnostics, vaccines and therapeutics. However, SARS-CoV-2 antibody epitopes remain largely uncharacterized, and it is unknown whether and how the response may cross-react with related viruses. Here, we use a multiplexed peptide assay (‘PepSeq’) to generate an epitope-resolved view of reactivity across all human coronaviruses. PepSeq accurately detects SARS-CoV-2 exposure and resolves epitopes across the Spike and Nucleocapsid proteins. Two of these represent recurrent reactivities to conserved, functionally-important sites in the Spike S2 subunit, regions that we show are also targeted for the endemic coronaviruses in pre-pandemic controls. At one of these sites, we demonstrate that the SARS-CoV-2 response strongly and recurrently cross-reacts with the endemic virus hCoV-OC43. Our analyses reveal new diagnostic and therapeutic targets, including a site at which SARS-CoV-2 may recruit common pre-existing antibodies and with the potential for broadly-neutralizing responses.

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Na Zhu, Dingyu Zhang, Wenling Wang … (2020)
          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

            Roujian Lu, Xiang Zhao, Juan Li … (2021)
            Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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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): 27 July 2020
                Electronic Location Identifier: 2020.07.27.222943
                Affiliations
                [1 ]The Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA
                [2 ]The Translational Genomics Research Institute (TGen), Phoenix and Flagstaff, AZ, USA
                [3 ]Walter Reed National Military Medical Center, Bethesda, MD, USA
                [4 ]Vitalant Research Institute, San Francisco, CA, USA
                [5 ]Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, USA
                [6 ]Division of Infectious Diseases, City of Hope National Medical Center, Duarte, CA, USA
                [7 ]Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
                [8 ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
                [9 ]Department of Medical Microbiology, St. Olavs Hospital, Trondheim, Norway
                [10 ]Department of Immunology and Transfusion Medicine, St. Olavs Hospital, Trondheim, Norway
                [11 ]Encodia Inc, San Diego, CA, USA
                Author notes

                Author Contributions

                Categories are as defined by CRediT taxonomy. Authors are listed in the same order as the byline.

                Conceptualization: JTL, JAA; Methodology: JTL, NM, MSC, JAA; Software: JTL, ZWF; Formal Analysis: JTL, JAA; Investigation: SNH, ASB, ALE, FR; Resources: JD, KES, MS, WD, SD, JY, MAC, MB, MHF, SAN, DEK; Data Curation: JTL, ZWK, SAS; Writing - Original Draft: JTL, JAA; Writing - Review & Editing: SNH, ASB, ALE, ZWF, FR, DEK, SAS; Visualization: JTL, SAS, JAA; Supervision: JTL, JAA; Project Administration: JTL, JAA; Funding Acquisition: JTL, JAA.

                Article
                DOI: 10.1101/2020.07.27.222943
                PMC ID: 7386487
                PubMed ID: 32743570
                SO-VID: 3c75c8f7-1998-473d-8223-c1635e8184e1
                License:

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

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