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Nat Commun ; 12(1): 1715, 2021 03 17.
Article in English | MEDLINE | ID: covidwho-1139739


The coronavirus spike glycoprotein, located on the virion surface, is the key mediator of cell entry and the focus for development of protective antibodies and vaccines. Structural studies show exposed sites on the spike trimer that might be targeted by antibodies with cross-species specificity. Here we isolated two human monoclonal antibodies from immunized humanized mice that display a remarkable cross-reactivity against distinct spike proteins of betacoronaviruses including SARS-CoV, SARS-CoV-2, MERS-CoV and the endemic human coronavirus HCoV-OC43. Both cross-reactive antibodies target the stem helix in the spike S2 fusion subunit which, in the prefusion conformation of trimeric spike, forms a surface exposed membrane-proximal helical bundle. Both antibodies block MERS-CoV infection in cells and provide protection to mice from lethal MERS-CoV challenge in prophylactic and/or therapeutic models. Our work highlights an immunogenic and vulnerable site on the betacoronavirus spike protein enabling elicitation of antibodies with unusual binding breadth.

Antibodies, Monoclonal, Humanized/immunology , Betacoronavirus/immunology , Epitopes/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/immunology , Betacoronavirus/classification , Camelus , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cross Reactions , Epitopes/chemistry , Epitopes/genetics , Humans , Mice , Protein Conformation , Protein Subunits , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
Emerg Microbes Infect ; 9(1): 1080-1091, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-429885


Middle East respiratory syndrome coronavirus (MERS-CoV) is a WHO priority pathogen for which vaccines are urgently needed. Using an immune-focusing approach, we created self-assembling particles multivalently displaying critical regions of the MERS-CoV spike protein ─fusion peptide, heptad repeat 2, and receptor binding domain (RBD) ─ and tested their immunogenicity and protective capacity in rabbits. Using a "plug-and-display" SpyTag/SpyCatcher system, we coupled RBD to lumazine synthase (LS) particles producing multimeric RBD-presenting particles (RBD-LS). RBD-LS vaccination induced antibody responses of high magnitude and quality (avidity, MERS-CoV neutralizing capacity, and mucosal immunity) with cross-clade neutralization. The antibody responses were associated with blocking viral replication and upper and lower respiratory tract protection against MERS-CoV infection in rabbits. This arrayed multivalent presentation of the viral RBD using the antigen-SpyTag/LS-SpyCatcher is a promising MERS-CoV vaccine candidate and this platform may be applied for the rapid development of vaccines against other emerging viruses such as SARS-CoV-2.

Antibody Formation , Antigen Presentation , Coronavirus Infections/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Affinity , Binding Sites , Coronavirus Infections/prevention & control , Enzyme-Linked Immunosorbent Assay , Female , Genetic Vectors , HEK293 Cells , Humans , Immunogenicity, Vaccine , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , Neutralization Tests , Protein Binding , Protein Domains , Rabbits , Spike Glycoprotein, Coronavirus/biosynthesis , Virus Replication
Emerg Infect Dis ; 26(5): 1024-1027, 2020 May.
Article in English | MEDLINE | ID: covidwho-5763


We developed and validated 2 species-independent protein-based assays to detect Middle East respiratory syndrome coronavirus functional antibodies that can block virus receptor-binding or sialic acid-attachment. Antibody levels measured in both assays correlated strongly with virus-neutralizing antibody titers, proving their use for serologic confirmatory diagnosis of Middle East respiratory syndrome.

Antibodies, Viral/blood , Coronavirus Infections/diagnosis , Enzyme-Linked Immunosorbent Assay/methods , Immunoassay/methods , Middle East Respiratory Syndrome Coronavirus/immunology , Serologic Tests/methods , Antibodies, Neutralizing/blood , Coronavirus Infections/blood , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Species Specificity