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Stabilized coronavirus spike stem elicits a broadly protective antibody

ABSTRACT: Current coronavirus (CoV) vaccines primarily target immunodominant epitopes in the S1 subunit, which are poorly conserved and susceptible to escape mutations, thus threatening vaccine efficacy. Here, we use structure-guided protein engineering to remove the S1 subunit from the Middle East respiratory syndrome (MERS)-CoV spike (S) glycoprotein and develop stabilized stem (SS) antigens. Vaccination with MERS SS elicits cross-reactive β-CoV antibody responses and protects mice against lethal MERS-CoV challenge. High-throughput screening of antibody-secreting cells from MERS SS-immunized mice led to the discovery of a panel of cross-reactive monoclonal antibodies. Among them, antibody IgG22 binds with high affinity to both MERS-CoV and severe acute respiratory syndrome (SARS)-CoV-2 S proteins, and a combination of electron microscopy and crystal structures localizes the epitope to a conserved coiled-coil region in the S2 subunit. Passive transfer of IgG22 protects mice against both MERS-CoV and SARS-CoV-2 challenge. Collectively, these results provide a proof of principle for cross-reactive CoV antibodies and inform the development of pan-CoV vaccines and therapeutic antibodies. Graphical abstract Hsieh et al. generate MERS-CoV spike stabilized stem (SS) antigens using a structure-guided approach. Mice immunized with MERS SS are protected against MERS-CoV challenge and used for isolation of cross-reactive monoclonal antibodies, including IgG22, which protects mice against MERS-CoV and SARS-CoV-2 challenges. Structures of Fab22-spike complexes reveal a conserved epitope.

SUBMITTER: Hsieh C

PROVIDER: S-EPMC8519809 | biostudies-literature |

REPOSITORIES: biostudies-literature

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