Stabilized coronavirus spike stem elicits a broadly protective antibody

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 b-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 devel

Automated summary

This study developed stabilized stem (SS) antigens by removing the S1 subunit from the Middle East respiratory syndrome (MERS)-CoV spike (S) glycoprotein using structure-guided protein engineering. Vaccination with MERS SS elicited cross-reactive b-CoV antibody responses and protected mice against lethal MERS-CoV challenge. The discovery of a panel of cross-reactive monoclonal antibodies, among which IgG22 showed high affinity binding to both MERS-CoV and severe acute respiratory syndrome (SARS)-CoV-2 S proteins, indicates the potential for cross-reactive CoV antibodies.