Stabilized coronavirus spike stem elicits a broadly protective antibody

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Current coronavirus (CoV) vaccines focus on the S1 subunit of the spike glycoprotein, which is prone to mutations, limiting vaccine effectiveness.
• The S1 subunit contains immunodominant epitopes that are not well-conserved across different CoV strains, leading to escape mutations and reduced vaccine efficacy.

Purpose of the Study:

• To engineer novel stabilized stem (SS) antigens from the Middle East respiratory syndrome (MERS)-CoV spike (S) glycoprotein by removing the S1 subunit.
• To evaluate the immunogenicity and protective efficacy of MERS SS antigens.
• To discover cross-reactive monoclonal antibodies targeting conserved CoV epitopes.

Main Methods:

• Structure-guided protein engineering was employed to create MERS SS antigens.
• Immunization of mice with MERS SS elicited antibody responses.
• High-throughput screening identified cross-reactive monoclonal antibodies.
• Electron microscopy and crystal structures were used to determine the epitope of a cross-reactive antibody (IgG22).
• Passive transfer studies assessed the protective efficacy of IgG22.

Main Results:

• Vaccination with MERS SS induced cross-reactive antibody responses against beta-coronaviruses (β-CoVs).
• MERS SS vaccination protected mice from lethal MERS-CoV challenge.
• A cross-reactive monoclonal antibody, IgG22, was identified, binding both MERS-CoV and SARS-CoV-2 spike proteins with high affinity.
• The epitope for IgG22 was mapped to a conserved coiled-coil region in the S2 subunit of the spike glycoprotein.
• Passive transfer of IgG22 provided protection against both MERS-CoV and SARS-CoV-2 challenge in mice.

Conclusions:

• The development of stabilized stem (SS) antigens offers a viable strategy for eliciting cross-reactive antibody responses against coronaviruses.
• Targeting conserved epitopes in the S2 subunit of the spike glycoprotein can lead to broadly protective antibodies.
• These findings provide a proof of principle for developing pan-coronavirus vaccines and therapeutic antibodies.