Engineered Immunogens to Elicit Antibodies Against Conserved Coronavirus Epitopes

Area of Science:

• Virology
• Immunology
• Vaccine Development

Background:

• The receptor binding domain (RBD) of SARS-CoV-2 spike protein is immunodominant but mutates, leading to immune escape.
• Conserved regions in the spike S2 subunit, including the stem helix and residues 815-823, are recognized by broadly reactive antibodies.
• Developing vaccines targeting conserved epitopes offers potential protection against current and emergent sarbecoviruses.

Approach:

• Computational modeling was used to design novel scaffolded immunogens displaying conserved spike protein epitopes (815-823 peptide and stem helix).
• These immunogens were engineered to omit the highly mutable RBD to focus immune responses.
• The binding affinity and specificity of engineered proteins to human antibodies were assessed.

Key Points:

• Engineered epitope scaffolds demonstrated high-affinity binding to mature and germline broadly protective human antibodies.
• Scaffolds effectively interacted with sera and monoclonal antibodies from individuals with pre-existing SARS-CoV-2 immunity.
• Immunization with epitope scaffolds elicited sera with broad betacoronavirus reactivity.

Conclusions:

• Scaffolded immunogens targeting conserved spike protein regions can elicit broadly reactive antibodies.
• These immunogens showed protective efficacy in a mouse model, highlighting their potential for a pancoronavirus vaccine.
• The approach offers a promising strategy for developing vaccines against diverse and future coronavirus threats.