The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by...

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant vaccines exhibit low immunogenicity.
• Omicron's spike protein contains sequences that hinder immune responses, particularly macrophage interactions.

Purpose of the Study:

• To identify mutations that enhance the immunogenicity of Omicron-specific vaccines.
• To investigate the mechanism by which Omicron's spike protein evades immune detection.
• To develop an improved bivalent nanoparticle vaccine.

Main Methods:

• Utilized reverse mutagenesis to alter the Omicron spike protein sequence.
• Analyzed the effect of mutations on macrophage uptake and phagocytosis of viral particles.
• Assessed the immunogenicity and neutralizing antibody (nAb) response of a novel bivalent vaccine in animal models.

Main Results:

• A phenylalanine-to-serine mutation at position 375 (F375S) in the Omicron spike protein reverted it to ancestral sequences, significantly enhancing vaccine immunogenicity.
• The Omicron spike sequence FAPFFAF (positions 371-377) inhibits macrophage uptake and antigen presentation via Siglec-9 binding, which is abrogated by the F375S mutation.
• A bivalent vaccine containing F375S Omicron RBD and Delta-RBD nanoparticles elicited potent and broad neutralizing antibodies in mice, rabbits, and rhesus macaques.

Conclusions:

• The F375S mutation is a key factor in enhancing Omicron vaccine immunogenicity.
• Targeting the Siglec-9 pathway by modifying spike protein sequences offers a promising strategy for improving vaccine efficacy against SARS-CoV-2.
• The developed bivalent nanoparticle vaccine demonstrates potential for broad protection against SARS-CoV-2 variants.