Rationally Modified SARS-CoV-2 Spike Protein Impairs ACE2 Binding While Preserving Immunogenicity in Mice

Area of Science:

• Vaccinology
• Molecular Biology
• Immunology

Background:

• COVID-19 vaccines utilize the SARS-CoV-2 spike protein to elicit immune responses.
• The spike protein binds to the ACE2 receptor, a key regulator of physiological processes.
• Spike-ACE2 interactions are hypothesized to contribute to rare vaccine-related adverse effects.

Purpose of the Study:

• To engineer SARS-CoV-2 spike protein mutants with reduced binding affinity to the human ACE2 receptor.
• To evaluate the immunogenicity and protective capacity of these engineered spike mutants.

Main Methods:

• Rational design of spike point mutants to impair ACE2 binding.
• In vitro and in vivo validation of engineered spike mutants.
• Assessment of immunogenicity and protective responses in animal models.

Main Results:

• Engineered spike mutants demonstrated significantly reduced binding to ACE2.
• Mutants retained or exhibited enhanced immunogenic properties compared to wild-type spike.
• Vaccination with engineered mutants generated protective immune responses in animals.

Conclusions:

• A feasible molecular strategy for designing vaccines with limited antigen-host receptor interactions was established.
• This approach maintains immunogenicity while potentially mitigating off-target physiological effects.
• The strategy offers a promising avenue for future vaccine development to enhance safety profiles.