Rapid Identification of Neutralizing Antibodies against SARS-CoV-2 Variants by mRNA Display

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Emerging SARS-CoV-2 variants possess mutations enabling immune evasion, necessitating novel therapeutic strategies.
• Existing humoral immunity from infection or vaccination is challenged by these variants, highlighting the need for broadly-reactive neutralizing antibodies (nAbs).

Approach:

• Employed mRNA display technology to identify a diverse panel of antibodies targeting the SARS-CoV-2 spike (S) protein.
• Conducted structural characterization of identified nAbs to elucidate their binding mechanisms and epitope recognition sites within the S1 subunit.

Key Points:

• Structural analyses revealed distinct antibody binding modes, including targeting of cryptic epitopes within the S protein's receptor-binding domain (RBD) and S1 subdomain 1.
• A potent ACE2-blocking nAb was engineered for enhanced binding to the S RBD, retaining efficacy against key mutations (E484K, L452R) present in SARS-CoV-2 variants.
• Demonstrated the capability of mRNA display for rapid discovery of nAbs with potential for combination therapy against diverse viral strains.

Conclusions:

• mRNA display is a powerful platform for identifying broadly-neutralizing antibodies against rapidly evolving viruses like SARS-CoV-2.
• Engineered antibodies show promise in overcoming variant-specific immune escape mechanisms.
• The identified nAbs offer potential therapeutic candidates for managing current and future SARS-CoV-2 outbreaks.