Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Emerging SARS-CoV-2 variants of concern (VOCs) reduce the efficacy of existing monoclonal antibodies (mAbs).
• Antibodies targeting cryptic receptor binding domain (RBD) epitopes show broad activity but moderate neutralization, hindering clinical use.

Purpose of the Study:

• To identify and enhance antibodies targeting a cryptic class 6 epitope on the SARS-CoV-2 spike protein.
• To investigate the role of high antibody affinity in neutralizing SARS-CoV-2 VOCs and providing protection.

Main Methods:

• In vitro display technology for antibody identification and affinity maturation.
• Cryo-electron microscopy and crystal structure analysis of antibody-RBD complexes.
• Viral neutralization assays and in vivo protection studies in hACE2 mice.

Main Results:

• Affinity-matured antibodies achieved picomolar binding affinity.
• These antibodies potently neutralized SARS-CoV-2 VOCs and protected mice from infection.
• Structural analysis revealed epitopes distal from common VOC mutation sites.

Conclusions:

• Very high antibody affinity (picomolar range) is essential for potent neutralization of SARS-CoV-2 variants.
• Class 6 epitope antibodies are present in natural immunity and can be induced.
• Achieving high affinity is critical for developing effective vaccines and therapeutics against SARS-CoV-2.