Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• The rapid emergence of SARS-CoV-2 variants poses a significant challenge to controlling the COVID-19 pandemic.
• Existing antibody therapies may face reduced efficacy against new viral strains.

Purpose of the Study:

• To identify and characterize novel cross-neutralizing antibodies targeting conserved regions of Sarbecoviruses.
• To evaluate the efficacy of these antibodies against authentic SARS-CoV-2 and its variants.

Main Methods:

• Isolation and characterization of neutralizing antibodies (7D6 and 6D6).
• Determination of antibody binding affinities and neutralization potency.
• X-ray crystallography to elucidate the binding site and mechanism of action.
• Assessment of antibody resistance to mutations in SARS-CoV-2 variants.

Main Results:

• Two antibodies, 7D6 and 6D6, were obtained with sub-picomolar affinity for the Sarbecovirus receptor-binding domain (RBD).
• These antibodies bind to a conserved, cryptic site on the RBD, distinct from known antibody targets.
• Structural analysis revealed that antibody binding disrupts the viral spike protein.
• Both antibodies demonstrated potent neutralization of authentic SARS-CoV-2 and retained efficacy against current variants.

Conclusions:

• Antibodies 7D6 and 6D6 represent promising candidates for passive antibody therapeutics and prophylactics against SARS-CoV-2 and related viruses.
• The identified conserved binding site can inform the development of pan-sarbecovirus vaccines.
• These findings have direct implications for public health strategies in combating the COVID-19 pandemic.