Structural insights into the molecular mechanism of broad-spectrum neutralization of SARS-CoV-2 variants by bnAbs

The COVID-19 pandemic, driven by the rapid evolution of SARS-CoV-2, continues to pose significant global health challenges nowadays. The virus’s ability to evolve to variants of concern (VOCs) such as Alpha, Beta, Delta, and notably Omicron, has enhanced its immune escape capabilities, complicating prevention and treatment efforts. Our study focuses on broadly neutralizing antibodies (bnAbs) isolated from vaccinated patients who experienced Omicron BA.2/BA.5 breakthrough infections. These bnAbs have demonstrated potent neutralizing activities against a range of SARS-CoV-2 variants, including the newly identified JN.1 and KP.2. Our research reveals the neutralization mechanism by cryo-EM based structural determination. All the four identified bnAbs, namely ZCP3B4, ZCP4C9, ZCP4D5, and CUP2G3, target the receptor-binding domain (RBD) of the Spike (S) protein located on the virus membrane, effectively blocking its interaction with the ACE2 receptor. This blockade is facilitated by the antibodies recognizing the RBD in its “up” conformation, which inhibits the receptor engagement and viral entry. Epitope mapping indicated that the interactions are predominantly mediated by highly conserved residues in the RBD, explaining the antibodies’ broad neutralization capabilities. Detailed interaction studies highlighted that the binding involves nearly all variable regions of the antibodies, including CDR-H1, CHR-H2, CDR-H3, CDRL1, and CDRL3, showcasing their high efficiency and specificity. The large buried surface areas of these interactions correlate with the high affinity observed between the antibodies and the RBD. These findings underscore the potential of these bnAbs as therapeutic candidates for COVID-19, capable of neutralizing current and emergent variants. This study not only provides a deeper understanding of the neutralization breadth of bnAbs but also supports ongoing efforts in vaccine and therapeutic antibody development against SARS-CoV-2.