Structural basis of a shared antibody response to SARS-CoV-2

Summary

Molecular understanding of neutralizing antibody responses to SARS-CoV-2 could accelerate vaccine design and drug discovery. We analyzed 294 anti-SARS-CoV-2 antibodies and found that IGHV3-53 is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of the two IGHV3-53 neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33 to 3.20. A resolution revealed that the germline-encoded residues dominate recognition of the ACE2 binding site. This binding mode limits the IGHV3-53 antibodies to short CDR H3 loops, but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate design of antigens that elicit this type of neutralizing response.

Highlights

• Our structural analysis reveals two key motifs in the IGHV3-53 germline sequence that are important for RBD binding, namely an NY motif at VH residues 32 and 33 in the CDR HI, and an SGGS motif at VH residues 53 to 56 in the CDR H2.
• This demonstrates that IGHV3-53 provides a versatile framework to target the ACE2 binding site in SARS-CoV-2 RED.
• Besides IGHV3-53, several other IGHV genes such as IGHVl- 2, IGHV3-9, and IGHV3-30 are also more frequently observed than other germlines in SARS-CoV-2 RED-targeting antibodies.
• The molecular mechanisms of these IGHV responses to SARS-CoV-2 need characterization, as well as whether other germline gene segments, including IGHD and the light chain contribute in recurring motifs to the SARS-CoV-2 antibody re­sponse.
• The characterization of these IGHV3-53 antibodies to SARS-CoV-2 is a promising starting point for rational vaccine design, given that limited to no affinity maturation is re­quired to achieve a highly potent neutralizing antibody response to the RED.
• As IGHV3-53 is found at a reasonable frequency in healthy individuals, this particular antibody response could be commonly elicited during vaccination.