An analysis of nearly 300 recently identified human SARS-CoV-2 antibodies uncovered a gene frequently used in antibodies that most effectively target the virus. The results contribute to growing structural insight that will be needed for successful vaccine development against SARS-CoV-2.

As the global COVID-19 pandemic continues, multiple vaccine candidates have entered clinical trials. Yet, the molecular features that contribute to the most effective antibody response remain unclear.

The spike protein of SARS-CoV-2 uses its receptor binding domain (RBD) to infect the host receptor, ACE2, on human cells. Antibodies that could target RBD and block binding to ACE2 are highly sought, and a number have been discovered.

The researchers compiled a list of 294 such RBD-targeting antibodies. By analyzing them, they found that a gene in the IGHV gene family, known as IGHV3-53, is the most frequently used IGHV gene for targeting the RBD of the virus spike protein. IGHV3-53 antibodies, the authors say, not only have lower mutation rates but are also more potent.

By studying the crystal structures of two IGHV3-53 antibodies bound to the RBD with or without Fab CR3022, at 2.33 to 3.20 Å 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.

This detailed insight into IGHV-53 neutralizing antibodies should facilitate design of vaccine antigens that elicit this type of neutralizing antibody response, the authors say. "As IGHV3-53 is found at a reasonable frequency in healthy individuals, this particular antibody response could be commonly elicited during vaccination," they write.

https://science.sciencemag.org/content/early/2020/07/10/science.abd2321

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