Emerging SARS-CoV-2 sublineage RE.2.2 displays distinct structural features

Researchers from the Institute of Microbiology at the Chinese Academy of Sciences have discovered the structural and functional characteristics of a new SARS-CoV-2 sublineage, known as RE.2.2. This sublineage, derived from the omicron BA.3 variant, has been spreading rapidly across multiple regions worldwide. By examining RE.2.2, the research team aimed to understand its unique properties, including enhanced binding to the human ACE2 receptor, distinct antibody escape patterns, and a novel N-linked glycosylation site on the spike (S) protein.

Using advanced techniques such as surface plasmon resonance and cryo-electron microscopy, the researchers found that the receptor-binding domain of RE.2.2 displays a high affinity for human ACE2, with a reverse mutation (R493Q) forming an additional hydrogen bond with the hACE2 residue K31. This binding enhancement is a primary factor contributing to the heightened receptor engagement.

Additionally, the researchers tested RE.2.2's interaction with ACE2 proteins from various animal species and found that its host range is broadly comparable to other Omicron variants. The study also revealed that RE.2.2 can evade multiple antibody classes, but several broadly neutralizing antibodies previously lost their activity against earlier Omicron lineages regained potent neutralizing capacity against RE.2.2.

A key structural alteration, the G446D substitution, directly facilitates antibody interactions, indicating that viral antigenic evolution is constrained by structural requirements. Lastly, the research found a new N-linked glycosylation site at position N529 on the RBD, which stabilizes the spike in a closed conformation, balancing high receptor affinity with regulated viral entry.

These findings provide valuable insights into the unique characteristics of the RE.2.2 sublineage and its implications for vaccine and treatment development.