Abstract
The immune escape of Omicron-sublineage variants significantly subsides by the third dose of an mRNA vaccine. However, it is unclear how Omicron variant-neutralizing antibodies develop under repeated vaccination. We collected blood samples from 41 BNT162b2 vaccinees following the course of three injections and analyzed their B-cell receptor (BCR) repertoires at six time points in total. Five Omicron variant-neutralizing BCR heavy chain (HC) clonotypes were tracked chronologically in identical vaccinees before and after the third dose. Before the third injection, all five BCR HC clonotypes showed reactivity to the ancestral receptor-binding domain (RBD), and two BCR HC clonotypes developed similar reactivity to the Omicron RBD. The other three BCR HC clonotypes showed minimal or reduced reactivity to the Omicron RBD before the third dose, which induced further somatic hypermutation (SHM) and dramatically increased their affinity for the Omicron RBD. In the public IGHV3-53/3-66 and IGHJ6 clonotypes found in 19 vaccinees (46%), concomitant reactivity to the ancestral and Omicron RBDs resulted from SHMs such as Y58F and F27V and diversification of HCDR3 by SHM. Our findings suggest that SHM occurrence in the BCR space to broaden its specificity for unseen antigens is a counterprotective mechanism against the immune escape of virus variants.
Competing Interest Statement
The authors have declared no competing interest.
