An ancestral SARS-CoV-2 vaccine induces anti-Omicron variants antibodies by hypermutation

The immune escape of Omicron variants significantly subsides by the third dose of an mRNA vaccine, but how Omicron-neutralizing antibodies develop with repeated vaccination is unclear. We analyzed blood samples from 41 BNT162b2 vaccinees across three injections at six time points and profiled their B-cell receptor (BCR) repertoires. Combinatorial reactivity to both Omicron and ancestral receptor-binding domains (RBDs) was achieved by a limited number of BCR clonotypes, dependent on the accumulation of somatic hypermutation (SHM) after the third dose. These findings suggest that broadening of BCR specificity through SHM provides a counterprotective mechanism against immune escape by SARS-CoV-2 variants.