SARS-CoV-2 Omicron-neutralizing memory B cells are elicited by two doses of BNT162b2 mRNA vaccine

TLDR

SARS‑CoV‑2 variants such as Beta and Omicron carry spike RBD mutations that enable escape from neutralizing antibodies elicited by two doses of BNT162b2, and while a third dose or breakthrough infection broadens neutralization, the underlying mechanism remains unclear. The study aimed to longitudinally profile RBD‑binding memory B‑cell subsets and their antibody binding and neutralization against variants following the second mRNA vaccine dose. We characterized the cellular composition of RBD‑binding memory B cells and assessed their antibody binding and neutralizing activity over time up to 4.9 months post‑vaccination. After two vaccine doses, plasma neutralizing activity against Beta and Omicron was limited, yet an expanding subset of resting IgG⁺ memory B cells broadened their receptor repertoire and produced Beta/Omicron‑neutralizing antibodies in vitro, accounting for the robust recall of Omicron neutralization seen after boosting or breakthrough infection.

Abstract

Multiple SARS-CoV-2 variants have mutations in the spike receptor binding domain (RBD) with potential to evade neutralizing antibody. In particular, the Beta and Omicron variants escape from antibody neutralizing activity in those who received two doses of BNT162b2 mRNA vaccine. Nonetheless, boosting with a third vaccine dose or by breakthrough infection improves the overall breadth of the neutralizing antibodies, but the mechanism remains unclear. Here, we longitudinally profiled the cellular composition of RBD-binding memory B cell subsets and their antibody binding and neutralizing activity against SARS-CoV-2 variants after the second dose of mRNA vaccine. Two doses of the mRNA vaccine elicited plasma neutralizing antibodies with a limited activity against Beta and Omicron but induced an expanded antibody breadth overtime, up to 4.9 months after vaccination. In contrast, more than one-third of RBD-binding IgG+ memory B cells with a resting phenotype initially bound the Beta and Omicron variants and steadily increased the B cell receptor breadth overtime. As a result, a fraction of the resting memory B cell subset secreted Beta and Omicron-neutralizing antibody when stimulated in vitro. The neutralizing breadth of the resting memory B cell subset helps us understand the prominent recall of Omicron-neutralizing antibodies after an additional booster or breakthrough infection in fully vaccinated individuals.