# Efficient boosting of Omicron-reactive memory B cells after breakthrough infection protects from repeated exposure

## TL;DR

Memory B cells from Omicron breakthrough infections help protect against future exposures and maintain long-term immunity.

## Contribution

The study reveals how Omicron-specific memory B cells mature and protect against repeated infections after breakthrough events.

## Key findings

- Omicron-specific memory B cells remain stable and mature over time despite declining antibody levels.
- Pre-existing Omicron-specific MBCs help prevent secondary Omicron infections.
- High neutralization samples show increased B cell expansion and V(D)J gene rearrangements.

## Abstract

Exploring the impact of persistent mutations in SARS-CoV-2 variants and reduced immunity on breakthrough infections (BTIs) is crucial, particularly in understanding how antigen-specific memory B cells (MBCs) respond to new variants. We followed 107 participants who received the ancestral inactivated vaccine and experienced one or two Omicron BTIs over six months. Using flow cytometry, SARS-CoV-2 antigen probes, single-cell RNA sequencing, and B cell receptor (BCR) profiling, we assessed MBCs and immune diversity. Our findings revealed that although neutralizing antibody levels decreased over time, the number of specific MBCs remained stable and matured progressively. Notably, pre-existing Omicron-specific MBCs played a key role in preventing secondary Omicron infections. Differential gene analysis showed enrichment in antigen processing and immune regulation pathways, while clonal lineage analysis revealed more B cell expansion and V(D)J gene-specific rearrangements in high neutralization samples. These results emphasize MBCs’ critical role in long-term immunity and inform future vaccination strategies.

•Moderate group have higher and broader SARS-CoV-2-specific MBCs responses•Moderate group exhibits stronger cross-reactive MBCs responses•SARS-CoV-2-specific MBCs play a potential role in preventing secondary BTI•B cell expansion and V(D)J rearrangements in the high neutralization group

Moderate group have higher and broader SARS-CoV-2-specific MBCs responses

Moderate group exhibits stronger cross-reactive MBCs responses

SARS-CoV-2-specific MBCs play a potential role in preventing secondary BTI

B cell expansion and V(D)J rearrangements in the high neutralization group

Immunology; Cell biology