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To understand how intranasal booster induces mucosal sIgA response in humans, we first used liquid chromatography\u2013tandem mass spectrometry for peptide identification of immunoglobulin (MS Ig-seq) and single-cell B cell receptor sequencing (scBCR-seq) to identify 42 mucosal spike-specific sIgA monoclonal antibodies (mAbs) after intranasal booster. These mucosal sIgA mAbs exhibited enhanced neutralization up to 100-fold against SARS-CoV-2 variants compared with their monomeric IgG and IgA isotypes. Deep sequencing and longitudinal analysis of B cell receptor repertoires revealed that intranasal booster restimulates memory B cells primed by intramuscular vaccination to undergo IgA class switching, somatic hypermutation, and clonal expansion. Single-cell RNA-seq (scRNA-seq) revealed that intranasal booster upregulated the expression of mucosal homing receptors in spike-specific IgA-expressing B cells. This increase coincided with a transient increase of cytokines and chemokines that facilitate B cell recruitment in the nasal mucosa. Our findings demonstrate that intranasal booster can be an effective strategy for inducing upper respiratory mucosal sIgA and establishing mucosal immune protection.<\/jats:p>","DOI":"10.1172\/jci.insight.198045","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T17:01:07Z","timestamp":1766509267000},"source":"Crossref","is-referenced-by-count":5,"title":["Intranasal booster drives class switching and homing of memory B cells for mucosal IgA response"],"prefix":"10.1172","volume":"11","author":[{"given":"Si","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China."},{"name":"Guangzhou Institute of Infectious Disease, Guangzhou Eighth People\u2019s Hospital, Guangzhou Medical University, Guangzhou, China."},{"name":"State Key Laboratory of Respiratory Disease, Human 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