Intranasal booster drives class switching and homing of memory B cells for mucosal IgA response
Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen
Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen
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Research Article Immunology Infectious disease Public Health

Intranasal booster drives class switching and homing of memory B cells for mucosal IgA response

Abstract

Mucosal secretory IgA (sIgA) plays a central role in protecting against the invasion of respiratory pathogen via the upper respiratory tract. To understand how intranasal booster induces mucosal sIgA response in humans, we first used liquid chromatography–tandem 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.

Authors

Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen

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Figure 3

Clonotypes of nasal mucosal mAbs in BCR repertoires at different time points after intramuscular and intranasal vaccination.

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Clonotypes of nasal mucosal mAbs in BCR repertoires at different time po...
(A) Sample collection scheme for sequencing BCR IgH repertoires. The schematic was drawn using BioRender. Five million peripheral mononuclear cells (PBMC) were obtained from a donor at each time point and subjected to bulk BCR sequencing as described in the methods. These time points are: before vaccination (before Vx), 3 weeks after intramuscular injection with inactivated whole-virus vaccine, 2 weeks after second intramuscular injection with inactivated whole-virus vaccine, 2 weeks after the first intranasal vaccination with Ad5-spike-BA.1, 2 weeks after the second intranasal booster, and 3 months after second intranasal booster. The total number of reads and unique reads in the heavy-chain repertoires are shown in the table. (B) The presence of 719-3, 719-4, 719-16, 719-19, 719-25, 719-40, and 719-43 clonotypes in circulating B cells at different time points after vaccination. Different shapes represent distinct clonotypes. (C) The isotype percentages and somatic hypermutation rates of 719-3, 719-4, 719-16, 719-19, 719-25, 719-40, and 719-43 clonotypes in circulating B cells at different time points after vaccination. (D) Class switch recombination (CSR) patterns of 719-4 clonotypes after intramuscular vaccination and intranasal vaccination. The color of each circle represents an Ig isotype, and the size of the circle reflects the relative number of unique Ig sequences. The arrow represents the direction of class-switching. The arrow’s thickness represents the probability of CSR, and the dashed line indicates no CSR occurrence.