Analysis of B Cell Receptor Repertoires Reveals Key Signatures of the Systemic B Cell Response after SARS-CoV-2 Infection

Abstract

A comprehensive study of the B cell response against SARS-CoV-2 could be significant for understanding the immune response and developing therapeutical antibodies and vaccines. To define the dynamics and characteristics of the antibody repertoire following SARS-CoV-2 infection, we analyzed the mRNA transcripts of immunoglobulin heavy chain (IgH) repertoires of 24 peripheral blood samples collected between 3 and 111 days after symptom onset from 10 COVID-19 patients. Massive clonal expansion of naïve B cells with limited somatic hypermutation (SHM) was observed in the second week after symptom onset. The proportion of low-SHM IgG clones strongly correlated with spike-specific IgG antibody titers, highlighting the significant activation of naïve B cells in response to a novel virus infection. The antibody isotype switching landscape showed a transient IgA surge in the first week after symptom onset, followed by a sustained IgG elevation that lasted for at least 3 months. SARS-CoV-2 infection elicited poly-germline reactive antibody responses. Interestingly, 17 different IGHV germline genes recombined with IGHJ6 showed significant clonal expansion. By comparing the IgH repertoires that we sequenced with the 774 reported SARS-CoV-2–reactive monoclonal antibodies (mAbs), 13 shared spike-specific IgH clusters were found. These shared spike-specific IgH clusters are derived from the same lineage of several recently published neutralizing mAbs, including CC12.1, CC12.3, C102, REGN10977, and 4A8. Furthermore, identical spike-specific IgH sequences were found in different COVID-19 patients, suggesting a highly convergent antibody response to SARS-CoV-2. Our analysis based on sequencing antibody repertoires from different individuals revealed key signatures of the systemic B cell response induced by SARS-CoV-2 infection. IMPORTANCE Although the canonical delineation of serum antibody responses following SARS-CoV-2 infection has been well established, the dynamics of antibody repertoire at the mRNA transcriptional level has not been well understood, especially the correlation between serum antibody titers and the antibody mRNA transcripts. In this study, we analyzed the IgH transcripts and characterized the B cell clonal expansion and differentiation, isotype switching, and somatic hypermutation in COVID-19 patients. This study provided insights at the repertoire level for the B cell response after SARS-CoV-2 infection.

A population antibody response against SARS-CoV-2 with differential neutralization activities towards the Delta and Omicron variants

“…The hypothesis that recurrent substitutions at 452 is related to evasion of R1-32 like antibodies suggested that R1-32 like antibodies may be common within the population. We searched immunoglobulin heavy chain (IgH) repertoires of 20 COVID-19 patients and 25 healthy donors (Niu et al, 2020;Yan et al, 2021;Zhang et al, 2021b), for VH1-69 transcripts having at least 80% amino acid homology and looking for GYSGYG/D motif in HCDR3 (Fig. 4f).…”

“…To determine the prevalence of R1-32 like antibodies, we analyzed nearly 2 billion IgH sequences from 3 datasets that described previously (Niu et al, 2020;Yan et al, 2021;Zhang et al, 2021b). Germline gene usage was determined using MIXCR v3.0.3 (Bolotin et al, 2015), and IGHV1-69-encoded IgH sequences were extracted for downstream analysis.…”

SARS-CoV-2 breakthrough infections induce somatically hypermutated broadly neutralizing antibodies against heterologous variants

“…It has been widely reported that SARS-CoV-2 infections elicit germline like antibodies with low SHM rates, indicating an acute activation of naïve B cells. These studies were mostly based on non-vaccinated COVID-19 patients infected in initial stages of the pandemic [4][5][6] .…”

“…The recently emerged Omicron variant effectively evades most characterized antibodies 2 likely contributing to an increased rate of breakthrough infections 3 . Studies of antibody responses in naive individuals infected by the original SARS-CoV-2 strain revealed that germline-like antibodies are widely and rapidly induced [4][5][6] . Antibody isolation and informatics studies revealed that germline antibodies of different clonotypes preferentially target specific spike protein surfaces generating antibodies of 4 different classes as define by epitope locations 7 .…”

B-cell receptor repertoire sequencing: Deeper digging into the mechanisms and clinical aspects of immune-mediated diseases

“…Advances in high-throughput sequencing continue to improve our understanding of diseases, especially in the application of BCR repertoire ( Yaari and Kleinstein, 2015 ). In recent years, BCR repertoire sequencing has been reported to be applied to dozens of immune-mediated diseases, especially in systemic lupus erythematosus (SLE) ( Bashford-Rogers et al., 2019 ; Liu et al., 2017 ; Zheng et al., 2021 ), COVID-19 ( Bieberich et al., 2021 ; Galson et al., 2020 ; Jin et al., 2021 ; Montague et al., 2021 ; Niu et al., 2020 ; Paschold et al., 2021 ; Schultheiβ et al., 2020 ; Xiang et al., 2022 ; Zhang et al., 2020a , 2022 ; Zhou et al., 2021 ) and vaccination ( Lee et al., 2016a ; Miyasaka et al., 2019 ; Schneikart et al., 2020 ; Strauli and Hernandez, 2016 ; Zhao et al., 2021a , 2021b ). With the advent of bioinformatics and the development of a variety of bioinformatics analysis tools, we have grasped a more comprehensive understanding of diseases, and meanwhile, disease diagnosis and treatment have become increasingly diversified ( Liu et al., 2021 ).…”