Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

Montague, Zachary; Lv, Huibin; Otwinowski, Jakub; DeWitt, William S; Isacchini, Giulio; Yip, Garrick K.; Ng, Wilfred; Tsang, Owen Tak‐Yin; Yuan, Meng; Liu, Hejun; Wilson, Ian A.; Peiris, J. S. Malik; Wu, Nicholas C.; Nourmohammad, Armita; Mok, Chris Ka Pun

doi:10.1101/2020.07.13.20153114

Cited by 4 publications

(6 citation statements)

References 87 publications

(202 reference statements)

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“…IGHV1-69 and IGHV3-23 were among the top 7 and 10 antibodies detected, respectively, and some of the BCR heavy chains detected in the lung lobe were also frequently detected (9,12). Bulk BCR heavy chain analysis in the PBMCs from 19 patients showed that IGHV4 families expression levels were higher compared with those from HDs, whereas IGHV1-69 and IGHV3-23 were expressed at higher levels in the HD groups (8). However, it was indicated that IGHV1-69 was highly reactive against RBD-and IGHV3-23 against N-terminal domain (NTD)-sorted mAbs for SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 94%

“…Understanding the diversity of BCRs, their response to SARS-CoV-2 infection, and detection of specific BCRs may help in the development of therapeutic antibodies for patients with COVID-19. The life cycle of SARS-CoV-2 has been revealed (3), and multiple studies have investigated the development of neutralizing monoclonal antibodies targeting the SARS-CoV-2 spike (S) protein (4)(5)(6)(7)(8)(9)(10)(11)(12). Candidate antibodies are usually obtained by analyzing BCRs in the peripheral blood mononuclear cells (PBMCs) obtained from patients with COVID-19 compared with those from healthy donors (HDs).…”

Section: Introductionmentioning

confidence: 99%

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B cell receptor repertoire analysis from autopsy samples of COVID-19 patients

Iwabuchi

Tsukahara²,

Okayama³

et al. 2023

Front. Immunol.

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Neutralizing antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being developed world over. We investigated the possibility of producing artificial antibodies from the formalin fixation and paraffin-embedding (FFPE) lung lobes of a patient who died by coronavirus disease 2019 (COVID-19). The B-cell receptors repertoire in the lung tissue where SARS-CoV-2 was detected were considered to have highly sensitive virus-neutralizing activity, and artificial antibodies were produced by combining the most frequently detected heavy and light chains. Some neutralizing effects against the SARS-CoV-2 were observed, and mixing two different artificial antibodies had a higher tendency to suppress the virus. The neutralizing effects were similar to the immunoglobulin G obtained from healthy donors who had received a COVID-19 mRNA vaccine. Therefore, the use of FFPE lung tissue, which preserves the condition of direct virus sensitization, to generate artificial antibodies may be useful against future unknown infectious diseases.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

B cell receptor repertoire analysis from autopsy samples of COVID-19 patients

Iwabuchi

Tsukahara²,

Okayama³

et al. 2023

Front. Immunol.

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“…The RAPID output indicates that SRR12190252 and SRR12190293 have longer CDR3s compared to the reference groups (Figure 3B) (42). In addition, the COVID-19 samples have shorter deletions and longer insertions (Figures 3C, E) (43). SHM in the germinal center is the key process for antibody affinity maturation.…”

Section: Rep-seq Dataset Analysis Platformmentioning

confidence: 97%

RAPID: A Rep-Seq Dataset Analysis Platform With an Integrated Antibody Database

et al. 2021

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The antibody repertoire is a critical component of the adaptive immune system and is believed to reflect an individual’s immune history and current immune status. Delineating the antibody repertoire has advanced our understanding of humoral immunity, facilitated antibody discovery, and showed great potential for improving the diagnosis and treatment of disease. However, no tool to date has effectively integrated big Rep-seq data and prior knowledge of functional antibodies to elucidate the remarkably diverse antibody repertoire. We developed a Rep-seq dataset Analysis Platform with an Integrated antibody Database (RAPID; https://rapid.zzhlab.org/), a free and web-based tool that allows researchers to process and analyse Rep-seq datasets. RAPID consolidates 521 WHO-recognized therapeutic antibodies, 88,059 antigen- or disease-specific antibodies, and 306 million clones extracted from 2,449 human IGH Rep-seq datasets generated from individuals with 29 different health conditions. RAPID also integrates a standardized Rep-seq dataset analysis pipeline to enable users to upload and analyse their datasets. In the process, users can also select set of existing repertoires for comparison. RAPID automatically annotates clones based on integrated therapeutic and known antibodies, and users can easily query antibodies or repertoires based on sequence or optional keywords. With its powerful analysis functions and rich set of antibody and antibody repertoire information, RAPID will benefit researchers in adaptive immune studies.

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“…'Public' antibodies, those that are raised independently across multiple individuals against an immunodominant epitope, are of high interest to several fields of research, from vaccinology to drug discovery (67)(68)(69). Several studies have already identified public SARS-CoV-2 response antibodies based on convergence towards particular clonotype lineages (12)(13)(14)(15)(16)(17)(18), but none have yet considered the fact that antibodies from different lineages can exert similar functions. As demonstrated above, structural clustering enables us to group together clonally-distinct antibodies with a high chance of engaging the same epitope.…”

Section: Structural Clusters Frequently Span Multiple Clonal Lineagesmentioning

confidence: 99%

“…As a result, leniency is often introduced to the clonotyping protocol, by lowering the sequence identity threshold to 80% (11), ignoring J-gene annotations, and/or only considering the heavy chain (VH-only clonotyping) (4). Convergent lenient VH-only clonotypes have been identified between multiple SARS-CoV-2 infected or convalescent individuals (12)(13)(14)(15)(16)(17)(18) and across different studies, for example the overlap between the clonotypes found by Galson et al (4) and Nielsen et al (19). Several papers have compared BCR sequences from individuals to verified SARS-CoV-2 binders in CoV-Ab-Dab and identified clonal similarities (e.g.…”

Section: Introductionmentioning

confidence: 99%

Epitope profiling of coronavirus-binding antibodies using computational structural modelling

Raybould

Marks

et al. 2021

Preprint

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Identifying the epitope of an antibody is a key step in understanding its function and its potential as a therapeutic. It is well-established in the literature that sequence-based clonal clustering can identify antibodies with similar epitope complementarity. However, there is growing evidence that antibodies from markedly different lineages but with similar structures can engage the same epitope with near-identical binding modes. Here, we describe a novel computational method for epitope profiling based on structural modelling and clustering, and show how it can identify sequence-dissimilar antibodies that engage the same epitope. We start by searching for evidence of structural conservation across the latest solved SARS-CoV-2-binding antibody crystal structures. Despite the relatively small number of solved structures, we find numerous examples of sequence-diverse but structurally-similar coronavirus-binding antibodies engaging the same epitope. We therefore developed a high-throughput structural modeling and clustering method to identify functionally-similar antibodies across the set of thousands of coronavirus-binding antibody sequences in the Coronavirus Antibody Database (CoV-AbDab). In the resulting multiple-occupancy structural clusters, 92% bind to consistent domains based on CoV-AbDab metadata. Our approach functionally links antibodies with distinct genetic lineages, species origins, and coronavirus specificities. This indicates greater convergence exists in the immune responses to coronaviruses than would be suggested by sequence-based approaches. Our results show that applying structural analytics to large class-specific antibody databases will enable high confidence structure-function relationships to be drawn, yielding new opportunities to identify functional convergence hitherto missed by sequence-only analysis.

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Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

Cited by 4 publications

References 87 publications

B cell receptor repertoire analysis from autopsy samples of COVID-19 patients

B cell receptor repertoire analysis from autopsy samples of COVID-19 patients

RAPID: A Rep-Seq Dataset Analysis Platform With an Integrated Antibody Database

Epitope profiling of coronavirus-binding antibodies using computational structural modelling

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