Convergent antibody evolution and clonotype expansion following influenza virus vaccination

Forgacs, David; Abreu, Rodrigo B.; Kirchenbaum, Greg A.; Drábek, Elliott F.; Williamson, Kevin; Kim, Dongkyoon; Emerling, Daniel; Ross, Ted M.

doi:10.1371/journal.pone.0247253

Cited by 23 publications

(19 citation statements)

References 74 publications

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“…Our work supports the following model, generalizing observed constraints on gene usage by some antibodies 2–8,10,12,14–24 . In nature, many heavy chain configurations yield effective binding of a given antibody target.…”

Section: Discussionsupporting

confidence: 86%

“…A clonotype can therefore be treated as the minimal functional group of antibodies. Next, as has been observed, nature repeats itself by creating similar clonotypes that appear to have the same function 2-21 , and these might be combined into groups. Such recurrences have been observed between donors, but also occur within single donors, as we will demonstrate.…”

Section: A Novel Approach To Grouping Antibodies Reveals Light Chain ...mentioning

confidence: 91%

“…Each chain contains three complementarity-determining regions (CDR1-3), contributing to antigen specificity. Certain heavy and light chains are preferred for particular antigens 2–21 . We considered pairs of B cells sharing the same heavy chain V gene and CDRH3 amino acid sequence and isolated from different donors, also known as public clonotypes 22,23 .…”

mentioning

confidence: 99%

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Functional antibodies exhibit light chain coherence

Jaffe

Shahi

Adams

et al. 2022

Preprint

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The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies binding particular antigens1. In most mammals, antibodies are composed of a heavy and a light chain which are sequentially generated by recombination of V, D (for heavy chains), J, and C gene segments. Each chain contains three complementarity-determining regions (CDR1-3), contributing to antigen specificity. Certain heavy and light chains are preferred for particular antigens2–21. We considered pairs of B cells sharing the same heavy chain V gene and CDRH3 amino acid sequence and isolated from different donors, also known as public clonotypes22,23. We show that for naive antibodies (not yet adapted to antigens), the probability that they use the same light chain V gene is ∼10%, whereas for memory (functional) antibodies it is ∼80%. This property of functional antibodies is a phenomenon we call light chain coherence. We also observe it when similar heavy chains recur within a donor. Thus, though naive antibodies appear to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

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Section: Discussionsupporting

confidence: 86%

Section: A Novel Approach To Grouping Antibodies Reveals Light Chain ...mentioning

confidence: 91%

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Functional antibodies exhibit light chain coherence

Jaffe

Shahi

Adams

et al. 2022

Preprint

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“…'Public' response antibodies. '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 [70][71][72].…”

Section: (Sc57)mentioning

confidence: 99%

Epitope profiling using computational structural modelling demonstrated on coronavirus-binding antibodies

et al. 2021

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Identifying the epitope of an antibody is a key step in understanding its function and its potential as a therapeutic. Sequence-based clonal clustering can identify antibodies with similar epitope complementarity, however, antibodies from markedly different lineages but with similar structures can engage the same epitope. We describe a novel computational method for epitope profiling based on structural modelling and clustering. Using the method, we demonstrate that sequence dissimilar but functionally similar antibodies can be found across the Coronavirus Antibody Database, with high accuracy (92% of antibodies in multiple-occupancy structural clusters bind to consistent domains). 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 is 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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“…'Public' Response Antibodies. '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.…”

Section: Structural Clusters Frequently Span Multiple Clonal Lineagesmentioning

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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Convergent antibody evolution and clonotype expansion following influenza virus vaccination

Cited by 23 publications

References 74 publications

Functional antibodies exhibit light chain coherence

Functional antibodies exhibit light chain coherence

Epitope profiling using computational structural modelling demonstrated on coronavirus-binding antibodies

Epitope profiling of coronavirus-binding antibodies using computational structural modelling

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