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Statistical Inference of a Convergent Antibody Repertoire Response to Influenza Vaccine

Nicolas Strauli, Ryan Hernandez
doi: https://doi.org/10.1101/025098
Nicolas Strauli
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA
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Ryan Hernandez
2Department of Bioengineering and Therapeutic Sciences, University of California, Byers Hall, 1700 4th Street, San Francisco, CA 94158
3Institute for Human Genetics, University of California, San Francisco, CA, USA
4Institute for Quantitative Biosciences (QB3), University of California, San Francisco, CA, USA
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Abstract

Background Vaccines dramatically affect an individual’s adaptive immune system, and thus provide an excellent means to study human immunity. Upon vaccination, the B cells that express antibodies (Abs) that happen to bind the vaccine are stimulated to proliferate and undergo mutagenesis at their Ab locus. This process may alter the composition of B cell lineages within an individual, which are known collectively as the antibody repertoire (AbR). Antibodies are also highly expressed in whole blood, potentially enabling unbiased RNA sequencing technologies to query this diversity. Less is known about the diversity of AbR responses across individuals to a given vaccine and if individuals tend to yield a similar response to the same antigenic stimulus.

Methods Here we implement a bioinformatic pipeline that extracts the AbR information from a time-series RNA-seq dataset of 5 patients who were administered a seasonal trivalent influenza vaccine (TIV). We harness the detailed time-series nature of this dataset and use methods based in functional data analysis (FDA) to identify the B cell lineages that respond to the vaccine. We then design and implement rigorous statistical tests in order to ask whether or not these patients exhibit a convergent AbR response to the same TIV.

Results We find that high-resolution time-series data can be used to help identify the Ab lineages that respond to an antigenic stimulus, and that this response can exhibit a convergent nature across patients inoculated with the same vaccine. However, correlations in AbR diversity among individuals prior to inoculation can confound inference of a convergent signal unless it is taken into account.

Conclusions We developed a framework to identify the elements of an AbR that respond to an antigen. This information could be used to understand the diversity of different immune responses in different individuals, as well as to gauge the effectiveness of the immune response to a given stimulus within an individual. We also present a framework for testing a convergent hypothesis between AbRs; a hypothesis that is more difficult to test than previously appreciated. Our discovery of a convergent signal suggests that similar epitopes do select for antibodies with similar sequence characteristics.

  • List of abbreviations used

    Ab
    Antibody
    AbR
    Antibody repertoire
    CDR3
    Complementarity determining region 3
    D
    Diversity antibody gene segment
    FDA
    Functional data analysis
    FPCA
    Functional principal components analysis
    HAI
    Hemagglutinin inhibition assay
    IGH
    Heavy chain of antibody
    IGHV
    Variable gene on heavy chain
    IGK
    Kappa light chain of antibody
    IGKV
    Variable gene on kappa chain
    IGL
    Lambda light chain of antibody
    IGLV
    Variable gene on lambda chain
    J
    Joining antibody gene segment
    mAb
    Monoclonal antibody
    NGS
    Next generation sequencing
    PBMC
    Peripheral blood mononuclear cell
    PRISMA
    Preferred reporting items for systematic reviews and meta-analyses
    RSS
    Residual sum of squares
    SGS
    Sum of gene significances
    SHM
    Somatic hyper mutation
    TIV
    Tri-valent influenza vaccine
    V
    Variable antibody gene segment
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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    Posted August 20, 2015.
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    Statistical Inference of a Convergent Antibody Repertoire Response to Influenza Vaccine
    Nicolas Strauli, Ryan Hernandez
    bioRxiv 025098; doi: https://doi.org/10.1101/025098
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    Statistical Inference of a Convergent Antibody Repertoire Response to Influenza Vaccine
    Nicolas Strauli, Ryan Hernandez
    bioRxiv 025098; doi: https://doi.org/10.1101/025098

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