Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving

  1. Kenneth B Hoehn
  2. Jackson S Turner
  3. Frederick I Miller
  4. Ruoyi Jiang
  5. Oliver G Pybus
  6. Ali H Ellebedy
  7. Steven H Kleinstein  Is a corresponding author
  1. Yale School of Medicine, United States
  2. Washington University School of Medicine, St Louis, United States
  3. Worcester Polytechnic Institute, United States
  4. University of Oxford, United Kingdom

Abstract

The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation (SHM) among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue using a phylogenetic test of measurable immunoglobulin sequence evolution. We first validate this test through simulations and survey measurable evolution across multiple conditions. We find significant heterogeneity in measurable B cell evolution across conditions, with enrichment in primary response conditions such as HIV infection and early childhood development. We then show that measurable evolution following influenza vaccination is highly compartmentalized: while lineages in the blood are rarely measurably evolving following influenza vaccination, lineages containing GC B cells are frequently measurably evolving. Many of these lineages appear to derive from memory B cells. We conclude from these findings that seasonal influenza virus vaccination can stimulate additional evolution of responding B cell lineages, and imply that the poor efficacy of seasonal influenza vaccination is not due to a complete inhibition of vaccine-specific B cell evolution.

Data availability

The manuscript is a computational study. All data used are publicaly available. Source code are available at https://bitbucket.org/kleinstein/projects.

The following previously published data sets were used

Article and author information

Author details

  1. Kenneth B Hoehn

    Yale School of Medicine, New Haven, United States
    Competing interests
    Kenneth B Hoehn, K.B.H. receives consulting fees from Prellis Biologics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0411-4307
  2. Jackson S Turner

    Washington University School of Medicine, St Louis, St Louis, United States
    Competing interests
    No competing interests declared.
  3. Frederick I Miller

    Worcester Polytechnic Institute, Worcester, United States
    Competing interests
    No competing interests declared.
  4. Ruoyi Jiang

    Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  5. Oliver G Pybus

    Department of Zoology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  6. Ali H Ellebedy

    Washington University School of Medicine, St Louis, St Louis, United States
    Competing interests
    Ali H Ellebedy, The Ellebedy laboratory received funding under sponsored research agreements from Emergent BioSolutions and AbbVie..
  7. Steven H Kleinstein

    Yale School of Medicine, New Haven, United States
    For correspondence
    steven.kleinstein@yale.edu
    Competing interests
    Steven H Kleinstein, receives consulting fees from Northrop Grumman..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4957-1544

Funding

National Institute of Allergy and Infectious Diseases (R01 AI104739)

  • Steven H Kleinstein

FP7 Ideas: European Research Council (614725-PATHPHYLODYN)

  • Oliver G Pybus

National Institute of Allergy and Infectious Diseases (R21 AI139813)

  • Ali H Ellebedy

National Institute of Allergy and Infectious Diseases (U01 AI141990)

  • Ali H Ellebedy

National Institute of Allergy and Infectious Diseases (HHSN272201400006C)

  • Ali H Ellebedy

National Institute of Allergy and Infectious Diseases (5T32CA009547)

  • Jackson S Turner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Armita Nourmohammad, University of Washington, United States

Publication history

  1. Preprint posted: January 7, 2021 (view preprint)
  2. Received: June 1, 2021
  3. Accepted: November 11, 2021
  4. Accepted Manuscript published: November 17, 2021 (version 1)
  5. Accepted Manuscript updated: November 25, 2021 (version 2)
  6. Version of Record published: January 7, 2022 (version 3)

Copyright

© 2021, Hoehn et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,218
    Page views
  • 225
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kenneth B Hoehn
  2. Jackson S Turner
  3. Frederick I Miller
  4. Ruoyi Jiang
  5. Oliver G Pybus
  6. Ali H Ellebedy
  7. Steven H Kleinstein
(2021)
Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving
eLife 10:e70873.
https://doi.org/10.7554/eLife.70873

Further reading

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Vahid Akbari et al.
    Research Article

    Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. Direct nanopore sequencing of DNA provides a means to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here, we used publicly available nanopore sequencing data for 12 standard B-lymphocyte cell lines to acquire the genome-wide mapping of imprinted intervals in humans. Using the sequencing data, we were able to phase 95% of the human methylome and detect 94% of the previously well-characterized, imprinted DMRs. In addition, we found 42 novel imprinted DMRs (16 germline and 26 somatic), which were confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mouse (Mus musculus), rhesus monkey (Macaca mulatta), and chimpanzee (Pan troglodytes) suggested that 17 of these imprinted DMRs are conserved. Some of the novel imprinted intervals are within or close to imprinted genes without a known DMR. We also detected subtle parental methylation bias, spanning several kilobases at seven known imprinted clusters. At these blocks, hypermethylation occurs at the gene body of expressed allele(s) with mutually exclusive H3K36me3 and H3K27me3 allelic histone marks. These results expand upon our current knowledge of imprinting and the potential of nanopore sequencing to identify imprinting regions using only parent-offspring trios, as opposed to the large multi-generational pedigrees that have previously been required.

    1. Computational and Systems Biology
    2. Neuroscience
    Maryam H Mofrad et al.
    Tools and Resources

    Sleep is generally considered to be a state of large-scale synchrony across thalamus and neocortex; however, recent work has challenged this idea by reporting isolated sleep rhythms such as slow oscillations and spindles. What is the spatial scale of sleep rhythms? To answer this question, we adapted deep learning algorithms initially developed for detecting earthquakes and gravitational waves in high-noise settings for analysis of neural recordings in sleep. We then studied sleep spindles in non-human primate electrocorticography (ECoG), human electroencephalogram (EEG), and clinical intracranial electroencephalogram (iEEG) recordings in the human. Within each recording type, we find widespread spindles occur much more frequently than previously reported. We then analyzed the spatiotemporal patterns of these large-scale, multi-area spindles and, in the EEG recordings, how spindle patterns change following a visual memory task. Our results reveal a potential role for widespread, multi-area spindles in consolidation of memories in networks widely distributed across primate cortex.