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. Dr Ali 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. Dr Ali Ellebedy

    Washington University School of Medicine, St Louis, St Louis, United States
    Competing interests
    Dr Ali 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)

  • Dr Ali Ellebedy

National Institute of Allergy and Infectious Diseases (U01 AI141990)

  • Dr Ali Ellebedy

National Institute of Allergy and Infectious Diseases (HHSN272201400006C)

  • Dr Ali 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.

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  1. Kenneth B Hoehn
  2. Jackson S Turner
  3. Frederick I Miller
  4. Ruoyi Jiang
  5. Oliver G Pybus
  6. Dr Ali 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

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