Long term intrinsic cycling in human life course antibody responses to influenza A(H3N2): an observational and modelling study

  1. Bingyi Yang  Is a corresponding author
  2. Bernardo García-Carreras
  3. Justin Lessler
  4. Jonathan M Read
  5. Huachen Zhu
  6. C Jessica E Metcalf
  7. James A Hay
  8. Kin O Kwok
  9. Ruiyun Shen
  10. Chao Q Jiang
  11. Yi Guan
  12. Steven Riley  Is a corresponding author
  13. Derek A Cummings  Is a corresponding author
  1. University of Hong Kong, Hong Kong
  2. University of Florida, United States
  3. University of North Carolina at Chapel Hill, United States
  4. Lancaster University, United Kingdom
  5. Princeton University, United States
  6. Harvard TH Chan School of Public Health, United States
  7. Chinese University of Hong Kong, China
  8. Guangzhou Number 12 People's Hospital, China
  9. Imperial College London, United Kingdom

Abstract

Background: Over a life-course, human adaptive immunity to antigenically mutable pathogens exhibits competitive and facilitative interactions. We hypothesize that such interactions may lead to cyclic dynamics in immune responses over a lifetime.

Methods: To investigate the cyclic behavior, we analyzed hemagglutination inhibition titers against 21 historical influenza A(H3N2) strains spanning 47 years from a cohort in Guangzhou, China and applied Fourier spectrum analysis. To investigate possible biological mechanisms, we simulated individual antibody profiles encompassing known feedbacks and interactions due to generally recognized immunological mechanisms.

Results: We demonstrated a long-term periodicity (about 24 years) in individual antibody responses. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explain the reported cycle. We showed that the reported cycles are predictable at both individual and birth-cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of seroconversion to circulating strains, after accounting for age and pre-existing titers of the circulating strains.

Conclusions: Our findings reveal the existence of long-term periodicities in individual antibody responses to A(H3N2). We hypothesize that these cycles are driven by pre-existing antibody responses blunting responses to antigenically similar pathogens (by preventing infection and/or robust antibody responses upon infection), leading to reductions in antigen specific responses over time until individual's increasing risk leads to an infection with an antigenically distant enough virus to generate a robust immune response. These findings could help disentangle cohort-effects from individual-level exposure histories, improve our understanding of observed heterogeneous antibody responses to immunizations, and inform targeted vaccine strategy.

Funding: This study was supported by grants from the NIH R56AG048075 (D.A.T.C., J.L.), NIH R01AI114703 (D.A.T.C., B.Y.), the Wellcome Trust 200861/Z/16/Z (S.R.) and 200187/Z/15/Z (S.R.). This work was also supported by research grants from Guangdong Government HZQB-KCZYZ-2021014 and 2019B121205009 (Y.G. and H.Z.). D.A.T.C., J.M.R. and S.R. acknowledge support from the National Institutes of Health Fogarty Institute (R01TW0008246). J.M.R. acknowledges support from the Medical Research Council (MR/S004793/1) and the Engineering and Physical Sciences Research Council (EP/N014499/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 to 4.

Article and author information

Author details

  1. Bingyi Yang

    Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
    For correspondence
    byyang@connect.hku.hk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0811-8332
  2. Bernardo García-Carreras

    Department of Biology, University of Florida, Gainesville, United States
    Competing interests
    Bernardo García-Carreras, BGC received financial research support through his institution from Merck for unrelated work.
  3. Justin Lessler

    UNC Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Justin Lessler, JL receives research support from CDC and NIH-NIGMS for for unrelated work..
  4. Jonathan M Read

    Centre for Health Informatics Computing and Statistics, Lancaster University, Lancaster, United Kingdom
    Competing interests
    No competing interests declared.
  5. Huachen Zhu

    Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  6. C Jessica E Metcalf

    Department of Ecology and Evolutionary Biology, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3166-7521
  7. James A Hay

    Center for Communicable Disease Dynamics, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1998-1844
  8. Kin O Kwok

    The Jockey Club School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China
    Competing interests
    No competing interests declared.
  9. Ruiyun Shen

    Guangzhou Number 12 People's Hospital, Guangzhou, China
    Competing interests
    No competing interests declared.
  10. Chao Q Jiang

    Guangzhou Number 12 People's Hospital, Guangzhou, China
    Competing interests
    No competing interests declared.
  11. Yi Guan

    Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    No competing interests declared.
  12. Steven Riley

    Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
    For correspondence
    s.riley@imperial.ac.uk
    Competing interests
    Steven Riley, SR receives grants from Wellcome Trust..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7904-4804
  13. Derek A Cummings

    Department of Biology, University of Florida, Gainesville, United States
    For correspondence
    datc@ufl.edu
    Competing interests
    Derek A Cummings, DATC received financial research support through his institution from Merck for unrelated work.

Funding

National Institute on Aging (R56AG048075)

  • Justin Lessler
  • Derek A Cummings

Wellcome Trust (200861/Z/16/Z)

  • Steven Riley

National Institute of Allergy and Infectious Diseases (R01AI114703)

  • Derek A Cummings

Guangzhou Government (2019B121205009)

  • Huachen Zhu
  • Yi Guan

Guangzhou Government (HZQB-KCZYZ-2021014)

  • Huachen Zhu
  • Yi Guan

National Institutes of Health (R01TW0008246)

  • Jonathan M Read
  • Steven Riley
  • Derek A Cummings

Wellcome Trust (200187/Z/15/Z)

  • Steven Riley

Medical Research Council (MR/S004793/1)

  • Jonathan M Read

Physical Sciences Research Council (EP/N014499/1)

  • Jonathan M Read

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

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Ethics

Human subjects: The following institutional review boards approved the study protocols: Johns Hopkins Bloomberg School of Public Health(IRB 1716), University of Florida (IRB201601953), University of Liverpool, University of Hong Kong (UW 09-020) and Guangzhou No. 12 Hospital ("Research on human influenza virus immunity in Southern China"). Written informed consent was obtained from all participants over 12 years old; verbal assent was obtained from participants 12 years old or younger. Written permission of a legally authorized representative was obtained for all participants under 18 years old.

Version history

  1. Preprint posted: June 27, 2022 (view preprint)
  2. Received: June 28, 2022
  3. Accepted: December 1, 2022
  4. Accepted Manuscript published: December 2, 2022 (version 1)
  5. Version of Record published: December 16, 2022 (version 2)

Copyright

© 2022, Yang 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. Bingyi Yang
  2. Bernardo García-Carreras
  3. Justin Lessler
  4. Jonathan M Read
  5. Huachen Zhu
  6. C Jessica E Metcalf
  7. James A Hay
  8. Kin O Kwok
  9. Ruiyun Shen
  10. Chao Q Jiang
  11. Yi Guan
  12. Steven Riley
  13. Derek A Cummings
(2022)
Long term intrinsic cycling in human life course antibody responses to influenza A(H3N2): an observational and modelling study
eLife 11:e81457.
https://doi.org/10.7554/eLife.81457

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https://doi.org/10.7554/eLife.81457

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