Long term intrinsic cycling in human life course antibody responses to influenza A(H3N2): an observational and modelling study
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
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
- 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
- Preprint posted: June 27, 2022 (view preprint)
- Received: June 28, 2022
- Accepted: December 1, 2022
- Accepted Manuscript published: December 2, 2022 (version 1)
- 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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Further reading
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- Epidemiology and Global Health
Background:
The aim of our study was to test the hypothesis that the community contact tracing strategy of testing contacts in households immediately instead of at the end of quarantine had an impact on the transmission of SARS-CoV-2 in schools in Reggio Emilia Province.
Methods:
We analysed surveillance data on notification of COVID-19 cases in schools between 1 September 2020 and 4 April 2021. We have applied a mediation analysis that allows for interaction between the intervention (before/after period) and the mediator.
Results:
Median tracing delay decreased from 7 to 3.1 days and the percentage of the known infection source increased from 34–54.8% (incident rate ratio-IRR 1.61 1.40–1.86). Implementation of prompt contact tracing was associated with a 10% decrease in the number of secondary cases (excess relative risk –0.1 95% CI –0.35–0.15). Knowing the source of infection of the index case led to a decrease in secondary transmission (IRR 0.75 95% CI 0.63–0.91) while the decrease in tracing delay was associated with decreased risk of secondary cases (1/IRR 0.97 95% CI 0.94–1.01 per one day of delay). The direct effect of the intervention accounted for the 29% decrease in the number of secondary cases (excess relative risk –0.29 95%–0.61 to 0.03).
Conclusions:
Prompt contact testing in the community reduces the time of contact tracing and increases the ability to identify the source of infection in school outbreaks. Although there are strong reasons for thinking it is a causal link, observed differences can be also due to differences in the force of infection and to other control measures put in place.
Funding:
This project was carried out with the technical and financial support of the Italian Ministry of Health – CCM 2020 and Ricerca Corrente Annual Program 2023.
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- Epidemiology and Global Health
In biomedical science, it is a reality that many published results do not withstand deeper investigation, and there is growing concern over a replicability crisis in science. Recently, Ellipse of Insignificance (EOI) analysis was introduced as a tool to allow researchers to gauge the robustness of reported results in dichotomous outcome design trials, giving precise deterministic values for the degree of miscoding between events and non-events tolerable simultaneously in both control and experimental arms (Grimes, 2022). While this is useful for situations where potential miscoding might transpire, it does not account for situations where apparently significant findings might result from accidental or deliberate data redaction in either the control or experimental arms of an experiment, or from missing data or systematic redaction. To address these scenarios, we introduce Region of Attainable Redaction (ROAR), a tool that extends EOI analysis to account for situations of potential data redaction. This produces a bounded cubic curve rather than an ellipse, and we outline how this can be used to identify potential redaction through an approach analogous to EOI. Applications are illustrated, and source code, including a web-based implementation that performs EOI and ROAR analysis in tandem for dichotomous outcome trials is provided.