Long term intrinsic cycling in human life course antibody responses to influenza A(H3N2): an observational and modelling study
- University of Hong Kong, Hong Kong
- University of Florida, United States
- University of North Carolina at Chapel Hill, United States
- Lancaster University, United Kingdom
- Princeton University, United States
- Harvard TH Chan School of Public Health, United States
- Chinese University of Hong Kong, China
- Guangzhou Number 12 People's Hospital, China
- 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
C Jessica E Metcalf
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.
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.
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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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
Further reading
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- Epidemiology and Global Health
Background:
The role of circulating metabolites on child development is understudied. We investigated associations between children’s serum metabolome and early childhood development (ECD).
Methods:
Untargeted metabolomics was performed on serum samples of 5004 children aged 6–59 months, a subset of participants from the Brazilian National Survey on Child Nutrition (ENANI-2019). ECD was assessed using the Survey of Well-being of Young Children’s milestones questionnaire. The graded response model was used to estimate developmental age. Developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Partial least square regression selected metabolites with a variable importance projection ≥1. The interaction between significant metabolites and the child’s age was tested.
Results:
Twenty-eight top-ranked metabolites were included in linear regression models adjusted for the child’s nutritional status, diet quality, and infant age. Cresol sulfate (β=–0.07; adjusted-p <0.001), hippuric acid (β=–0.06; adjusted-p <0.001), phenylacetylglutamine (β=–0.06; adjusted-p <0.001), and trimethylamine-N-oxide (β=–0.05; adjusted-p=0.002) showed inverse associations with DQ. We observed opposite directions in the association of DQ for creatinine (for children aged –1 SD: β=–0.05; pP=0.01;+1 SD: β=0.05; p=0.02) and methylhistidine (–1 SD: β = - 0.04; p=0.04;+1 SD: β=0.04; p=0.03).
Conclusions:
Serum biomarkers, including dietary and microbial-derived metabolites involved in the gut-brain axis, may potentially be used to track children at risk for developmental delays.
Funding:
Supported by the Brazilian Ministry of Health and the Brazilian National Research Council.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Several areas of the world suffer a notably high incidence of Shiga toxin-producing Escherichia coli. To assess the impact of persistent cross-species transmission systems on the epidemiology of E. coli O157:H7 in Alberta, Canada, we sequenced and assembled E. coli O157:H7 isolates originating from collocated cattle and human populations, 2007–2015. We constructed a timed phylogeny using BEAST2 using a structured coalescent model. We then extended the tree with human isolates through 2019 to assess the long-term disease impact of locally persistent lineages. During 2007–2015, we estimated that 88.5% of human lineages arose from cattle lineages. We identified 11 persistent lineages local to Alberta, which were associated with 38.0% (95% CI 29.3%, 47.3%) of human isolates. During the later period, six locally persistent lineages continued to be associated with human illness, including 74.7% (95% CI 68.3%, 80.3%) of reported cases in 2018 and 2019. Our study identified multiple locally evolving lineages transmitted between cattle and humans persistently associated with E. coli O157:H7 illnesses for up to 13 y. Locally persistent lineages may be a principal cause of the high incidence of E. coli O157:H7 in locations such as Alberta and provide opportunities for focused control efforts.
