1. Epidemiology and Global Health
  2. Immunology and Inflammation

A recombinant protein containing influenza viral conserved epitopes and superantigen induces broad-spectrum protection

  1. Yansheng Li
  2. Mingkai Xu  Is a corresponding author
  3. Yongqiang Li
  4. Wu Gu
  5. Gulinare Halimu
  6. Yuqi Li
  7. Zhichun Zhang
  8. Libao Zhou
  9. Hui Liao
  10. Songyuan Yao
  11. Huiwen Zhang
  12. Chenggang Zhang
  1. Chinese Academy of Sciences, China
  2. Chengda Biotechnology Co Ltd, China
https://doi.org/10.7554/eLife.71725
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Cite this article
  1. Yansheng Li
  2. Mingkai Xu
  3. Yongqiang Li
  4. Wu Gu
  5. Gulinare Halimu
  6. Yuqi Li
  7. Zhichun Zhang
  8. Libao Zhou
  9. Hui Liao
  10. Songyuan Yao
  11. Huiwen Zhang
  12. Chenggang Zhang
(2021)
A recombinant protein containing influenza viral conserved epitopes and superantigen induces broad-spectrum protection
eLife 10:e71725.
https://doi.org/10.7554/eLife.71725
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Abstract

Influenza pandemics pose public health threats annually for lacking vaccine which provides cross-protection against novel and emerging influenza viruses. Combining conserved antigens that induce cross-protective antibody responses with epitopes that activate cross-protective T cell responses might be an attractive strategy for developing a universal vaccine. In this study, we constructed a recombinant protein named NMHC which consist of influenza viral conserved epitopes and a superantigen fragment. NMHC promoted the maturation of bone marrow-derived dendritic cells and induced CD4+ T cells to differentiate into Th1, Th2, and Th17 subtypes. Mice vaccinated with NMHC produced high levels of immunoglobulins that cross-bound to HA fragments from six influenza virus subtypes with high antibody titers. Anti-NMHC serum showed potent hemagglutinin inhibition effects to highly divergent group 1 (H1 subtype) and group 2 (H3 subtype) influenza virus strains. Furthermore, purified anti-NMHC antibodies bound to multiple HAs with high affinities. NMHC vaccination effectively protected mice from infection and lung damage when exposed to two subtypes of H1N1 influenza virus. Moreover, NMHC vaccination elicited CD4+ and CD8+ T cell responses that cleared the virus from infected tissues and prevented virus spread. In conclusion, this study provides proof of concept that NMHC vaccination triggers B and T cell immune responses against multiple influenza virus infections. Therefore, NMHC might be a candidate universal broad-spectrum vaccine for the prevention and treatment of multiple influenza viruses.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Yansheng Li

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Mingkai Xu

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    For correspondence
    mkxu@iae.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9889-6287

  3. Yongqiang Li

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Wu Gu

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Gulinare Halimu

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Yuqi Li

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Zhichun Zhang

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Libao Zhou

    Chengda Biotechnology Co Ltd, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Hui Liao

    Chengda Biotechnology Co Ltd, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Songyuan Yao

    Chengda Biotechnology Co Ltd, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  11. Huiwen Zhang

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

  12. Chenggang Zhang

    Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.

Funding

Strategic Priority Research Progrem of the Chinese Academy of Sciences Grant (XDA12020225)

  • Mingkai Xu

Liaoning Revitalization Talents Program (XLYC1807226)

  • Mingkai Xu

Science and Technolog Plan Projects of Shenyang City Grants (Z17-7-013)

  • Mingkai Xu

Shengyang High level Innovative Talents Program (RC190060)

  • Mingkai Xu

Science and Technology Agency Livelihood Program of Liaoning Province of China (2021JH2/10300075)

  • Mingkai Xu

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health . All animal procedures were performed according to approved Institutional Animal Care and Use Committee (IACUC) guidelines of University of Chinese Academy of Sciences (permit-number IAE.No20191010A0120). All surgery was performed under tribromoethanol anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Version history

  1. Received: June 28, 2021
  2. Preprint posted: July 8, 2021 (view preprint)
  3. Accepted: November 13, 2021
  4. Accepted Manuscript published: November 16, 2021 (version 1)
  5. Version of Record published: December 1, 2021 (version 2)

Copyright

© 2021, Li 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. Yansheng Li
  2. Mingkai Xu
  3. Yongqiang Li
  4. Wu Gu
  5. Gulinare Halimu
  6. Yuqi Li
  7. Zhichun Zhang
  8. Libao Zhou
  9. Hui Liao
  10. Songyuan Yao
  11. Huiwen Zhang
  12. Chenggang Zhang
(2021)
A recombinant protein containing influenza viral conserved epitopes and superantigen induces broad-spectrum protection
eLife 10:e71725.
https://doi.org/10.7554/eLife.71725

Categories and tags

Research organism

Further reading

    1. Epidemiology and Global Health
    2. Medicine

    Association between bisphosphonate use and COVID-19 related outcomes

    Jeffrey Thompson, Yidi Wang ... Ulrich H von Andrian
    Research Article Updated

    Background:

    Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

    Methods:

    A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

    Results:

    A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

    Conclusions:

    Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

    Funding:

    This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).

    1. Epidemiology and Global Health

    Sleep: Another benefit of regular sleep

    Tianyi Huang
    Insight

    A large observational study has found that irregular sleep-wake patterns are associated with a higher risk of overall mortality, and also mortality from cancers and cardiovascular disease.

    1. Epidemiology and Global Health

    Sleep regularity and mortality: a prospective analysis in the UK Biobank

    Lachlan Cribb, Ramon Sha ... Matthew P Pase
    Research Article

    Background:

    Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort.

    Methods:

    The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0–100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models.

    Results:

    The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern.

    Conclusions:

    Irregular sleep-wake patterns are associated with higher mortality risk.

    Funding:

    National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer’s Association (2018-AARG-591358), and the Banting Fellowship Program (#454104).