Induction of trained immunity by influenza vaccination - impact on COVID-19

  1. Priya A. Debisarun
  2. Katharina L. Gössling
  3. Ozlem Bulut
  4. Gizem Kilic
  5. Martijn Zoodsma
  6. Zhaoli Liu
  7. Marina Oldenburg
  8. Nadine Rüchel
  9. Bowen Zhang
  10. Cheng-Jian Xu
  11. Patrick Struycken
  12. Valerie A. C. M. Koeken
  13. Jorge Domínguez-Andrés
  14. Simone J. C. F. M. Moorlag
  15. Esther Taks
  16. Philipp N. Ostermann
  17. Lisa Müller
  18. Heiner Schaal
  19. Ortwin Adams
  20. Arndt Borkhardt
  21. Jaap ten Oever
  22. Reinout van Crevel
  23. Yang Li
  24. Mihai G. Netea

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Abstract

Non-specific protective effects of certain vaccines have been reported, and long-term boosting of innate immunity, termed trained immunity , has been proposed as one of the mechanisms mediating these effects. Several epidemiological studies suggested cross-protection between influenza vaccination and COVID-19. In a large academic Dutch hospital, we found that SARS-CoV-2 infection was less common among employees who had received a previous influenza vaccination: relative risk reductions of 37% and 49% were observed following influenza vaccination during the first and second COVID-19 waves, respectively. The quadrivalent inactivated influenza vaccine induced a trained immunity program that boosted innate immune responses against various viral stimuli and fine-tuned the anti-SARS-CoV-2 response, which may result in better protection against COVID-19. Influenza vaccination led to transcriptional reprogramming of monocytes and reduced systemic inflammation. These epidemiological and immunological data argue for potential benefits of influenza vaccination against COVID-19, and future randomized trials are warranted to test this possibility.

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  1. Version published to 10.1371/journal.ppat.1009928
  2. ScreenIT

    SciScore for 10.1101/2021.09.03.21263028: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Giving the observational nature of this study, ethical waiver was obtained from the Arnhem-Nijmegen Ethical Committee.
    Consent: After giving written informed consent, blood was collected by venous blood puncture 1 week before and 6 weeks after vaccination.
    Sex as a biological variableThe average age and BMI were 34.9±8.9 and 22.8±2.8, respectively. 61% of the study participants were female.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data analysis: Hospital database analysis was done using GraphPad Prism 8 (CA, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Participants were vaccinated with 0.5 mL of Influvac Tetra (Abbott Biologicals, IL, USA) intramuscularly.
    Abbott Biologicals
    suggested: None
    R package limma was used for differential expression analysis and p-values < 0.05 after Benjamini-Hochberg adjustment were considered significant.
    limma
    suggested: (LIMMA, RRID:SCR_010943)
    Equal number of cells (3,300 per individual) from 4 different individuals were pooled together and then loaded into the Chromium™ Controller to separate single cells into Gel Beads-in-emulsion (GEMs)
    GEMs
    suggested: (GEMS, RRID:SCR_009188)
    Significantly differentially expressed genes between the conditions were retrieved per cell type and used as input for GO enrichment using ClusterProfiler (v.3.18.1) (44).
    ClusterProfiler
    suggested: (clusterProfiler, RRID:SCR_016884)
    Enrichment of genes was tested both in Gene Ontologies (GO) and within the Kyoto Encyclopedia of Genes and Genomes (KEGG) and considered significant if the Benjamini-Hochberg adjusted p-value was < 0.05.
    KEGG
    suggested: (KEGG, RRID:SCR_012773)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study also has important limitations. The hospital population database analysis performed in this study did not allow correction for confounders, as we were not able to access individual characteristics due to hospital privacy policies. A critical possible confounder could be direct patient contact within influenza vaccinated and unvaccinated personnel. However, earlier studies have reported that most SARS-CoV-2 infections in hospital personnel occur in society rather than through patient contact in the hospitals (39-41). Furthermore, there was no information on comorbidities or other exposures outside the hospital environment. While comorbidities are an important factor related to COVID-19 susceptibility and severity, there are no reasons to expect an unequal distribution of comorbidities among influenza vaccinated and unvaccinated personnel for it to cause skewing of the results. Lastly, one cannot rule out healthy-vaccinee bias, which might lead healthier people to better adhere to annual influenza vaccine recommendations. In addition, the in vivo trained immunity effect by influenza vaccination had not been studied as part of a placebo-controlled clinical trial, since healthy volunteers, who had decided autonomously to get vaccinated, were recruited. In conclusion, we provide observational data suggesting a negative association between the quadrivalent inactivated influenza vaccine and COVID-19 incidence. Additionally, we report first insights into the immunological m...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04328441Active, not recruitingReducing Health Care Workers Absenteeism in Covid-19 Pandemi…
    NCT04348370RecruitingBCG Vaccine for Health Care Workers as Defense Against COVID…
    NCT04327206Active, not recruitingBCG Vaccination to Protect Healthcare Workers Against COVID-…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.09.03.21263028v1 on medRxiv