The effect of influenza vaccination on trained immunity: impact on COVID-19

  1. Priya A. Debisarun
  2. Patrick Struycken
  3. Jorge Domínguez-Andrés
  4. Simone J.C.F.M. Moorlag
  5. Esther Taks
  6. Katharina L. Gössling
  7. Philipp N. Ostermann
  8. Lisa Müller
  9. Heiner Schaal
  10. Jaap ten Oever
  11. Reinout van Crevel
  12. Mihai G. Netea

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Abstract

Every year, influenza causes 290.000 to 650.000 deaths worldwide and vaccination is encouraged to prevent infection in high-risk individuals. Interestingly, cross-protective effects of vaccination against heterologous infections have been reported, and long-term boosting of innate immunity (also termed trained immunity ) has been proposed as the underlying mechanism. Several epidemiological studies also suggested cross-protection between influenza vaccination and COVID-19 during the current pandemic. However, the mechanism behind such an effect is unknown. Using an established in-vitro model of trained immunity, we demonstrate that the quadrivalent inactivated influenza vaccine used in the Netherlands in the 2019-2020 influenza season can induce a trained immunity response, including an improvement of cytokine responses after stimulation of human immune cells with SARS-CoV-2. In addition, we found that SARS-CoV-2 infection was less common among Dutch hospital employees who had received influenza vaccination during the 2019/2020 winter season (RR = 0,61 (95% CI, 0.4585 - 0.8195, P = 0.001). In conclusion, a quadrivalent inactivated influenza vaccine can induce trained immunity responses against SARS-CoV-2, which may result in relative protection against COVID-19. These data, coupled with similar recent independent reports, argue for a beneficial effect of influenza vaccination against influenza as well as COVID-19, and suggests its effective deployment in the 2020-2021 influenza season to protect against both infections.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.14.20212498: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Blood donors: Buffy coats from healthy adult donors were obtained after written informed consent (Sanquin blood bank, Nijmegen, The Netherlands).
    IRB: The study was approved by the Arnhem-Nijmegen Medical Ethical Committee.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data analysis: Hospital database analysis was done using IBM SPSS statistics 25.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)
    Data were analyzed using Graphpad 8.02 (La Jolla, San Diego, CA, USA).
    Graphpad
    suggested: (GraphPad, RRID:SCR_000306)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    However, ecological studies also have several limitations. In this respect, there can be systematic differences in how countries and areas report disease, mortality and exposures. For example, in Italy any deceased person with a positive SARS-CoV-2 test is registered as a SARS-CoV-2 related death [28]. Besides this, information on confounding factors and effect modifiers can be missing and correction for confounders sometimes is impossible, causing over- or underestimation of outcomes. Wals et al. reviewed 18 studies in which influenza and its associations with other respiratory infections as well as COVID-19 were assessed. The conclusion was that live influenza vaccines are safe, however data on trivalent inactivated vaccines were not reassuring, followed by the suggestion to vaccinate with live vaccines when possible [29]. Aside from ecological studies, there is a recent cross sectional study conducted in Brazil, also supportive of a negative correlation between an inactivated trivalent influenza and COVID-19 attributed mortality (17% lower odds, 95%CI [0.75,0.89]), need of intensive care treatment (8% lower odds, 95%CI [0.86,0.99]) and need of invasive respiratory support (18% lower odds, 95%CI [0.74,0.88]). Correction for comorbidities, several sociodemographic factors and healthcare facilities was performed [30]. Many of these studies hypothesized that trained immunity may be the mechanism underlying these observations [21, 31-33]. The most extensively studied vaccine th...

    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…
    NCT04327206RecruitingBCG 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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Rapid Reviews Infectious Diseases

    Samer Singh

    Review 2: "The effect of influenza vaccination on trained immunity: impact on COVID-19"

    This study explores whether the influenza vaccine elicits protection against SARS-CoV-2 via trained immunity. While some of the study's findings are compelling, the work's major claims are generally unsubstantiated by the data offered.

  4. Rapid Reviews Infectious Diseases

    Ming-Jim Yang

    Review 1: "The effect of influenza vaccination on trained immunity: impact on COVID-19"

    This study explores whether the influenza vaccine elicits protection against SARS-CoV-2 via trained immunity. While some of the study's findings are compelling, the work's major claims are generally unsubstantiated by the data offered.

  5. Version published to 10.1101/2020.10.14.20212498v1 on medRxiv