Association of Bacille Calmette-Guérin (BCG), Adult Pneumococcal and Adult Seasonal Influenza Vaccines with Covid-19 Adjusted Mortality Rates in Level 4 European countries

  1. Joe Gallagher
  2. Chris Watson
  3. Mark Ledwidge

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Abstract

Introduction

Non-specific effects of vaccines have gained increasing interest during the Covid-19 pandemic. In particular, population use of BCG vaccine has been associated with improved outcomes. This study sought to determine the association of population use of BCG, adult pneumococcal and adult seasonal influenza vaccination with Covid-19 mortality when adjusted for a number of confounding variables.

Methods

Using publicly available data, mortality adjusted for the timeframe of crisis, population size and population characteristics was calculated. The primary analysis was the relationship between each of the day 15 and day 30 standardised mortality rates and BCG, adult pneumococcal and influenza vaccination scores using unadjusted measures and with adjustment for population structure and case fatality rates. Secondary analyses were measures of case increases and mortality increases from day 15 to day 30 for each of the relative vaccination scores. Finally, we also analysed the peak Z score reflecting increases in total mortality from historical averages reported by EuroMOMO (Euromomo.eu),

Results

Following adjustment for the effects of population size, median age, population density, the proportion of population living in an urban setting, life-expectancy, the elderly dependency ratio (or proportion over 65 years), net migration, days from day 1 to lockdown and case-fatality rate, only BCG vaccination score remained significantly associated with Covid-19 mortality at day 30. In the best fit model, BCG vaccination score was associated with a 64% reduction in log(10) mortality per 10 million population (OR 0.362 reduction [95% CI 0.188 to 0.698]), following adjustment for population size, median age, density, urbanization, elderly dependency ratio, days to lockdown, yearly migration and case fatality rate.

Conclusion

BCG vaccine was associated with reduced mortality rates in level 4 countries while adult pneumococcal and adult seasonal influenza vaccines were not when adjusted for a number of confounding variables. A number of trials are ongoing to determine if BCG is protective against severe Covid-19 infection.

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  1. ScreenIT

    SciScore for 10.1101/2020.06.03.20121624: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Graphs were presented using GraphPad Prism v6 and statistical analysis was performed using the R statistical software package (Version 3.6.2, 2019–12–12, Copyright 2019 The R Foundation).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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:
    While this ecological study may be the first to evaluate BCG vaccination in models with standardisation of mortality rates for timeframe of the outbreak as well as population size, as well as incorporating extensive covariate adjustment related to population structure, the major limitation is that it demonstrates correlation but cannot definitively assign causation. There may be many other confounding variables, which could account for the relationship between BCG vaccination and mortality. Furthermore, it is well accepted that differences in recording mortality between countries have been reported which may affect numbers. Finally, the BCG vaccination score is an estimate of the population coverage with BCG and may not accurately reflect the true population vaccination. Conversely, the extensive covariate adjustment as well as differential relationship between BCG and influenza/pneumococcal vaccination scores, may support the hypothesis that BCG vaccination is associated with protection from the severest consequences of Covid 19. There is a persistent relationship between BCG vaccination and a variety of mortality and morbidity measures, including peak standardised Z-scores reported for the pandemic. The present study builds on a growing body of evidence that BCG vaccination may be associated with decreased illness severity unrelated to mycobacterium infection. Many have been epidemiological studies looking at overall mortality rates but others have looked at specific unrela...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

  2. Version published to 10.1101/2020.06.03.20121624v1 on medRxiv