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Cited by 43Immune responses and vaccinationsTuberculosis Research and EpidemiologySARS-CoV-2 and COVID-19 Research

Bacille Calmette-Guérin Vaccination in Infancy Does Not Protect Against Coronavirus Disease 2019 (COVID-19): Evidence From a Natural Experiment in Sweden

Open access
de Chaisemartin, Clément, de Chaisemartin, Luc·2021·Clinical Infectious Diseases
DOI 10.1093/cid/ciaa1223

Published version of a preprint

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Abstract

BACKGROUND: The bacille Calmette-Guérin (BCG) tuberculosis vaccine has immunity benefits against respiratory infections. Accordingly, it has been hypothesized to have a protective effect against coronavirus disease 2019 (COVID-19). Recent research found that countries with universal BCG childhood vaccination policies tend to be less affected by the COVID-19 pandemic. However, such ecological studies are biased by numerous confounders. Instead, this paper reports on a rare nationwide natural experiment that occurred in Sweden in 1975, where discontinuation of newborns' BCG vaccination led to a dramatic decrease in BCG coverage rate, thus allowing us to estimate BCG's effect without the biases associated with cross-country comparisons. METHODS: Numbers of COVID-19 cases and hospitalizations were recorded for birth cohorts born just before and just after 1975, representing 1 026 304 and 1 018 544 individuals, respectively. We used regression discontinuity to assess the effect of BCG vaccination on COVID-19-related outcomes. On such a large population, this method allows for a precision that would be hard to achieve using a randomized controlled trial. RESULTS: The odds ratios (95% CI) for COVID-19 cases and COVID-19-related hospitalizations were 1.0005 (.8130-1.1881) and 1.2046 (.7532-1.6560), allowing us to reject fairly modest effects of universal BCG vaccination. We can reject with 95% confidence that universal BCG vaccination reduces the number of cases by 19% and the number of hospitalizations by 25%. CONCLUSIONS: While the effect of a recent vaccination must be evaluated, we provide strong evidence that receiving the BCG vaccine at birth does not have a protective effect against COVID-19 among middle-aged individuals.

Integrity signals

Registry

Crossref · 10.1093/cid/ciaa1223

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 11 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    After accounting for foreign-born residents, the 1975 policy change reduced the BCG vaccination rate by 65.5%.

    “Taking into account foreign-born residents (27.2% of the Swedish population born in 1975), who were not affected by the policy, the policy led to a drop in the vaccination rate of 65.5%.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The BCG vaccination rate of foreign-born residents in Sweden was the same just before and just after April 1975.
    • Rests on an assumption: No other European country changed its BCG vaccination policy in 1975.
  • Findingown data

    The number of COVID-19 cases per 1000 inhabitants does not jump at the April 1975 threshold.

    “Accordingly, Figure 1 shows no discontinuity in the numbers of COVID-19 cases per 1000 inhabitants for cohorts born just before and just after April 1975.”
    Quote in the paperSubstantial claim
  • Findingown data

    COVID-19 death rates do not differ significantly between the 1972-1973-1974 and 1975-1976-1977 yearly birth cohorts.

    “For deaths per capita, we find that the death rates in the 1972-1973-1974 and 1975-1976-1977 YBCs are not significantly different (see Supplementary Materials).”
    Quote in the paperSubstantial claim
  • Findingown data

    With 95% confidence, one can reject that universal BCG vaccination lowers COVID-19 cases by 19% and hospitalizations by 25%.

    “We can reject with 95% confidence that universal BCG vaccination reduces the number of cases by 19% and the number of hospitalizations by 25%.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Sweden's BCG vaccination coverage fell from 92% to 2% for cohorts born just before and just after April 1975.

    “In April 1975, it stopped its newborn BCG vaccination program, leading to a dramatic drop in the BCG vaccination rate from 92% to 2% for cohorts born just before and just after the change [16].”
    • Also stated in: § DISCUSSION · plain
      “Based on nationwide reports on the vaccination status of children younger than 7 years sent to the National Bacteriological Laboratory in 1981, 92% of children born in 1974 got vaccinated, compared with 26% of those born in 1975 and less than 2% of those born between 1976 and 1980 [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Romanus, 1992, The impact of changing BCG coverage on tuberculosis incidence in Swedish-born children between 1969 and 1989, Tuber Lung Dis source

      Not checked in the free run.

  • May combine two claims. 8
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    The BCG vaccination policy had no statistically significant effect on COVID-19 cases per 1000 inhabitants or hospitalizations per 1000 inhabitants.

    “They show that the effects of the BCG vaccination policy on cases per 1000 inhabitants and hospitalizations per 1000 inhabitants are not statistically different from 0.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The number of COVID-19 hospitalizations per 1000 inhabitants and the number of COVID-19 deaths per 1000 inhabitants also do not jump at the April 1975 threshold.

    “Figures 2 and 3 show that similar conclusions apply when one looks at the number of COVID-19 hospitalizations per 1000 inhabitants and at the number of COVID-19 deaths per 1000 inhabitants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For people born around April 1975, the odds ratios for COVID-19 cases and COVID-19-related hospitalizations were 1.0005 (95% CI .8130-1.1881) and 1.2046 (95% CI .7532-1.6560), respectively, and neither differed significantly from 1.

    “The odds ratios (95% CI) for COVID-19 cases and COVID-19-related hospitalizations were 1.0005 (.8130-1.1881) and 1.2046 (.7532-1.6560), allowing us to reject fairly modest effects of universal BCG vaccination.”
    • Also stated in: § RESULTS · plain
      “For odds ratios, the effects thus obtained are 1.0005 (95% CI, .8130-1.1881) for COVID-19 cases and 1.2046 (95% CI, .7532-1.6560) for COVID-19-related hospitalizations.These odds ratios are not significantly different from 1, confirming the absence of effect of BCG vaccination at birth on COVID-19-related outcomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Imbens, 1994, Identification and estimation of local average treatment effects, Econometrica source

      Not checked in the free run.

    • The authors state this as an assumption: The BCG vaccination rate of foreign-born residents in Sweden was the same just before and just after April 1975.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 4304 COVID-19 cases and 1020 hospitalizations among people born in the 1970s.

    “although there are still 4304 cases and 1020 hospitalizations among individuals born in the 1970s, the decade when the reform we studied took place.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    COVID-19 cases and hospitalizations are more numerous in older birth cohorts than in younger ones.

    “Those numbers are higher for older than for younger cohorts, although there are still 4304 cases and 1020 hospitalizations among individuals born in the 1970s, the decade when the reform we studied took place.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The t-test used for death rates is less robust than the regression discontinuity method because it does not account for the 3-year difference in average age between treated and control groups.

    “This method is less robust than the RD method we use for cases and hospitalizations, as it does not account for the fact that the average age of the treated and control groups differs by 3 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The study's estimates apply only to people born around 1 April 1975, who were in their mid-40s during the pandemic, and cannot be generalized to the whole population.

    “Furthermore, RD estimates only apply to units close to the eligibility threshold.For instance, this study estimates the effect of universal BCG vaccination for individuals born around 1 April 1975, who are in their mid-40s during the COVID-19 pandemic, and cannot be generalized to the entire population.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The BCG vaccine has been proven effective against tuberculosis, particularly severe forms such as meningeal and miliary tuberculosis.

    “The bacille Calmette-Guérin (BCG) vaccine is an attenuated live vaccine that has been proven to be effective against tuberculosis, in particular its severe manifestations such as meningeal and miliary tuberculosis [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mangtani, 2014, Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials, Clin Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The study had high statistical precision, enabling it to reject fairly small BCG vaccine effects.

    “Another strength of this study is its statistical precision.Since we could gather nationwide data in a country where COVID-19 rates are high, we were able to reject fairly small effects of the BCG vaccine.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The regression discontinuity estimator assumes that the variable determining exposure is continuous, but it has also been used when that variable is discrete but takes many values.

    “The RD estimator in Calonico et al [19] assumes that the variable determining exposure is continuous, but it has also been used when that variable is discrete but takes a large number of values.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Calonico, 2014, Robust nonparametric confidence intervals for regression-discontinuity designs, Econometrica source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The Swedish Public Health Agency's COVID-19 case count probably underestimates the true number of cases because it includes only laboratory-confirmed cases.

    “As in many other countries, the Folkhälsomyndigheten case count probably underestimates the true number of cases, because it only includes cases confirmed by a laboratory test.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The study does not measure the COVID-19 immunity benefit from a recent BCG vaccination.

    “Moreover, this study does not measure the COVID-19 immunity benefit conferred by a recent BCG vaccination, as individuals born just before Q2-1975 were vaccinated 45 years ago.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The study's results are available much earlier than those of the ongoing randomized controlled trials and with greater precision.

    “While RCTs will complement this study by measuring the effect of a recent vaccination, this study comes much before results of the RCTs will be made available, and with a greater precision.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The regression discontinuity design removes confounders from cross-country comparisons and confounders such as sex or socioeconomic status.

    “This allowed us to eliminate all confounders linked to cross-country comparisons, and confounders such as sex or socioeconomic status, which are often present in observational studies that do not rely on a quasi-experimental design, unlike ours.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The Swedish Public Health Agency's COVID-19 death count probably underestimates the true number of COVID-19 deaths.

    “Its death count probably underestimates the true number of COVID-19 deaths as well, as it only includes deaths where a COVID-19 diagnosis has been confirmed during the past 30 days.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The BCG vaccine provides immunity benefits against respiratory infections.

    “Besides its specific effects, the vaccine has immunity benefits against nontargeted pathogens [2], and in particular against respiratory infections caused by RNA viruses like influenza [3].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Aaby, 2020, The non-specific and sex-differential effects of vaccines, Nat Rev Immunol source

      Not checked in the free run.

    • cites [3] Moorlag, 2019, Non-specific effects of BCG vaccine on viral infections, Clin Microbiol Infect source

      Not checked in the free run.

16 of 16

  • The authors state this as an assumption.

    The BCG vaccination rate of foreign-born residents in Sweden was the same just before and just after April 1975.

    “Our computation of the change in the vaccination rate induced by the 1975 policy relies on the assumption that the BCG vaccination rate of foreign-born residents is the same just before and just after April 1975.”

  • The paper relies on this without support.

    No other European country changed its BCG vaccination policy in 1975.

    “However, this is a reasonable assumption, since no other European country changed its BCG vaccination policy in 1975.”
2 of 2

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Related

Authors
de Chaisemartin, C., & de Chaisemartin, L.
Affiliations
  • Department of Economics, University of California, Santa Barbara, Santa Barbara, California, USA
  • Immunology Department, Assistance Publique - Hôpitaux de Paris, Nord-Université de Paris, Bichat Hospital, Paris, France
ORCID
de Chaisemartin, Luc
Venue
Clinical Infectious Diseases
Publisher
Oxford University Press (OUP)
Published
2020-08-23
Volume
72
Issue
10
Pages
e501-e505
ISSN
  • 1058-4838 (ISSN-L)
  • 1537-6591
DOI
10.1093/cid/ciaa1223
OpenAlex
W3080146469
Cited by
43
References
24
Citations by year
2025: 2 · 2022: 16 · 2021: 19 · 2020: 6
FWCI
3.59
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Clinical Infectious Diseases (publishedVersion)
  • medRxiv (acceptedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Public Health Agency
  • Folkhälsomyndigheten
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
BCG vaccine, COVID-19 pandemic, SARS-CoV-2, childhood immunization, COVID-19 hospitalization, COVID-19 cases, natural experiment, Sweden, birth cohort
MeSH terms
COVID-19, SARS-CoV-2, BCG Vaccine, Humans, Infant, Infant, Newborn, Middle Aged, Sweden, Vaccination, Cohort Studies, Pandemics

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