Abstract
We compared whether the national BCG vaccination (BCGV) policy influenced coronavirus disease 2019 (COVID-19) in Organisation for Economic Co-operation and Development (OECD) countries. Those currently implementing BCGV have a reduced number of COVID-19 morbidity and mortality cases, compared to those who have never implemented a BCGV policy, suggesting the potential protective effect of BCGV against COVID-19.
Keywords: COVID-19, coronavirus infections, epidemiology, Bacillus Calmette-Guerin vaccine, OECD
Background
The reported morbidity and mortality associated with coronavirus disease 2019 (COVID-19) are heterogeneous across countries, an intriguing observation that could be partially attributed to the national implementation of Bacille Calmette-Guérin vaccination (BCGV) programmes. Several studies suggest its protective effects on reducing susceptibility to non-specific respiratory infections by epigenetic reprogramming of monocytes, accompanied by functional changes that promote acquired immunity. Hence, clinical studies assessing the link between BCGV and COVID-19 have been initiated in some countries (Arts et al., 2018; de Vrieze, 2020; Klein et al., 2015). Consequently, our investigation explored whether a correlation exists between the epidemic trend of COVID-19 and BCGV policies.
Methods
Thirty-five countries of the Organisation for Economic Co-operation and Development (OECD) (excluding Iceland due to lack of data), as well as China and Taiwan, were included in this study. The incidence and mortality data related to COVID-19 were collected from the COVID-19 situation reports of the World Health Organization (WHO) published on 20 April 2020, and adjusted by the respective population of the countries using publicly available data (WHO, 2020).
The countries were categorised into the following three groups, based on their status of implementing BCGV programmes, which was determined using the World BCG Atlas (2017): Category 1, currently implemented (n = 15); Category 2, previously implemented (n = 17); and Category 3, never implemented (n = 5). The continuous variables were compared using the Tukey (equal variance), one-way ANOVA and Kruskal–Wallis (unequal variance) tests, followed by post-hoc Bonferroni correction. All statistical analyses were performed using the R software (Version 3.6.3; the R Foundation for Statistical Computing, Vienna, Austria).
Ethical approval from the institutional review board was not necessary, because the study did not include any patients.
Results
The Bartlett test on the number of COVID-19 morbidity and mortality cases per 100,000 population were performed to compare between the groups, Categories 1, 2 and 3. The COVID-19 morbidity data showed equal variance (P = 0.110), whereas mortality showed unequal variance (P < 0.001). Thus, we adopted the one-way ANOVA for analysing the COVID-19 morbidity data and the Kruskal–Wallis test for COVID-19 associated mortality, respectively. The correlation with BCGV policies was statistically significant for both morbidity (P = 0.0186) and mortality (P = 0.00266). Moreover, the Tukey test for COVID-19 morbidity showed a statistically significant difference between Categories 1 and 3 (P = 0.0392). The Bonferroni-corrected threshold for COVID-19 associated mortality also showed significant difference between Categories 1 and 3 (P = 0.0027) (Figure 1).
Figure 1.
The relationship between COVID-19 and national BCG vaccination policy. The COVID-19 morbidity (number of infected per 100,000 people) and mortality (number of deceased per 100,000 people) rates are indicated on the left and right, respectively. Category 1 represents currently implemented BCGV countries, Category 2 represents countries with a previously implemented BCGV policy and Category 3 represents countries in which BCGV was never implemented. IQR, interquartile range; SE, standard error.
Discussion
Among the countries included in the study (OECD countries, China and Taiwan), where the standard of medical care is relatively higher than in low-income countries, we have observed reduced COVID-19 morbidity and mortality in countries currently implementing a BCGV policy compared to those who have never implemented a BCGV policy.
Our findings support the observation made by Miller et al. (2020) and Sala et al. (2020) who published preliminary preprint studies using COVID-19-associated mortality up to March 2020, regarding the lowered COVID-19-associated mortality in countries with a BCGV policy. Notably, both studies merely compared the COVID-19 mortality in countries with more than 1 million inhabitants, whereas we have included all the OECD countries with available data. Furthermore, this study additionally included COVID-19 morbidity and mortality data that were accumulated over a one-month period, specifically April 2020. Hence, our study further validates a potential association between implementation of BCGV policy and COVID-19-associated morbidity and mortality presented by Miller et al. (2020) and Sala et al. (2020) The countries included in the study have a relatively high medical and economic status compared to low-income countries; thus, one of the strengths of our study is that economic status is eliminated as a possible confounding factor. Previous ecological investigations have suggested a correlation between increased mortality associated with acute respiratory illness and a country’s low economic status (Sonego et al., 2015). In addition, a recent study also presented a strong correlation of the country’s income status and life expectancy with mortality of COVID-19 (Miller et al., 2020; Sala et al., 2020). Therefore, it is imperative to consider the country’s economic status as a potential confounding factor in analysis.
Our study has several limitations. First, the included countries are at different epidemic stages of COVID-19, which might have a differential impact on the effect of BCGV implementation on COVID-19-related incidences and deaths. Second, we excluded other possible confounding factors, such as life expectancies, number of doctors and BCGV strains. Third, as our study is based on cross-sectional analysis, only a predictive correlation is suggested, rather than a causal relationship.
In conclusion, we observed a statistically significant correlation between national BCGV policies and mortality and morbidity of COVID-19 among OECD countries, China and Taiwan. While the WHO recommends the BCGV at birth, particularly in tuberculosis-endemic areas, many high-income countries have discontinued their mandatory vaccination due to the decrease in cases of tuberculosis (de Vrieze 2020). However, as BCGV is one of the oldest and safest vaccines available, even in low-income countries, further considerations may be needed for BGCVs as a public health measure, not only for tuberculosis but also for COVID-19.
Footnotes
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Tanimoto reports personal fees from MNES Inc., and Medical Network Systems outside of the submitted work. All the other authors declare that they have no competing interests.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Peer review statement: Not commissioned; blind peer-reviewed.
ORCID iDs: Yuki Senoo 
https://orcid.org/0000-0001-7289-5016
Kenzo Takahashi
https://orcid.org/0000-0001-5672-3273
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