key: cord-1045282-grnhx1pp authors: Ebina-Shibuya, Risa; Horita, Nobuyuki; Namkoong, Ho; Kaneko, Takeshi title: Current national policies for infant universal bacille Calmette-Guérin vaccination were associated with lower mortality from coronavirus disease 2019 date: 2020-07-31 journal: Clin Exp Vaccine Res DOI: 10.7774/cevr.2020.9.2.179 sha: fc5cb2cd12e03b6bc35bc6cd2ad2bb489134c39d doc_id: 1045282 cord_uid: grnhx1pp An exciting debate has emerged whether bacille Calmette-Guérin (BCG) vaccination is effective for the coronavirus disease 2019 (COVID-19) pandemic. Some advocated that BCG-vaccinated people are less suffered from the virus because BCG vaccination is recommendedin COVID-19 high burden countries. However, the others objected because this seemingly attractive relationship is explainable with confounding factors. In a multiple regression with 171 countries adjusting socioeconomical and climatic covariates, countries with current universal pediatric BCG policy were associated with 30-fold (95% confidence interval, 17–52) decrease of COVID-19 mortality per population compared to countries without the policy. ingful also because higher mortality from COVID-19 were observed for the elderly. Population density was adopted because this may associate with social distance. Annual average temperature was included as an explanatory variable because confirmed cases and death cases were rare in tropical countries near the equator. Countries and regions were divided into currently recommended countries (CRC) and currently not recommended countries (CNRC) based on the national policy for the vaccination. Following data sources were used: (1) number of death cases as of April 10, 2020 from each countries and region: Worldometer "COVID-19 Coronavirus Pandemic" [1] ; population size and population density: United Nations "World Population Prospects 2019" [7] ; national BCG vaccination policy: "The BCG World Atlas" [6] ; gross national income per capita and life expectancy at birth: United Nations Development Programme "Human Development Report 2019" [8] ; and infant mortality out of live births and annual average temperature: the World Bank "Data Catalog" [9] . Mann-Whitney test was used to compare continuous variables in two groups. Multiple regression analysis was used to adjust covariables. COVID-19 mortality per population, gross national income per capita, infant mortality, and population density were log10 transformed before the regression analysis because these variables were long tailed. A half of the minimal mortality next to null was substituted instead of null mortality before log10 transformation. BellCurve 2015 (SSRI, Tokyo, Japan) and GraphPad PRISM ver. 7.0 (GraphPad Software, San Diego, CA, USA) were used. Out of 189 countries and regions presented on Human Development Report 2019, 18 countries were excluded from our analysis due to lack of description of national policy on the BCG World Atlas. One hundred and seventy-one analyzable countries consisted of 146 CRC, most of which recommend the vaccine for infant, and 25 CNRC. Median country level mortalities from COVID-19 per 106 population were 0.42 (interquartile range [IQR], 0-2.02) for CRC and 35.4 (IQR, 11.1-132.0) for CNRC (Fig. 1 ). This great discrepancy was compatible with previous reports [2] [3] [4] . However, CNRC was also significantly associated with higher gross national income per capita (8 [ (Fig. 1) . In a multiple regression analysis using the six parameters as independent variables, CNRC was still related to log10 mortality from COVID-19 (partial regression coefficient, 1.48; 95% (Table 1) . CNRC was further divided into countries that had previously recommended the vaccination and that had never recommended the vaccination [6] . The mortality from COVID-19 did not significantly differ (p=0.400) between countries wherein BCG had previously recommended (N=19; median, 32.7; IQR, 11.1-101.0; per 10 6 population) and those wherein BCG had never been recommended (N=6; median, 101.6; IQR, 25.5-232.0). Possible cross-immunization between BCG vaccination and SARS-CoV-2 is a serious concern around the world because it is far from easy to develop a novel vaccine that specifically targets SARS-Cov-2. Biological rationale of this hypothesis is trained immunity by non-specific cross-protection against non-TB pathogens. The large social, economic, and climatic inconsistency between CRC and CNRC made it difficult to derive the conclusion from a cross-sectional study. To date, no peer-reviewed report has presented data that were adjusted for multiple possible confounders. Insufficient adjustment of covariable factors may lead to biased result. Based on our data, infant universal BCG vaccination prevents death from COVID-19. We need to comment a few limitations. First, our data is preliminary until confirmed by randomized trial because unknown confounders including biological, medical, and social factor may exist. Second, we do not recommend BCG vacci-nation for adult and children of school age because our data is based on the current policy that recommends the vaccination mainly for infant. Development of novel vaccination for adult is still anticipated. We would like people not to rash for BCG vaccination because this may lead to a supply shortage for infants, increasing their chances of TB meningitis and miliary TB [10] . In conclusion, population based COVID-19 mortality was lower in countries with universal infant BCG vaccination policy. However, a univariable analysis for this topic introduces a strong bias because COVID-19 high-burden countries are TB low-burden developed countries. Based on our analysis of 171 countries and regions, the vaccination policy linked to 30-fold lower mortality after adjusting five socioeconomical covariates. Nobuyuki Horita https://orcid.org/0000-0002-8200-0340 Equivalent to 30-fold (95% CI, 17 to 52) increase of mortality/million population for CNRC compared to CRC. Worldometer COVID-19 coronavirus pandemic Correlation between universal BCG vaccination policy and reduced morbidity and mortality for CO-VID-19: an epidemiological study Association of BCG vaccination policy with prevalence and mortality of COVID-19 Cold Spring Harbor Laboratory Mandated Bacillus Calmette-Guerin (BCG) vaccination predicts flattened curves for the spread of COVID-19 Cold Spring Harbor Laboratory Does TB vaccination reduce COVID-19 infection?: no evidence from a regression discontinuity analysis The BCG Atlas Team. The BCG World Atlas: a database of global BCG vaccination policies and practices United Nations Human Development Report 2019: beyond income, beyond averages, beyond today: inequalities in human development in the 21st century The World Bank. Data Catalog The World Bank Concern over a COVID-19-related BCG shortage