A series of epidemiological explorations has suggested a negative association between national bacillus Calmette–Guérin (BCG) vaccination policy and the prevalence and mortality of coronavirus disease 2019 (COVID-19). However, these comparisons are difficult to validate due to broad differences between countries such as socioeconomic status, demographic structure, rural vs. urban settings, time of arrival of the pandemic, number of diagnostic tests and criteria for testing, and national control strategies to limit the spread of COVID-19. We review evidence for a potential biological basis of BCG cross-protection from severe COVID-19, and refine the epidemiological analysis to mitigate effects of potentially confounding factors (e.g., stage of the COVID-19 epidemic, development, rurality, population density, and age structure). A strong correlation between the BCG index, an estimation of the degree of universal BCG vaccination deployment in a country, and COVID-19 mortality in different socially similar European countries was observed (r² = 0.88; P = 8 × 10⁻⁷), indicating that every 10% increase in the BCG index was associated with a 10.4% reduction in COVID-19 mortality. Results fail to confirm the null hypothesis of no association between BCG vaccination and COVID-19 mortality, and suggest that BCG could have a protective effect. Nevertheless, the analyses are restricted to coarse-scale signals and should be considered with caution. BCG vaccination clinical trials are required to corroborate the patterns detected here, and to establish causality between BCG vaccination and protection from severe COVID-19. Public health implications of a plausible BCG cross-protection from severe COVID-19 are discussed.

一系列的流行病学研究表明，国家卡介苗（BCG）疫苗接种政策与2019年冠状病毒病（COVID-19）的患病率和死亡率之间存在负相关关系。但是，由于各国之间的广泛差异，例如社会经济状况，人口结构，农村与城市环境，大流行的到来时间，诊断检测的数量和检测标准以及限制使用的国家控制策略，这些比较难以验证COVID-19的传播。我们审查了从严重COVID-19到BCG交叉保护的潜在生物学基础的证据，并完善了流行病学分析以减轻潜在混杂因素（例如，COVID-19流行阶段，发展，农村地区，人口密度和年龄结构）。r ² = 0.88；P = 8×10 ^-7），表明BCG指数每升高10％，COVID-19死亡率降低10.4％。结果未能证实BCG疫苗接种与COVID-19死亡率之间无关联的无效假设，并提示BCG可能具有保护作用。但是，分析仅限于粗尺度信号，应谨慎考虑。需要进行BCG疫苗接种临床试验，以证实此处检测到的模式，并确定BCG疫苗接种与保护免受严重COVID-19的因果关系。讨论了合理的BCG交叉保护免受严重COVID-19的公共卫生影响。