key: cord-1044974-n99xi61y
authors: Khera, Daisy; Chugh, Ankita; Khasbage, Sameer; Singh, Surjit
title: Does Bacille Calmette–Guérin Vaccination Provides Protection against COVID-19: A Systematic Review and Meta-analysis
date: 2021-12-08
journal: Indian J Community Med
DOI: 10.4103/ijcm.ijcm_952_20
sha: 9b3ae002e996b30d66b08539323bd4a39b6a0230
doc_id: 1044974
cord_uid: n99xi61y

BACKGROUND: Lower morbidity and mortality in few geographic locations on the globe suffering with SARS-CoV-2 has been associated with the existing or previously followed long-standing Bacille Calmette–Guérin (BCG) vaccination policy among infants. However, does it hold true that today after years of BCG vaccination, few adults have better prognosis or is it just confounding due to differential disease burden, population density, testing facilities, or improper reporting. The purpose was to evaluate and correlate this effect systematically. METHODS: Detailed electronic search for randomized controlled trials (RCTs) and observational studies in PubMed, Cochrane Library, and ClinicalTrials.gov for eligible studies was performed. RESULTS: One hundred and fourteen studies were yielded on search strategy and 28 observational studies were finally included for analysis. From our results, we can say that BCG vaccination causes a decrease in COVID-19 incidence and mortality. However, these results must be interpreted cautiously as lot of confounding factors were present in included studies, which can affect the outcome. CONCLUSION: The evidence of BCG vaccination for the protection against COVID-19 cannot be ruled out as evidence from many studies support the hypothesis, but the evidence of well-conducted RCTs and observational studies can strengthen the evidence. REGISTRATION NUMBER: PROSPERO (International Prospective Register of Systematic Reviews) database (CRD42020204466).

Most scientists speculate that protection by BCG vaccination against COVID-19 is due to nonspecific effects of BCG vaccine. On the contrary to obvious correlation between SARS-CoV-2 and BCG, many believe the variations in epidemiological data are influenced by various factors such as burden of disease, differing phases of the pandemic in various countries, testing rates, and other demographic differences. Hence, these are prone to confounders and bias and vested political and economic concerns are at stake. Other reasons presented by authorities not accepting this correlation are an implausible and questionable theory that how BCG vaccine administered decades back can alleviate severity of COVID in today's elderly. [4] However, conclusion drawn from many observational studies of reduced mortality rates of COVID-19 in countries having universal BCGVPC compared to that of the countries without it cannot be negated completely. A thorough and systematic evaluation of the COVID data available from both set of nations is the aim of this review.

Electronic search in PubMed, Cochrane Library, and ClinicalTrials.gov for eligible studies was performed on August 17, 2020, with restriction to English language. Bibliography search was done for the included articles to find other studies.

Search strategy was synthesized using the terms SARS-CoV-2, COVID-19, and BCG vaccination. Two authors independently assessed the articles for inclusion and exclusion criteria and extracted data. All types of studies except case reports and case series were included. Any discrepancy was resolved with the help of the third author. We were unable to perform meta-analysis of all outcomes for the included studies as the outcomes were not similar across studies. Many of the studies have studied only correlation and not the number of events with regard to mortality rates. However, we performed meta-analysis to provide pooled estimate of correlation of mortality with BCGVPC from 4 studies which had given the correlation (r) values.

A total of 28 studies were included [ Figure 1 ]. The studies in which correlation between COVID-19 mortality and morbidity with BCG vaccination was analyzed were included.

The characteristics and outcome data of studies [2, are represented in Tables 1 and 2 . According to Miller et al., death per million was significantly less in higher income countries with BCGVPC compared to non-BCGVPC countries. Hensel et al. also showed lower mortality due to COVID-19 with BCGVPC compared to no or past BCGVPC, but did not achieve statistical significance. Analysis done by Goswami et al. interpreted that no significant difference occurred in COVID-19 mortality in BCG vaccination countries with <95% vaccination coverage versus >95% coverage. However, significant difference was observed in European and American countries for COVID-19 mortality. A negative correlation, i.e. decreased mortality in BCGVPC, was shown by many. [5, 9, 16, 17] 

A number of observational studies have reported inverse correlation between BCG vaccination program and SARS-CoV2 infections.

Miller et al. [2] found that countries with higher income having a current universal BCG program (55 countries) had fewer deaths per million people. Higher income countries without a universal BCG program (5 countries) had a greater number of deaths. The number of cases per million inhabitants was 4 times higher in the higher income countries without a universal BCG program. Berg et al. [5] in their analysis showed that mandated BCG vaccination is associated with decreased incidence of COVID-19. They controlled for age, gross domestic product per capita, density and size of population, rate of migration, and other cultural factors in their study.

Sala et al. [22] employed multiple regression analysis to control for potential confounders and found that BCGVPC is associated with reduction in both incidence and mortality due to COVID-19. Shet et al. [26] used linear regression model to adjust for confounders such as GDP per capita and proportion of elderly and assessed the association between BCG vaccination and mortality with COVID-19. Mortality per million population was 5.8 times less in countries with BCG vaccination programs versus countries without any BCG vaccination policies. Dayal et al. [7] in their study observed a significant decrease in mean case fatality rate with BCG vaccination. Goswami et al. [10] found that in US and European world, countries with greater coverage of population with BCG vaccine resulted in significant decrease in mortality in comparison to countries with population having poor BCG coverage. Hegarty et al. [13] found that incidence and mortality in countries with BCG vaccination was much lower than the countries without such a program. Similar results with significantly lower mortality were reported. [21, 24, 28, 29] There are few studies which could not establish a correlation of BCG vaccination with COVID-19. Hensel et al. included countries performing more than 2500 COV-2 tests per million population in their analysis and found no significant association between numbers of COVID-19 cases per million population with BCG vaccination. Kirov et al. [15] performed linear regression for cofactors and COVID-19 cases and mortality and significant correlation was observed with income level and median age but not with BCG policy. Szigeti et al. were unable to establish correlation between COVID-19 case fatality rates and the period of introduction of universal BCG vaccination programs. [27] Meena et al. adjusted for confounding variables such as age, comorbidities such as diabetes mellitus, cardiovascular diseases, gross domestic product, hospital beds, and number of beds as per population, but failed to find significant correlation between BCG vaccination rates and COVID-19 burden. [20] However, there is no control group in the study done by Meena et al. Therefore, the conclusion of no correlation cannot be drawn from this study. Hamiel et al. reported no difference in the incidence of COVID-19 among the BCG-vaccinated versus nonvaccinated population. [12] However, the population were different with regard to age group, as BCG vaccinated were born between 1979 and 1981 and unvaccinated were from 1983 to 1985. Whole population data with regard to vaccination were not used. It is like a subgroup study, hence increasing chances of alpha error. In addition, the severity 

Author and year (study design)

Macedo and Febra 2020 [18] (observational) Madan et al., 2020 [19] (observational) Mean of cases per population ratio is statistically significantly lower in BCG-vaccinated countries than in BCG-nonvaccinated countries (0.0147±0.027 vs. 0.1892±0.244, respectively, P<0.0001) globally. Mean of deaths per population ratio is significantly lower in BCG-vaccinated versus BCG-nonvaccinated countries (0.0004±0.001 vs. 0.0113±0.020, respectively, P<0.0001). Mean of deaths per cases ratio is also significantly lower in BCG-vaccinated countries (3.4232±3.688 vs. 5.3429±4.830, respectively, P<0.05) Limitations: Did not account for confounding factors Sala and Miyakawa [22] (ecological study) Fujita Health University School of Medicine, Japan BCGVPC versus non-BCGVPC Countries with populations of at least 1 million for which at least 15 days of data since the detection of the first case were available as of April the 26 th (142 countries) BCG vaccination policy and incidence of TB is associated with a reduction in both COVID-19 cases and deaths, and the effects of these two variables are additive (≈5% to 15% of total unique variance explained) Limitations: Did not exclude the effect of unknown confounding factors Samrah et al. 2020 [23] of disease and mortality were not assessed. Wassenaar et al. did not find any correlation between countries that had never used the vaccine, had used it previously but stopped some years back, or were currently vaccinating with BCG with COVID-19 case fatality rate. [30] However, the authors misinterpreted the results as the countries with past or present BCGVPC revealed less number of cases and death as compared to non-BCGVPC. The authors further stated that countries like India have high attack rates, though less number of deaths as deaths lag behind the number of cases. The study was done in May 2020. As per the current scenario (dated September 21, 2020), India has 5,487,580 cases and 87,909 deaths. Despite having high number of cases and adequate number of tests per million, case fatality rate in India is 1.60%. Similarly, South Africa has case fatality rate of 2.4% (total cases = 661,211 and death = 15,953), which is less as compared to US (CFR = 7,004,768/204,118 = 2.9), where BCG vaccination was never implemented. This is despite the fact that USA is much more advanced on medical and technological front than any of the other two nations.

The pooled correlation from four studies revealed a significant negative correlation of BCG vaccination with COVID-19 mortality.

There is moderate quality evidence to conclude that BCG vaccine can prevent COVID-19. One main strength of our review is that we performed a meta-analysis which showed significant protective effect of BCG vaccination. The studies included in our review are all observational studies and many of them have limitations like ignoring the fact that different countries have varying time of onset of the disease and many BCG-using countries have not yet flattened their curve. Another major limitation is that many studies have not adjusted for important confounders, such as testing rates and differences in social and economic development, population size, and age structure.

Most importantly, unless we have robust evidence from randomized controlled trials, we cannot conclude that BCG vaccination can prevent COVID-19 or reduce mortality associated with COVID-19. Therefore, the evidence of well-conducted observational studies can strengthen the evidence. Although it cannot be concluded that BCG vaccination provides protection against COVID-19 or reduces the mortality, the evidence from many studies do support the hypothesis.

Nil.

There are no conflicts of interest.

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