BCG vaccination provides protection against COVID 19: A Systematic review and meta-analysis


 Context: 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 BCG vaccination policy amongst infants. But does that 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.Evidence acquisition: Detailed electronic search for randomised controlled trials and observational studies in PubMed, Cochrane database and clinicaltrials.gov for eligible studies was performed. We performed a meta-analysis to provide pooled esimate of correlation of mortality with BCG vaccination policy from 4 studies.Results: 114 number of 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. But 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 protection against COVID-19 can’t 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.


Introduction
COVID 2019 pandemic that began in December 2019 from a localized city, Wuhan in China has spread worldwide to become a global threat and is still showing dubious patterns in terms of its spread and severity of infectivity. A successful vaccine for it in the near future is also not certain. It has become a dynamic situation with many answers yet to be found. Whether any existing vaccine can provide an innate or trained immunity was a matter of concern.
BCG vaccination in wide use among infants and neonates for prevention against tuberculous meningitis and disseminated tuberculosis since 1921 is known to offer heterologous protection against other diseases especially of respiratory origin. [1] Many non-speci c antiviral effects of the BCG vaccination resulted in decreased viral load, thus causing a reduction in respiratory tract infections in children. Nations in the world that do not have universal BCG vaccination policy, like Italy and USA, have had higher COVID 19 mortality than countries with long-standing universal BCG vaccination programs, like South Korea and Japan. [2] Even the countries that withdrew universal BCG vaccination program, due to decrease in the incidence of tuberculosis, have reported increased number of cases and deaths due to COVID-19, compared to the ones that retained BCG as a part of at-birth vaccination policy. [3] This geographical variation triggered anxiousness about the mechanism by which this trained immunity enhances body's innate response. BCG may lead to heterologous immunity with antigen-independent mechanism of B and T cells stimulation. It could also cause long-term activation, programming and memory of natural killer cells. So metabolic and epigenetic changes induced by this live vaccine might cause decreased viral load of SARS-COV-2, thus resulting in decrease severity of COVID-19.
Most scientists speculate that protection offered by BCG vaccination against COVID-19 is due to non-speci c effects of BCG vaccine. On the contrary to obvious correlation between SARS-CoV-2 and BCG many believe the variations in epidemiological data is in uenced by various factors like burden of disease, differing phases of the pandemic in various countries, testing rates and other demographic differences. So these are prone to confounders and bias and vested political and economic concerns are at stake. Other reason 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] But conclusion drawn from many observational studies of reduced mortality rates of COVID-19 in countries having universal BCG vaccination policy 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.

Methods
The "PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)" statement was used for reporting of systematic review. The study protocol was registered with "PROSPERO (International Prospective Register of Systematic Reviews)" database (CRD42020204466).
Electronic search in PubMed, Cochrane database and clinicaltrials.gov for eligible studies was performed on 17 th August, 2020. Bibliography search was done of included articles to nd other studies. Language restriction was applied as only studies published in English were included. No publication restriction was applied.
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. All types of studies like RCT as well as observational were included in review. Case reports and case series were not part of review. Any discrepancy in the inclusion were resolved with the help of third author. Two authors independently extracted the data like study patient characteristics, design of study, groups and outcomes. We were unable to perform meta-analysis of all outcomes for 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 esimate of correlation of mortality with BCG vaccination policy from 4 studies which had given the correlation (r) values.

Evidence from studies
We did an extensive database search of PubMed, Medline and Cochrane for relevant studies. PRISMA owchart is shown in Figure 1. A total of 28 studies were included. The studies in which correlation between COVID-19 mortality and morbidity with BCG vaccination was analysed were included.
Mortality Bene t: The characteristics and outcome data of studies [2,  From above results we can say that BCG vaccination causes a decrease in COVID-19 incidence and mortality. But these results must be interpreted very cautiously as there are lot of confounding factors too in various studies, which can affect the outcomes. 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 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 his 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. Escobar et al found a strong correlation between the BCG index, a measure of the extent of universal BCG vaccination implementation in a country and mortality attributed to COVID 19 in various European countries with similar social background. Sala et al [22] employed multiple regression analysis to control for potential confounders and found that BCG vaccination policy 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 like 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 signi cant 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 signi cant 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. There are few studies which were unable to 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 signi cant 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 signi cant correlation was observed with income level and median age but not with BCG policy. Szigeti et al was 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 like age, comorbidities like diabetes mellitus, cardiovascular diseases, gross domestic product, hospital beds and number of beds as per population but failed to nd signi cant 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 can't be drawn from this study. In the study by Hamiel et al, there was no difference in the incidence of COVID 19 among the BCG vaccinated population versus non vaccinated population. [12] In this study the population were different with regard to age group, as BCG vaccinated were born between 1979-81 and unvaccinated were from 1983-85. Whole population data with regard to vaccination was not used. It is like a sub-group study, hence increasing chances of alpha error. In addition, the severity of disease and mortality were not assessed. Wassenaar et al did not nd 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. 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 metaanalysis which showed signi cant 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 attened 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 randomised controlled trials (RCT), we cannot conclude that BCG vaccination can prevent COVID-19 or reduce mortality associated with COVID-19. But it is di cult to prove the current hypothesis with RCTs. Therefore, the evidence of well conducted observational studies can strengthen the evidence. Though, it cannot be concluded that BCG vaccination provides protection against COVID-19 or reduces the mortality, but the evidence from many studies do support the hypothesis.     Madan et al 2020 [19] (Observational)