key: cord-0976818-sa0j1sox
authors: Riccò, Matteo; Gualerzi, Giovanni; Ranzieri, Silvia; Bragazzi, Nicola Luigi
title: Stop playing with data: there is no sound evidence that Bacille Calmette-Guérin may avoid SARS-CoV-2 infection (for now)
date: 2020-05-11
journal: Acta Biomed
DOI: 10.23750/abm.v91i2.9700
sha: 003470e3c707f16a3e4062e500664c4a31e4f328
doc_id: 976818
cord_uid: sa0j1sox

Since the beginning of the COVID-19 epidemic, a possible explanation for the high heterogeneity of infection/mortality rates across involved countries was hinted in the prevalence of tuberculosis vaccination with Bacille Calmette-Guérin (BCG). A systematic review was therefore performed on May 2, 2020. A total of 13 articles were ultimately retrieved, 12 of them as preprint papers. All articles were ecological studies of low quality. Most of them did not include main confounding factors (i.e. demographic of the assessed countries, share of people residing in urban settings, etc.), and simply assessed the differences among incidence/mortality of COVID-19 with vaccination rates or by having vs. having not any vaccination policy for BCG. Even though all studies shared the very same information sources (i.e. international registries for BCG vaccination rates and open source data for COVID-19 epidemics), results were conflicting, with later studies apparently denying any true correlation between COVID-19 occurrence and BCG vaccination rates and/or policies. As a consequence, there is no sound evidence to recommend BCG vaccination for the prevention of COVID-19. (www.actabiomedica.it)

The Bacille Calmette-Guérin (BCG) is a live attenuated vaccine against tuberculosis (1, 2) . Following early reports demonstrating that BCG may reduce infant mortality independent of its effects on tuberculosis (3) , some studies have shown that BCG can enhance the reactivity of the innate immune system. Through an increased secretion of pro-inflammatory cytokines (i.e. "trained immunity"), BCG would improve reactivity against tumor cells (e.g. urothelial cancer), but also against some pathogens (e.g. staphylococci, candidiasis, yellow fever) (4), including respiratory viruses such as respiratory syncytial virus and influenza virus (5, 6) . More precisely, a study by Leentjens et al has shown that sequential BCG -influenza vaccination may elicit a more pronounced antibody response against influenza A(H1N1) (7) .

Because of the ongoing unavailability of specific preventive and/or therapeutic measures against SARS-CoV-2 infection, several stakeholders have suggested that the BCG vaccine may be repurposed as a preventive and/or therapeutic option against COVID-19. As some conflicting results have been reported, an updated synthesis of the literature is required in order to better inform health policies and guidelines.

A systematic review and meta-analysis was undertaken following the "Preferred Reporting Items for Systematic Reviews and Meta-Analysis" (PRISMA) guidelines (8) . We searched different scholarly databases (namely, PubMed/MEDLINE and EMBASE) as well as the preprint server medrxiv.org for relevant studies from inception up to 02/05/2020, without applying any backwards chronological restrictions. The search strategy was a combination of the following keywords (free text and Medical Subject Heading [MeSH] terms, where appropriate): (COVID-19 OR SARS-CoV-2 OR Coronarivus) AND (Bacille Calmette Guérin OR Bacillus Calmette Guérin). Records were handled using a references management software (Mendeley Desktop Version 1.19.5, Mendeley Ltd 2019), and duplicates were removed. Articles eligible for review were original research publications available online or through inter-library loan. A language filter was applied, by retaining articles written in Italian, English, German, French or Spanish, the languages spoken by the investigators. Two independent reviewers reviewed titles, abstracts, and the full-text of articles. Titles were screened for relevance with respect to the subject under study. Any articles reporting original results, which met one or more of the inclusion criteria, were retained for the full-text review. The investigators independently read full-text versions of eligible articles. Disagreements were resolved by consensus between the two reviewers; when it was not possible to reach consensus, input from the main investigator was searched and obtained. Further studies were retrieved from reference lists of relevant articles and consultation with experts in the field.

Briefly, a total of 161 entries were ultimately retrieved (more precisely: 4 in PubMed/Medline, 138 in Scopus, 19 in medrxiv.org). After removal of duplicates, and screening of titles and abstracts, a total of 13 full-text articles were retained, 12 of them not peer-reviewed preprint. As shown in Table 1 , all the available studies were ecological ones, with raw data (i.e. COVID-19 epidemics, BCG vaccination coverage) derived from the same institutional sources.

In summary, three different blueprints were identified: a) studies comparing COVID-19 rates (i.e. incidence, mortality and case fatality rates, in absolute terms or focusing on their doubling time) in countries having a BCG vaccination policy vs. countries having not and/ or having discontinued (No. = 5) (4, (9) (10) (11) (12) ; b) studies assessing through regression models how a BCG vaccination policy may have affected the ongoing epidemic in terms of incidence and/or mortality (No. = 4) (13-16); c) assessing how BCG vaccination rates may have affected incidence and mortality for COVID-19 (No. = 4) (17) (18) (19) (20) . All studies were based on the same institutional databases, and differed on the modelling of the statistical analyses. Even among studies reporting an analogous study design, models were quite heterogeneous, particularly when focusing on control variables. For instance, only 4 studies (11, 14, 15, 17) included in their modeling the demographic of the study population, with a further study that rather controlled the analyses for life expectancy (13) . Moreover, only 6 studies included in the statistical models socio-economic factors, either as a raw data (e.g. Gross Domestic Income) or a synthetic index (e.g. Human development index; Healthcare Access and Quality Index, etc.) (12, (14) (15) (16) (17) 19) . Eventually, only two studies controlled the analyses for a critical factor such as the risk of social interaction, either through a proxy (i.e. percentage of total population residing in urban areas) (17) , or by means of synthetic indices (16) .

Not coincidentally, the results are conflicting. Despite the substantial sharing of the information sources, while certain studies hinted towards higher incidence and/ or mortality rates in countries having and/or having implemented BCG vaccination policies, studies performed with different design and modeling substantially denied such a correlation (17, 20) . As the latter studies were performed more recently, it is reasonable that the timeframe and the dynamics of the COVID-19 epidemic may a common distorting bias from the original reports. However, available estimates should be cautiously retained, as all studies were affected by similar shortcomings.

Firstly, most of reports assessed the effector variable BCG vaccination as the presence/absence of BCG policies. Even though some countries are deprived of national policies for BCG vaccine, certain population groups such as healthcare workers (HCWs) may be selectively vaccinated following specific recommendation (21) . Despite nearly all Italian HCWs who began their formal education before 2000 were actively vaccinated against BCG, Italian National Institute for Occupational Injuries (IN-AIL) recently reported that around 10% of all COV-ID-19 positive cases had occurred among HCWs, with Growth rate for COVID-19 cases (b = -0.027, p < 0.001) and deaths (b = -0.038, p < 0.001) higher in countries without mandatory BCG vaccination.

(continued on the next page) 150 deaths among medical professionals, most of them aged 65 years or more (22) (23) (24) .

Second, it should be stressed that all estimates depended on the quality of raw data on COVID-19 (22) . On the one hand, some countries may have unreliably reported the number of cases for a variety of reasons, including the availability and the reliability of diagnostic tests, and the locally implemented policies (25) (26) (27) . On the other hand, the incidence rate is rather a notification rate, whose significance is better understood when compared with the total number of processed samples -a figure that only few international authorities properly record (22, (25) (26) (27) (28) .

Eventually, the COVID-19 pandemic had a distinctive progression, with an initial outbreak in mainland China. Even though China had a universal BCG policy since 1950s (29) , extensive BCG vaccination did not impaired Wuhan to becoming the initial epicenter of COV-ID-19 pandemic. Moreover, after a significant but limited involvement of nearby countries such as South Korea and Vietnam, COVID-19 pandemic had a sudden spread to Western Europe (22, 28) . As Western Europe has progressively become a low-notification area for tuberculosis, also national vaccination policies have progressively restrained the official recommendations for BCG (2) . In other words, as the global diffusion of SARS-CoV-2 has clearly followed economic highways connecting mainland China with high-developed areas in Europe and North America, we are dealing with higher occurrence of COV-ID-19 in highly-developed, highly interconnected areas rather than in countries deprived of vaccination policies for BCG. Similarly, as estimates from countries implementing a national policy for BCG vaccine (e.g. Russian Federation, African countries) have only recently showed the exponential increase that has previously affected Europe and North America, available figures are presumptively underestimating the actual morbidity of COVID-19 in countries with a national BCG policy (30) .

In conclusion, there is no evidence that the BCG may protect people against infection with SARS-CoV-2. As a consequence, there is no evidence to recommend BCG vaccination for the prevention of COVID-19.

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Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article