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Vol. 48. Issue 5.
Pages 507-517 (September - October 2020)
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Vol. 48. Issue 5.
Pages 507-517 (September - October 2020)
Review
DOI: 10.1016/j.aller.2020.05.002
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BCG as a game-changer to prevent the infection and severity of COVID-19 pandemic?
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A.R. Sharmaa,b, G. Batraa,b, M. Kumara,c, A. Mishraa,c, R. Singlaa,c, A. Singha,c, R.S. Singha,c, B. Medhia,c,
Corresponding author
drbikashus@yahoo.com

Corresponding author.
a Post Graduate Institute for Medical Education and Research (PGIMER), Chandigarh, India
b Department of Neurology, India
c Department of Pharmacology, India
Received 21 May 2020. Accepted 28 May 2020
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Statistics
Tables (2)
Table 1. SARS CoV-2 infection in non-BCG implemented countries.
Table 2. SARS-CoV-2 infection in BCG implemented countries.
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Abstract

The impact of COVID-19 is changing with country wise and depend on universal immunization policies. COVID-19 badly affects countries that did not have universal immunization policies or having them only for the selective population of countries (highly prominent population) like Italy, USA, UK, Netherland, etc. Universal immunization of BCG can provide great protection against the COVID-19 infection because the BCG vaccine gives broad protection against respiratory infections. BCG vaccine induces expressions of the gene that are involved in the antiviral innate immune response against viral infections with long-term maintenance of BCG vaccine-induced cellular immunity. COVID-19 cases are reported very much less in the countries with universal BCG vaccination policies such as India, Afghanistan, Nepal, Bhutan, Bangladesh, Israel, Japan, etc. as compared to without BCG implemented countries such as the USA, Italy, Spain, Canada, UK, etc. BCG vaccine provides protection for 50–60 years of immunization, so the elderly population needs to be revaccinated with BCG. Several countries started clinical trials of the BCG vaccine for health care workers and elderly people. BCG can be uses as a prophylactic treatment until the availability of the COVID-19 vaccine.

Keywords:
BCG
COVID-19
HCW
Revaccination
Immune response
Antigen specific immunity
Full Text
Introduction

The recent COVID-19 outbreak from Wuhan city in China and spread globally with 4,648,479 confirmed cases and 309,008 deaths (as of May 16, 2020).1 SARS-CoV2 is pathogenically stronger than the previous outbreaks of coronavirus (Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS)).2 SARS-CoV2 is transmitted from one person to another during sneezing or coughing droplets, reported in family settings as well as hospitals3 and is also transmitted from contaminated surfaces or contaminated consumables by self-inoculation through the eyes, mouth and nose.4,5 SARS-Cov-2 is closely related to the previous SARS coronavirus and the origin of SARS-Cov-2 is from the same reservoir bat host.6 Zoonotic transmission of the SARS coronavirus between bat and human by intermediate hosts palm civets and raccoon dogs,7 but the intermediate hosts for COVID-19 transmission within bats and humans are still unknown. All highly pathogenic SARS coronavirus (MERS-CoV, SARS-CoV, and SARS-CoV2) are related to the bat coronavirus genus compared to low pathogenic coronavirus (HCoVHKU1, HCoV-OC43, HCoV-NL63, and HCoV-229E). There is no curative therapy or vaccine for all types of coronaviruses to date, although a few vaccines have been developed and registered in clinical trials against the SARS-Cov-2 virus.8 COVID-19 enters into the host cell by using their transmembrane spike (S) proteins. Spike proteins are glycoproteins that bind with host cells ACE-2 cell membrane receptors.9 Current data is emphasizing that the available vaccines prevent viral infections by activation of the antiviral immune response, such as BCG. According to the literature available, BCG activates the human immune system against several types of viruses such as human Respiratory Syncytial Virus (hRSV), and human papillomavirus (HPV).10 This review deals with the importance of BCG in the prevention of COVID-19 expansion and its severity. Literature and surveys exhibiting the COVID-19 spread and severity are much greater in those countries which did not have any BCG vaccination regimen.

Different countries implemented different policies for BCG immunization because of their undefined efficacy.11 Various countries, such as India, Japan, etc., are having a universal BCG immunization program, whereas other countries such as Canada, USA, Italy, Spain, etc. implemented for the high-risk community. BCG immunization procedures differ from one country to another in favor of age, administration route, and doses of the vaccine. Most of the countries previously used three booster doses of BCG vaccine but nowadays only a single dose is used by an intradermal route at an early age, around the first year of life in newborns.12 No scientific evidence is available for booster doses or revaccination of BCG13 so the World Health Organization (WHO) Global Programme on Tuberculosis and Vaccines in 1995 did not recommend repeat BCG schemes. The WHO recommends that one dose of the BCG vaccine should be administered in all neonates of countries with a high incidence of TB.14 Immunization policies are revised or changed country-wise from time to time, depending on health policies, variation in evidence, community perception, the difference in TB, and comorbid incidence (HIV).11 The meta-analysis found the variation in BCG vaccine efficacy reduced the TB risk by 50% in controlled trials and the duration of the vaccine susceptibility remains unknown.15,16 One study reported that the TB mortality attributed to vaccination in a 20-year BCG and placebo-controlled trial fell by 82%.17,18 In that clinical trial, vaccination started from 1935 to 1938, and prospective TB cases finding by 1947.18 Another controlled trial stated the efficacy of the BCG vaccine with long term protection, approximately 60 years of age after vaccination.19

Why BCG vaccine only

BCG vaccination provides a wide range of safety against bacterial and viral infections but there is no evidence regarding BCG, whether it directly reduced the COVID-19 infection or not.10 A study has shown the correlation between BCG vaccination and COVID-19 infection, and studies have also shown fewer COVID-19 cases in universally implemented countries. The universal use of the BCG vaccine for the community might decrease the spread of COVID-19, and it can help to stop the transmission of the disease.20 Randomized controlled trials are needed to determine the role of BCG vaccination in immune activation against COVID-19. Nevertheless, BCG has shown a number of side effects (blood in urine, joint pain, nausea, vomiting, painful urination, etc.) in immune-compromised people and pregnant women.21 The BCG vaccine may boost the immune system’s ability to fight off pathogens, including the deadly coronavirus. Various investigations showed that the BCG vaccine also defends against viral infections affecting the respiratory tract in humans and mice. BCG protects against bacterial infection and also protects against respiratory viral infections.10,22 In this study, mice who have BCG vaccination before infection have low Influenza A load in their blood with less damage to the lungs.23,24 Several studies have stated that the BCG vaccine stimulates the resistance against viral infection in animals by inducing the epigenetic modifications in macrophages, monocytes, dendritic cells, and other immune cells. These immune cells enhance the production of pro-inflammatory cytokines such as INF-γ, TNF-α, and IL-1b, and develop the resistance for herpes type 1 and 2 viruses.24,25 These studies provide an idea that BCG vaccination might activate the immune system against viral infection. Thus, there is a path by which vaccine provides protection and reduces the risk of severely infectious diseases. Further studies also revealed that the BCG vaccine increases resistance in laboratory animals against other viruses, and ensure that it can be uses as a method of COVID-19 treatment. COVID-19 spread extensively in those countries which did not implement BCG vaccination, such as the USA, Italy, Spain, France, Germany, South Korea, Iran, etc. whereas those countries that have implemented BCG vaccination earlier showed a slower spread and low severity of COVID-19. Italy implemented the BCG vaccination. Four clinical trials are recruited in clinicaltrial.gov with BCG vaccination to prevent or reduce the severity of COVID-19 in the elderly population and Health Care Workers.26 To manage the COVID-19 infection, the whole world is busy with developing the vaccine against this pandemic based on proteins, RNA, DNA, and viral vectors technology. Few of them are registered in clinicaltrials.gov, such as the Minigene vaccine, Adenovirus type 5 vector recombinant vaccine, Pathogen-specific aAPC vaccine, ChAdOx1 nCoV-19/MenACWY/COV001, bacTRL spike vaccine, and mRNA-1273 and immunize the population against the COVID-19 infection (clinicaltrials.gov).

The minigene and Pathogen aPAC vaccines are synthetic vaccines developed by using the conserved domains of COVID-19’s polyprotein protease, and structural proteins. The COVID-19 virus interacts with ACE-2 receptors of host cells by using the Spike protein. Viral replication inside the host cell depends on the molecular mechanisms of viral proteins. This clinical trial aims to develop and examine the COVID-19 minigenes vaccine, based on multiple viral genes. For the expression of viral genes and immunomodulatory genes a powerful lentivirus (NHP/TYF) is used as a vector, which might activate T cells and modify the dendritic cells and antigen presenting cell (aAPC).27,28

Adenovirus type 5 vector recombinant vaccine trial is planned to estimate the potential to activate the immune system and safety of Ad5-nCoV, full-length spike (S) protein encodes for SARS-CoV-2.29

bacTRL spike vaccine contains live Bifidobacterium longum as colony-forming-units (CFU), which is designed to deliver synthetic DNA with spike Proteins of SARS-CoV-2 containing plasmids.30

mRNA-1273 vaccine trial is planned to evaluate the immunogenicity, reactogenicity, and safety of the mRNA vaccine constructed by ModernaTX, Inc. It is encapsulated by a novel lipid nanoparticle (LNP) that encodes SARS-CoV-2′s prefusion stabilized spike (S) protein.31 mRNA vaccines are essential for generating the specific immune response against infections by immune system activation with quickly exposing the immune cells to the antigen. mRNA vaccine development is very critical and problematic because the efficacy of the mRNA vaccine could be altered at the time of manufacturing and can cause side effects.

Proteins encoded by synthetic mRNA of interest are used as a cellular mRNA to the immediate translation of the antigen genes.32 The efficacy of mRNA vaccines can be improved by choosing or developing appropriate methods. Developers faced several technical problems at the time of mRNA vaccine production and might overcome this by verifying whether the vaccine works accurately or not.33 Unintentional properties of the mRNA vaccine can produce an unwanted immune response. To overcome this problem, requires designing the mRNA vaccine sequences and confirming that they should mimic those mRNAs transcribed by mammalian cells. Successful delivery of the vaccine into the cell is a major challenge because free RNA quickly degrades in the body. For successful delivery of the RNA, the vaccine RNA strands should be incorporated with a bigger molecule that provides stability into nanoparticles or liposomes. Several mRNA vaccines have to be frozen or refrigerated like conventional vaccines.33

Role of BCG in activation of immune system against the viruses

After BCG vaccination, BCG initiates the body’s immune response against the foreigner BCG antigen. At the site of vaccine administration, local immune cells (Dendritic cells, neutrophils, and macrophages) get activated and interact with the bacterial colony.34,35 Immune cells recognize the pathogen through the different types of pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors (PRRs), which preserved molecular signatures of bacteria and viruses. PAMPs like peptidoglycans, cell wall proteins, lipopolysaccharides, mycolic acids, glycoproteins, etc. bind with PRRs that present on immune cells. Toll-like receptors such as TLR2 and TLR4 are associated with BCG recognition.34 TLRs perform an essential function in pathogen recognition for a different variety of PAMPs. It is known that six represent a subclass of TLRs that recognize the ligands of viruses.36 TLR2 and TLR4 receptors are present on the cell surface activated by viral glycoproteins or by other foreigner proteins produced by extracellular milieu. Antiviral innate immune activation depends on the particular type of TLR signaling mechanism that is stimulated through the particular type of pathogen.36–40 Studies have shown that BCG expressed different proteins that activate TLRs and activate macrophages and dendritic cells. After the activation of these cells, they produce pro-inflammatory cytokines.41 DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a C-type lectin that interacts with bacterial wall constituents, and helps to recognize and internalize the process of BCG.42 Dendritic cells get activated after interactions with the pathogen and initiate dendritic cell migration and maturation, which is described by the upregulation of CD40, CD80, CD83, and CD86 co-stimulatory molecules.43 Antigen 85 expresses on the M.TB surface also present on the BCG surface, which induced the secretion of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and, interleukin- 1beta (IL-1β).44,45 It could activate immune cells by generating pro-inflammatory cytokines.43 Adaptive immune response initiates by antigen presentation when an antigen-presenting cell presents an antigen peptide with major histocompatible complex (MHC) molecules to naive T cells, found spleen to be the most affected organ or any secondary lymphoid tissues.46 In vitroandin vivo studies have reported that the skin dendritic cells having BCG inside migrate to the lymph nodes and activate both types of T cells CD4+ and CD8+T cells by the secretion of TNF-α, IL-6, and IL-12.47–50 Surprisingly, it has been stated that the stimulation of antigen-specific T cell responses by the BCG infected dendritic cells is induced by infected neutrophils.51

After BCG vaccination, adaptive immune cells (CD4+ and CD8+T cells) become activated, initiate the immune response against the BCG antigens46,52 and increase the secretion of IFN-γ. IFN-γ improves the potential against mycobacteria of the macrophages,45,46 and it also activates against viruses. IFN-γ, the specific cell type of cytokine that involved in B cells activation and differentiation, B-cells differentiated into plasma B cells, and memory B cells where plasma B cells produced antibodies against the particular antigen. Activated CD8+ T cells proliferate into specific CD8+ T cells against BCG antigen and persist for ten weeks in peripheral blood.53 Specific CD8+T cells against an antigen released IFN-γ, and also express the perforins and granzymes to the cytotoxic activity of CD8+T cells.53,54 CD4+ and CD8+ T cells specific for BCG antigen converted into effector memory T cells with their functional features of IFN-γ secretion.55,56 One study has reported the strong lymphoproliferative activity of effector memory T cells, sustained for many months, against the TB antigens in mice.56

BCG can be a game changer for SARS-CoV-2 infection

Several clinical trials started to treat the SARS-CoV-2 using the BCG vaccination. A study has been published by the New York Institute of Technology (NYIT) exploring that the BCG vaccine could be a game-changer in the fight against SARS-CoV-2.20 The BCG vaccine is used all over the world (except the USA, Germany, Spain, Italy, etc.) to defeat TB infection. The researchers observed that the countries without universal BCG vaccination policies, are having ten-times more severe COVID-19 infections and high mortality.20 Five clinical trials have started in different countries using the BCG vaccine as a preventive treatment for the COVID-19 in Health Care Workers and the elderly population.26 According to the available literature, the BCG vaccine might help in reducing the incidence of COVID-19 infections with less morbidity and mortality; BCG vaccine might be a game-changer in preventing the spread of the COVID-19 pandemic.

Safety of revaccination

Revaccination of BCG did not provide any extra protection against TB.13 Control and prevention of tuberculosis provided guidelines that people who work in hospital settings regardless of age, those unvaccinated earlier, and those having Heaf grade 1 or negative on tuberculin testing, might be vaccinated for the BCG vaccine. The HCW were directly dealing with TB patients and did not have a BCG scar so revaccination might be recommended.57,58 The BCG vaccine causes swelling at the site of vaccination. However, cross-reactions of BCG may occur in people with a compromised immune system and pregnant women, so extra protection could be provided to pregnant women and immune-compromised people before BCG vaccination.13 A study has shown that after revaccination in students, the relative risk of adverse reactions with the scar was twice, as compared to without scar.59 The researchers reported that the second dose of BCG or revaccination did not generally cause any adverse reactions - sometimes it can cause adverse reactions but these are very rare. The study reporting in American Indians and Alaskan natives BCG vaccination provided that the long-lasting potency and it has shown that a dose of BCG provides safety for 50–60 years.60 The clinical trials also observed the same efficacy of the BCG vaccine in observational case-control studies, but unknown in the elderly population.59 Another study performed on elderly guinea pigs revealed that the revaccination of the BCG-Tokyo vaccine against the infection reduced the replication of bacteria in the lungs, spleen, and alveolar lymph nodes.61

COVID-19 status in BCG implemented and non-implemented countries (May 16, 2020)

The preliminary studies have observed a correlation between countries which have universal policies of BCG vaccination for their citizens, showing fewer COVID-19 confirmed cases with a very low mortality rate.10 Estimation of the correlation of BCG with the spread of COVID-19 infection in different countries started the clinical trials to determine whether the BCG vaccine provides any protection against the COVID-19 pandemic. Status of the coronavirus infection is shown in the tables with or without a universal BCG immunization program. Data of COVID-19 collected from the worldometer (https://www.worldometers.info/coronavirus/) and converted into the death percentage, percentage of recovered cases, and total infected cases in the form of BCG implemented countries status and non-implemented countries status. BCG vaccination data was collected country-wise from the BCG World Atlas Database site (Tables 1 and 2).

Table 1.

SARS CoV-2 infection in non-BCG implemented countries.

Sr. No.  Countries  COVID-19 Infected Cases  Total Deaths  Deaths as %  Total Recovered Cases  Recovered cases as % 
1.  Andorra  761  49  604  79 
2.  Anguilla    33 
3.  Antigua and Barbuda  25  12  19  76 
4.  Australia  7035  98  6353  90 
5.  Bahamas  96  11  11  41  43 
6.  Bahrain  6583  12  2640  40 
7.  Barbados  85  65  76 
8.  Bermuda  122  66  54 
9.  Canada  74,613  5562  36,895  49 
10.  Caribbean Netherlands    100 
11.  Cayman Islands  94  55  59 
12.  Channel Islands  549  48  457  83 
13.  Curacao  16  14  88 
14.  Cyprus  910  17  481  53 
15.  Denmark  10,791  537  8959  83 
16.  Diamond Princess  712  13  651  91 
18.  Faeroe Islands  187    187  100 
19.  Falkland Islands  13    13  100 
20.  French Guiana  189  124  66 
21.  French Polynesia  60    59  98 
22.  Germany  175,699  8001  151,700  86 
23.  Gibraltar  147    144  98 
24.  Greenland  11    11  100 
25.  Grenada  22    14  64 
26.  Guadeloupe  155  13  109  70 
27.  Hong Kong  1053  1019  97 
28.  Iceland  1802  10  1782  99 
29.  Isle of Man  334  24  285  85 
30.  Italy  223,885  31,610  14  120,205  54 
31.  Ivory Coast  2017  24  942  47 
33.  Lebanon  891  26  246  28 
34.  Liechtenstein  82  55  67 
35.  Luxembourg  3923  104  3682  94 
36.  Macao  45    43  96 
37.  Martinique  192  14  91  47 
38.  Mayotte  1210  16  627  52 
40.  Montserrat  11  10  91 
41.  MS Zaandam  22  78 
42.  Netherlands  43,681  5643  13  N/A  #VALUE! 
43.  New Caledonia  18    18  100 
45.  Norway  8219  232  32 
47.  Reunion  441    354  80 
49.  Saint Martin  39  30  77 
50.  Saint Pierre Miquelon    100 
51.  San Marino  652  41  189  29 
52.  Sint Maarten  76  15  20  46  61 
53.  Spain  274,367  27,459  10  188,967  69 
54.  St. Barth    100 
55.  St. Vincent Grenadines  17    14  82 
56.  Suriname  10  10  90 
57.  Switzerland  30,514  1878  27,100  89 
58.  Taiwan  440  387  88 
59.  Trinidad and Tobago  116  107  92 
60.  Turks and Caicos  12  10  83 
61.  UK  236,711  33,998  14  N/A  #VALUE! 
62.  USA  1,484,285  88,507  326,242  22 
63.  Vatican City  12    17 
64.  Western Sahara    100 
  Total  2,593,955  204,012  882,176  34 
  Average  44,723  4857  11  15,753  35 
Table 2.

SARS-CoV-2 infection in BCG implemented countries.

Sr. No.  Countries  COVID-19 Infected Cases  Total Deaths  Death % in total cases  Recovered Cases  Recovered cases as % 
1.  Afghanistan  6053  153  2.527672229  745  12.30794647 
2.  Albania  916  31  3.384279476  705  76.9650655 
3.  Algeria  6629  536  8.085684115  3271  49.34379243 
4.  Angola  761  0.262812089  17  2.23390276 
5.  Argentina  7479  356  4.759994652  2497  33.38681642 
6.  Armenia  4283  55  1.284146626  1791  41.81648377 
7.  Austria  7037  98  1.392638909  6353  90.27994884 
8.  Azerbaijan  2980  36  1.208053691  1886  63.2885906 
9.  Bangladesh  20,995  314  1.495594189  4117  19.60943082 
10.  Belarus  27,730  156  0.562567616  8807  31.7598269 
11.  Belize  18  11.11111111  16  88.88888889 
12.  Benin  339  0.589970501  83  24.48377581 
13.  Bhutan  21    23.80952381 
14.  Bolivia (Plurinational State of)  3577  164  4.584847638  434  12.13307241 
15.  Bosnia and Herzegovina  2236  128  5.72450805  1336  59.74955277 
16.  Botswana  24  4.166666667  17  70.83333333 
17.  Brazil  220,291  14,962  6.791925226  84,970  38.57170742 
18.  Brunei Darussalam  141  0.709219858  136  96.45390071 
19.  Bulgaria  2175  105  4.827586207  573  26.34482759 
20.  Burkina Faso  780  51  6.538461538  595  76.28205128 
21.  Burundi  15  6.666666667  46.66666667 
22.  Cambodia  122    122  100 
23.  Cameroon  3105  140  4.508856683  1567  50.46698873 
24.  Cabo Verde  326  0.613496933  67  20.55214724 
25.  Central African Republic  301    13  4.318936877 
26.  Chad  428  48  11.21495327  88  20.56074766 
27.  Chile  39,542  394  0.996408882  16,614  42.01608416 
28.  China  82,941  4633  5.58589841  78,219  94.3067964 
29.  Colombia  14,216  546  3.840742825  3460  24.33877321 
30.  Comoros  11  9.090909091  27.27272727 
31.  Congo  391  15  3.836317136  87  22.25063939 
32.  Cook Islands 
33.  Costa Rica  843  10  1.18623962  542  64.29418743 
34.  Croatia  2222  95  4.275427543  1869  84.11341134 
35.  Cuba  1840  79  4.293478261  1425  77.44565217 
36.  Czechia  8404  295  3.510233222  5381  64.02903379 
37.  Côte d'Ivoire 
38.  Democratic People's Republic of Korea 
40.  Djibouti  1309  0.305576776  935  71.42857143 
41.  Dominica  16    15  93.75 
42.  Dominican Republic  11,739  424  3.611891984  3557  30.30070704 
43.  Ecuador  31,467  2594  8.243556742  3433  10.90984206 
44.  Egypt  11,228  592  5.272532953  2799  24.92874955 
45.  El Salvador  1265  25  1.976284585  441  34.86166008 
46.  Equatorial Guinea  594  1.178451178  22  3.703703704 
47.  Eritrea  39  39  100 
48.  Estonia  1770  63  3.559322034  934  52.76836158 
49.  Ethiopia  287  1.742160279  112  39.02439024 
50.  Fiji  18  15  83.33333333 
51.  Finland  6228  293  4.704560051  5000  80.28259473 
52.  France  179,506  27,529  15.33597763  60,448  33.6746404 
53.  Gabon  1209  10  0.827129859  219  18.11414392 
54.  Gambia  23  4.347826087  12  52.17391304 
55.  Georgia  677  12  1.772525849  419  61.89069424 
56.  Ghana  5638  28  0.496630011  1460  25.8957077 
57.  Greece  2810  160  5.693950178  1374  48.89679715 
58.  Guatemala  1643  30  1.82592818  135  8.216676811 
59.  Guinea  2531  15  0.592651126  1094  43.22402213 
60.  Guinea-Bissau  913  0.328587076  26  2.847754655 
61.  Guyana  116  10  8.620689655  43  37.06896552 
62.  Haiti  310  20  6.451612903  29  9.35483871 
63.  Honduras  2460  134  5.447154472  264  10.73170732 
64.  Hungary  3474  448  12.89579735  1371  39.46459413 
65.  India  86,508  2760  3.190456374  30,773  35.57243261 
66.  Indonesia  17,025  1089  6.396475771  3911  22.97209985 
67.  Iran (Islamic Republic of)  116,635  6902  5.917606207  91,836  78.73794316 
68.  Iraq  3193  117  3.664265581  2089  65.4243658 
69.  Ireland  23,956  1518  6.336617131  19,470  81.27400234 
70.  Israel  16,606  267  1.607852583  12,820  77.20101168 
71.  Jamaica  511  1.761252446  121  23.67906067 
72.  Japan  16,203  713  4.400419675  10,338  63.80299944 
73.  Jordan  596  1.510067114  401  67.28187919 
74.  Kazakhstan  5850  34  0.581196581  2707  46.27350427 
75.  Kenya  781  45  5.76184379  284  36.36363636 
76.  Kiribati 
77.  Kuwait  12,860  96  0.746500778  3640  28.30482115 
78.  Kyrgyzstan  1117  14  1.253357207  783  70.09847807 
79.  Lao People's Democratic Republic  19  14  73.68421053 
80.  Latvia  997  19  1.905717151  662  66.39919759 
81.  Lesotho  100 
82.  Liberia  219  20  9.132420091  108  49.31506849 
83.  Libya  64  4.6875  28  43.75 
84.  Lithuania  1534  55  3.585397653  988  64.40677966 
85.  Madagascar  238    112  47.05882353 
86.  Malawi  63  4.761904762  24  38.0952381 
87.  Malaysia  6872  113  1.6443539  5512  80.20954598 
88.  Maldives  1031  0.387972842  49  4.752667313 
89.  Mali  806  46  5.70719603  455  56.4516129 
90.  Malta  532  1.127819549  458  86.09022556 
91.  Marshall Islands 
92.  Mauritania  29  10.34482759  24.13793103 
93.  Mauritius  332  10  3.012048193  322  96.98795181 
94.  Mexico  45,032  4767  10.58580565  30,451  67.62080298 
95.  Micronesia (Federated States of) 
96.  Monaco  96  4.166666667  87  90.625 
97.  Mongolia  135    20  14.81481481 
98.  Morocco  6652  190  2.856283824  3400  51.11244738 
99.  Mozambique  119    42  35.29411765 
100.  Myanmar  182  3.296703297  89  48.9010989 
101.  Namibia  16    13  81.25 
102.  Nauru 
103.  Nepal  276    36  13.04347826 
104.  Nicaragua  25  32  28 
105.  Niger  885  51  5.762711864  684  77.28813559 
106.  Nigeria  5450  171  3.137614679  1320  24.22018349 
107.  Niue 
108.  Oman  5029  20  0.397693378  1436  28.55438457 
109.  Pakistan  38,799  834  2.149539937  10,880  28.04195984 
110.  Panama  9268  266  2.870090634  6080  65.60207164 
111.  Papua New Guinea  100 
112.  Paraguay  759  11  1.449275362  193  25.42819499 
113.  Peru  84,495  2392  2.830936742  27,147  32.12852832 
114.  Philippines  12,305  817  6.639577408  2561  20.81267777 
115.  Poland  18,184  912  5.015398152  7175  39.45776507 
116.  Portugal  28,583  1190  4.163313858  3328  11.64328447 
117.  Qatar  29,583  14  0.047324477  3546  11.98661393 
118.  South Korea  11,037  262  2.373833469  9851  89.25432636 
119.  Republic of Moldova  5745  202  3.516100957  2228  38.78154917 
120.  Romania  16,437  1070  6.509703717  9370  57.00553629 
121.  Russia  272,043  2537  0.932573159  63,166  23.21912345 
122.  Rwanda  287  177  61.67247387 
123.  Saint Kitts and Nevis  15  14  93.33333333 
124.  Saint Lucia  18  18  100 
125.  Saint Vincent and the Grenadines 
126.  Samoa 
127.  Sao Tome and Principe  235  2.978723404  1.70212766 
128.  Saudi Arabia  49,176  292  0.593785586  21,869  44.4708801 
129.  Senegal  2310  25  1.082251082  890  38.52813853 
130.  Serbia  10,438  225  2.155585361  4301  41.20521173 
131.  Seychelles  11  10  90.90909091 
132.  Sierra Leone  447  27  6.040268456  97  21.70022371 
133.  Singapore  27,356  21  0.076765609  7248  26.49510162 
134.  Slovakia  1493  28  1.87541862  1151  77.09310114 
135.  Slovenia  1465  103  7.030716724  279  19.0443686 
136.  Solomon Islands 
137.  Somalia  1284  53  4.127725857  135  10.51401869 
138.  South Africa  13,524  247  1.826382727  6083  44.97929607 
139.  Sri Lanka  935  0.962566845  520  55.61497326 
140.  Sudan  1964  91  4.633401222  205  10.43788187 
141.  Eswatini  190  1.052631579  66  34.73684211 
142.  Sweden  29,207  3646  12.4833088  4971  17.01989249 
143.  Syrian Arab Republic  50  36  72 
144.  Tajikistan  1118  33  2.951699463 
145.  Thailand  3025  56  1.851239669  2855  94.38016529 
146.  Republic of North Macedonia  1740  97  5.574712644  1251  71.89655172 
147.  Timor-Leste  24  24  100 
148.  Togo  263  11  4.182509506  96  36.50190114 
149.  Tonga 
150.  Tunisia  1035  45  4.347826087  802  77.48792271 
151.  Turkey  146,457  4055  2.768730754  106,133  72.46700397 
152.  Turkmenistan 
153.  Tuvalu 
154.  Uganda  203  63  31.03448276 
155.  Ukraine  17,858  497  2.783066413  4906  27.47228133 
156.  United Arab Emirates  21,831  210  0.961934863  7328  33.56694609 
157.  United Republic of Tanzania  509  21  4.125736739  183  35.95284872 
158.  Uruguay  732  19  2.595628415  553  75.54644809 
159.  Uzbekistan  2691  11  0.408769974  2158  80.19323671 
160.  Vanuatu 
161.  Venezuela (Bolivarian Republic of)  459  10  2.178649237  229  49.89106754 
162.  Vietnam  314  260  82.80254777 
163.  Yemen  106  15  14.1509434  0.943396226 
164.  Zambia  668  1.047904192  152  22.75449102 
165.  Zimbabwe  42  9.523809524  13  30.95238095 
166.  Montenegro  324  2.777777778  311  95.98765432 
167.  South Sudan  236  1.694915254  1.694915254 
  Total  1,981,967  95,277  4.807194065  858,437  43.31237604 
  Average  11940.98193  606.8853503  5.082373912  5171.331325  43.30742109 

The average of the total number of COVID-19 cases was 44,723 in without BCG implemented countries, whereas implemented countries have a very lower average of infected cases 11940.98. BCG implemented countries have fewer deaths percentage, around 5.08%, as compared to the 11% in without implemented countries. Moreover, the recovered cases percentage was also high in BCG implemented countries, around 43%, whereas in without implemented countries it was 35%.

Conclusion

The SARS-Cov-2 pandemic is spreading rapidly and the entire world under the grip of this severe pulmonary disease. The countries are fighting this pandemic with their ability but developed countries such as the USA, Italy, Spain, UK, etc., have been badly affected. People of these countries have a low immune response against any type of infection like COVID-19 because these countries have no universal immunization program or it was removed by the government at an earlier time. Other countries such as India, Afghanistan, Nepal, Bhutan, China, Pakistan, Bangladesh, etc. have universal immunization programs like the BCG vaccination program. The BCG vaccine has the potential to activate the immune response against the viral infection. The severity of the COVID-19 pandemic is very low with a slower spread in those countries that have the universal BCG immunization program. Australia, Germany, USA, etc., started the clinical trial of the BCG vaccine in Health Care Workers and the Elderly Population to prevent the infection of COVID-19. The correlation of BCG vaccination with COVID-19 has shown fewer confirmed cases with low mortality and a high recovered rate in universal BCG immunization countries. Table 1 contains the data of BCG unimplemented countries, and Table 2 contains the data of universal BCG implemented countries. Several new vaccines are being developed by different companies and clinical trials have started, until approval or success of any clinical trial for the specific vaccine of COVID-19 the BCG vaccine might be used as a preventive treatment for the COVID-19 pandemic.

Conflicts of interest

The authors declare that they have no conflict of interest.

Funding statement

None.

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