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. 2020 Jul 3;48(5):507–517. doi: 10.1016/j.aller.2020.05.002

BCG as a game-changer to prevent the infection and severity of COVID-19 pandemic?

AR Sharma a,b, G Batra a,b, M Kumar a,c, A Mishra a,c, R Singla a,c, A Singh a,c, RS Singh a,c, B Medhi a,c,⁎
PMCID: PMC7332934  PMID: 32653224

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

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, 37, 38, 39, 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, 48, 49, 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 (Table 1, Table 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 6 604 79
2. Anguilla 3 0 1 33
3. Antigua and Barbuda 25 3 12 19 76
4. Australia 7035 98 1 6353 90
5. Bahamas 96 11 11 41 43
6. Bahrain 6583 12 0 2640 40
7. Barbados 85 7 8 65 76
8. Bermuda 122 9 7 66 54
9. Canada 74,613 5562 7 36,895 49
10. Caribbean Netherlands 6 0 6 100
11. Cayman Islands 94 1 1 55 59
12. Channel Islands 549 48 9 457 83
13. Curacao 16 1 6 14 88
14. Cyprus 910 17 2 481 53
15. Denmark 10,791 537 5 8959 83
16. Diamond Princess 712 13 2 651 91
18. Faeroe Islands 187 0 187 100
19. Falkland Islands 13 0 13 100
20. French Guiana 189 1 1 124 66
21. French Polynesia 60 0 59 98
22. Germany 175,699 8001 5 151,700 86
23. Gibraltar 147 0 144 98
24. Greenland 11 0 11 100
25. Grenada 22 0 14 64
26. Guadeloupe 155 13 8 109 70
27. Hong Kong 1053 4 0 1019 97
28. Iceland 1802 10 1 1782 99
29. Isle of Man 334 24 7 285 85
30. Italy 223,885 31,610 14 120,205 54
31. Ivory Coast 2017 24 1 942 47
33. Lebanon 891 26 3 246 28
34. Liechtenstein 82 1 1 55 67
35. Luxembourg 3923 104 3 3682 94
36. Macao 45 0 43 96
37. Martinique 192 14 7 91 47
38. Mayotte 1210 16 1 627 52
40. Montserrat 11 1 9 10 91
41. MS Zaandam 9 2 22 7 78
42. Netherlands 43,681 5643 13 N/A #VALUE!
43. New Caledonia 18 0 18 100
45. Norway 8219 232 3 32 0
47. Reunion 441 0 354 80
49. Saint Martin 39 3 8 30 77
50. Saint Pierre Miquelon 1 0 1 100
51. San Marino 652 41 6 189 29
52. Sint Maarten 76 15 20 46 61
53. Spain 274,367 27,459 10 188,967 69
54. St. Barth 6 0 6 100
55. St. Vincent Grenadines 17 0 14 82
56. Suriname 10 1 10 9 90
57. Switzerland 30,514 1878 6 27,100 89
58. Taiwan 440 7 2 387 88
59. Trinidad and Tobago 116 8 7 107 92
60. Turks and Caicos 12 1 8 10 83
61. UK 236,711 33,998 14 N/A #VALUE!
62. USA 1,484,285 88,507 6 326,242 22
63. Vatican City 12 0 2 17
64. Western Sahara 6 0 6 100
Total 2,593,955 204,012 8 882,176 34
Average 44,723 4857 11 15,753 35
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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 2 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 2 11.11111111 16 88.88888889
12. Benin 339 2 0.589970501 83 24.48377581
13. Bhutan 21 0 5 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 1 4.166666667 17 70.83333333
17. Brazil 220,291 14,962 6.791925226 84,970 38.57170742
18. Brunei Darussalam 141 1 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 1 6.666666667 7 46.66666667
22. Cambodia 122 0 122 100
23. Cameroon 3105 140 4.508856683 1567 50.46698873
24. Cabo Verde 326 2 0.613496933 67 20.55214724
25. Central African Republic 301 0 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 1 9.090909091 3 27.27272727
31. Congo 391 15 3.836317136 87 22.25063939
32. Cook Islands 0 0 0 0 0
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 0 0 0 0 0
38. Democratic People's Republic of Korea 0 0 0 0 0
40. Djibouti 1309 4 0.305576776 935 71.42857143
41. Dominica 16 0 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 7 1.178451178 22 3.703703704
47. Eritrea 39 0 0 39 100
48. Estonia 1770 63 3.559322034 934 52.76836158
49. Ethiopia 287 5 1.742160279 112 39.02439024
50. Fiji 18 0 0 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 1 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 3 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 9 1.761252446 121 23.67906067
72. Japan 16,203 713 4.400419675 10,338 63.80299944
73. Jordan 596 9 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 0 0 0 0 0
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 0 0 14 73.68421053
80. Latvia 997 19 1.905717151 662 66.39919759
81. Lesotho 1 0 0 1 100
82. Liberia 219 20 9.132420091 108 49.31506849
83. Libya 64 3 4.6875 28 43.75
84. Lithuania 1534 55 3.585397653 988 64.40677966
85. Madagascar 238 0 112 47.05882353
86. Malawi 63 3 4.761904762 24 38.0952381
87. Malaysia 6872 113 1.6443539 5512 80.20954598
88. Maldives 1031 4 0.387972842 49 4.752667313
89. Mali 806 46 5.70719603 455 56.4516129
90. Malta 532 6 1.127819549 458 86.09022556
91. Marshall Islands 0 0 0 0 0
92. Mauritania 29 3 10.34482759 7 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) 0 0 0 0 0
96. Monaco 96 4 4.166666667 87 90.625
97. Mongolia 135 0 20 14.81481481
98. Morocco 6652 190 2.856283824 3400 51.11244738
99. Mozambique 119 0 42 35.29411765
100. Myanmar 182 6 3.296703297 89 48.9010989
101. Namibia 16 0 13 81.25
102. Nauru 0 0 0 0 0
103. Nepal 276 0 36 13.04347826
104. Nicaragua 25 8 32 7 28
105. Niger 885 51 5.762711864 684 77.28813559
106. Nigeria 5450 171 3.137614679 1320 24.22018349
107. Niue 0 0 0 0 0
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 8 0 0 8 100
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 0 0 177 61.67247387
123. Saint Kitts and Nevis 15 0 0 14 93.33333333
124. Saint Lucia 18 0 0 18 100
125. Saint Vincent and the Grenadines 0 0 0 0 0
126. Samoa 0 0 0 0 0
127. Sao Tome and Principe 235 7 2.978723404 4 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 0 0 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 0 0 0 0 0
137. Somalia 1284 53 4.127725857 135 10.51401869
138. South Africa 13,524 247 1.826382727 6083 44.97929607
139. Sri Lanka 935 9 0.962566845 520 55.61497326
140. Sudan 1964 91 4.633401222 205 10.43788187
141. Eswatini 190 2 1.052631579 66 34.73684211
142. Sweden 29,207 3646 12.4833088 4971 17.01989249
143. Syrian Arab Republic 50 3 6 36 72
144. Tajikistan 1118 33 2.951699463 0 0
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 0 0 24 100
148. Togo 263 11 4.182509506 96 36.50190114
149. Tonga 0 0 0 0 0
150. Tunisia 1035 45 4.347826087 802 77.48792271
151. Turkey 146,457 4055 2.768730754 106,133 72.46700397
152. Turkmenistan 0 0 0 0 0
153. Tuvalu 0 0 0 0 0
154. Uganda 203 0 0 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 0 0 0 0 0
161. Venezuela (Bolivarian Republic of) 459 10 2.178649237 229 49.89106754
162. Vietnam 314 0 0 260 82.80254777
163. Yemen 106 15 14.1509434 1 0.943396226
164. Zambia 668 7 1.047904192 152 22.75449102
165. Zimbabwe 42 4 9.523809524 13 30.95238095
166. Montenegro 324 9 2.777777778 311 95.98765432
167. South Sudan 236 4 1.694915254 4 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
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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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