Bacillus Calmette–Guérin vaccine, antimalarial, age and gender relation to COVID-19 spread and mortality

Vaccine 38 (2020) 5564–5568


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Ahmed Osama El-Gendy a, Haitham Saeed b, Ahmed M.A. Ali c,d, Hossam M. Zawbaa e, Dina Gomaa f,g, Hadeer S. Harb b, Yasmin M. Madney b, Hasnaa Osama b, Mona A. Abdelrahman b,
Mohamed E.A. Abdelrahim b,⇑

a Microbiology and Immunology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt b Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
c Pharmaceutics Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
d Pharmaceutics Department, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia

e Faculty of Computers and Artificial Intelligence, Beni-Suef University f Egyptian Drug authority, Cairo, Egypt
g RAMEDA pharmaceuticals, Cairo, Egypt


article info

Article history:

Received 11 April 2020
Received in revised form 18 May 2020 Accepted 30 June 2020
Available online 3 July 2020


COVID 19 Antimalarial Gender

1. Introduction

COVID-19 affected around 5,000,000 around the world with a different percentage of mortality with overall mortality rate of about 6.6% [1]. COVID-19 disease is related to the respiratory infec- tious diseases caused by coronavirus, the recent attacks of coron- avirus were in 2003 caused the severe acute respiratory syndrome (SARS) followed by the Middle east respiratory syn- drome (MERS) in 2012 [2,3]. Animals are the source for coron- aviruses, the Camel for MERS and Civet for SARS, the virus is transferred to these animals from bats [3,4].

The COVID-19 is transmitted during close contact with infected subject via droplets and fomites. Till now the airborne spread of new coronavirus has not been proven and so this route of trans- mission is not believed to be the main driver of virus transmission, but also it is possible for the new virus to be transmitted through

⇑ Corresponding author: Department of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.

E-mail address: (M.E.A. Abdelrahim).

0264-410X/! 2020 Elsevier Ltd. All rights reserved.


COVID-19 is affecting different countries all over the world with great variation in infection rate and death ratio. Some reports suggested a relation between the Bacillus Calmette-Guérin (BCG) vaccine and the malaria treatment to the prevention of SARS-CoV-2 infection. Some reports related infant’s lower susceptibility to the BCG vaccine. Some other reports a higher risk in males compared to females in such COVID-19 pandemic. Also, some other reports claimed the possible use of chloroquine and hydroxy- chloroquine as prophylactic in such a pandemic. The present commentary is to discuss the possible rela- tion between those factors and SARS-CoV-2 infection.


! 2020 Elsevier Ltd. All rights reserved.

airborne in specific conditions (e.g. aerosol generating procedures) [5,6].

Another route which is suspected to play a role in transmission of the infection is the fecal-oral route [7]. This possibility was sup- ported by the results of stool samples analysis through PCR for 8 subjects that were confirmed to be infected with the new coron- avirus [7]. Also, another study showed that the genome of the new coronavirus was also detected in the esophagus, stomach, and intestine and this support the possibility of the gastrointestinal route transmission [8].

The majority of subjects have a mild presentation to the infec- tion and mainly start with fever and dry cough that recovers with- out any interventions; also the flu-like symptoms, malaise, headache, and muscle pain might develop early [9]. Younger sub- jects represent the majority of mild cases [10]. These mild symp- toms might develop to more severe presentation presented as shortness of the breath, that mainly occurs after one week from initial presentation [11], and pneumonia which require hospital- ization of the infected subjects. The severity of the infection might progress to develop respiratory failure, multi-organ failure or septic shock [11].


2. Vaccine, age and gender relation to COVID-19 infection

The infection started in China in which more than 80,000 con- firmed cases were diagnosed with the new coronavirus, the death rate in China is around 4%, while it is greater than 10% in Italy. SARS-CoV-2 transferred from China to most countries around the world. The spread of the disease became higher in Europe and the USA compared to China (Table 1). The number of confirmed SARS-CoV-2 cases detected in countries neighbouring China e.g. Kazakhstan, India, and Korea was lower than that detected in The USA and Europe e.g. Italy, Spain, France, and the UK. To the extent that a close contact area to COVID-19 source, Hong Kong, has around 1000 confirmed-cases with very low mortality-rate of 0.71%. The USA now became the highest country with confirmed COVID-19 cases and progressing. One confusing debate raised right now is the possible relation between the vaccination schedule in different countries and its possible relation to the prevention of the spread of SARS-CoV-2 infection. Also, during the current COVID-19 outbreak, it was reported that infants are less suscepti- ble to such a violent virus [10,12]. One of the proposed explana- tions is the presence of cross reaction between SARS-CoV-2 and any of childhood vaccines [13]. One of the vaccines that were related to COVID-19 is the Bacillus Calmette–Guérin (BCG) which originates from an attenuated strain of Mycobacterium Bovis for prevention of Mycobacterium tuberculosis infection that causes dis- seminated and meningeal tuberculosis [14]. Many countries stopped using BCG vaccine except for high risk vulnerable groups [15] e.g. Italy, the USA, the UK, Spain, and France. Other countries are still using BCG vaccine till now e.g. African and Asian countries as shown in Fig. 1A [16]. Correlating different countries’ SARS-CoV- 2 infections and the recorded death rates (Table 1 and Fig. 1B) with Fig. 1A suggests that there is a possible effect of BCG vaccination in decreasing COVID-19 spread and mortality rates in those countries receiving the BCG vaccine. The USA, Spain, Italy, and the UK have the highest number of confirmed cases of SARS-CoV-2 infection and mortality even compared to the disease country of origin, China (Table 1 and Fig. 1B).

This possibility could be due to the expected preventive immu- nization role of the BCG vaccine on the lungs and other organs. What is noticeably parallel between Mycobacterium tuberculosis

Table 1

(TB) and SARS-CoV-2 is that both of them attack primarily the lungs and interfere with host immunity. Besides the main role of the BCG vaccine in the prevention of TB but there is also a sequence of non-specific effects that could be harboured [17]. Such non- specific effects are termed heterologous effects which are com- monly accompanied by live attenuated vaccines e.g., BCG, measles vaccine, oral polio vaccine, smallpox vaccine) that have been shown to non-specifically lessen mortality in addition to preven- tion of the targeted infections especially in low income countries following immunization programs [18] It was reported that live attenuated measles-mumps-rubella vaccine (MMR) could protect against nosocomial infectious diseases and respiratory syncytial virus [19] Heterologous effects of BCG accordingly can protect against non-mycobacterial infections to generally lower respira- tory tract infections in children through activation of innate immu- nity memory based myeloid cells, a process termed trained immunity [20–22]. BCG vaccination is associated with a 30% reduc- tion in mortality rate by pathogens especially in developing coun- tries [23] and 50% reduction in mortality related to pneumonia [24]. The favourable non-specific effects of the BCG vaccine persist for a time after the neonatal period up to 10 years [25]. Trained immunity is referred to innate immune system that could display memory characteristics, after spiked by pathogens or certain live attenuated vaccines (‘‘training effect”), not only toward the same infectious agents but also non-specifically against different patho- gens (cross-protection). Trained immunity cannot be defined as sole innate as it is induced only secondary to primary infection. Meanwhile, it is different than adaptive because it shows non- specific response compared to T/B cell responses [26]. The overall values of trained immunity is attributed to long-term sensitivity of innate immune cells to any microbial stimuli, increasing the response to the same and different subsequent stimuli, and conse- quently increased cytokine production (not only against TB but also against bacteria, viruses, and even parasites) mediated by monocytes and natural-killer (NK) cells with a memory-like effect via and chromatin remodelling through histone modifications, leading to an enhanced gene transcription upon re-stimulation (especially the up-regulation of IL-1ß) [27], and changes in intra- cellular metabolism [28–31]. When trained immunity is induced in monocytes in response to microbial molecules as ß-glucan, there

A. Osama El-Gendy et al. / Vaccine 38 (2020) 5564–5568 5565

Comparative illustration of relationship between vaccination schedule and total deaths per 1 million people in different countries in a descending arrangement; (data collected on 18 May 2020).



Belgium Spain
France Sweden Netherlands USA Switzerland Canada Germany Austria Poland Croatia Russia Bulgaria Egypt

S. Korea China Kazakhstan India


No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Total cases

55,280 277,719 225,435 243,695 179,569 30,143 43,995 1,527,664 30,587 77,002 176,651 16,242 6,347 2,226 281,752 2,235 12,229 11,065 82,954 6,440 96,169 1,056

Total cases/1 million people

4,772 5,940 3,728 3,592 2,752 2,987 2,568 4,619 3,537 2,042 2,109 1,805 1,146 542 1,931 321 120 216 58 343 70 141

Total deaths

9,052 27,650 31,908 34,636 28,108 3,679 5,680 90,978 1,881 5,782 8,049 629 298 95 2,631 110 630 263 4,634 34 3,029 4

Total deaths/1 million people

781 591 528 511 431 365 332 275 218 153 96 70 54 23 18 16 6

5 3 2 2 0.5

Hong Kong
BCG (Bacillus Calmette-Guérin), MMR (Mumps-Measles-Rubella), OPV (Oral Poliovirus Vaccine).

5566 A. Osama El-Gendy et al. / Vaccine 38 (2020) 5564–5568

Fig. 1. A. Map displaying BCG-vaccination policy by country (adopted from [16]); B. Number of confirmed COVID-19 cases and death cases in certain countries; C. The-estimate of world malaria burden (adopted from [57]); D Number of confirmed COVID-19 cases and death cases for countries receiving antimalarial treatment.

is a relevant increase in cellular aerobic glycolysis and glutamine metabolism via a central regulatory mechanism of mTOR-HIF1a pathway [32,33]. Cytokines production after BCG vaccination, illus- trated and figured by different studies [34,35], are represented in increasing Interferon-gamma (IFNc) and pro-inflammatory cytoki- nes Interleukins IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17 and tumor necrosis factor (TNF) as a response to non-mycobacterial stimula- tion in both infants and adults [22,30,36,37], with higher produc- tion in vaccinated females and hence the beneficial effects of BCG is more evident in females [38]. This is remarkable by looking into the percentage of deaths to COVID-19 that was higher in males rather than females. Cytotoxic T-lymphocytes could also be driven by IL-2, IL-12, TNF, and IFN-c. IFN-c is secreted by T-cells and Natural-killer (NK) cells and has many roles as antiviral activity, strong regulatory of the-immune response, stimulation of phago- cytic bactericidal activity, induction of antigen presentation through major histocompatibility-complex (MHC) molecules, arrangement of leukocyte-endothelium interactions and effects on cell proliferation and apoptosis [39]. IL-8 is crucial in the innate response to bacterial infection by stimulating neutrophil chemo- taxis and macrophage triggering [22]. TNF could lead to the activa- tion of beneficial regulatory T cells [30].

For such non-specific mechanisms and evidences, we assume that BCG can be used as an immune modulator to protect against COVID-19 by allocating pulmonary cells under continuous stress which is unfavourable for multiplication of SARS-CoV-2 inside. This strategy will be very helpful in epidemic-control, preventing the spread of infection, limiting the course of the disease and reducing morbidity and mortality rate. This is not the first time to recom- mend BCG to non-specifically protect or even treat many patho- gens other than TB and diseases especially pulmonary diseases. BCG has shown a protective effect against leprosy which is likely due to cross reactivity with mycobacterial antigens [40]. Other

studies reinforced the nonspecific effects against leishmania and malaria decreasing their risks and neonatal mortality [41,42]. Some experimental studies showed that BCG can protect against viral pathogens [41]. BCG was considered as a supplementary treatment for non-muscle-invasive bladder cancer by triggering the body’s immune system to release cytokines and activating cytotoxic cells to destroy tumour cells after/with transurethral resection of blad- der tumour (TURBT) cytotoxic cells [43,44]. Also, it has a protective effect against other cancers showing an inhibitory effect on tumour growth and was reported to reduce the risk of leukemia and lung cancer [45,46]. BCG has been reported to prevent lung injury by improving the alveolar surface area which is attributed to the pre- served IL-13 expression and up-regulation of Nuclear Factor Kappa-B Subunit-1 (NFkB1), Fibroblast growth factor binding protein-1 (FGF.BP1) and Vascular endothelial growth factor A (VEGF-A) genes [47]. Researchers noticed a decreased rate of aller- gic asthma in children immunized with the BCG vaccine with the general improvement of lung function through increasing the secretion of T-helper type-1 (Th1) cytokines [48,49].

Our advice to reallocate BCG for protection against COVID-19 is built on the capability of the BCG vaccine to induce increased cyto- kine production which will decrease the infectivity of SARS-CoV-2 through antiviral inhibitory cytokines, activated natural-killer cells and activated cytotoxic T-cells. Other studies suggested such corre- lation between universal BCG vaccination policy at birth and reduced morbidity and mortality for COVID-19 suggesting the induction of trained immunity and consequently protection against SARS-CoV-2 [34,35,50].

Another assumption is based on the continuous cytokine pro- duction in pulmonary cells after vaccination with BCG [51] will promote pulmonary cells to be more trained and adapted to cytoki- nes for a long time and will be less responsive to side effects of cytokine storm induced by COVID-19 knowing that the cytokine

storm is the main cause of respiratory failure and death of COVID- References 19. [52,53] The cytokine storm of COVID-19 is a lethal immune

condition characterized by activation and proliferation of macro- phages, NK cells, T cytotoxic cells and the overproduction of inflammatory cytokines and mediators. The uncontrolled release of pro-inflammatory mediators, IL-6, IL-8, IL-1b, and GM-CSF in addition to reactive oxygen species (ROS) could cause acute respi- ratory distress syndrome (ARDS) leading to pulmonary fibrosis and death [52]. It worth to mention that there are three established ongoing clinical trials, started in March and April 2020, to address such role of BCG vaccination in protection against COVID-19 espe- cially for healthcare workers and WHO will evaluate the evidence when it is available [54-56].

On the other hand, in African countries, the number of con- firmed cases is considered very low compared to Europe or even China. The highest country with confirmed cases is Egypt with around 10,000 confirmed cases. Malaria disease is considered as a common disease in those countries, as shown in Fig. 1C [57]. They mostly receive malaria treatment e.g. Angola, Benin, and Ethiopia, with their very low number of confirmed cases and death with low mortality rates (Fig. 1D). This finding in countries encountered malaria could be related to the malaria treatment e.g. chloroquine, which has around 50 days half-life [58], and hydroxychloroquine, which have around 40 days half-life [58], that were proven effec- tive against SARS-CoV-2 virus [59]. This long biological half-life could be the reason for such a low number of confirmed cases and worth further investigation. Hydroxychloroquine lowers the pH which can interfere with the replication of the virus through inhibition of lysosomal activity in antigen presenting cells involv- ing B-cells and the plasmacytoid dendritic cells. This will prevent processing of the antigen [60]. In addition to the role of chloro- quine and hydroxychloroquine in immunity modulation, also they have an inhibitory effect on two essential steps needed by the new coronavirus to enter the cells, these steps are binding to receptor (angiotensin-converting enzyme 2 (ACE2)) and fusion to cell mem- brane through the interfering with the glycosylation of the recep- tor [61,62]. Again, while the full details are not known, the chloroquine and hydroxychloroquine could be recommended for the preventio of SARS-CoV-2 infection [62]. Hydroxychloroquine, also, is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T-cell activation. It has a safer clinical profile and is suitable for those who are preg- nant and inexpensive and more readily available. [62] However, the side effect of the chloroquine and hydroxychloroquine and any possible interaction should be taken into account [63,64].

3. Conclusions

BCG vaccine has a very important role in stimulating the immune system but requires time to do so and help in SARS- CoV-2 infection prevention. Antimalarial like chloroquine and hydroxychloroquine has a possible role as prophylactics against SARS-CoV-2 infection and transmission and worth further investigation.

We recommend people in countries like Europe and the USA to take BCG vaccine early enough to stimulate their immune systems to help in any possible next winter COVID-19 pandemic occurrence if a proper production of a vaccine for SARS-CoV-2 virus was not lunched.

Declaration of Competing Interest

The authors declare that they have no known competing finan- cial interests or personal relationships that could have appeared to influence the work reported in this paper.

[1] 2020 [cited 2020 17 May, 2020]; Available from: https://

[2] Stockman LJ, Bellamy R, Garner P, Low D. SARS: Systematic Review of Treatment Effects. PLoS Med 2006;3(9). e343.

[3] Azhar, E.I., et al., Evidence for camel-to-human transmission of MERS coronavirus. 2014. 370(26): p. 2499-2505

[4] Wang L-F, Eaton BT. Bats civets and the emergence of SARS, in Wildlife and emerging zoonotic diseases: the biology. In: Circumstances and consequences of cross-species transmission. Springer; 2007. p. 325–44.

[5] Organization, W.H., Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations: scientific brief, 27 March 2020, 2020, World Health Organization.

[6] Morawska Lidia, Cao Junji. Airborne transmission of SARS-CoV-2: The world should face the reality. Environ Int 2020;139:105730. j.envint.2020.105730.

[7] Xu Yi, Li Xufang, Zhu Bing, Liang Huiying, Fang Chunxiao, Gong Yu, Guo Qiaozhi, Sun Xin, Zhao Danyang, Shen Jun, Zhang Huayan, Liu Hongsheng, Xia Huimin, Tang Jinling, Zhang Kang, Gong Sitang. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med 2020;26(4):502–5. 0817-4.

[8] Xiao Fei, Tang Meiwen, Zheng Xiaobin, Liu Ye, Li Xiaofeng, Shan Hong. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology 2020;158 (6):1831–1833.e3.

[9] Chen, J., et al., Clinical progression of patients with COVID-19 in Shanghai, China. 2020

[10] Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 2020. 395(10223): p. 497-506

[11] Zhou, F., et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 2020.

[12] Xiao-Wei X et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ: British Med J (Online) 2020:368.

[13] del Rio Carlos, Malani Preeti N. 2019 Novel Coronavirus—Important Information for Clinicians. JAMA 2020;323(11):1039. 10.1001/jama.2020.1490.

[14] Lundgren, F., et al., Vaccination in the prevention of infectious respiratory diseases in adults. 2014. 60(1): p. 4-15.

[15] Boman G. The ongoing story of the Bacille Calmette-Guérin (BCG) vaccination. Acta Paediatr 2016;105(12):1417–20.

[16] Zwerling A et al. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med 2011:8(3).

[17] Bassat Q, Moncunill G, Dobaño C. Making sense of emerging evidence on the non-specific effects of the BCG vaccine on malaria risk and neonatal mortality. BMJ Specialist J. 2020.

[18] Shann F. Nonspecific effects of vaccines and the reduction of mortality in children. Clinical Therapeut. 2013;35(2):109–14.

[19] Sørup S et al. Measles–mumps–rubella vaccination and respiratory syncytial virus-associated hospital contact. Vaccine 2015;33(1):237–45.

[20] Hollm-Delgado M-G, Stuart EA, Black RE. Acute lower respiratory infection among Bacille Calmette-Guérin (BCG)–vaccinated children. Pediatrics 2014;133(1):e73–81.

[21] de Castro MJ, Pardo-Seco J, Martinón-Torres F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin Infect Dis 2015;60(11):1611–9.

[22] Freyne B et al. Neonatal BCG vaccination reduces interferon gamma responsiveness to heterologous pathogens in infants from a randomised controlled trial. J Infect Dis 2020.

[23] Zimmermann, P., A. Finn, and N. Curtis, Does BCG Vaccination Protect Against Nontuberculous Mycobacterial Infection? A Systematic Review and. 2018.

[24] Stensballe LG et al. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch Dis Childhood 2017;102(3):224–31.

[25] Schrager LK et al. The status of tuberculosis vaccine development. Lancet Infect Dis 2020.

[26] Netea MG, Quintin J, Van Der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe 2011;9(5):355–61.

[27] Arts RJ et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity.. Cell Host Microbe 2018;23(1):89–100. e5.

[28] Namakula R et al. Monocytes from neonates and adults have a similar capacity to adapt their cytokine production after previous exposure to BCG and b- glucan. PLoS ONE 2020;15(2):e0229287.

[29] Netea MG et al. Trained immunity: a program of innate immune memory in health and disease. Science 2016;352(6284). p. aaf1098.

[30] Kleinnijenhuis J et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc National Academy Sci 2012;109(43):17537–42.

[31] Saeed S et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 2014;345 (6204):1251086.

[32] Cheng S-C et al. mTOR-and HIF-1a–mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014;345(6204):1250684.

A. Osama El-Gendy et al. / Vaccine 38 (2020) 5564–5568 5567


5568 A. Osama El-Gendy et al. / Vaccine 38 (2020) 5564–5568

. [33]  Arts RJ et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 2016;17(10):2562–71.

. [34]  Covián C et al. BCG-induced cross-protection and development of trained immunity. Implication for vaccine design. Front. Immunol 2019;10:2806.

. [35]  Covián C et al. Could BCG vaccination induce protective trained immunity for
SARS-CoV-2?. Front Immunol 2020;11:970.

. [36]  Smith SG et al. Whole blood profiling of bacillus Calmette–Guérin-induced
trained innate immunity in infants identifies epidermal growth factor, IL-6, platelet-derived growth factor-AB/BB, and natural killer cell activation. Front Immunol 2017;8:644.

. [37]  Jensen KJ et al. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J Infect Dis 2015;211(6):956–67.

. [38]  Biering-Sørensen S et al. Rapid protective effects of early BCG on neonatal mortality among low birth weight boys: observations from randomized trials. J Infect Dis 2018;217(5):759–66.

. [39]  Boehm U et al. Cellular responses to interferon-c. Ann Rev Immunol 1997;15 (1):749–95.

. [40]  Eisenhut M et al. BCG vaccination reduces risk of infection with Mycobacterium tuberculosis as detected by gamma interferon release assay. Vaccine 2009;27(44):6116–20.

. [41]  Moorlag S et al. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect 2019;25(12):1473–8.

. [42]  Berendsen ML et al. BCG vaccination is associated with reduced malaria prevalence in children under the age of 5 years in sub-Saharan Africa. BMJ Global Health 2019;4(6).

. [43]  Meyer JP, Persad R, Gillatt D. Use of bacille Calmette-Guérin in superficial bladder cancer. Postgraduate Med J 2002;78(922):449–54.

. [44]  Kassouf W et al. Canadian guidelines for treatment of non-muscle invasive bladder cancer: a focus on intravesical therapy. Canadian Urological Association J 2010;4(3):168.

. [45]  Morra ME et al. Early vaccination protects against childhood leukemia: a systematic review and meta-analysis. Sci Rep 2017;7(1):1–9.

. [46]  Usher NT et al. Association of BCG Vaccination in Childhood With Subsequent Cancer Diagnoses: A 60-Year Follow-up of a Clinical Trial. JAMA Network Open 2019;2(9). e1912014 e1912014.

. [47]  van Dam AD et al. BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice. Atherosclerosis 2016;251:6–14.

. [48]  Shirakawa T et al. The inverse association between tuberculin responses and atopic disorder. Science 1997;275(5296):77–9.

[49] Choi IS, Koh YI. Therapeutic effects of BCG vaccination in adult asthmatic patients: a randomized, controlled trial. Ann Allergy Asthma Immunol 2002;88(6):584–91.

[50] Miller A et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID- 19: an epidemiological study. MedRxiv 2020.

[51] Kaveh DA et al. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 TEM cells which expand following virulent mycobacterial challenge. PLoS ONE 2011;6(6).

[52] Sun X et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev 2020.

[53] Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033–4.

[54] University, T.A.M. BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS). 2020 18.05.2020]; Available from: https://clinicaltrials. gov/ct2/show/NCT04348370.

[55] Institute, M.C.R. BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE). 2020 18.05.2020]; Available from: https://clinicaltrials. gov/ct2/show/NCT04327206.

[56] MJM Bonten and U. Utrecht. Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine (BCG-CORONA). 2020 18.05.2020]; Available from:

[57] Ricci F. Social implications of malaria and their relationships with poverty. Mediterranean J Hematol Infect Dis 2012;4(1).

[58] Tett S et al. Bioavailability of hydroxychloroquine tablets in healthy volunteers. British J Clin Pharmacol 1989;27(6):771–9.

[59] Wang, M., et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. 2020. 30(3): p. 269-271.

[60] Lotteau, V., et al., Intracellular transport of class II MHC molecules directed by invariant chain. 1990. 348(6302): p. 600-605.

[61] Vincent, M.J., et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. 2005. 2(1): p. 69.

[62] Zhou D, Dai S-M, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother 2020.

[63] Lopez-Izquierdo, A., et al., Chloroquine blocks a mutant Kir2. 1 channel responsible for short QT syndrome and normalizes repolarization properties in silico. 2009. 24(3-4): p. 153-160.

[64] Vereckei, A., et al., Chloroquine cardiotoxicity mimicking connective tissue disease heart involvement. 2013. 35(2): p. 304-306.

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