Vaccine 38 (2020) 5564–5568
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Contents lists available at ScienceDirect Vaccine
journal homepage: http://www.elsevier.com/locate/vaccine
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
Received 11 April 2020
Received in revised form 18 May 2020 Accepted 30 June 2020
Available online 3 July 2020
COVID 19 Antimalarial Gender
COVID-19 affected around 5,000,000 around the world with a different percentage of mortality with overall mortality rate of about 6.6% . 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: email@example.com (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.
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! 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 . 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 . 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 .
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 . Younger sub- jects represent the majority of mild cases . 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 , 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 .
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 . 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 . Many countries stopped using BCG vaccine except for high risk vulnerable groups  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 . 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
(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 . 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  It was reported that live attenuated measles-mumps-rubella vaccine (MMR) could protect against nosocomial infectious diseases and respiratory syncytial virus  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  and 50% reduction in mortality related to pneumonia . The favourable non-specific effects of the BCG vaccine persist for a time after the neonatal period up to 10 years . 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 . 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) , 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).
France Sweden Netherlands USA Switzerland Canada Germany Austria Poland Croatia Russia Bulgaria Egypt
S. Korea China Kazakhstan India
BCG MMR OPV
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
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
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
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 ); B. Number of confirmed COVID-19 cases and death cases in certain countries; C. The-estimate of world malaria burden (adopted from ); 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 . 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 . IL-8 is crucial in the innate response to bacterial infection by stimulating neutrophil chemo- taxis and macrophage triggering . TNF could lead to the activa- tion of beneficial regulatory T cells .
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 . 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 . 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 . 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  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 . 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 . 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 , and hydroxychloroquine, which have around 40 days half-life , that were proven effec- tive against SARS-CoV-2 virus . 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 . 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 . 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.  However, the side effect of the chloroquine and hydroxychloroquine and any possible interaction should be taken into account [63,64].
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.
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