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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 105-110

Bacillus calmette-guerin as a quick and temporary solution to coronavirus disease-2019


1 Experimental Animal Facility, National JALMA Institute of Leprosy and other Mycobacterial Diseases, Agra, Uttar Pradesh; School of Studies in Biotechnology, Jiwaji University, Gwalior, Madhya Pradesh, India
2 Experimental Animal Facility, National JALMA Institute of Leprosy and other Mycobacterial Diseases, Agra, Uttar Pradesh, India
3 School of Studies in Biotechnology, Jiwaji University, Gwalior, Madhya Pradesh, India

Date of Submission19-Apr-2021
Date of Acceptance01-May-2021
Date of Web Publication14-Jun-2021

Correspondence Address:
Sameer Suresh Bhagyawant
School of Studies in Biotechnology, Jiwaji University, Gwalior, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_86_21

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  Abstract 


The coronavirus disease-2019 (COVID-19) pandemic is one of the most devastating things that happened in the world which has taken the lives of millions of people and has brutally shattered the world economy. This pandemic has instigated an urgent need for a vaccine to reduce the ongoing morbidity and mortality. Bacillus Calmette-Guerin (BCG) apart from being used as an effective and old vaccine against tuberculosis has some known off-target protection effect and is getting more attention in this scenario. BCG confers nonspecific innate immune-boosting effects called trained immunity against secondary infection. Various recent publications have proposed the inverse relationship between the COVID-19 morbidity and mortality with that of BCG coverage of that country on the basis of epidemiological studies. However, these studies have not considered the confounding factors, and a lot of recent articles are contradicting these epidemiological and observational data. Several random control trials for BCG on health-care workers and elderly people are ongoing worldwide and could depict the actual relation between COVID-19 and BCG protection. Although a recent trial has found a protective function of BCG against COVID-19 in health-care workers, more results of the trials can only give approval on this. There has been a shortage of BCG worldwide due to its use in bladder cancer and vaccination in neonates, and hence, its use should be carefully regulated. In this review, we have tried to summarize the various issue and conflicts on BCG to be used as a temporary solution to COVID-19.

Keywords: Bacillus Calmette-Guerin, clinical trials, coronavirus disease-2019, severe acute respiratory syndrome coronavirus 2, trained immunity, vaccine


How to cite this article:
Kumari P, Gupta UD, Bhagyawant SS. Bacillus calmette-guerin as a quick and temporary solution to coronavirus disease-2019. Int J Mycobacteriol 2021;10:105-10

How to cite this URL:
Kumari P, Gupta UD, Bhagyawant SS. Bacillus calmette-guerin as a quick and temporary solution to coronavirus disease-2019. Int J Mycobacteriol [serial online] 2021 [cited 2021 Sep 17];10:105-10. Available from: https://www.ijmyco.org/text.asp?2021/10/2/105/318393




  Introduction Top


Coronavirus disease-2019 (COVID-19) disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated from the Wuhan city of China and has been declared as a pandemic by the WHO on March 11, 2020.[1] An effective vaccine is urgently needed to stop this viral disease from spreading and vaccine production takes time. Bacillus Calmette-Guerin (BCG) comes as a great candidate in this case, as it is known to confer nonspecific immunity against various pathogens.[2],[3],[4],[5] In this review, the possible reasons which justify the use of BCG vaccine for COVID-19, clinical trials, and controversies emerging on its use are discussed.


  Coronavirus Disease-2019 Top


SARS-CoV-2 is a single-stranded positive-sense RNA virus that belongs to the coronaviridae family of viruses and causes the disease COVID-19.[6],[7] This zoonotic virus is a β-coronavirus that was isolated due to an outbreak of the respiratory disease in Wuhan town, Hubei province, China.[8] Individuals infected with the virus may be asymptomatic or may show mild-to-severe symptoms such as fever, dry cough, tiredness, aches and pains, nasal congestion, headache, conjunctivitis, sore throat, diarrhea, loss of taste or smell, or a rash on skin or discoloration of fingers or toes.[9],[10] The extent of development of these symptoms may be complicated in older people or persons with other medical issues such as high blood pressure, heart and lung problems, diabetes, or cancer and can lead to immediate hospitalization or even death.[11] The disease which started in China has infected people globally with Europe, United States, Brazil, and India as the new hotspots of the pandemic. Nearly 216 countries are struggling from this disease, and at the time of writing, this review has infected around 140,322,903 people worldwide and has taken the life of almost 3,003,794[12] people. This pandemic has brutally shattered the world economy, and there is an immediate need of a vaccine that can provide immunity to save human life globally. Vaccine development is a time-taking process as it requires an understanding of the structure of the pathogen, immunogenicity of the antigen, and it undergoes the various phases of clinical trials.[13] The other important parameters include the huge funding required for the trials, study size, number of doses required to eliminate the pathogen, and safety issues. In this scenario, BCG is emerging as a choice of vaccine for COVID-19 as it is known to provide trained immunity against viral infection and is already available in the market.[4]


  What is Bacillus Calmette-Guerin and how does it Help in Providing Protection against Mycobacterium tuberculosis? Top


BCG is a 100-year-old vaccine originally developed by Calmette and Guerin by in vitro passaging of Mycobacterium bovis strain for 230 times between the year 1908 and 1921 and is administered to prevent tuberculosis.[14] BCG vaccine represents a group of phenotypically different live attenuated strains of M. bovis which have developed due to continuous passaging of these strains under different laboratory conditions (as these strains cannot be frozen for viable bacteria).[14] Deletion of the region of difference 1 compared to Mycobacterium tuberculosis (MTB) encoding the genes for bacterial ESX-1 secretion system has been found to be an important cause of attenuation of BCG strain.[15] This vaccine has been used worldwide to provide cross-protection from M. tuberculosis to infants providing an efficacy of ~50%.[16] Although the BCG vaccine is the only licensed vaccine for tuberculosis and has been in use for more than 90 years, its efficacy is still controversial with proven safety.[17] Furthermore, we still do not know exactly the basis for the defense of BCG and the degree to which that defense is mediated by CD4 + T-cells or by innate immunity.[18]


  Bacillus Calmette-Guerin Confers Cross-Protection from to other Infections Making it a Quick and Temporary Solution to CoronaVirus Disease-2019 Top


Aside from being an effective tuberculosis vaccine, BCG is also known to provide nonspecific immunological protection against a wide range of unrelated pathogens and diseases such as bladder cancer [Figure 1].[19] A series of random trials and studies discussed below suggests the nonspecific effects of BCG; (a) BCG has been found to be effective in declining the childhood mortality rate by decreasing the sepsis and respiratory infections in childhood,[20],[21] (b) it has been found to be effective in reducing acute upper respiratory tract infections in the elderly people (60–75-year-old) in Indonesia,[22] (c) it has shown reduced atopy and asthma in a study conducted on Korean adults,[23] (d) it has been found to be effective in the prevention of child asthma in a meta-analysis of epidemiological study possibly by modulating immune maturation process,[24] (e) in an another study reported in 1931, Swedish children who obtained BCG vaccine at birth had a mortality rate nearly threefold lower than unvaccinated infants, and similar trend in the reduction of mortality rate of children were observed in other parts of world in the same decade,[19] (f) In West Africa, a BCG vaccination scar and a positive tuberculin reaction were linked to improved early childhood survival in an area with high mortality whereas this has not been observed with other infant vaccines,[25] (g) in Guinea-Bissau, BCG vaccination has shown beneficial effect in the neonatal period mainly due to fewer cases of neonatal sepsis, respiratory infection and fever,[26] (h) in an another study conducted in the same region, BCG vaccination has shown nontargeted protective effect and appears to confer broad enhanced immunity to respiratory infections than controls matched,[27] (i) BCG-Danish has decreased respiratory tract infections in adolescents by 73% by a study conducted in South Africa,[28] (j) BCG-Danish has also been found to reduce the neonatal mortality by 38% when administered in low-weight neonates (<2500 g) in Guinea-Bissau, mainly because there were fewer deaths from pneumonia and sepsis,[29] (k) protection against pneumonia was also observed in clinical trial performed in Japan demonstrated on tuberculin-negative older individuals,[30] (l) the hospitalizations due to respiratory infections and sepsis (not attributable to TB) in the children of 0–14-year-old in Spain were considerably lower in BCG-vaccinated children relative to non-BCG-vaccinated children,[31] (j) BCG has been found to reduce viremia in response to the yellow fever vaccine which is a live attenuated vaccine by epigenetic reprogramming of the innate immune system in trials on volunteers in the Netherlands and was found to reduce the severity of mengovirus (encephalomyocarditis virus) infection in two studies in mice,[7] (k) In addition to this, other laboratory studies have indicated that BCG can protect against viral pathogens, including the human papilloma virus, respiratory syncytial virus and herpes simplex virus[32] and (l) apart from protection from bacterial and viral infection, BCG has been found to confer protection against fungi such as Candida albicans and protozoa such as Leishmania braziliensis.[5],[33] All these random trials, epidemiological studies, and reviews suggested the nonantigen-specific immunological memory of BCG which makes it a suitable vaccine candidate to boost the immunity bridging the time-gap to develop the specific vaccine for SARS-CoV2 virus.
Figure 1: Bacillus Calmette–Guerin vaccine impart specific immune response against Mycobacterium tuberculosis and nonspecific immune response against wide range of pathogen and disease such as bladder cancer

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  Bacillus Calmette-Guerin and its Immunologic Mechanism for Nonspecific Immunity Top


BCG is known to impart trained immunity which is immunological memory of the innate immune system of the past insults [Figure 2].[34] Trained immunity is conferred by the innate immune cells such as monocytes/macrophages and natural-killer cells.[19] Monocytes from these vaccinated individuals have enhanced protective inflammatory response by the production of pro-inflammatory cytokines, such as interleukin (IL)-1 β, tumor necrosis factor, and IL-6, when challenged by unrelated pathogens through pattern recognition receptors and thereby provide host defence.[3],[19] The heterologous effects observed for the BCG vaccine are by the transcriptional, epigenetic, and metabolic reprogramming of the myeloid cells not by genetic mutations or recombination which is indispensable for adaptive immunity.[35] The epigenetic changes are expressed as the histone's chemical modifications (methylation and acetylation), resulting in increased accessibility to chromatin, easier gene transcription essential for antimicrobial responses, and improved cell function.[35] Furthermore, metabolic reprogramming leads to selective build-up or reduction of certain metabolites which function as cofactors for several classes of enzymes that facilitate the epigenetic changes.[36] Apart from its effect on innate immunity, BCG has been found to induce a long-term nonspecific effect on adaptive immune responses termed as heterologous immunity.[33] The heterologous effect of BCG vaccination is marked by the significant increase on the Th1 and Th17 response by a consistent increase in the expression of interferon-gamma, IL-22, and IL-17 in response to nonmycobacterial stimulation of monocyte cells taken after 1 year from vaccinated participants.[33] Hence, these double effects of BCG vaccination through trained immunity and heterologous T-cell responses deliver a possible reason for both short- and long-term nonantigen-specific immunological responses to reinfection.
Figure 2: Schematic representation of protection conferred by Bacillus Calmette–Guerin vaccination. Bacillus Calmette–Guerin vaccination elicits trained immunity and heterologous immunity against coronavirus disease-2019 viral infection, by modulating epigenetic, metabolic, and functional changes which lead to better protection from disease. Non-Bacillus Calmette–Guerin vaccinated individuals lack trained immunity which leads to a severe form of coronavirus disease-2019 disease

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  Clinical Trials Data for Measuring the Efficacy of Bacillus Calmette-Guerin for CoronaVirus Disease-2019 Top


BCG vaccination has been adopted in the national policy of various countries such as Russia, China, and India, whereas countries such as United States and Italy have never employed it nationwide and only target high-risk individuals. Recent publications have shed light on the current scenario and have indicated the inverse correlation between the mortality rate due to COVID-19 cases and universal BCG vaccination policy.[37],[38] Although these shreds of evidences are circumstantial and the differences in COVID-19 mortality between various locations may be explained by many factors other than the BCG vaccination program. Several observational and interventional clinical trial studies are underway to determine the impact of BCG vaccination against COVID-19 in health-care workers and elderly people as they are most vulnerable to this disease. The clinical trials for evaluating the efficacy of BCG vaccination versus placebo on health-care workers have been started in countries such as the Netherlands, the United States, Australia, Denmark, Iran, France, Mexico, Brazil, Egypt, and South Africa where the primary outcome of a measurement is to evaluate the incidence of COVID-19 and severity of symptoms, morbidity, mortality, and in some studies SARS-CoV-2 seroconversion to check asymptomatic individuals, whereas in another group of clinical studies conducted in countries such as the Netherland, Denmark, and Guinea-Bissau the primary outcome of a measurement is health-care worker absenteeism.[39] The second study is underway to assess the effect of BCG vaccination on the prevention of COVID-19 among elderly people wherein reduction in hospital admission of the elderly is monitored in the Netherlands and reduction of senior citizens' risk of acute infection is monitored in Denmark.[39] In another clinical trial study conducted in the Netherland, impact of BCG on the prevention of COVID-19 and other respiratory infections on elderly people are under investigation and in another trial ongoing in Greece hospitalized elderly patients were vaccinated with single doses of placebo or BCG on the day of hospital discharge.[39] In Egypt, observational case–control research has started to evaluate the severity of disease in COVID-19-positive patients in those who tested positive for past BCG exposure or immunization with those tested to be negative.[39] India is the second most affected country by COVID-19 and several trials are undergoing to see the effectiveness of BCG vaccination by monitoring the prevention of morbidity and mortality in elderly individuals aged between 60 and 80 years living in COVID-19 hotspots in India, incidence and severity of COVID-19 in the high-risk population, protective effect of re-vaccination with BCG against COVID-19 in health-care workers and role of BCG as a potential therapy for COVID-19 are ongoing.[40]

BCG is not the only vaccine that provides trained immunity other studies have indicated that trained innate immunity is also generated by other live vaccines such as measles and oral polio vaccine and new recombinant MTB-based vaccines, such as VPM1002.[32] VPM1002 is a genetically modified BCG strain with improved immunogenicity in which urease C-encoding gene with the listeriolysin-encoding gene from Listeria monocytogenes and presently being used in clinical trials in India, Canada, and Germany.[32],[41] Currently, measles, mumps, rubella (MMR) vaccine is used in a clinical trial, and in another study, BCG-plus which is a combination of BCG and the MMR vaccine against COVID-19 is used in the Netherland.[6],[42] Trained immunity has also been found to be elicited by fungal cell wall component β-glucan and by C. albicans.[5],[43]


  A Conflicting Puzzle whether or not Bacillus Calmette-Guerin is Efficient in Combating Coronavirus Disease-2019? Top


After the start of publication of reports suggesting the possible role of BCG in combatting COVID-19, several trials have started worldwide to test this hypothesis. The possible role of BCG as a quick and short solution to COVID-19 by training the innate immunity came from various observational, epidemiological, ecological, statistical studies where researchers have assessed the inverse relationship between the data available for vaccination coverage rates per vaccine in countries worldwide, BCG coverage among the countries with universal BCG vaccination policy with that of data available for COVID-19 incidence and its mortality rate.[44],[45],[46],[47] In another study which is a meta-regression of global data from 160 countries where the confounding factors have been adjusted has found that BCG is associated with reduced COVID-19 infections if the BCG vaccine coverage is over 70%.[48] However, various recent publications have contradicted this inverse association between BCG and COVID-19 mortality emphasizing the fact that these epidemiological and observational studies do not consider the confounding factors like differences in the demographic and genetic structure of the populations of the assessed countries, the share of people residing in urban settings, differences in testing rates, isolation policies, national disease burden, etc., and therefore use of BCG for protection against COVID-19 should not be fortified until the result of large scale clinical trials become available.[49],[50],[51] Furthermore, the data from countries such as Finland and Australia have shown that although these countries have ceased their BCG vaccination policy they have a very low mortality rate due to COVID-19 owing to better health and hospital management facilities whereas countries such as Iran, Israel, India, and Egypt have national BCG vaccination policy but are one of the most affected COVID-19 country.[52],[53],[54] This dilemma for the use of the BCG vaccine will become clear only after the data from randomized clinical trials ongoing in different countries will be available.


  Conclusion Top


BCG apart from being as one of the most effective and old vaccine against tuberculosis have been found to impart off-target effects or nonantigen-specific immunological memory against reinfection termed as trained immunity which makes it a suitable candidate for use against COVID-19 till the specific vaccine has not been developed. However, there are various reports which have contradictory views on the use of BCG for COVID-19. The use of BCG for COVID-19 should be regulated so that there is no shortage of it for the urology practices and for countries which have the national policy of BCG vaccination for infants and concern for the shortage of BCG for infants has been raised by countries like Japan and by the various urologist and WHO has also has raised a caution about the regulatory use of BCG.[55],[56],[57] Various clinical trials are ongoing on health-care workers, elderly people, and another group of candidates to test this and recent reports such as by Noval Rivas et al. have shown that BCG vaccinated health-care workers from Los Angeles health-care organization have less COVID-19 diagnosis and serology relative to unvaccinated health-care workers.[58] Although BCG vaccine is not a permanent solution to COVID-19 and administration of specific COVID-19 vaccine has already started in various countries, but still, it will take more than a year to vaccinate a country and in that scenario, BCG can help be a short solution to evade COVID-19 till everyone gets the vaccine.

Acknowledgments

PK is thankful to ICMR, Government of India for Senior Research Fellowship. This review was written as part of work in School of Studies in Biotechnology, Jiwaji University, Gwalior, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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