RAPID REVIEW

Should Bacillus Calmette–Guérin (BCG) vaccine

be used in the prophylaxis of COVID-19?

Daisy O. Sanchez-Mostiero, MD1 and Abigail F. Melicor, MD2

1Department of Clinical Epidemiology, College of Medicine, University of the Philippines Manila

2Asia Pacific Center for Evidence Based Healthcare, Manila, Philippines

KEY FINDINGS

At present, there is insufficient evidence to support the use of BCG vaccine as prophylaxis for COVID-19.

•Bacillus Calmette Guerin (BCG) vaccine is an attenuated microorganism derived from bovine tubercle bacillus and is being given to prevent severe tuberculosis.

•BCG vaccination may enhance production of antibodies and pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF). BCG may lead to increased CD4 and CD8 T-cell activity on subsequent viral infection.

•Ecological studies on the effect of BCG vaccination policy on COVID-19 outcomes have conflicting results and are prone to bias from confounders.

•There is insufficient evidence on the efficacy and safety of BCG vaccine for COVID-19 prophylaxis.

•Thirteen clinical trials are ongoing among high-risk groups (healthcare workers, elderly, police officers) to evaluate the efficacy and safety of BCG vaccine in preventing COVID-19 and its severe symptoms.

•WHO does not recommend the use of BCG vaccine as prophylaxis against COVID-19.

•Adverse events of BCG vaccine range from mild local cutaneous reactions to systemic adverse events such as abscess, lymphadenopathy and osteomyelitis.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Bacillus Calmette Guerin (BCG) vaccine is an attenuated microorganism derived from bovine tubercle bacillus and was first introduced in humans in 1921. It is currently being given to prevent severe tuberculosis in countries with high disease prevalence.

Aside from the protective effects of BCG against tuberculosis, the BCG vaccine also enhances antibody production. Children vaccinated with BCG were less likely to have septicemia, acute respiratory infection, and Respiratory Syncytial Virus infection. Previous or concurrent administration of BCG was also associated with significantly higher levels of antibodies against hepatitis B, polio, pneumococcus and influenza.1

Protective effect against infections caused by viral pathogens were from various in vitro and in vivo studies in mice and then later, have shown to protect against an experimental viral infection with attenuated yellow fever virus vaccine strain in humans. BCG effects are thought to be mediated via the induction of innate immune memory and heterologous lymphocyte activation, thus, resulting in enhanced cytokine production (interleukin-1β and tumor necrosis factor α), macrophage activity, T-cell responses and antibody titers. Human data on cytokine induction after BCG administration are inconclusive because available studies

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Should BCG vaccine be used in the prophylaxis of COVID-19?

have low numbers of study participants, heterogeneous study designs, and variable formulations are used. Even though some patterns emerge such as BCG Denmark and BCG Japan perhaps being more immunogenic, generalizability of conclusions is difficult due to problems stated above.2-3

Majority of BCG vaccinations are associated with mild local adverse reactions, from formation of a papule with progression to the characteristic BCG scar. Serious adverse reactions have also been reported such as abscess formation, lymphadenopathy and osteomyelitis. Disseminated BCG infection occurred in those with underlying immunodeficiency disorders. 4-5 Clinical trials that investigate the efficacy and safety of BCG vaccine as prophylaxis to COVID-19 are still limited.

This rapid review summarizes the available evidence on the efficacy and safety of BCG vaccine in preventing COVID-19 infection.

METHODS

An electronic search of Medline and Google scholar was done for published and unpublished studies on the role of BCG vaccination in the prevention of COVID-19. A search of Clinicaltrials.gov was also done for ongoing trials. References of retrieved articles were also checked for additional studies. The search terms used were BCG vaccine, COVID-19 and SARS-CoV-2 in MESH and free text. The search strategy is summarized in Appendix 1.

Screening and selection of studies were done by two reviewers based on the following inclusion criteria:

•Population: general population

•Intervention: BCG vaccination, any dose

•Comparator: placebo, any active control, no BCG vaccination

•Outcomes: Incidence of COVID-19, incidence of severe symptoms from COVID-19

•Study designs: randomized controlled trials (RCTs), non-randomized studies (cohort studies, case control, cross-sectional)

The quality of the included studies was assessed by two reviewers. Disagreements were resolved through discussion. The following data were extracted from the included studies: title, author, study design, country, population and key findings.

RESULTS

Characteristics of included studies

There are no completed clinical trials on BCG vaccine as prophylaxis for COVID-19. However, we found 15 population studies that investigated the association of a BCG vaccination policy and COVID-19 outcomes. Ten studies reported decreased incidence and mortality rates for countries with BCG vaccination policy.6-15  The effect of BCG

vaccination policy on case fatality rates (CFR) had conflicting results with three studies reporting a significant decrease and one study showing no significant difference.9-10,15-16 However, a study by Li et al. reported BCG immunization coverage from 1980-1985 had no significant effect on the crude growth rate and case fatality rate of COVID-19 at the tenth day after cumulative cases exceed 100 in a country. Findings remained the same when measured at a different stage in the COVID-19 epidemic.17 Three other studies also reported BCG vaccination coverage had no significant effect on COVID-19 mortality. 18-20 Characteristics of these studies are summarized in Appendix 2.

Currently, there are 13 ongoing randomized clinical trials that investigate whether BCG vaccination protects against COVD-19 and reduces severity of symptoms in high-risk groups: healthcare workers (9 trials), elderly people (3 trials) and police officers (1 trial). One study in the Netherlands has completed recruitment, 7 trials are ongoing recruitment (2 in Germany, 1 in Australia, 1 in Netherlands, 1 in the United States of America, 1 in South Africa, 1 in Greece) and 5 trials (1 in Egypt, 1 in Colombia, 1 in Denmark, 1 in France, 1 in Canada) are not yet recruiting. Characteristics of these trials are summarized in Appendix 3.

Critical Appraisal

Findings from 15 population studies with low quality evidence have conflicting results. Majority of the studies reported similar findings suggesting better COVID-19 outcomes in countries with BCG vaccination policy 6-16 but their analysis did not account for confounders that may affect these outcomes such as population characteristics, level of testing, healthcare systems, control measures, burden of disease and stage of epidemic. In contrast, four studies reported BCG vaccination policy had no effect on COVID-19 outcomes when epidemic stage, level of testing and socioeconomic status were taken into consideration.17-20 Clinical trials are needed to determine whether BCG vaccine plays a beneficial role in COVID-19.

Recommendations from other guidelines

The WHO does not recommend the use of BCG vaccine as prophylaxis against COVID-19 because there are no clinical trials to prove its efficacy. Ecological studies conducted on BCG and COVID-19 are prone to bias from many confounders. WHO continues to recommend neonatal BCG vaccination in countries with high incidence of tuberculosis. Diversion of BCG supplies may compromise ongoing BCG vaccination programs and increase the cases and deaths from tuberculosis.21

CONCLUSION

Presently, there is insufficient evidence regarding the use of BCG vaccine as prophylaxis to COVID-19. The results of ongoing clinical trials are needed.

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Declaration of conflict of interest

No conflict of interest.

REFERENCES

1. Zimmermann P, Curtis N, The influence of BCG on vaccine responses

– a systematic review. Expert Rev Vaccines. 2018 Jun; 17(6):547- 554. doi: 10.1080/14760584.2018.1483727.

2.Angelidou A, Diray-Arce J, Conti M, Smolen KK, van Haren SD, Dowling DJ, et al. BCG as a Case Study for Precision Vaccine Development: Lessons from Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny. Front Microbiol. 2020 Mar; 11:332. doi:10.3389/fmicb.2020.00332.

3.Moorlag, SJCFM, Arts RJW, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019 Dec; 25(12):1473-8. doi:10.1016/j.cmi.2019.04.020.

4.Clothier HJ, Hosking L, Crawford NW, Russell M, Easton ML, Quinn J, et al. Bacillus Calmette-Guérin (BCG) vaccine adverse events in Victoria, Australia: analysis of reports to an enhanced passive surveillance system. Drug Saf. 2015 Jan; 38(1):79-86. doi: 10.1007/ s40264-014-0248-6.

5.Deeks SL, Clark M, Scheifele DW, Law BJ, Dawar M, Ahmadipour N, et al. Serious adverse events associated with Bacille Calmette-Guérin vaccine in Canada. Pediatr Infect Dis J. 2005 Jun; 24(6):538-41. doi: 10.1097/01.inf.0000164769.22033.2c.

6.Miller A, Reandelar MJ., Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination

policy and reduced

morbidity and

mortality for COVID-19:

an epidemiological

study. medRxiv

[preprint]. MedRxiv 2020.

doi: 10.1101/2020.03.24.20042937.

 

7.Hegarty PK, Zafirakis H, Kamat A, Dinardo A. BCG vaccination may be protective against COVID-19. 2020 March [preprint] doi: 10.13140/RG.2.2.35948.10880.

8.Dolgikh S. Further Evidence of a Possible Correlation Between the Severity of Covid-19 and BCG Immunization. MedRxiv [preprint]. MedRxiv 2020. doi: 10.1101/2020.04.07.20056994.

9.Bodova K, Boza V, Brejova B, Kollar R, Mikusova K, Vinar T. Time-adjusted Analysis Shows Weak Associations Between BCG Vaccination Policy and COVID-19 Disease Progression. medRxiv [preprint]. medRxiv 2020 May 6. doi:10.1101/2020.05.01.20087809.

10.Kuratani N. Association of national Bacille Calmette-Guérin vaccination policy with COVID-19 epidemiology: an ecological study in 78 countries. medRxiv [preprint]. medRxiv 2020 May 16. doi: 10.1101/2020.05.13.20100156.

11.Roy S. Does the Bacillus Calmette–Guérin vaccine provide protection from COVID-19? Indian J Med Sci. 2020 Apr; 72(1): 17–20. doi: 10.25259/IJMS_37_2020.

12.Klinger D, Blass I, Rappoport N, Linial M. Significantly Improved COVID-19 Outcomes in Countries with Higher BCG Vaccination Coverage: A Multivariable Analysis. medRxiv [preprint]. medRxiv 2020 May 23. doi:10.1101/2020.04.23.20077123.

13.Mariita R, Musila J. A study on the relationship between BCG vaccination and Covid-19 prevalence: Do other confounders warrant investigation? medRxiv [preprint]. meRxiv 2020 May 11. doi:10.1101 /2020.05.06.20093138.

14.Ouanes Y, Bibi M, Baradai N, Boukhriset M, Chaker K, Kacem A, et al. Does BCG protect against SARS-CoV-2 infection?: elements of proof. medRxiv [preprint]. medRxiv 2020 May 06. doi: 10.1101/2020.05.01.20087437.

15.Singh BR, Gandharva R, Karthikeyan R, Singh SV, Yadav A, Kumar ORV, et al. Epidemiological Determinants of Acute Respiratory Syndrome Coronavirus-2 Disease Pandemic and The Role of the Bacille-Calmette-Guerin Vaccine in Reducing Morbidity and Mortality. J Pure Appl Microbiol. 2020;14:6224.

16.Dayal, D, Gupta S. Connecting BCG Vaccination and COVID-19: Additional Data. medRxiv [preprint]. medRxiv 2020. doi:10.1101 /2020.04.07.20053272.

17.Li Y, Zhao S, Zhuang Z, Cao P, Yang L, He D.The correlation between BCG immunization coverage and the severity of COVID-19. SSRN Electronic Journal [preprint]. 2020. doi: 10.2139/ssrn.3568954.

18.Squalli J. Evaluating the determinants of COVID-19 mortality: A cross-country study. medRxiv [preprint]. medRxiv 2020 May 17. doi: https://doi.org/10.1101/2020.05.12.20099093.

19.Paredes JA, Garduno V, Torres J. COVID-19 Related Mortality: Is the BCG Vaccine Truly Effective? medRxiv 2020 May 6. doi: https://doi.org/10.1101/2020.05.01.20087411.

20.Shivendu S, Chakraborty S, Onuchowska A, Patidar A, Srivastava A. Is there evidence that BCG vaccination has non-specific protective effects for COVID 19 infections or is it an illusion created by lack of testing? April 19, 2020). SSRN [preprint]. 2020. doi:10.2139/ ssrn.3579847.

21.World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19 Scientific Brief [Internet]. 2020 [cited 2020 Apr 27]. Available from: https://www.who.int/news-room/ commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)- vaccination-and-covid-19.

APPENDICES

Appendix 1. Literature search

Database

Search strategy / search terms

Medline

(BCG vaccine) AND (("Coronavirus Infections"[Mesh] OR "Coronavirus"[Mesh]

 

OR coronavirus OR novel coronavirus OR NCOV OR "COVID-19" [Supplementary

 

Concept] OR covid19 OR covid 19 OR covid-19 OR "severe acute respiratory

 

syndrome coronavirus 2" [Supplementary Concept] OR severe acute respiratory

 

syndrome coronavirus 2 OR SARS2 OR SARS 2 OR SARS COV2 OR SARS COV 2

 

OR SARS-COV-2))

Date and time

Results

of search

Yield

Eligible

June 15, 2020

19

1

12:15:00 GMT+8

 

 

Google Scholar

BCG vaccine, COVID 19

June 15, 2020

322

14

 

Filter: 2019

12:02:00 GMT+8

 

 

Trial Registries

 

 

 

 

ClinicalTrials.gov

BCG vaccine, COVID 19

June 25, 2020

14

13

 

 

15:30:00 GMT+8

 

 

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Appendix 2. Characteristics of included studies

 

 

 

 

 

 

 

No.

Title/Author

Study design

Country

Population

Intervention Group(s)

Comparison Group(s)

Outcomes

Key findings

1 Correlation between universal BCG vaccination

Population study

USA

Countries affected with

BCG vaccination

No BCG vaccination policy

Mortality rate

Lower mortality rates were reported for countries with BCG vaccination policy.

 

policy and reduced morbidity and mortality for

 

 

COVID-19 with more than

policy

 

 

Variability of mortality rates was noted for middle-high income countries with

 

COVID-19: an epidemiological study

 

 

1 million inhabitants

 

 

 

BCG vaccination policy.

 

Miller A, Reandelar MJ, Fasciglione K,

 

 

 

 

 

 

 

 

Roumenova V, Li Y, Otazu G

 

 

 

 

 

 

 

2 BCG vaccination may be protective against

Population study

USA

Countries affected with

BCG vaccination

No BCG vaccination policy

COVID-19 incidence

Countries with BCG vaccination program

 

COVID-19

 

 

COVID-19 (n=178)

policy

 

Mortality rate

incidence: 38.4 per million

 

Hegarty PK, Zafirakis H, Kamat A, Dinardo A

 

 

 

 

 

 

mortality rate: 4.28 per million

 

 

 

 

 

 

 

Countries without BCG vaccination program incidence: 358.4 per million

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

mortality rate: 40 per million

3 Further Evidence of a Possible Correlation Between

Population study

Ukraine

Countries affected

BCG vaccination

No BCG vaccination policy

COVID-19 cases per capita

Italy, Spain, France, USA had severe COVID-19 disease compared to mild

 

the Severity of Covid-19 and BCG Immunization

 

 

with COVID-19

policy

 

COVID-19 mortality per capita

COVID-19 cases in Taiwan, Germany, many East European jurisdiction

 

Dolgikh S

 

 

 

 

 

 

Vaccination level of different countries were correlated with the reported impact

 

 

 

 

 

 

 

 

of COVID-19 on countries grouped according to mortality per capita (m.p.c.),

 

 

 

 

 

 

 

 

which is a measure of epidemic impact. Countries in which the m.p.c. is <1 have

 

 

 

 

 

 

 

 

universal immunization program (UIP) against tuberculosis Countries in which

 

 

 

 

 

 

 

 

m.p.c. <10 have ongoing UIP against tuberculosis or has limited use (Canada,

 

 

 

 

 

 

 

 

Norway). Countries who had never had a UIP or significant BCG immunization

 

 

 

 

 

 

 

 

program have m.p.c. greater than or near 100.

 

 

 

 

 

 

 

 

Time of cessation of UIP/BCG and the m.p.c. value of COVID-19 impact showed

 

 

 

 

 

 

 

 

a significant correlation. The later the cessation of UIP/BCG, the lower the m.p.c.

 

 

 

 

 

 

 

 

This, however, was not observed in Australia. Thus, further studies are suggested.

 

 

 

 

 

 

 

 

UIP/BCG offered at an older age age (UK and possible France) have m.p.c. rates

 

 

 

 

 

 

 

 

between 65-100. Portugal, Spain, Canada have regional variations in UIP/BCG.

 

 

 

 

 

 

 

 

Areas were immunization were widely used have significantly lower COVID-19

 

 

 

 

 

 

 

 

cases such as Japan, South Korea, Taiwan and Singapore with a current BCG

 

 

 

 

 

 

 

 

policy which have less severe COVID-19 impacts with m.p.c. in the range of

 

 

 

 

 

 

 

 

<1% or lower.

4 Time-adjusted Analysis Shows Weak Associations

Population study

Slovakia

40 countries- 12 with

Countries with

Countries with no BCG

Case Fatality Rates in countries

Countries with recent BCG vaccination showed a statistically significant lower

 

Between BCG Vaccination Policy and COVID-19

 

 

BCG status; 28 with

recent universal BCG

vaccination policies

with BCG and no BCG

Reproduction Number

 

Disease Progression

 

 

no BCG status

vaccination policies

 

Reproduction number of

Death rate from COVID-19 was significantly lower in East Germany than

 

 

 

 

 

 

 

 

Katarína Bodová, Vladimír Boža, Brona Brejová,

 

 

 

 

 

COVID-19 in BCG and no

West Germany

 

et al.

 

 

 

 

 

BCG countries

No correlation between BCG vaccination policy and CFR

 

 

 

 

 

 

 

 

5 Association of national Bacille Calmette-Guérin

Ecological study

Japan

78 countries

54 BCG countries

24 non-BCG countries

Case Fatality Rates of

National BCG policy decreases in the country-specific risk of death by COVID-19

 

vaccination policy with COVID-19 epidemiology:

 

 

 

 

 

COVID-19 in BCG and

 

 

an ecological study in 78 countries

 

 

 

 

 

non-BCG countries

Pooled CFR stratified by national BCG policy was significantly lower mortality in

 

Kuratani N

 

 

 

 

 

Speed of COVID-19 increase in

the BCG countries than in the non-BCG countries

 

 

 

 

 

 

 

 

 

 

 

 

 

 

BCG and non-BCG countries

 

6 Significantly Improved COVID-19 Outcomes in

Population study

Israel

55 countries

Countries with

Countries that have

COVID-19 outcome and

Years of BCG administration, impact of recent vaccination, and the role of young

 

Countries with Higher BCG Vaccination Coverage:

 

 

 

current or past

only administered BCG

years of BCG administration

population in the spread of COVID-19, are correlated with COVID-19 outcome

 

A Multivariable Analysis

 

 

 

national mandatory

vaccinations to specific

 

 

 

 

 

 

 

vaccination policy

groups at risk (6 countries)

Impact of recent vaccination

 

 

Danielle Klinger, Ido Blass, Nadav Rappoport,

 

 

 

(49 countries)

 

 

 

 

Michal Linial

 

 

 

 

 

Role of young population in

 

 

 

 

 

 

 

 

the spread of COVID-19

 

7 Does the Bacillus Calmette–Guérin vaccine

Population study India

50 countries

29 countries with

21 countries without

Number of COVID-19 cases

provide protection from COVID-19?

 

 

universal BCG policy

universal BCG policy

per 1M population in countries

 

 

 

 

 

with BCG and no BCG policy

Soumya Roy

 

 

 

 

Total number of deaths per

 

 

 

 

 

 

 

 

 

 

1M population in countries

 

 

 

 

 

with BCG and no BCG policy

Countries with no BCG policy had a mean of 1272.9 cases per million with 80.7 deaths per million

Countries with a universal BCG vaccination policy had a mean 131.2 cases per million and 4 death per million population (P<0.001)

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Should BCG vaccine be used in the prophylaxis of COVID-19?

Appendix 2. Characteristics of included studies (continued)

No.

Title/Author

Study design

Country

Population

Intervention Group(s)

Comparison Group(s)

Outcomes

Key findings

8 A study on the relationship between BCG

Population study

USA

Countries with

Countries with BCG

Countries without BCG

COVID-19 cases

BCG vaccination coverage had negative correlation with COVID-19 cases

 

vaccination and Covid-19 prevalence:

 

 

COVID-19 cases

vaccination policy

vaccination policy

 

(R2=0.5707, p<0.0001). There was a strong association between low numbers

 

Do other confounders warrant investigation?

 

 

 

 

 

 

of COVID-19 cases and BCG vaccination (mean value 75.54%).

 

Mariita R, Musila J.

 

 

 

 

 

 

Other factors such as comorbidity, age and socioeconomic factors may influence

 

 

 

 

 

 

 

 

the results.

9 Does BCG protect against SARS-CoV-2 infection?:

Epidemiological

Tunisia

Countries with COVID-19

Countries with BCG

elements of proof

study

 

cases that did not meet the

vaccination policy

Ouanes Y, Bibi M, Baradai N, et al.

 

 

following exclusion criteria:

Group A: low-middle

 

 

 

 

 

 

Less than one million

income countries

 

 

 

inhabitants

 

 

 

 

Low-income countries

Group B: upper

 

 

 

Cases less than 500

middle and high

 

 

 

Less than 500 tests per

income

 

 

 

million performed

 

Countries that stopped or never had BCG vaccination policy

Group C: upper middle and high income countries that had BCG vaccination policy but stopped

Group D: Countries that never had BCG vaccination policy

Mortality

Rd = deaths per million inhabitants/diagnostic tests per inhabitants

Upper middle and high income countries (group D) with no BCG vaccination policy had a significant higher mortality and higher Rd index compared to the other groups.

Upper middle and high income countries with BCG vaccination policy (group B) had better survival than those that stopped their BCG vaccination policy (group C).

10 Epidemiological Determinants of Acute Respiratory

Population study

India

Countries with

Countries with BCG

Countries without BCG

Morbidity

COVID-19 morbidity and mortality was decreased in countries with BCG

Syndrome Coronavirus-2 Disease Pandemic and

 

 

COVID-19 cases

vaccination policy

vaccination policy

Mortality

vaccination policy. However, CFR showed no statistically significant difference.

The Role of the Bacille-Calmette-Guerin Vaccine

 

 

 

 

 

Case fatality rate

 

in Reducing Morbidity and Mortality

 

 

 

 

 

 

 

Singh BR, Gandharva R, Karthikeyan R, et al.

 

 

 

 

 

 

 

11 Connecting BCG Vaccination and COVID-19:

Population study

India

Countries affected with

BCG revaccination

High disease burden of

COVID-19 case fatality rate

Mean CFR between the two groups of countries (5.2% versus 0.6%,

Additional Data

 

 

COVID-19

policy

COVID-19 with no BCG

 

p-value <0.0001) with an RR 0.11, (95% CI:0.09-0.14)

Dayal D, Gupta S

 

 

 

 

revaccination policy

 

 

 

 

 

 

 

 

 

12 The correlation between BCG immunization

Population study

Hongkong,

Countries with COVID-19

BCG immunization

No BCG immunization

Growth rate of confirmed cases

No significant difference in the crude growth rate between countries with

coverage and the severity of COVID-19

 

China

cases with at least ten

coverage for 1980-

coverage for 1980-1985

Case fatality rate

BCG coverage and countries without BCG coverage (p-value=0.3948,

 

 

 

days data after cumulative

1985 as proxy of

 

 

two-sample-t-test).

Li Y, Zhao S, Zhuang Z, Cao P, Yang L, He D

 

 

confirmations exceed 100

BCG coverage among

 

 

 

 

 

 

 

34-39 years old

 

 

Countries with BCG coverage had a slightly higher growth rate of 8.56 versus

 

 

 

 

cohort

 

 

7.23 (increase in cumulative number over 10 days).

 

 

 

 

 

 

 

The group of countries with BCG coverage had higher case-fatality-rate (CFR)

 

 

 

 

 

 

 

than those without BCG coverage (0.022 versus 0.014), but the difference is not

 

 

 

 

 

 

 

significant (p-value=0.06).

 

 

 

 

 

 

 

Countries without BCG coverage may have better medical conditions and living

 

 

 

 

 

 

 

environment, thus, the lower growth rate and case fatality rate.

 

 

 

 

 

 

 

No significant effects of BCG coverage (1980-1985, i.e., 34-39 age cohort when

 

 

 

 

 

 

 

they were born) on the crude growth rate and case fatality rate on the tenth day

 

 

 

 

 

 

 

after cumulative exceeding 100 in a country. Findings remained the same after

 

 

 

 

 

 

 

extending to 20-day range and changing the threshold to 50 cases.

13 Evaluating the determinants of COVID-19

Cross-country

UAE

140 countries

Countries with BCG

Countries without BCG

COVID-19 mortality

No link between COVID-19 mortality and BCG vaccination

mortality: A cross-country study

Study

 

 

vaccination policy

 

 

 

Jay Squalli

 

 

 

 

 

 

 

14 COVID-19 Related Mortality: Is the BCG Vaccine

Population study

Mexico

High income countries with

Countries with BCG

Countries that never had

Mortality

The mean number of deaths per 1 million population and the deaths at 1000th

Truly Effective?

 

 

at least 1000 cases and at

vaccination policy

BCG vaccination policy

- Total deaths

case between countries with existing BCG vaccination policy and those without

 

 

 

least 1 million inhabitants

 

 

- Deaths at 1M

were not statistically significant.

Paredes JA, Garduno V, Torres J.

 

 

 

 

Countries with previous

- Deaths at 1000th case

 

 

 

 

 

 

BCG vaccination policy

 

 

15 Is there evidence that BCG vaccination has non-

Population study

USA

Countries with

Countries with BCG

Countries without

COVID-19 cases

BCG vaccination policy had no significant effects on COVID-19 cases and

specific protective effects for COVID-19 infections

 

 

COVID-19 cases

vaccination policy

BCG vaccination policy

COVID-19 deaths

mortality when COVID testing was taken into consideration.

or is it an illusion created by lack of testing?

 

 

 

 

 

 

 

Shivendu S, Chakraborty S, et al.

 

 

 

 

 

 

 

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Appendix 3. Characteristics of ongoing clinical trials

 

 

 

 

 

 

 

No.

Clinical Trial ID / Title

Status

Start and estimated primary

Study design

Country

Population

Intervention Group(s)

Comparison

Outcomes

completion date

Group(s)

 

 

 

 

 

 

 

 

1 Reducing Health Care Workers Absenteeism

Recruiting

Start date: 03/25/2020

Multicenter randomized

Netherlands

1000 nurses and physicians

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: Number of days of unplanned absenteeism

 

in Sars-Cov-2 Pandemic Through Bacillus

 

 

controlled trial,

 

working at emergency rooms and

intracutaneously

of 0.9% NaCl

 

 

Calmette-Guérin Vaccination, A Randomized

 

Estimated primary completion

placebo controlled

 

wards where COVID-infected

 

intracutaneously

Secondary:

 

Controlled Trial (BCG-CORONA)

 

date: 10/25/2020

 

 

patients are treated

 

 

Incidence of documented SARS-CoV-2 infection

 

 

 

 

 

 

 

 

 

Incidence of severe respiratory symptoms, hospital admission,

 

ClinicalTrials.gov Identifier: NCT04328441

 

 

 

 

 

 

 

intensive care admission and death from SARS-CoV-2 infection

 

 

 

 

 

 

 

 

 

Number of days of fever, respiratory symptoms

 

 

 

 

 

 

 

 

 

Incidence of SARS-CoV-2 antibodies

2 BCG Vaccination to Protect Healthcare Workers

Recruiting

Start date: 03/30/2020

Multicenter, open

Australia

4000 healthcare workers in

BCG vaccine 0.1 ml

None

Primary: Incidence of COVID-19 disease and severe

 

Against COVID-19 (BRACE)

 

 

label randomized

 

hospital sites

intradermally

 

COVID-19 disease

 

 

 

Estimate primary completion

controlled trial

 

 

 

 

 

 

ClinicalTrials.gov Identifier: NCT04327206

 

date: 10/30/2020

 

 

 

 

 

Secondary:

 

 

 

 

 

 

 

 

 

Time to first symptom and duration of symptoms of COVID-19

Work absenteeism

Hospital admission, critical care admission

Need for oxygen therapy, mechanical ventilation

Mortality

Local and systemic adverse events to BCG

3 Application of BCG Vaccine for Immune-

Not yet

Start date: 04/20/2020

Multicenter randomized Egypt

prophylaxis Among Egyptian Healthcare Workers

recruiting

 

controlled trial,

During the Pandemic of COVID-19

 

Estimate primary completion

placebo controlled

 

 

date: 10/01/2020

 

ClinicalTrials.gov Identifier: NCT04350931

 

 

 

900 healthcare workers at

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: incidence of confirmed COVID-19

emergency rooms, ICUs and

intradermally

of 0.9% NaCl

 

wards of isolation hospitals

 

intradermally

Secondary:

 

 

 

Number of days of absenteeism Incidence of hospital

 

 

 

admission

 

 

 

Incidence of ICU admission

 

 

 

Mortality

4 Performance Evaluation of BCG Vaccination

Not yet

Start date: 04/2020

Multicenter, randomized Colombia

in Healthcare Personnel to Reduce the

recruiting

 

controlled trial

Severity of SARS-COV-2 Infection

 

Estimate primary completion

 

ClinicalTrials.gov Identifier: NCT04362124

 

date: 06/2021

 

 

 

 

1000 healthcare workers

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: incidence of confirmed and probable COVID-19 cases

directly involved in the care of

intradermally

of 0.9% NaCl

 

COVID-19 patients

 

intradermally

Secondary:

 

 

 

Incidence of severe COVID-19 infection

 

 

 

Mortality

 

 

 

Safety of BCG vaccination (adverse events)

5 BCG Vaccine for Health Care Workers as

Recruiting

Start date: 04/20/2020

Multicenter randomized

USA

1800 healthcare workers involved

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: incidence of COVID-19 infection

Defense Against COVID-19 (BADAS)

 

 

controlled trial

 

in the care of suspected and

intradermally

of 0.9% NaCl

 

 

 

Estimate primary completion

 

 

confirmed COVID-19 patients

 

intradermally

Secondary:

ClinicalTrials.gov Identifier: NCT04348370

 

date: 05/2021

 

 

with at least 25 hours per

 

 

Disease severity (Covid Severity Scale Scoring)

 

 

 

 

 

week of direct patient care

 

 

 

6 Reducing COVID-19 Related Hospital Admission

Active, not

Start date: 04/16/2020

Placebo-controlled

Netherlands

2014 Elderly people

BCG vaccine

Placebo: 0.9%

Primary: SARS-CoV-2 related hospital admission

in Elderly by BCG Vaccination

recruiting

 

adaptive multi-

 

(≥ 60 years of age)

 

NaCl

 

 

 

Estimate primary completion

center randomized

 

 

 

 

Secondary

ClinicalTrials.gov Identifier: NCT04417335

 

date: 05/2021

controlled trial

 

 

 

 

Duration of hospital stay

 

 

 

 

 

 

 

 

Cumulative incidence of infection, symptoms, intensive care

 

 

 

 

 

 

 

 

admission and death

7 BCG Vaccination for Healthcare Workers in

Recruiting

Start date: 05/04/2020

Randomized controlled

South Africa

500 healthcare workers

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: Incidence of healthcare workers admitted due to

COVID-19 Pandemic

 

 

trial, placebo controlled

 

 

intradermally

of 0.9% NaCl

COVID-19

 

 

Estimate primary completion

 

 

 

 

intradermally

 

ClinicalTrials.gov Identifier: NCT04379336

 

date: 04/28/2021

 

 

 

 

 

Secondary:

 

 

 

 

 

 

 

 

Incidence of SARS-CoV-2 infection

 

 

 

 

 

 

 

 

Incidence of upper respiratory tract infection

 

 

 

 

 

 

 

 

Incidence of ICU admission

 

 

 

 

 

 

 

 

Incidence of death

 

 

 

 

 

 

 

 

Days of unplanned absenteeism due to COVID-19

 

 

 

 

 

 

 

 

Prevalence of latent TB infection

 

 

 

 

 

 

 

 

Incidence of active TB

 

 

 

 

 

 

 

 

Incidence of adverse events

8 Bacillus Calmette-guérin Vaccination to Prevent

Recruiting

Start date: 05/26/2020

Prospective

Greece

900 elderly patients hospitalized

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: Positive for the respiratory questionnaire on

COVID-19 (ACTIVATEII)

 

 

randomized open-

 

at the 4th Department of Internal

intradermally

of 0.9% NaCl

appearance of COVID-related symptoms

 

 

Estimate primary completion

label controlled trial

 

Medicine of ATTIKON University

 

intradermally

Positive IgM or IgG antibodies against SARS-CoV-2

ClinicalTrials.gov Identifier: NCT04414267

 

date: 05/25/2021

 

 

General Hospital

 

 

 

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Should BCG vaccine be used in the prophylaxis of COVID-19?

Should BCG vaccine be used in the prophylaxis of COVID-19?

Appendix 3. Characteristics of ongoing clinical trials (continued)

No.

Clinical Trial ID / Title

Status

Start and estimated primary

Study design

Country

Population

Intervention Group(s)

Comparison

Outcomes

completion date

Group(s)

 

 

 

 

 

 

 

 

9

Using BCG Vaccine to Protect Health Care

Not yet

Start date: 05/2020

Multi-center

Denmark

1500 healthcare workers with

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary: Number of days of unplanned absenteeism for any

 

Workers in the COVID-19 Pandemic

recruiting

 

randomized placebo-

 

direct patient contacts; nurses,

intradermally

of 0.9% NaCl

reason

 

 

 

Estimate primary completion

controlled trial

 

physicians and other medical staff

 

intradermally

 

 

ClinicalTrials.gov Identifier: NCT04373291

 

date: 12/2020

 

 

working at emergency rooms or

 

 

Secondary:

 

 

 

 

 

 

wards where COVID-19 patients

 

 

Cumulative incidence of COVID infection, hospital admission,

 

 

 

 

 

 

are treated

 

 

ICU admission, days of unplanned absenteeism due to COVID

10

Efficacy of BCG Vaccination in the Prevention

Not yet

Start date:

Randomized,

France

1120 healthcare workers

BCG vaccine 0.1 ml

Placebo: 0.1 ml

Primary:

 

of COVID19 Via the Strengthening of Innate

recruiting

05/11/2020

multicenter, phase III,

 

 

intradermally

of 0.9% NaCl

Incidence of COVID-19 infection

 

Immunity in Health Care Workers (COVID-BCG)

 

Estimate primary completion

controlled trial

 

 

 

intradermally

Secondary:

 

 

 

 

 

 

 

 

 

ClinicalTrials.gov Identifier: NCT04384549

 

date: 02/11/2021

 

 

 

 

 

Number of patients requiring ICU admission, oxygen, ECMO or

 

 

 

 

 

 

 

 

 

artificial ventilation

 

 

 

 

 

 

 

 

 

Incidence of asymptomatic COVID-19

 

 

 

 

 

 

 

 

 

Incidence of respiratory infection

 

 

 

 

 

 

 

 

 

Number of sick days and sick leaves

 

 

 

 

 

 

 

 

 

BCG-related adverse events

 

 

 

 

 

 

 

 

 

Changes in innate immune markers

11

Efficacy and Safety of VPM1002 in Reducing

Not yet

Start date:

Double-blind,

Canada

3626 front-line police officers

Recombinant BCG

Placebo: 0.1 ml

Primary:

 

SARS-CoV-2 (COVID-19) Infection Rate and

recruiting

06/14/2020

randomized

 

 

vaccine 0.1 ml

of 0.9% NaCl

COVID-19 infection

 

Severity (COBRA)

 

Estimate primary completion

controlled trial

 

 

intradermally

intradermally

Secondary:

 

 

 

 

 

 

 

 

 

ClinicalTrials.gov Identifier: NCT04439045

 

date: 04/01/2021

 

 

 

 

 

Incidence of hospitalization, ICU admission, ARDS,

 

 

 

 

 

 

 

 

 

mechanical ventilation, secondary infection, mortality and

 

 

 

 

 

 

 

 

 

innate trained immunity

 

 

 

 

 

 

 

 

 

Adverse events

12 Study to Assess VPM1002 in Reducing

Recruiting

Start date: 05/25/2020

Phase III, Double-

Germany

Healthcare Professionals' Absenteeism in

 

 

blind, Randomized,

 

COVID-19 Pandemic

 

Estimate primary completion

Placebo-controlled

 

ClinicalTrials.gov Identifier: NCT04387409

 

date: 06/30/2021

Multicentre Clinical Trial

 

 

 

 

 

1200 healthcare professionals

Recombinant BCG

Placebo: 0.1 ml

Primary: Number of days absent from work due to respiratory

(doctors, nurses, paramedical staff)

vaccine 0.1 ml

of 0.9% NaCl

disease

working in emergency departments,

intradermally

intradermally

 

ICU, infectious disease wards,

 

 

Secondary:

COVID-19 wards, isolation wards

 

 

Incidence of COVID-19 related symptoms, SARS-CoV-2

 

 

 

infection, mortality, ICU admission, hospital admission,

13 Study to Assess VPM1002 in Reducing

Recruiting Start date: 06/2020

Phase III, Randomized, Germany

2038 adults aged 60 and above

Recombinant BCG

Placebo: 0.1 ml

Primary: Number of days with severe respiratory disease

Hospital Admissions and/or Severe

 

Double-blind, Placebo-

 

vaccine 0.1 ml

of 0.9% NaCl

 

Respiratory Infectious Diseases in Elderly in

Estimate primary completion

controlled, Multicentre,

 

intradermally

intradermally

Secondary:

COVID-19 Pandemic

date: 05/31/2021

Clinical Trial

 

 

 

Cumulative incidence of hospital admissions, SARS-CoV-2

 

 

 

 

 

 

infection, respiratory symptoms, hospital admission,

ClinicalTrials.gov Identifier: NCT04435379

 

 

 

 

 

ICU admission, mortality

 

 

 

 

 

 

Number of days with COVID-19 related symptoms

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