Does BCG vaccination protect against acute respiratory infections and COVID-19? A rapid review of current evidence

April 24, 2020

Ranin Soliman, Jon Brassey, Annette Plüddemann, Carl Heneghan

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford


VERDICT
There is systematic review evidence with low to moderate risk of bias that BCG vaccination prevents respiratory infections (pneumonia and influenza) in children and the elderly. These non-specific effects are mediated by induction of innate immune memory (trained immunity).

There is a lack of evidence that BCG vaccine protects against COVID-19. Currently, two clinical trials are ongoing to determine if BCG vaccination protects healthcare workers during the COVID-19 pandemic.

 

BACKGROUND
The spread of COVID-19 and impact varies across countries in the world. The frequency of cases and mortalities are lower in developing countries based on the WHO COVID-19 situation report – 71 [1].

Could this be partly attributed to trained immunity in some developing countries which have in place universal vaccination policies such as Bacille Calmette–Guerin (BCG) vaccination?

The BCG vaccine is the most commonly used vaccine against tuberculosis (TB) worldwide, and also shows beneficial non-specific effects (NSE) and innate immune memory against other non-mycobacterial diseases [2]. Observational evidence reports that BCG-vaccinated is related to better survival in children in low-income countries, especially for girls [3].

This review evaluates the current evidence about the protective effects of BCG vaccine against acute respiratory infections and COVID-19.

CURRENT EVIDENCE
Our search results yielded 157 records on PubMed, 96 on Google Scholar and no relevant articles on TRIP and LitCovid databases. From these we included 19 relevant articles about BCG vaccine and acute respiratory infections, and 9 preprints from medrxiv and 1 from ResearchGate about BCG vaccine and COVID-19.

BCG vaccine and acute respiratory infections

The relevant 19 articles included 2 systematic reviews, 4 RCTs, 8 observational studies, 2 narrative reviews and 3 animal studies. Summary of evidence for the 19 included articles is shown in Table 1.

Systematic reviews

In a systematic review and meta-analysis including 9 studies; 2 randomized trials and 7 observational studies (27867 children), Cruz, et al (2017) found that BCG vaccine approximately halved all-cause mortality in children <5 years old in low-income countries, largely due to fewer deaths from pneumonia and sepsis [4]. Meta-analysis of all 9 studies using a random effects model yielded an effect estimate of 0.56 (95% CI 0.46-0.69); the combined estimate for the 7 observational studies of 0.57 (95% CI 0.46-0.71) was similar to that for the 2 randomized trials of 0.52 (95% CI 0.33-0.82), reflecting low source of bias [4]. In another systematic review, 3 studies investigated the influence of BCG vaccine on influenza vaccination (1470 adults), and 2 studies determined the influence on pneumococcal vaccination (408 neonates), Zimmermann, et al (2018) reported that administration of BCG vaccine is associated with higher levels of antibodies against pneumococcus and influenza A (H1N1)pdm09 virus vaccines [5].

Randomized trials

Four randomized trials were conducted that studied potential non-specific effects of BCG vaccine on preventing respiratory infections. A randomized trial conducted by Aaby and colleagues (2011) in West Africa found that infant mortality was reduced by 17% at 12 months after receiving early BCG (vs. delayed) vaccination in low-birth weight children, and was mainly attributed to fewer cases of neonatal sepsis, respiratory infection [6]. This was followed by another small randomized trial by Biering-Sørensen, et al (2012) which showed that administration of BCG vaccine (vs. control group) may contribute to lower mortality due to fewer deaths from pneumonia/sepsis [7]. In a placebo-controlled randomized trial, Leentjens and colleagues (2015) observed that BCG vaccine enhances the immunogenicity of the 2009 pandemic influenza A (H1N1) vaccine in healthy adults [8]. Whereas, a multi-centre trial by Kjærgaard et al (2016) in Denmark found no impact of BCG vaccination on parent-reported pneumonia and cold [9].

Two prospective studies tested the impact of BCG vaccine to prevent respiratory infections in the elderly; Ohrui, et al (2005) noted that the BCG vaccine decreased the risk of pneumonia in elderly people >65 years with comorbidities [10], while Wardhana, et al (2011) found that BCG vaccine in elderly, once a month for 3 months, significantly prevent the acute upper respiratory tract infections [11]. In a global prospective study across 19 countries over 25 years by Hollm-Delgado, et al (2014), BCG vaccination was associated with a 17% to 37% risk reduction (RR: 0.83, 95% CI: 0.7 – 0.9) for suspected childhood acute respiratory tract infections [12].

Observational studies

A large retrospective cohort study in Spain by de Castro et al (2015) showed an average of 40% decrease in hospitalization rates in children due to respiratory infections in BCG vaccinated children compared to unvaccinated cases, due to heterologous protection of BCG vaccine [13]. Whereas, another population-based retrospective cohort study in Greenland by Haahr, et al (2016) showed no association between BCG vaccinated and unvaccinated children’s hospitalization rates due to respiratory infections [14]. Three case-control studies showed protective effects of BCG vaccination in children on pneumonia-related mortality [15], acute lower respiratory tract infections [16], and in severely malnourished children with pneumonia and bacteraemia [17].

Narrative reviews

A narrative review of 5 studies (1 systematic review, 4 studies) by Pollard, et al (2017) suggests there is current evidence about the beneficial effect of BCG vaccination on reducing non-TB (respiratory) infections [18]. Another recent review by Moorlag, et al (2019) shows that BCG protects against various DNA/RNA viruses in mice, such as influenza viruses, and that the effect of BCG on an experimental viral infection in humans has been demonstrated [19].

Animal studies

The non-specific effects of BCG vaccine against some respiratory infections were demonstrated on animal studies. Mukherjee, et al (2017) found that BCG vaccine boosts efferocytosis in alveolar space in mice and protects host against influenza pneumonia [20] and Soto, et al (2018) showed that rBCG strains could be effective against other respiratory viruses with similar biology as hRSV and hMPV, which are leading agents causing acute lower respiratory tract infections (ALRTIs) affecting young infants, the elderly, and immunocompromised patients worldwide [21]. While Yu, et al (2007) found that children’s vaccines (including BCG vaccine) do not induce cross reactivity against SARS-CoV [22].

Ongoing clinical trials  

Currently, the MIS BAIR, an RCT, is ongoing in Australia, to determine the non-specific effects of neonatal BCG vaccine including respiratory infections in a low-mortality setting [23].

Emerging evidence in COVID-19

Search results on 10th April 2020 revealed some non-peer reviewed work [9 preprints on medRxiv and 1 on ResearchGate] studying the correlation between BCG vaccination policy and COVID-19 morbidity and mortality across countries, summarized in Table 2 [24–33] Seven out of the 9 studies showed significant correlation between BCG vaccination and COVID-19 frequency of cases and/or mortality, where countries with universal BCG vaccination policies showed fewer cases and/or deaths [24–30, 32]. Four studies tested these effects after adjusting for other confounding factors [27,29–31]. The significant correlation was maintained by Berg, et al after controlling for median age, GDP per capita, population density and size, geographic region, net migration rate, and other factors [30], and by Shet, et al after adjusting for country income status, age structure of population (>65 years), and timing of the epidemic [27]. Hensel, et al showed that the most significant confounding factor is COVID-19 testing rate (tests per 1 M inhabitants), where countries with high testing rates (>2,500 test/M), no longer showed statistically significant association between BCG policy and COVID-19 incidence and deaths [29]. Whereas, Kirov and Szigeti, et al showed no correlation between BCG vaccination policy and COVID-19 infections [31,33].

This calls for imperative caution when interpreting the relation between BCG vaccination policies and COVID-19 morbidity and mortality [29,33]. These findings do not provide adequate evidence that BCG vaccine protects against COVID-19. This is in line with the WHO scientific report published on 12th April 2020, which stated that there is no current evidence that BCG vaccine protects against COVID-19 [34].  Solid evidence should be generated through prospective evaluation in RCTs [27].

Ongoing clinical trials 

Currently 3 clinical trials are active and recruiting to determine if BCG vaccination protects healthcare workers (HCW) during the COVID-19 pandemic; BRACE is a phase III RCT, conducted in Australia, that will recruit up to 4170 HCW to determine if the BCG vaccine reduces incidence and severity of COVID-19 [35]; and BCG-CORONA is another phase III RCT, conducted in the Netherlands, that will enrol up to 1500 HCW  to reduce absenteeism among HCW with direct patient contacts during the COVID-19 [36]; and the BADAS study, a phase 4 randomized trial, is conducted in the US to determine if the BCG vaccine for healthcare workers acts as a defence against COVID-19, which will enrol 1800 participants [37].

Strengths and Limitations of the current evidence

The current evidence about BCG vaccination and prevention of acute respiratory infections is of high quality, as it is supported by results from 2 systematic reviews (one including meta-analysis) and 4 RCTs, which provide high level of evidence for prevention studies [38].

However, low-quality evidence that BCG vaccine can prevent COVID-19 is due to a number of limitations in some studies including: (1) not considering that different countries have varying onsets in the pandemic making it imprudent to jump to immature conclusions, while still at the midst of the pandemic, where COVID-19 cases/deaths may still increase over time in some BCG-using countries; (2) not adjusting for important confounding factors, such as testing rates; and (3) not mentioning study limitations. Besides, non-peer reviewed work is liable to methodological errors and inaccurate interpretation of study results. Finally, and most importantly, solid evidence for prevention studies in a pandemic should be obtained from prospective RCTs, rather than retrospective studies.

Implications for practice and policy

Although there is evidence that BCG vaccine has non-specific effects against (respiratory) infections, we are currently not certain about the magnitude and duration of these non-specific effects, and thus cannot determine the implications on practice and policy [18]. The WHO concluded in evidence-based recommendations that current evidence does not justify changes to current global immunisation policy [39]. Further studies are needed of adequate size and quality to determine the non-specific effects of vaccines on all-cause mortality [18]. Findings that show significant correlation between BCG vaccine and COVID-19 provide inadequate evidence and should not be reflected on any practices or policies at the current time, outside the contexts of RCTs.

CONCLUSIONS

  • There is systematic review evidence with low to moderate risk of bias that BCG vaccination prevents respiratory infections (pneumonia and influenza) in children and the elderly.
  • BCG vaccine modulates humoral responses to pneumococcus and influenza vaccines.
  • Further research is needed to study the magnitude and duration of the non-specific effects of BCG vaccine on all-cause mortality before considering implications for practice and policy.
  • There is currently no evidence that BCG vaccine protects against COVID-19, and caution should be considered when studying and interpreting the correlation between them.
  • Being still in the midst of the COVID-19 pandemic, it is too early to jump to immature conclusions, where COVID-19 cases/deaths may still increase over time in some BCG-using countries.
  • Good evidence should be obtained from prospective randomized trials before reflecting on practice and policy.

Disclaimer: the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.

AUTHORS
Ranin Soliman is a doctoral researcher in Evidence-based Healthcare, based in the Department for Continuing Education at the University of Oxford.
Jon Brassey is the Director of Trip Database Ltd, Lead for Knowledge Mobilisation at Public Health Wales (NHS) and an Associate Editor at the BMJ Evidence-Based Medicine
Annette Plüddemann is Senior Research Fellow in the Centre for Evidence-Based Medicine (bio here)
Carl Heneghan is Professor of Evidence-Based  Medicine and Director of the Centre for Evidence-Based Medicine (Full bio and disclosure statement  here)

SEARCH STRATEGY
We searched PubMed, Google Scholar, TRIP and LitCovid databases on 10th April using the search terms “BCG vaccine”, “respiratory tract infections”, and “COVID-19”. Main conditions of interest in respiratory infections included bronchitis, common cold, influenza, pneumonia, SARS. We screened titles and abstracts of all search results, and included relevant animal and human studies, systematic reviews, narrative reviews (in case they provided additional information not covered in other studies), and preprints. We also manually searched in-text citations of relevant studies to include all related references. Then, we reviewed full-texts of all studies, except for 2 studies that were only reviewed from abstract as their full-texts were not available in the English language. We restricted search on PubMed to articles published within the last 10 years. Another search was carried out on 11th March to include any recently published work. We provide narrative summary of current evidence.

Search terms
(“BCG Vaccine”[Majr]) AND “Respiratory Tract Infections”[Majr] AND bronchitis OR common cold OR influenza OR pneumonia OR SARS; BCG vaccine AND COVID-19.

PubMed Link
https://pubmed.ncbi.nlm.nih.gov/? term=%28%22BCG+Vaccine%22%5BMajr%5D%29+AND+%22Respiratory+Tract+Infections%22%5BMajr%5D&filter=ds1.y_10 

REFERENCES

    1. Coronavirus disease 2019 (COVID-19 – Situation report 71. Available at
      https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200331-sitrep-71-covid-19.pdf?sfvrsn=4360e92b_6
    1. Netea MG, van Crevel R. BCG-induced protection: effects on innate immune memory. Semin Immunol. 2014;26(6):512–517.
    2. Roth A, Garly ML, Jensen H, Nielsen J, Aaby P. Bacillus Calmette-Guérin vaccination and infant mortality. Expert Rev Vaccines. 2006;5(2):277–293.
    3. Cruz CT, Almeida B, Troster E, et al. Systematic Review of the Non-Specific Effects of Bacillus Calmette-Guérin Vaccine on Child. Mortality. J Infec Dis Treat. 2017, 3:1.
    4. Zimmermann P and Curtis N. The influence of BCG on vaccine responses – a systematic review. Expert Rev. Vaccines. 2018. 17:6, 547-554.
    5. Aaby P, Roth A, and Ravn H, et al. Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period? J Infect Dis. 2011 Jul 15;204(2):245-52.
    6. Biering-Sørensen S, Aaby P, Napirna BM, et al. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J. 2012;31(3):306–308.
    7. Leentjens J, Kox M, Stokman R, et al. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015;212(12):1930–1938.
    8. Kjærgaard J, Birk NM, Nissen TN, et al. Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial. Pediatr Res. 2016;80(5):681–685.
    9. Ohrui T, Nakayama K, Fukushima T, Chiba H, Sasaki H. [Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations]. Japanese Journal of Geriatrics. 2005 Jan;42(1):34-36.
    10. Wardhana, Datau EA, Sultana A, Mandang VV, Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med Indones. 2011;43(3):185–190.
    11. Hollm-Delgado M, Stuart E, and Black R. Acute Lower Respiratory Infection Among Bacille Calmette-Guérin (BCG)–Vaccinated Children. Pediatrics 2014;133:e73–e81.
    12. 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):1611–1619.
    13. Haahr S, Michelsen SW, Andersson M, et al. Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study. Int J Epidemiol. 2016;45(6):2122–2130.
    14. Niobey FM, Duchiade MP, Vasconcelos AG, de Carvalho ML, Leal Mdo C, Valente JG. [Risk factors for death caused by pneumonia in children younger than 1 year old in a metropolitan region of southeastern Brazil. A case- control study]. Rev Saude Publica. 1992;26(4):229–238.
    15. Stensballe L, Nante E, Jensen I, et al. Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls Community based case–control study. Vaccine 23 (2005) 1251–1257.
    16. Chisti MJ, Salam MA, Ahmed T, et al. Lack of BCG vaccination and other risk factors for bacteraemia in severely malnourished children with pneumonia. Epidemiol Infect. 2015;143(4):799–803. doi:10.1017/S0950268814001368.
    17. Pollard A, Finn A, and Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Dis. Child. 2017 102(11).
    18. Moorlag S, Arts R, Crevel R, and Netea M. Non-specific effects of BCG vaccine on viral infections. Narrative review. 2019 25(12).
    19. Mukherjee S, Subramaniam R, Chen H, Smith A, Keshava S, et al. (2017) Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia. PLOS ONE 12(7): e0180143.
    20. Soto JA, Gálvez NMS, Rivera CA, et al. Recombinant BCG Vaccines Reduce Pneumovirus-Caused Airway Pathology by Inducing Protective Humoral Immunity. Front Immunol. 2018;9:2875. s
    21. Yu Y, Jin H, Chen Z, et al. Children’s vaccines do not induce cross reactivity against SARS-CoV. J Clin Pathol. 2007;60(2):208–211.
    22. Messina NL, Gardiner K, Donath S, et al. Study protocol for the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial to determine the non-specific effects of neonatal BCG vaccination in a low-mortality setting. BMJ Open 2019;9:e032844.
    23. Miller A, Reandelar M, Fasciglione K, et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. [preprint]. medRxiv. 2020.03.24.20042937.
    24. Hegarty P, Kamat A, Zafirakis H, and DiNardo A. BCG vaccination may be protective against Covid-19. [preprint]. ResearchGate. Available at: https://www.researchgate.net/publication/340224580_BCG_vaccination_may_be_protective_against_Covid-19
    25. Sala G and Miyakawa T. Association of BCG vaccination policy with prevalence and mortality of COVID-19. [preprint]. medRxiv. 2020.03.30.20048165.
    26. Shet A, Ray D, Malavige N, Santosham M, and Bar-Zeev N. Differential COVID-19-attributable mortality and BCG vaccine use in countries. [preprint]. medRxiv04.01.20049478.
    27. Goswami R, Mittal D, and Goswami R. Interaction between malaria transmission and BCG vaccination with COVID-19 incidence in the world map: A cross-sectional study. [preprint]. medRxiv 04.03.20052563.
    28. Hensel J, McGrail D, and McAndrews K, et al. Exercising caution in correlating COVID-19 incidence and mortality rates with BCG vaccination policies due to variable rates of SARS CoV-2 testing. [preprint]. medRxiv04.08.20056051.
    29. Berg M, Yu Q, Salvador C, et al. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. [preprint]. medRxiv04.05.20054163.
    30. Kirov S. Association Between BCG Policy is Significantly Confounded by Age and is Unlikely to Alter Infection or Mortality Rates. [preprint]. medRxiv 04.06.20055616.
    31. Dayal D and Gupta S. Connecting BCG Vaccination and COVID-19: Additional Data. [preprint]. medRxiv04.07.20053272.
    32. Szigeti R, Kellermayer D, and Kellermayer R. BCG protects against COVID-19? A word of caution. [preprint]. medRxiv04.09.20056903.
    33. Bacille Calmette-Guérin (BCG) vaccination and COVID-19. Scientific brief. Available at: https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19
    34. Curtis N, and Gardiner K. BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE). Mar 2020. (Identifier: NCT04327206).
    35. Bonten MJM, Utrecht UMC. Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine (BCG-CORONA). Mar 2020. (Identifier: NCT04328441).
    36. Cirillo J and DiNardo A. BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS) (Identifier: NCT04348370).
    37. CEBM Levels of Evidence (March 2009). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
    38. Group Sn-seovW. Evidence-based recommendations on non-specific effects of BCG, DTP-containing and measles-containing vaccines on mortality in children under 5 years of age Geneva: WHO; 2014.

    Table 1: Summary of evidence for included studies about BCG vaccine and acute respiratory infections

    Authors (Year)CountryStudy (article) typeSample sizeCondition(s) studied (outcome)Main findings
    Cruz, et al (2017) [4]BrazilSystematic reviewAll-cause mortality in children after BCG vaccinationBCG vaccination approximately halved all-cause mortality in children under five years in low-income countries, due to fewer deaths from pneumonia and sepsis. Effect size  0.56 (95% CI 0.46-0.69).
    Zimmermann, et al (2018) [5]AustraliaSystematic reviewInfluence of BCG on vaccine responsesBCG is associated with higher levels of antibodies against pneumococcus (serotype 9V, p<0.01; 18C, p=0.04) and influenza A (H1N1)pdm09 virus vaccines (p=0.04).
    Aaby, et al (2011) [6]Guinea-Bissau (West Africa)RCT2,320Infant mortality after early vs. delayed BCG vaccination in low-birth weight childrenInfant mortality was reduced by 17% (mortality rate ratio [MRR] 5 .83 [.63–1.08]) at 12 months after receiving early BCG vaccination. This was mainly attributed to fewer cases of neonatal sepsis and respiratory infection.
    Biering-Sørensen, et al (2012) [7]Guinea-Bissau (West Africa)RCT105Administration of BCG vaccine vs. control in low-birth weight childrenAdministration of BCG vaccine at first contact after birth may contribute to lower mortality [mortality rate

    ratio was 0.41 (0.14–1.18) (P _ 0.098) in infancy].

    This largely because of fewer deaths from pneumonia and sepsis in high-mortality regions.

    Leentjens, et al (2015) [8]NetherlandsPlacebo-controlled randomized trial40Influence of BCG vaccination on immune responses to influenza vaccination in adultsBCG vaccination prior to influenza vaccination results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic influenza A (H1N1) vaccine
    Kjærgaard, et al (2016) [9]DenmarkRCT

    (multi-centre)

    4,262Impact of BCG vaccination at birth on parent-reported incidence of childhood infections during first year of lifeThere is no overall impact of BCG vaccination on pneumonia [IRR 0.50 (95%CI 0.17-1.46, p=0.2) and cold [IRR 0.91 (95%CI 0.71-1.16, p=0.46] in children ≤13 mo.

     

    There is no support for the use of BCG to reduce the burden of infectious diseases in high-income settings in which the mothers have not had BCG themselves.

    Ohrui, et al. (2005) * [10]JapanProspective cohortNARisk of pneumonia post BCG vaccination in elderly over 65 yearsBCG vaccine decreased the risk of pneumonia in elderly people >65 years with comorbidities

     

    BCG vaccine may be effective to prevent pneumonia in elderly people with limited activities of daily living

     Wardhana, et al (2011) [11] IndonesiaProspective study (experimental)34 Efficacy of BCG vaccinations in elderly on the prevention of acute upper respiratory tract infection (AURTI)BCG vaccine in elderly can increase the IFN-γ level [treatment 0.07 pg/ml, control 0.04 pg/ml, p=0.007] and IL-10 [treatment 0.30 pg/ml, control 0.27 pg/ml, p=0.043], and may protect from influenza virus infection.
    Hollm-Delgado, et al (2014) [12]Global study

    (18 countries)

    Prospective cohort

    (2 cohorts)

    58,021

    93,301

    Impact of BCG vaccine on acute lower respiratory infection (ALRI) in children globallyBCG-vaccinated children had a lower risk of suspected ALRI (RR: 0.83, 95% CI: 0.7 – 0.9).

     

    BCG vaccination was associated with a 17% to 37% risk reduction for suspected childhood ALRI in both cohorts

    de Castro, et al (2015) [13] SpainRetrospective cohort(464 611 hospitalization episodes)Heterologous protective effects of BCG vaccination against respiratory infection (RI) and sepsis in children (not attributable to TB)BCG vaccination at birth may decrease hospitalization rate (HR) due to RI and sepsis not related to tuberculosis through heterologous protection.

     

    An average of 40% decrease in HR due to RI in BCG vaccinated children compared to unvaccinated cases, PF of 52.8% (43.8–60.7; P-value <.001).

    Haahr, et al (2016) [14]GreenlandRetrospective cohort19,363Nation-wide hospitalization rates due to infectious diseases (other than TB) among BCG vaccinated

    and unvaccinated children

    There was no association between BCG vaccinated and unvaccinated children’s’ hospitalization rates due to respiratory infections [IRR 1.07, 95% 0.96–1.20]

     

    Study results do not support the hypothesis that neonatal BCG vaccine reduces morbidity in children caused by (respiratory) infectious diseases other than TB

    Niobey, et al (1992) * [15]BrazilCase-control studyNAInfant mortality from pneumonia post BCG vaccinationBCG vaccination was associated with a 50% reduction in infant deaths (mortality rate ratio [MR]: 0.50; 95% confidence interval [CI]: 0.30–0.86)
    Stensballe, et al (2005) [16]

     

    Guinea-BissauMatched

    case-control

    386Acute lower respiratory tract infection (ALRI) in childrenBCG vaccination may have a non-targeted protective effect against ALRI, the effect being most marked in girls.

    [adjusted OR of BCG-vaccinated 2.87 (1.31–6.32), 1.72 (0.48–6.19) in boys and 4.45 (1.48–13.4) in girls].

     

    Children without BCG vaccination had a three-fold higher risk of getting lower respiratory tract infection

    Chisti, et al (2015) [17]BangladeshCase-control study405Effect of BCG vaccination on  severely acute malnourished (SAM) children with pneumonia and bacteremiaSAM children with pneumonia and bacteremia had a history of lack of BCG vaccination (odds ratio 7·39, 95% confidence interval 1·67–32·73, P<0·01).

     

    Continuation of BCG vaccination is important and may provide benefit beyond its primary purpose

    Pollard, et al (2017) [18]UKReviewNon-specific effects (NSE) of BCG vaccineRecent studies have suggested a beneficial effect of BCG vaccination on reducing (non-TB) respiratory infections.

     

    Whilst it is highly plausible that some vaccines do have non-specific effects, their magnitude and duration, and thus importance, remain uncertain

    Moorlag, et al (2019) [19]NetherlandsReviewNon-specific protection induced by BCG vaccine against viral infectionsBCG protects against various DNA/RNA viruses in mice, such as influenza viruses.

     

    Recently, the effect of BCG on an experimental viral infection in humans has been demonstrated, which

    could be mediated via induction of innate immune memory.

    Mukherjee, et al (2017) [20]USAAnimal studyEffect of pulmonary delivery of BCG on efferocytosis by alveolar phagocytes (Aps)BCG vaccine boosts efferocytosis in alveolar space in mice and protects host against influenza pneumonia
    Soto, et al (2018) [21]ChileAnimal studyEffect of recombinant BCG (rBCG) vaccine against hRSV and hMPV in micerBCG vaccines reduce pneumovirus-caused airway pathology by inducing protective humoral immunity

     

    rBCG strains could be considered as an effective vaccination approach against other respiratory viruses with similar biology as hRSV and hMPV.

    Yu, et al (2007) [22]ChinaAnimal studyEffect of childhood vaccines (including BCG vaccine) on cross immunity against SARS‐CoV in miceChildren’s vaccines (including BCG vaccine) do not induce cross reactivity against SARS-CoV

    * Studies reviewed based on abstracts only as full-articles were not published in English; Ohruir et al (2005) was published in Japanese; and Niobey, et al (1992) was published in Portuguese. Abbreviations: PF: preventive fraction. hRSV:  Human Respiratory Syncytial Virus; hMPV: Human Metapneumovirus. SARS-CoV:  Severe acute respiratory syndrome-corona virus.

    Table 2: Summary of non-peer reviewed work about BCG vaccine and COVID-19.

     

    Authors (Date/Year)CountryStudy/article  typeCondition(s) studied (outcome)FindingsStudy

    Limitations

    Miller, et al

    (24th Mar. 2020) [24]

    USARetrospective

    (correlational) study

    Correlation between BCG vaccination policy with morbidity and mortality (deaths per million inhabitants per country)BCG vaccination was correlated with a reduction in number of COVID-19 reported infections in a country.

     

    Countries without universal BCG vaccine policies were more severely affected than those without BCG vaccine (p=8.64e-04)

     

    There was a positive significant correlation (p=0.44, p=0.02) between the year of starting BCG vaccine and mortality rate

    Not included
     

    Hegarty, et al

    (24th Mar. 2020) [25]

     

    USARetrospective

    study

    Impact of national programs of BCG vaccination on COVID-19 incidence and mortalityCountries with national program of BCG vaccination appear to have a lower incidence and death rate from Covid-19.

     

    BCG vaccination may have a role in reducing the impact of COVID-19 and is being studied in a prospective trial

    Not included
    Sala & Miyakawa,

    (30th Mar. 2020) [26]

    JapanRetrospective

    (correlational) study

    Association between BCG vaccine & prevalence and mortality (per 1 M population) by COVID-19Number of total cases and deaths were significantly associated with the country’s BCG vaccination policy

     

    Ratio between deaths and cases was weakly affected by BCG policy, suggesting BCG vaccine may have hindered the overall spread of COVID-19 rather than reducing mortality rates

    Not included
    Shet, et al

    (1st Apr. 2020) [27]

    USARetrospective

    (correlational) study

    Impact of BCG use and COVID-19-attributable mortality per 1 M population (adjusted for confounders factors)COVID-19-attributable mortality among BCG-using countries was 5.8 times lower than in non BCG-using countries.

     

    LMIC, UMIC, HIC had median crude log-mortality of 0.4(IQR) 0.1, 0.4), 0.7 (IQR 0.2, 2.2) and 5.5 (IQR 1.6, 13.9), respectively.

    Included
    Goswami, et al

    (3rd Apr. 2020) [28]

    Indiacross-sectional studyRelation between BCG vaccination and COVID-19 incidence & mortality per 1000 populationIn Europe and Americas, countries, which have higher BCG vaccination coverage, had significantly less mortality compared to those with low BCG coverage (median 0.0002 (0-0.0005) vs 0.0029 (0.0002-0.0177), p=0.017).Included
    Hensel, et al

    (4th Apr. 2020) [29]

    USARetrospective

    (correlational) study

    Correlation between BCG vaccination policy and COVID-19 incidence and mortality, (adjusted for confounders factors)There is a correlation between current universal BCG vaccine policy & a lower incidence of COVID-19 infections and deaths

     

    COVID-19 testing rates were significantly different between

    countries with BCG vaccination policies (p = 6.5×10-5).

     

    Testing rate (per 1M inhabitants) was the most significant confounding factor. In countries with test rates >2,500 test/M, these parameters were no longer associated with BCG policy.

    Included
    Berg, et al

    (5th Apr. 2020)

    [30]

    USACorrelate flattening of

    COVID-19 curve with BCG vaccination policies across countries (adjusted for confounders factors)

    The presence of mandatory national policies for universal BCG vaccination is associated with flattened growth curves for confirmed cases of COVID-19 (b= -0.025, p= .020) and resulting deaths in the first 30-day period of country-wise outbreaks

     

    This effect was held after controlling for median age, GDP per capita, population density, population size, geographic region, net migration rate, and social distancing

    Included
    Kirov,

    (6th Apr. 2020) [31]

    NARetrospective

    (correlational) study

    Impact of confounding factors on COVID-19 cases per 1 M & mortality ratesMedian age of a population and income are significant confounding factor of COVID-19 cases/M (R=0.774), while BCG vaccine may have little causal link to infection rates (R=0.21)

     

    Mortality rates were greatly higher in countries with high BMI

    Not included
    Dayal & Gupta,  (7th Apr. 2020) [32]IndiaBrief reportImpact of COVID-19 case fatality rates (CFR) between countries with high disease burden & those with BCG revaccination policiesWe found a significant difference in the CFR between

    the two groups of countries (5.2% vs. 0.6%, p value <0.0001)

     

    Our data supports the view that universal BCG vaccination has a protective effect on the course of COVID-19 probably preventing progression to severe disease and death.

    Included
    Szigeti, et al

    (9th Apr. 2020) [33]

    USARetrospective

    (correlational) study

    Association between daily rates of COVID-19 case fatality (Death Per Case)/Days of the endemic [dpc/d]) and presence of universal BCG vaccination.There was no significant association between COVID-19 dpc/d and BCG vaccination before 1980 (p=0.258), or with year of establishment of universal vaccination (rs= -0.03136, p= 0.852)

     

    Physical distancing and use of PPE are the only epidemiologic measures which consistently associate with successful counteraction of morbidity/mortality during the pandemic.

    Not included

    Abbreviations: LMIC: lower-middle-income countries; UMIC: upper-middle-income countries; HIC: high-income countries; PPE: Personal Protective Equipment.; GDP: Gross Domestic Product