Efficacy and Safety of BCG Revaccination With M. bovis BCG Moscow to Prevent COVID-19 Infection in Health Care Workers: A Randomized Phase II Clinical Trial

Anjos, Laura Raniere Borges dos; Costa, Adeliane Castro da; Cardoso, Amanda da Rocha Oliveira; Guimarães, Rafael Alves; Rodrigues, Roberta Luiza; Ribeiro, Kaio Mota; Borges, Kellen Christina Malheiros; Carvalho, Ana Carolina de Oliveira; Dias, Carla Iré Schnier; Rezende, Aline de Oliveira; Souza, Carine de Castro; Ferreira, Renato Rodney Mota; Saraiva, Guylherme; Barbosa, Lília Cristina de Souza; Vieira, Tayro da Silva; Conte, Marcus Barreto; Rabahi, Marcelo Fouad; Kipnis, André; Junqueira-Kipnis, Ana Paula

doi:10.3389/fimmu.2022.841868

Cited by 40 publications

(63 citation statements)

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“…However, the little apparent pathology, the low circulating cytokine levels, and the bacterial loads at or below the limit of detection are consistent with our unpublished work in BCG-vaccinated C57BL/6 mice. Other studies have shown that recombinant BCG vaccination in mice ( 30 ), revaccination with BCG in a clinical trial ( 31 ), and other routes of vaccination (intravenous) affect SARS-CoV-2 morbidity and mortality ( 26 ), demonstrating BCG’s unique off-target effects and potential as an adjuvant or booster. However, our study attempted to best experimentally represent what BCG’s effect would be clinically on SARS-CoV-2 given current vaccination regimens, which are intradermal and given at birth.…”

Section: Discussionmentioning

confidence: 99%

Superinfection with SARS-CoV-2 Has Deleterious Effects on Mycobacterium bovis BCG Immunity and Promotes Dissemination of Mycobacterium tuberculosis

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Superinfection with SARS-CoV-2 Has Deleterious Effects on Mycobacterium bovis BCG Immunity and Promotes Dissemination of Mycobacterium tuberculosis

et al. 2022

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“…In addition, there was a trend towards reduced incidence of severe infections in the BCG arm. A single-centre phase II randomised control trial involving healthcare workers at high risk of COVID-19 infection in Brazil has shown a trend towards a reduction in the incidence of COVID-19 infection in those vaccinated with BCG [ 16 ]. In a multi-centre randomised double-blind trial conducted across three facilities in West Cape South Africa which included 1000 healthcare workers who received either BCG vaccination or placebo, there was no significant difference between the two groups in terms of COVID-19 incidence or hospitalisation due to COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Bacillus Calmette–Guérin (BCG) Vaccination in Reducing the Incidence and Severity of COVID-19 in High-Risk Population (BRIC): a Phase III, Multi-centre, Quadruple-Blind Randomised Control Trial

et al. 2022

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Introduction Universal coverage of vaccines alone cannot be relied upon to protect at-risk populations in lower- and middle-income countries against the impact of the coronavirus disease 2019 (COVID-19) pandemic and newer variants. Live vaccines, including Bacillus Calmette–Guérin (BCG), are being studied for their effectiveness in reducing the incidence and severity of COVID-19 infection. Methods In this multi-centre quadruple-blind, parallel assignment randomised control trial, 495 high-risk group adults (aged 18–60 years) were randomised into BCG and placebo arms and followed up for 9 months from the date of vaccination. The primary outcome was the difference in the incidence of COVID-19 infection at the end of 9 months. Secondary outcomes included the difference in the incidence of severe COVID-19 infections, hospitalisation rates, intensive care unit stay, oxygen requirement and mortality at the end of 9 months. The primary analysis was done on an intention-to-treat basis, while safety analysis was done per protocol. Results There was no significant difference in the incidence rates of cartridge-based nucleic acid amplification test (CB-NAAT) positive COVID-19 infection [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.54–2.14] in the two groups, but the BCG arm showed a statistically significant decrease in clinically diagnosed (symptomatic) probable COVID-19 infections (OR 0.38, 95% CI 0.20–0.72). Compared with the BCG arm, significantly more patients developed severe COVID-19 pneumonia (CB-NAAT positive) and required hospitalisation and oxygen in the placebo arm (six versus none; p = 0.03). One patient belonging to the placebo arm required intensive care unit (ICU) stay and died. BCG had a protective efficacy of 62% (95% CI 28–80%) for likely symptomatic COVID-19 infection. Conclusions BCG is protective in reducing the incidence of acute respiratory illness (probable symptomatic COVID-19 infection) and severity of the disease, including hospitalisation, in patients belonging to the high-risk group of COVID-19 infection, and the antibody response persists for quite a long time. A multi-centre study with a larger sample size will help to confirm the findings in this study. Clinical Trials Registry Clinical Trials Registry India (CTRI/2020/07/026668). Supplementary Information The online version contains supplementary material available at 10.1007/s40121-022-00703-y.

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“…Nine (60%) trials were conducted in healthy individuals, two (13%) included participants with various comorbidities, and four (27%) were done in low-birth-weight children (<2500g). The primary objectives of 14 (93%) trials [4–8,15,23,25–31] was to evaluate BCG-mediated NSE on mortality, infections of any origin, and respiratory infections; four (27%) trials [15,26,27,31] specifically investigated BCG-mediated NSE on COVID-19; one (7%) trial [24] was conducted to study prevention of M. tuberculosis infection with BCG revaccination. As intervention the BCG Denmark strain was used in ten (67%) trials; one (7%) trial used the BCG Glaxo-strain which is genetically close to the BCG Denmark strain; two trials used the BCG Moscow strain; the remaining two trials used the strains BCG Paris or BCG Russia respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Three of them were conducted in healthy newborns (weight 43.8%) [7,8,23], one in adolescents who already received BCG in infancy (weight 18%) [24], one in adults (weight 19.5%) [26], and three in elderly with unknown previous BCG exposure (weight 23.6%) [15,27,28]. Combined HRs from random-effects meta-analyses indicated a beneficial effect of the vaccine on non-tuberculosis respiratory infections (HR 0.51, 95% CI 0.33-0.80); heterogeneity between trials was substantial (I 2 =80%; p<0.00001) (Fig 2A).…”

Section: Resultsmentioning

confidence: 99%

Non-specific effects of Bacillus Calmette-Guérin - a systematic review and meta-analysis of randomized controlled trials

Trunk

Davidović

Bohlius

2022

Preprint

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Vaccines induce antigen-specific immunity which provides long-lived protection from the target pathogen. Trials especially from high infectious disease areas indicated that the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) induces in addition non-specific immunity against various pathogens and thereby reduces overall mortality. Although recent trials produced conflicting results, it was suggested that BCG might protect from non-tuberculosis respiratory infections and could be used to bridge time until a specific vaccine against novel respiratory diseases like COVID-19 is available. We performed a systematic search for randomized controlled trials (RCT) published between 2011 and August 5th, 2022 providing evidence about non-specific effects after BCG vaccination, assessed their potential for bias, and meta-analyzed relevant clinical outcomes. We excluded RCTs investigating vaccination with an additional vaccine, unless outcomes from a follow-up period before the second vaccination were reported. Our search identified 15 RCTs including 32160 participants. Vaccination with BCG caused an estimated 49% decrease in risk for respiratory infections (HR 0.51, 95% CI 0.33-0.80) with substantial heterogeneity between trials (I2=80%; p<0.00001). There was evidence for a protective effect on all-cause mortality of 22% if follow-up was restricted to one year (HR 0.78, 95% CI 0.63-0.96); we did not find evidence for an effect when we considered longer follow-up (HR 0.87, 95% CI 0.75-1.02). Infection-related mortality after BCG-vaccination was reduced by 33% (HR 0.67; 95% CI 0.46-0.99), mortality for sepsis by 38% (HR 0.62, 95% CI 0.41-0.93). There was no evidence for a protective effect of BCG vaccination on infections of any origin (HR 0.84, 95% CI 0.71-1.00), COVID-19 (HR 0.83, 95% CI 0.61-1.14), sepsis (HR 0.82, 95% CI 0.62-1.07) or hospitalization (HR 1.02, 95% CI 0.92-1.14). According to these results, depending on the setting, vaccination with BCG provides time-limited partial protection against non-tuberculosis respiratory infections and may reduce mortality. These findings underline BCGs potential 1) in pandemic preparedness against novel pathogens especially in developing countries with established BCG-vaccination programs but limited access to specific vaccines; 2) in reducing microbial infections, antimicrobial prescriptions and thus the development of antimicrobial resistance. There is a need for additional RCTs to clarify the circumstances under which BCGs non-specific protective effects are mediated.

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Efficacy and Safety of BCG Revaccination With M. bovis BCG Moscow to Prevent COVID-19 Infection in Health Care Workers: A Randomized Phase II Clinical Trial

Cited by 40 publications

References 46 publications

Superinfection with SARS-CoV-2 Has Deleterious Effects on Mycobacterium bovis BCG Immunity and Promotes Dissemination of Mycobacterium tuberculosis

Superinfection with SARS-CoV-2 Has Deleterious Effects on Mycobacterium bovis BCG Immunity and Promotes Dissemination of Mycobacterium tuberculosis

Efficacy of Bacillus Calmette–Guérin (BCG) Vaccination in Reducing the Incidence and Severity of COVID-19 in High-Risk Population (BRIC): a Phase III, Multi-centre, Quadruple-Blind Randomised Control Trial

Non-specific effects of Bacillus Calmette-Guérin - a systematic review and meta-analysis of randomized controlled trials

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