⚕️ Publications Sientifiques BCG

Developers of severe acute respiratory syndrome coronavirus 2 vaccines should consider some of the lessons from a “new” vaccine introduced in 1921, namely bacille Calmette-Guérin.

The Bacillus Calmette–Guérin (BCG) is a well-known vaccine with almost a century of use, with the apparent capability to improve cytokine production and epigenetics changes that could develop a better response to pathogens. It has been postulated that BCG protection against SARS-CoV-2 has a potential role in the pandemic, through the presence of homologous amino acid sequences. To identify a possible link between BCG vaccination coverage and COVID-19 cases, we used official epidemic data and Ecuadorian Ministry of Health and Pan American Health Organization vaccination information. BCG information before 1979 was available only at a national level. Therefore, projections based on the last 20 years were performed, to compare by specific geographic units. We used a Mann–Kendall test to identify BCG coverage variations, and mapping was conducted with a free geographic information system (QGIS). Nine provinces where BCG vaccine coverage was lower than 74.25% show a significant statistical association (χ2 Pearson’s = 4.800},
keywords = {#BCG4Covid19, BCG Vaccine, BCG Vaccine / coverage, COVID-19},
pubstate = {published},
tppubtype = {article}
}

Despite of the rapid development of the vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it will take several months to have enough doses and the proper infrastructure to vaccinate a good proportion of the world population. In this interim, the accessibility to the Bacille Calmette-Guerin (BCG) may mitigate the pandemic impact in some countries and the BCG vaccine offers significant advantages and flexibility in the way clinical vaccines are administered. BCG vaccination is a highly cost-effective intervention against tuberculosis (TB) and many low-and lower-middle-income countries would likely have the infrastructure, and health care personnel sufficiently familiar with the conventional TB vaccine to mount full-scale efforts to administer novel BCG-based vaccine for COVID-19. This suggests the potential for BCG to overcome future barriers to vaccine roll-out in the countries where health systems are fragile and where the effects of this new coronavirus could be catastrophic. Many studies have reported cross-protective effects of the BCG vaccine toward non-tuberculosis related diseases. Mechanistically, this cross-protective effect of the BCG vaccine can be explained, in part, by trained immunity, a recently discovered program of innate immune memory, which is characterized by non-permanent epigenetic reprogramming of macrophages that leads to increased inflammatory cytokine production and consequently potent immune responses. In this review, we summarize recent work highlighting the potential use of BCG for the treatment respiratory infectious diseases and ongoing SARS-CoV-2 clinical trials. In situations where no other specific prophylactic tools are available, the BCG vaccine could be used as a potential adjuvant, to decrease sickness of SARS-CoV-2 infection and/or to mitigate the effects of concurrent respiratory infections.

Introduction

The potential for bacillus Calmette–Guérin (BCG) vaccination to mitigate coronavirus disease 2019 (COVID-19) severity and perhaps infection susceptibility has been hypothesized, attracting global attention given its off-target benefits demonstrated in several respiratory viral infections.

Methods

In this retrospective study, patients with laboratory-confirmed COVID-19 from Wuhan Pulmonary Hospital, China were categorized into BCG vaccination and non-vaccination groups. Clinical records, demography, laboratory results, and chest computed tomography scans were extracted from electronic medical records and compared between the 2 groups.

Results

No adverse events were observed, except for an increased frequency of chills in the BCG-vaccinated group versus the unvaccinated group (\textit{p}=0.014). There were no significant differences in oxygen demand for breathing, computed tomography scans, treatments, or outcomes between the 2 groups. However, BCG vaccination was associated with significantly less severe pneumonia (\textit{p}=0.028) and milder deficiency in liver function, consistent with a lower death rate in comparison with the unvaccinated group.

Conclusions

BCG vaccination received in childhood is associated with less severe COVID-19 pneumonia and milder liver function deficiency in addition to a lower death rate in BCG-vaccinated patients versus non-vaccinated individuals.

While awaiting the COVID-19 vaccines, researchers have been actively exploring the effectiveness of existing vaccines against the new virus, among which the BCG vaccine (Bacillus Calmette-Guérin) receives the most attention. While many reports suggest a potential role for BCG immunization in ameliorating SARS-CoV-2 infection, these findings remain controversial. With country-level COVID-19 outbreak data from Johns Hopkins University Coronavirus Resource Center, and BCG program data from World Atlas of BCG Policies and Practices and WHO/UNICE, we estimated a dynamic model to investigate the effect of BCG vaccination across time during the pandemic. Our results reconcile these varying reports regarding protection by BCG against COVID-19 in a variety of clinical scenarios and model specifications. We observe a notable protective effect of the BCG vaccine during the early stage of the pandemic. However, we do not see any strong evidence for protection during the later stages. We also see that a higher proportion of vaccinated young population may confer some level of communal protection against the virus in the early pandemic period, even when the proportion of vaccination in the older population is low. Our results highlight that while BCG may offer some protection against COVID-19, we should be cautious in interpreting the estimated effectiveness as it may vary over time and depend on the age structure of the vaccinated population.

Introduction

The potential for bacillus Calmette–Guérin (BCG) vaccination to mitigate coronavirus disease 2019 (COVID-19) severity and perhaps infection susceptibility has been hypothesized, attracting global attention given its off-target benefits demonstrated in several respiratory viral infections.

Methods

In this retrospective study, patients with laboratory-confirmed COVID-19 from Wuhan Pulmonary Hospital, China were categorized into BCG vaccination and non-vaccination groups. Clinical records, demography, laboratory results, and chest computed tomography scans were extracted from electronic medical records and compared between the 2 groups.

Results

No adverse events were observed, except for an increased frequency of chills in the BCG-vaccinated group versus the unvaccinated group (\textit{p}=0.014). There were no significant differences in oxygen demand for breathing, computed tomography scans, treatments, or outcomes between the 2 groups. However, BCG vaccination was associated with significantly less severe pneumonia (\textit{p}=0.028) and milder deficiency in liver function, consistent with a lower death rate in comparison with the unvaccinated group.

Conclusions

BCG vaccination received in childhood is associated with less severe COVID-19 pneumonia and milder liver function deficiency in addition to a lower death rate in BCG-vaccinated patients versus non-vaccinated individuals.

As the SARS-CoV2 pandemic has progressed, there have been marked geographical differences in the pace and extent of its spread. We evaluated the association of BCG vaccination on morbidity and mortality of SARS-CoV2, adjusted for country-specific responses to the epidemic, demographics and health. SARS-CoV2 cases and deaths as reported by 31 May 2020 in the World Health Organization situation reports were used. Countries with at least 28 days following the first 100 cases, and available information on BCG were included. We used log-linear regression models to explore associations of cases and deaths with the BCG vaccination policy in each country, adjusted for population size, gross domestic product, proportion aged over 65 years, stringency level measures, testing levels, smoking proportion, and the time difference from date of reporting the 100th case to 31 May 2020. We further looked at the association that might have been found if the analyses were done at earlier time points. The study included 97 countries with 73 having a policy of current BCG vaccination, 13 having previously had BCG vaccination, and 11 having never had BCG vaccination. In a log-linear regression model there was no effect of country-level BCG status on SARS-CoV2 cases or deaths. Univariable log-linear regression models showed a trend towards a weakening of the association over time. We found no statistical evidence for an association between BCG vaccination policy and either SARS-CoV2 morbidity or mortality. We urge countries to rather consider alternative tools with evidence supporting their effectiveness for controlling SARS-CoV2 morbidity and mortality.

Ecological studies have suggested fewer COVID-19 morbidities and mortalities in Bacillus Calmette–Guérin (BCG)-vaccinated countries than BCG-non-vaccinated countries. However, these studies obtained data during the early phase of the pandemic and did not adjust for potential confounders, including PCR-test numbers per population (PCR-tests). Currently—more than four months after declaration of the pandemic—the BCG-hypothesis needs reexamining. An ecological study was conducted by obtaining data of 61 factors in 173 countries, including BCG vaccine coverage (%), using morbidity and mortality as outcomes, obtained from open resources. ‘Urban population (%)’ and ‘insufficient physical activity (%)’ in each country was positively associated with morbidity, but not mortality, after adjustment for PCR-tests. On the other hand, recent BCG vaccine coverage (%) was negatively associated with mortality, but not morbidity, even with adjustment for percentage of the population ≥ 60 years of age, morbidity, PCR-tests and other factors. The results of this study generated a hypothesis that a national BCG vaccination program seems to be associated with reduced mortality of COVID-19, although this needs to be further examined and proved by randomized clinical trials.

The COVID-19 pandemic that started in China has spread within 3 months to the entire globe. We tested the hypothesis that the vaccination against tuberculosis by Bacille Calmette–Guérin vaccine (BCG) correlates with a better outcome for COVID-19 patients. Our analysis covers 55 countries complying with predetermined thresholds on the population size and number of deaths per million (DPM). We found a strong negative correlation between the years of BCG administration and the DPM along with the progress of the pandemic, corroborated by permutation tests. The results from multivariable regression tests with 23 economic, demographic, health-related, and pandemic restriction-related quantitative properties, substantiate the dominant contribution of BCG years to the COVID-19 outcomes. The analysis of countries according to an age-group partition reveals that the strongest correlation is attributed to the coverage in BCG vaccination of the young population (0–24 years). Furthermore, a strong correlation and statistical significance are associated with the degree of BCG coverage for the most recent 15 years, but no association was observed in these years for other broadly used vaccination protocols for measles and rubella. We propose that BCG immunization coverage, especially among the most recently vaccinated population, contribute to attenuation of the spread and severity of the COVID-19 pandemic.