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Background Covid-19 virus has infected over 300,000 people and led to over 13,000 deaths in its first 3 months; yet the pattern of development is not uniform.. Mechanistic evidence exists to suggest that vaccination with Bacillus Calmette-Guérin (BCG), can have protective effects against viral infection. Herein we examine whether national programs which use BCG vaccination with the aim of reducing tuberculosis infections could account for the differential incidence and mortality observed in Covid-19 between various countries. Interpretation Countries with national program of whole population BCG vaccination appear to have a lower incidence and death rate from Covid-19. This may be due to the known immunological benefits of BCG vaccination. In the absence of a specific vaccination against Covid-19, population-based BCG vaccination may have a role in reducing the impact of this disease and is being studied in a prospective trial.
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BCG vaccination may be protective against Covid-19
Paul K. Hegarty, Ashish Kamat, Helen Zafirakis, Andrew DiNardo
Background Covid-19 virus has infected over 300,000 people and led to over 13,000 deaths
in its first 3 months; yet the pattern of development is not uniform.. Mechanistic evidence
exists to suggest that vaccination with Bacillus Calmette-Guérin (BCG), can have protective
effects against viral infection. Herein we examine whether national programs which use
BCG vaccination with the aim of reducing tuberculosis infections could account for the
differential incidence and mortality observed in Covid-19 between various countries.
Methods We accessed and collated data from three sources - accessed on March 24th 2020
- for the analysis: The European Centre for Disease Prevention and Control for the number
of cases and deaths attributed to Covid-19; The World Atlas of BCG for list of countries
describing programs of BCG vaccination; and for the population of all
Findings 178 countries had data from all three sources and formed the basis of our analysis.
Current national programs of BCG vaccination exist in 131 countries; 21 countries have no
current program of national BCG vaccination; and for 26 countries status is unknown. Over
preceding 15 days, incidence of Covid-19 was 38.4 per million in countries with BCG
vaccination compared to 358.4 per million in the absence of such a program. The death rate
was 4.28/million in countries with BCG programs compared to 40/million in countries
without such a program.
Interpretation Countries with national program of whole population BCG vaccination
appear to have a lower incidence and death rate from Covid-19. This may be due to the
known immunological benefits of BCG vaccination. In the absence of a specific vaccination
against Covid-19, population-based BCG vaccination may have a role in reducing the impact
of this disease and is being studied in a prospective trial.
Funding Nil
Word count: 802 (limit 3,500)
References: 25 (limit 30)
BCG vaccination may be protective against Covid-19
To date, in 3 months, coronavirus pandemic has infected more than 480,000 individuals
and caused over 13,000 deaths. Based on transmission in China and initial transmission in
Europe, the pandemic is expected to peak in June or July1, 2. To try and limit its spread,
stringent public health measures are being implemented to slow the spread and protect
those most vulnerable. Governments and communities are implementing social distancing
and quarantining those with disease to minimize spread.. A coronavirus vaccine is expected
to take a minimum of 12 to 18 months to develop. In the meantime, repurposing existing
and safe vaccines that induce non-specific immune benefits may be an additional tool3.
There is strong epidemiologic evidence that live, attenuated vaccines induce non-specific
mortality benefits. For example, Bacillus Calmette-Guérin (BCG), a live attenuated strain of
Mycobacterium bovis, the most commonly administered vaccine worldwide, induces an
~38-45% mortality reduction4, 5. Developed to combat tuberculosis (TB), the mortality
benefit from BCG is not TB-specific, but due to a decrease in neonatal sepsis and respiratory
tract infections6. Not limited to neonates and children, BCG vaccinated elderly (age 60-75)
individuals experience decreased respiratory infections7. For bladder cancer, intravesicular
BCG boosts host immunity, reduces tumor recurrence progression and decreases mortality
and has been approved for use in bladder cancer since the 1990s8.
The non-specific immune benefits of BCG have been known since the 1970s when BCG was
shown to improve immunity against listeria and influenza in murine models9, 10. More
recently, studies have demonstrated that the molecular mechanisms of the non-specific
benefits of BCG are due to NOD2 and mTOR mediated changes in the epigenetic landscape
of immune cells11-14. When medical students were vaccinated with BCG, 3 months later they
demonstrated improved immunity to Staphylococcus aureus and Candida12. The BCG
priming induces persistent chromatin conformational changes in innate and adaptive
immune cells that improves anti-mycobacterial, bacterial, fungal and viral immunity11, 12, 14-
18. BCG vaccinated healthy controls re-challenged with yellow fever virus demonstrated
improved anti-viral immunity and decreased viral loads. After BCG vaccination, the
epigenetic-mediated non-specific immune benefits last at least a year14. Therefore, while a
coronavirus-specific vaccine is being developed , there exists sufficient data to support
evaluating BCG vaccination as a means to prime host immunity and mitigate the current
To identify whether BCG vaccination does confer some natural protection, we decided to
evaluate the incidence and mortality patterns from Covid-19 with BCG vaccination
programs. When we looked at Europe, the current epicentre of the outbreak, we found
that the map of countries most affected in Europe bears striking resemblance to the map of
countries that do not have national programs of BCG vaccination (Fig 1).
Figure 1a, A - Country with current universal BCG program of vaccination; B Country no
longer has BCG vaccination program; C Country never had BCG vaccination program. Data
courtesy of the BCG World Atlas4.
Figure 1b. Screenshot of heatmap of SARS-CoV-2 cases in Europe ECDC website2 , accessed
March 24 2020.
To look at this further we collated all reported cases and fatalities of Covid-19 world-wide
from the European Centre for Disease Prevention and Control on the previous 15 days, on
March 24nd 202017. The per million incidence and fatality was then calculated using the
population numbers in 2020 as recorded on Worldometers.info18. Finally we collated the
countries that have programs of whole population vaccination still in place, as reported on
the World Atlas of BCG19.
Over the 15 day period from 9 March to 24 March 2020, the incidence of Covid-19 was 80
per million population, with a fatality of 0.55 per million. A total of 178 countries were in
the database: current national programs of BCG vaccination exist in 131 countries; 21
countries have no current program of national BCG vaccination; and for 26 countries status
is unknown. When we dichotomised the data according to those countries with and without
BCG programs, the incidence of Covid-19 was 38.4 per million in countries with BCG
vaccination whereas the incidence of Covid-19 was 358.4 per million in the absence of such
a program. Likewise, the fatality recorded in countries with BCG programs was 4.28/million,
compared to 40/million in countries without a national program. Calculating a crude case
fatality rate (CFR) by dividing deaths by cases, countries with a BCG program the CFR was
0.13% and 0.33% in countries without a BCG program. Countries that have a booster
injection of BCG 7 to 14 years later had no better outcomes than those with a single
inoculation only.
We recognize that these data are observational and based on a single time-point and that
there may be are several confounding issues such as limited testing and reporting in many
countries. However as these data are derived from 178 countries the trend is striking and
supports the mechanistic data that exists for BCG as a protective agent not only for viral and
other infections but also against cancer.
There are currently efforts under way to initiate a randomised, blinded, placebo-controlled
trial3. This would offer a low risk, high benefit proposition. BCG has been used for close to a
century and three billion doses have since been administered since it was developed in
192219 with a remarkable long-standing safety record. For individuals previously vaccinated,
recent studies have demonstrated revaccination is safe, well-tolerated and not associated
with an increased frequency or severity of local or systemic reactions than the primary BCG
vaccination20-24. While awaiting a coronavirus-specific vaccine, using an existing, available
and safe vaccine such as BCG to boost host immunity may represent an important tool
against coronavirus.
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... Recently, various reports suggest that countries with a non-BCG vaccine recipient population (Italy, Nederland, the United States) show higher case fatality rates compared with long-standing universal BCG policy-practicing countries (Hegarty et al., 2020;Miller et al., 2020). In addition, in the elderly population (Gursel and Gursel, 2020), BCG is suggestive of the notion that BCG protects the vaccinated elderly population. ...
... In addition, in the elderly population (Gursel and Gursel, 2020), BCG is suggestive of the notion that BCG protects the vaccinated elderly population. Its known protective immunological benefits, decreased incidences, hampered disease transmission and progression, and lowered mortality are suggestive of BCG vaccination as a potential nonspecific safe tool against COVID-19; however, various other factors make BCG efficacy against COVID-19 debatable (Dayal and Gupta, 2020;Gursel and Gursel, 2020;Hegarty et al., 2020;Hensel et al., 2020;Kirov, 2020;Miller et al., 2020). ...
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The coronavirus disease (COVID-19) is caused by a positive-stranded RNA virus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), belonging to the Coronaviridae family. This virus originated in Wuhan City, China, and became the cause of a multiwave pandemic that has killed 3.46 million people worldwide as of May 22, 2021. The havoc intensified with the emergence of SARS-CoV-2 variants (B.1.1.7; Alpha, B.1.351; Beta, P.1; Gamma, B.1.617; Delta, B.1.617.2; Delta-plus, B.1.525; Eta, and B.1.429; Epsilon etc.) due to mutations generated during replication. More variants may emerge to cause additional pandemic waves. The most promising approach for combating viruses and their emerging variants lies in prophylactic vaccines. Several vaccine candidates are being developed using various platforms, including nucleic acids, live attenuated virus, inactivated virus, viral vectors, and protein-based subunit vaccines. In this unprecedented time, 12 vaccines against SARS-CoV-2 have been phased in following WHO approval, 184 are in the preclinical stage, and 100 are in the clinical development process. Many of them are directed to elicit neutralizing antibodies against the viral spike protein (S) to inhibit viral entry through the ACE-2 receptor of host cells. Inactivated vaccines, to the contrary, provide a wide range of viral antigens for immune activation. Being an intracellular pathogen, the cytotoxic CD8+ T Cell (CTL) response remains crucial for all viruses, including SARS-CoV-2, and needs to be explored in detail. In this review, we try to describe and compare approved vaccines against SARS-CoV-2 that are currently being distributed either after phase III clinical trials or for emergency use. We discuss immune responses induced by various candidate vaccine formulations; their benefits, potential limitations, and effectiveness against variants; future challenges, such as antibody-dependent enhancement (ADE); and vaccine safety issues and their possible resolutions. Most of the current vaccines developed against SARS-CoV-2 are showing either promising or compromised efficacy against new variants. Multiple antigen-based vaccines (multivariant vaccines) should be developed on different platforms to tackle future variants. Alternatively, recombinant BCG, containing SARS-CoV-2 multiple antigens, as a live attenuated vaccine should be explored for long-term protection. Irrespective of their efficacy, all vaccines are efficient in providing protection from disease severity. We must insist on vaccine compliance for all age groups and work on vaccine hesitancy globally to achieve herd immunity and, eventually, to curb this pandemic.
... The study also showed that the death rate has been reducing in the countries with running BCG vaccination compared to the countries devoid of it. 40 In March 2020, a randomized trial of BCG vaccine was initiated to reduce the COVID-19 38,39 in the Netherlands with a moderate number of frontline health workers. 40 Simultaneously, a similar randomized trial has started in Australia in a similar population of health workers with four times larger numbers. ...
... The different newly developed vaccine candidates that are thought to have potentials against SARS-CoV-2 are antibodies, antivirals, cell-based, RNA-based, and scanning compounds to be repurposed. 39 (Table 1) ...
Full-text available
COVID-19 is an international public health emergency in need of effective and safe vaccines for SARS-CoV-2. A systematic review has been done to analyze the availability, development and status of new COVID-19 vaccine candidates as well as the status of vaccines for other diseases that might be effective against SARS-CoV-2 infection. PubMed, MEDLINE, EMBASE, Science Direct, Google Scholar, Cochrane library,, Web of Science and different trial registries were searched for currently available and probable future vaccines. Articles and ongoing clinical trials are included to ascertain the availability and developmental approaches of new vaccines that could limit the present and future outbreaks. Pharmaceutical companies and institutions are at different stages of developing new vaccines, and extensive studies and clinical trials are still required.
... Goswami et al. [10] found that in US and European world, countries with greater coverage of population with BCG vaccine resulted in significant decrease in mortality in comparison to countries with population having poor BCG coverage. Hegarty et al. [13] found that incidence and mortality in countries with BCG vaccination was much lower than the countries without such a program. Similar results with significantly lower mortality were reported. ...
Background: Lower morbidity and mortality in few geographic locations on the globe suffering with SARS-CoV-2 has been associated with the existing or previously followed long-standing Bacille Calmette–Guérin (BCG) vaccination policy among infants. However, does it hold true that today after years of BCG vaccination, few adults have better prognosis or is it just confounding due to differential disease burden, population density, testing facilities, or improper reporting. The purpose was to evaluate and correlate this effect systematically. Methods: Detailed electronic search for randomized controlled trials (RCTs) and observational studies in PubMed, Cochrane Library, and for eligible studies was performed. Results: One hundred and fourteen studies were yielded on search strategy and 28 observational studies were finally included for analysis. From our results, we can say that BCG vaccination causes a decrease in COVID-19 incidence and mortality. However, these results must be interpreted cautiously as lot of confounding factors were present in included studies, which can affect the outcome. Conclusion: The evidence of BCG vaccination for the protection against COVID-19 cannot be ruled out as evidence from many studies support the hypothesis, but the evidence of well-conducted RCTs and observational studies can strengthen the evidence. Registration Number: PROSPERO (International Prospective Register of Systematic Reviews) database (CRD42020204466).
... Miller et al. and Hegarty et al. reported an epidemiological report that indicated a correlation between BCG vaccination policy and reduced COVID-19 morbidity and mortality. 114,115 Further, Dayal et al. compared the case fatality rates (CFR) between countries with a significant effect of COVID-19 and countries where BCG revaccination policies promote a defensive immune response in the population against severe COVID-19. The data obtained from the findings further support the countries with a mandatory BCG vaccination program that offers protection against COVID-19, probably avoiding progression. ...
As of September 2021, 117 COVID-19 vaccines are in clinical development, and 194 are in preclinical development as per the World Health Organization (WHO) published draft landscape. Among the 117 vaccines undergoing clinical trials, the major platforms include protein subunit; RNA; inactivated virus; viral vector, among others. So far, USFDA recognized to approve the Pfizer-BioNTech (Comirnaty) COVID-19 vaccine for its full use in individuals of 16 years of age and older. Though the approved vaccines are being manufactured at a tremendous pace, the wealthiest countries have about 28% of total vaccines despite possessing only 10.8% of the total world population, suggesting an inequity of vaccine distribution. The review comprehensively summarizes the history of vaccines, mainly focusing on vaccines for SARS-CoV-2. The review also connects relevant topics, including measurement of vaccines efficacy against SARS-CoV-2 and its variants, associated challenges, and limitations, as hurdles in global vaccination are also kept forth.
... The results showed that, in countries with vaccination programs, the prevalence and mortality rate was estimated at 38.4 and 4.28 people per million, respectively. The death rate was 40/million in countries without BCG programs [227]. Therefore, it is hypothesized that the vaccine may reduce the incidence and severity of COVID-19 in healthcare workers. ...
Full-text available
Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor -α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively , will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host-pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.
... Second is that these south Asian countries have mandatory BCG vaccination against tuberculosis, which has been found to decrease susceptibility to the virus (Miller et al. 2020;Redelman-Sidi 2020). Supporting this idea, Portugal that has a BCG vaccination program also has lower numbers of SARS-CoV-2 infection if compared with Spain, which does not have this vaccination program and has witnessed catastrophic spread of the virus (Hegarty et al. 2020). However, the positive relation between the vaccination and low SARS-CoV-2 infection rates needs more statistical investigation to be proved. ...
Full-text available
AimThe outbreak of the new coronavirus pandemic (SARS-CoV-2) was initiated in December 2019, and within a couple of months it became a global health emergency. Given the importance to assess the evolution and transmissibility of SARS-CoV-2 and to forecast the next scenario of the pandemic, mainly in countries with limited healthcare systems, we estimated the reproductive number (R0) of SARS-CoV-2 in Jammu and Kashmir (J&K), India, and a possible scenario for this pandemic in the region.Subject and methodsWe estimated the reproductive number (R0) of SARS-CoV-2 in its first outbreak stage in the northwestern region of Himalaya, India, and we also predicted new daily cases for the next 90 days using different R0, testing a plausible end of the SARS-CoV-2 outbreak.ResultsOur results showed a considerable increase in the number of cases, but with a tendency to asymptote. Anantnag, Bandipora, Baramulla, Shopian, and Srinagar districts showed more than 100 cases and Kulgam and Kathua districts showed strong growth of the number of cases from the beginning of May, without a tendency to normalization. The estimated R0 for the J&K region was 1.041; but by decreasing the RO by 10, 25, and 50%, we observed a great decrease in the daily number of new cases, especially by decreasing by 50%.Conclusion In this study, we indicate positive effects of the preventive measures, such as lockdown and social distancing, taken in the J&K region, showing a stabilization of the growth curves of new cases of SARS-CoV-2, which tends to a strong decrease over time as the R0 decreases.
... Several other types of actions were taken by the state and UT governments to control the spread of the virus COVID-19 [5]. Apart from lockdown, people have certain conjectures about possible reasons behind India's relative success, e.g., measures like the travel ban relatively early, use of BCG vaccination to combat tuberculosis in the population that may have secondary effects against COVID-19 [6,7]. ...
Full-text available
Objectives: In December 2019, in Wuhan, China, a novel coronavirus disease (COVID-19), a highly infectious disease, was first described. The disease has spread to 210 countries and territories across the world and more than two million people have been infected (confirmed). In India, the disease was first detected on 30 January 2020 in Kerala in a student who returned from Wuhan. The disease has been continuously spreading all the state of India. The main objective of this study was to identify and classify affected districts into real clusters on the basis of observations of similarities within a cluster and dissimilarities among different clusters so that government policies, decisions, medical facilities (ventilators, testing kits, masks, treatment etc.), etc. could be improved for reducing the number of infected and deceased persons and hence cured cased could be increased. Materials and Methods: We concentrated on the COVID-19 affected states and UTs of India in the report. To fulfill the task, we applied cluster analysis, one of the data mining techniques. The study of variations among various clusters for each of the variables was performed using box plots. We used PAST software for getting for getting a scatter plot for each of the variables. Results: Results obtained from the clustering analysis and box plot methods for each of the variables. For confirmed cases, cluster I corresponded to the states AP, For cured cases, cluster II and for death cases, cluster III corresponded to all the states and UTs of India. Conclusions: The study showed that the state MH, AP, AR, DL and KL under cluster I have a high number of confirmed cases. The box plots and histogram shows variations among different clusters of the three cases. The trend in box plots and histograms showed a good percentage of cured cases in some of the states and UTs. It was observed that the states (MH, UP, KR, TN, DL and WB) under clusters III had severe conditions which need optimization of monitoring techniques which could help the government in making improvement government policies, actions, etc. to reduce the number of infected persons.
... P. Hegarty и соавт. представили сходные эпидемиологические данные по состоянию на 22 [7] и 24 марта 2020 г. [34], рассмотрев феномен тренированного иммунитета как возможный механизм защитного действия БЦЖ против COVID-19. ...
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It has long been known that Bacillus CalmetteGurin (BCG) vaccine provides nonspecific protection against many non-mycobacterial infections, which has been discussed in the last decade through the prism of the concept of trained immunity. Within the framework of this concept, a persistent increase in resistance to various pathogens, which occurs after an infectious disease or exposure to certain microbial agents, is associated with epigenetic reprogramming of innate immune cells and their bone marrow progenitors. The COVID-19 pandemic has drawn attention of scientists and practitioners to BCG as an inducer of trained immunity. A number of epidemiological studies have suggested a negative association between the coverage of the population with BCG vaccination and the burden of SARS-CoV-2 infection. A series of independent clinical studies of the effectiveness of this vaccine in non-specific prevention of COVID-19 has been initiated in different countries. Recently, the key role of cytosolic NOD2 receptors in BCG-induced trained immunity has been proven. This actualizes the search for effective immunoactive preparations for prevention of respiratory infections in the pandemic among low molecular weight peptidoglycan fragments of the bacterial cell wall, muramylpeptides (MPs), which are known to be NOD2 agonists. The review highlights the proven and proposed linkages between BCG, MPs, NOD2 and trained immunity in the light of the COVID-19 pandemic. Analysis of the data presented indicates the prospects for preclinical and clinical studies of MPs as potential drugs for nonspecific prevention of SARS-CoV-2 infection and/or other respiratory infections in risk groups during the pandemic. First of all, attention should be paid to glucosaminylmuramyl dipeptide, approved for clinical use in Russia and a number of post-Soviet countries for the complex treatment and prevention of acute and recurrent respiratory infections.
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Estimation of the prevalence and contagiousness of undocumented novel coronavirus (SARS-CoV2) infections is critical for understanding the overall prevalence and pandemic potential of this disease. Here we use observations of reported infection within China, in conjunction with mobility data, a networked dynamic metapopulation model and Bayesian inference, to infer critical epidemiological characteristics associated with SARS-CoV2, including the fraction of undocumented infections and their contagiousness. We estimate 86% of all infections were undocumented (95% CI: [82%–90%]) prior to 23 January 2020 travel restrictions. Per person, the transmission rate of undocumented infections was 55% of documented infections ([46%–62%]), yet, due to their greater numbers, undocumented infections were the infection source for 79% of documented cases. These findings explain the rapid geographic spread of SARS-CoV2 and indicate containment of this virus will be particularly challenging.
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Background Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette–Guérin (BCG) vaccination may offer partial protection against infection. Methods In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo. Results Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination. Conclusions In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates. (Funded by Aeras and others; C-040-404 number, NCT02075203.)
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The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.
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The reason for the largely variable protective effect against TB of the vaccine Bacille Calmette-Guerin (BCG) is not understood. In this study, we investigated whether epigenetic mechanisms are involved in the response of immune cells to the BCG vaccine. We isolated peripheral blood mononuclear cells (PBMCs) from BCG-vaccinated subjects and performed global DNA methylation analysis in combination with functional assays representative of innate immunity against Mycobacterium tuberculosis infection. Enhanced containment of replication was observed in monocyte-derived macrophages from a sub-group of BCG-vaccinated individuals (identified as 'responders'). A stable and robust differential DNA methylation pattern in response to BCG could be observed in PBMCs isolated from the responders but not from the non-responders. Gene ontology analysis revealed that promoters with altered DNA methylation pattern were strongly enriched among genes belonging to immune pathways in responders, however no enrichments could be observed in the non-responders. Our findings suggest that BCG-induced epigenetic reprogramming of immune cell function can enhance anti-mycobacterial immunity in macrophages. Understanding why BCG induces this response in responders but not in non-responders could provide clues to improvement of TB vaccine efficacy.
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The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation.
The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. We used a PBMC-based "mycobacterial-growth-inhibition-assay" (MGIA) to investigate the capacity to control outgrowth of Bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3-receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3-ligands are associated with trained immunity and critical factors in controlling mycobacterial outgrowth.In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing non-classical CD14dim monocyte subset.
Background BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods In 2008–2013, we randomized LW neonates to “early BCG-Denmark” (intervention group; n = 2083) or “control” (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47–1.04) and a 34% reduction (0.66; .44–1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35–.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46–.83) within the neonatal period and 16% (0.84; .71–1.00) by age 12 months. Conclusion Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration NCT00625482.
Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments.
The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.