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BCG vaccination may be protective against Covid-19

Authors:
Paul K Hegarty at National Health Service
Paul K Hegarty
Ashish M Kamat at University of Texas MD Anderson Cancer Center
Ashish M Kamat
Helen Zafirakis at Mater Private Hospital
Helen Zafirakis
Andrew Dinardo at Baylor College of Medicine
Andrew Dinardo
Preprints and early-stage research may not have been peer reviewed yet.
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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
ABSTRACT
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 Worldometer.info for the population of all
countries.
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
crisis3.
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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... India has taken several preemptive measures to war COVID-19 inappreciably faster organizes contrasted with particular international locations, which include go united states of America Lockdown from 25 March 2020. Apart from the lockdown, people have certain guesses about potential motives for India's relative success, e.g measures like the movement boycott pretty early, usage of Bacilli Calmette-Guerin (BCG) inoculation to warfare tuberculosis in the populace that can have non-compulsory influences on COVID-19 [20] [21] , openness to intestinal sickness and antimalarial pills [22] , warm and muggy weather easing back the transmission, etc. [23] [24] . Be that as it could, as of now, there's no stable proof to assist those guesses, albeit a few clinical preliminaries are in progress to look at a component of these [25] . ...
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... A few ecological papers are recently being published though still in the preprints stage; one such paper mentions that national differences in COVID-19 impacts could be partially explained by BCG vaccination policies (Miller et al., 2020). Another study also finds countries with universal vaccination policies associated with lower incidence and death rates from COVID-19 (Hegarty et al., 2020). A similar result is reported by another study positing a protective link of BCG vaccination (Dayal & Gupta, 2020). ...
View
... 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. ...
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  • Apr 2021
  • J Publ Health
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.
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COVID-19 Drug Repositioning: Present Status and Prospects
Chapter
  • Jan 2022
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 disease has gained the status of a pandemic worldwide. Till now no appropriate drug has been identified which can become the gold standard for coronavirus-2 and drugs such as Favipiravir, Hydroxychloroquine and Remdesivir used for the treatment of severe cases of COVID-19 have not yielded satisfactory results owing to many side effects. Although the entire scientific fraternity of the world is currently engaged to find a permanent cure for this deadly disease, clinical development of a new drug or vaccine precisely for SARS-CoV-2 will normally take time. Given the pressing need to quickly find effectual medications for COVID-19, existing drugs are being repositioned. The term “repositioning” or “repurposing” refers to the use of approved drugs originally used against other pathogens which can also be used against SARS-CoV-2. These therapeutics can be chosen from a wide spectrum of drugs used for cancer-induced inflammation, immune dysfunction, and coagulopathy. As all these symptoms prevail in patients affected by COVID-19, it is reasonable to consider testing above mentioned agents in a rational manner against this viral illness. The main idea behind the repositioning of the drug is to lessen the time and expenditure which is done to find a new drug and then ushering its transition from bench to bedside. For narrowing down the search as to which therapeutics can be considered for repositioning, Artificial Intelligence (AI) can be of great aid. AI can quickly detect drugs that can fight against COVID-19 pandemic. Besides, it is a cheaper, faster, and effective approach to find repurposed drugs from a vast array of therapeutics thereby minimizing the failures in clinical trials. AI-based Deep learning models can also predict drug structures that could potentially treat COVID -19 which can be a step forward in finding appropriate drugs for COVID -19. The present book chapter will comprehensively highlight all these points.KeywordsDrug repositioningCOVID-19CoronavirusArtificial intelligenceMachine learningDeep learning
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Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2)
Article
Full-text available
  • Mar 2020
Undetected cases The virus causing coronavirus disease 2019 (COVID-19) has now become pandemic. How has it managed to spread from China to all around the world within 3 to 4 months? Li et al. used multiple sources to infer the proportion of early infections that went undetected and their contribution to virus spread. The researchers combined data from Tencent, one of the world's largest social media and technology companies, with a networked dynamic metapopulation model and Bayesian inference to analyze early spread within China. They estimate that ∼86% of cases were undocumented before travel restrictions were put in place. Before travel restriction and personal isolation were implemented, the transmission rate of undocumented infections was a little more than half that of the known cases. However, because of their greater numbers, undocumented infections were the source for ∼80% of the documented cases. Immediately after travel restrictions were imposed, ∼65% of cases were documented. These findings help to explain the lightning-fast spread of this virus around the world. Science , this issue p. 489
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Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination
Article
Full-text available
  • Jul 2018
  • NEW ENGL J MED
Background Recent Mycobacterium tuberculosis (M.tb) infection predisposes to tuberculosis disease, the leading global infectious disease killer. We tested safety andefficacy of H4:IC31® vaccination or Bacille Calmette-Guerin (BCG) revaccination for prevention of M.tb infection. Methods QuantiFERON-TB Gold In-tube (QFT) negative, HIV-uninfected, remotely BCG-vaccinated adolescents were randomized 1:1:1 to placebo, H4:IC31® or BCG revaccination (NCT02075203). Primary outcomes were safety and acquisition of M.tb infection, defined by initial QFT conversion tested 6-monthly over two years. Secondary outcomes were immunogenicity and sustained M.tb infection, defined by sustained QFT conversion without reversion three and six months post-conversion. Statistical significance for efficacy proof-of-concept was set at 1-sided p<0.10. Results 990 participants were enrolled. Both vaccines had acceptable safety profiles and were immunogenic. QFT conversion occurred in 134 and sustained conversion in 82 participants. Neither H4:IC31® nor BCG prevented initial QFT conversion, with efficacy point estimates of 9.4% (95% confidence interval: -36.2, 39.7; one-sided p=0.32) and 20.1% (-21.0, 47.2; one-sided p=0.14), respectively. However, BCG did prevent sustained QFT conversion with an efficacy of 45.4% (6.4, 68.1; one-sided p=0.013); H4:IC31® efficacy was 30.5% (-15.8, 58.3; one-sided p=0.08). QFT reversion rate from positive to negative was 46% in BCG, 40% in H4:IC31 and 25% in placebo recipients. Conclusions This first proof-of-concept, prevention of M.tb infection trial showed that sustained infection can be prevented by vaccination in a high-transmission setting and confirmed feasibility of this strategy to inform clinical development of new vaccine candidates. Evaluation of BCG revaccination to prevent tuberculosis disease in M.tb- uninfected populations is warranted.
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Mycobacterial growth inhibition is associated with trained innate immunity
Article
Full-text available
  • Feb 2018
  • J CLIN INVEST
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.
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Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial
Article
Full-text available
  • Oct 2017
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.
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Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects
Article
Full-text available
  • Sep 2017
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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Immunometabolic Pathways in BCG-Induced Trained Immunity
Article
Full-text available
  • Dec 2016
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.
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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity
Article
  • Jan 2018
  • CELL HOST MICROBE
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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Bladder cancer
Article
  • Jun 2016
  • LANCET
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.
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Trained immunity: A program of innate immune memory in health and disease
Article
  • Apr 2016
Training immune cells to remember Classical immunological memory, carried out by T and B lymphocytes, ensures that we feel the ill effects of many pathogens only once. Netea et al. review how cells of the innate immune system, which lack the antigen specificity, clonality, and longevity of T cell and B cells, have some capacity to remember, too. Termed “trained immunity,” the property allows macrophages, monocytes, and natural killer cells to show enhanced responsiveness when they reencounter pathogens. Epigenetic changes largely drive trained immunity, which is shorter lived and less specific than classical memory but probably still gives us a leg up during many infections. Science , this issue p. 10.1126/science.aaf1098
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