Rationale for Randomized Clinical Trials Investigating the Potential of BCG Vaccination in Preventing COVID-19 Infection

Despite the implementation of mitigation measures, Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still spreading worldwide, and has caused more than 1 million deaths so far. Although recent reports indicate that three vaccine candidates are effective against SARS-CoV-2, more time is needed to generate enough doses for the general population. Meanwhile, frontline healthcare workers are at high risk of SARS-CoV-2 exposure. To avoid collapse of the medical care system, there is a need to develop novel approaches to limit SARS-CoV-2 spread. Through a process called trained immunity, the Bacillus Calmette-Guerin (BCG) vaccine boosts the action of innate immune cells, resulting in a nonspecific reduction in the incidence of viral infections. Due to this immunomodulatory action, the BCG vaccine is currently used as a therapeutic in bladder cancer. Data collected from epidemiological and observational studies indicate that BCG vaccination might provide protection against COVID-19. While these observations do not provide evidence of causality and are limited by cofounding and intrinsic biases, it is crucial to explore the hypothesis that BCG vaccination may provide a nonspecific innate immune boost and therefore protect against COVID-19 in randomized controlled clinical trials, particularly for people at higher risk of developing COVID-19, such as frontline healthcare workers.

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BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity

Frontiers in Immunology ◽

10.3389/fimmu.2021.692729 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peter J. Eggenhuizen ◽

Boaz H. Ng ◽

Janet Chang ◽

Ashleigh L. Fell ◽

Rachel M. Y. Cheong ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Epidemiological Studies ◽

Cross Reactivity ◽

Bcg Vaccine ◽

Protective Effects ◽

Cell Reactivity ◽

Bcg Vaccination ◽

T Cell Reactivity

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.

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COVID-19 and BCG vaccine: is there a link?

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-cab-1472 ◽

2020 ◽

Vol 10 (3) ◽

pp. 459-468

Author(s):

I. V. Lyadova ◽

A. A. Starikov

Keyword(s):

Clinical Trials ◽

Latent Tuberculosis Infection ◽

Latent Tuberculosis ◽

Risk Groups ◽

Bcg Vaccine ◽

Tuberculosis Infection ◽

Antiviral Immune Response ◽

Epidemiological Modeling ◽

Bcg Vaccination ◽

The Impact

The spread of the novel coronavirus infection (COVID-19) makes the search for new approaches to prevent the infection of great importance. As one of the relevant approaches, the vaccination of risk groups with BCG vaccine has recently been suggested. BCG (Mycobacterium bovis, Bacillus Calmette–Guérin) is a live vaccine for tuberculosis, which is used in many countries with a high tuberculosis prevalence and helps preventing childhood tuberculosis, primarily, military disease and tuberculosis meningitis. Whether BCG may be used to increase the protection against COVID-19 is currently a question of debates. The review considers scientific background underlying possible impact of BCG in increased protection against COVID-19. BCG is able of inducing the heterologous and trained immunity, and its capacity to stimulate antiviral immune response has been demonstrated in experimental animals and humans. Our comparison of the dynamics of COVID-19 morbidity and mortality in countries with different BCG vaccination policies has demonstrated a milder course of COVID-19 (i.e., a slower increase in disease cases and mortality) in countries where BCG vaccination is mandatory for all children. However, an association between BCG vaccination and a milder COVID-19 course is not obligatory direct. Other factors that may affect the association, such as the level of virus testing, the rigidity and the speed of quarantine implementation and others are discussed. An important argument against a role of BCG in the protection against COVID-19 is that BCG is given in childhood and may hardly induce long-lasting immunity. Because mandatory BCG vaccination is implemented in countries with high TB burden and because in these countries latent tuberculosis infection is widely spread, we suggest a hypothesis that latent tuberculosis infection may contribute to the maintenance of heterologous/trained antiviral immunity in countries with mandatory BCG vaccination. Four countries have recently initiated clinical trials to investigate whether BCG vaccination can increase the level of protection against COVID-19 in risk groups. The results of these studies, as well as COVID-19 epidemiological modeling will help understanding the impact of BCG in the level of the protection against COVID-19. Performing analogous clinical trials in Russia seems appropriate and scientifically sound.

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BCG Vaccination and Mortality of COVID-19 across 173 Countries: An Ecological Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17155589 ◽

2020 ◽

Vol 17 (15) ◽

pp. 5589 ◽

Cited By ~ 3

Author(s):

Mitsuyoshi Urashima ◽

Katharina Otani ◽

Yasutaka Hasegawa ◽

Taisuke Akutsu

Keyword(s):

Urban Population ◽

Ecological Study ◽

Randomized Clinical Trials ◽

Vaccine Coverage ◽

Bcg Vaccine ◽

Bacillus Calmette Guerin ◽

Ecological Studies ◽

Bcg Vaccination ◽

Insufficient Physical Activity ◽

Pcr Test

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.

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Adjuvant Intravesical Therapy for Superficial Bladder Cancer

Annals of Pharmacotherapy ◽

10.1177/106002809202601016 ◽

1992 ◽

Vol 26 (10) ◽

pp. 1270-1276 ◽

Cited By ~ 10

Author(s):

Cynthia N. Batts

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Tumor Recurrence ◽

Randomized Clinical Trials ◽

Therapeutic Response ◽

Superficial Bladder Cancer ◽

Bladder Neoplasms ◽

Bcg Vaccine ◽

Intravesical Therapy

OBJECTIVE: To review the results of clinical trials and adverse drug effects of thiotepa, BCG vaccine, mitomycin, and doxorubicin, which are used as adjuvant intravesical therapy for superficial bladder cancer. DATA SOURCE: Information was retrieved from a MEDLINE search, of the English-language literature. Indexing terms included adjuvant pharmaceutics, bladder neoplasms, thiotepa, mitomycin, BCG vaccine, and doxorubicin. DATA EXTRACTION: Data from several human and in vitro studies were assessed and evaluated, according to the strength of comparative data and therapeutic response. STUDY SELECTION: Emphasis was placed on clinical trials that assessed and evaluated dosage, therapeutic regimens, and therapeutic response of adjuvant intravesical therapy for superficial bladder cancer. DATA SYNTHESIS: Adjuvant intravesical therapy and long-term prophylaxis are effective for superficial bladder cancer. Studies have shown that doxorubicin, thiotepa, BCG, and mitomycin, when used as adjuvant therapy, provide better protection than transurethral resection alone against tumor recurrence and prolong the time to when cystectomy is required. CONCLUSIONS: Several randomized clinical trials suggest that BCG is superior to thiotepa, doxorubicin, and mitomycin in preventing bladder tumor recurrence and tumor progression. Local cystitis is an adverse effect produced by all four agents; however, BCG vaccine has been reported to cause a higher incidence of adverse reactions (e.g., dysuria, hematuria). BCG may also cause an influenza-like syndrome, arthralgias, and fever, but most of these reactions have resulted in few severe adverse effects when the drug is given in the relatively modest recommended doses.

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Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males

Journal of Immunology Research ◽

10.1155/2015/261864 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Linda A. C. Hamers ◽

Matthijs Kox ◽

Rob J. W. Arts ◽

Bastiaan Blok ◽

Jenneke Leentjens ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Ex Vivo ◽

Innate Immune ◽

Bcg Vaccine ◽

Controlled Study ◽

Bacille Calmette Guerin ◽

Bcg Vaccination ◽

Gamma Irradiated

Bacille Calmette-Guérin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humansin vivoduring experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG (n=10) or placebo (n=10) and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess thein vivoimmune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assessex vivoimmune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither thisin vivoimmune response, norex vivoleukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered withNCT02085590.

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Hypothetical Immunological and Immunogenetic Model of Heterogenous Effects of BCG Vaccination in SARS-CoV-2 Infections: BCG-induced Trained and Heterologous Immunity

Journal of Medical Science ◽

10.20883/medical.e551 ◽

2021 ◽

pp. e551

Author(s):

Dženan Kovačić ◽

Andrej A. Gajić ◽

Dado Latinović ◽

Adna Softić

Keyword(s):

Cross Reactivity ◽

Innate Immune ◽

Cytokine Secretion ◽

Bcg Vaccine ◽

Immune Memory ◽

Host Immune System ◽

Bcg Vaccination ◽

Heterologous Immunity ◽

Specific Effects ◽

Secretion Profile

Though SARS-CoV-2 infections are yet to be completely characterised in a host-pathogen interaction context, some of the mechanisms governing the interaction between the novel betacoronavirus and the human host, have been brought to light in satisfactory detail. Among the emerging evidence, postulates regarding potential benefits of innate immune memory and heterologous immunity have been put under discussion. Innate immune memory entails epigenetic reprogramming of innate immune cells caused by vaccination or infections, whereas heterologous immunity denotes cross-reactivity of T cells with unrelated epitopes and bystander CD8+ activation. Familiarization of the host immune system with a certain pathogen, educates monocytes, macrophages and other innate cells into phenotypes competent for combating unrelated pathogens. Indeed, the resolution at which non-specific innate immune memory occurs, is predominant at the level of enhanced cytokine secretion as a result of epigenetic alterations. One vaccine whose non-specific effects have been documented and harnessed in treating infections, cancer and autoimmunity, is the Bacillus Calmette–Guérin (BCG) vaccine currently used for immunization against pulmonary tuberculosis (TB). The BCG vaccine induces a diverse cytokine secretion profile in immunized subjects, which in turn may stimulate epigenetic changes mediated by immunoreceptor signalling. Herein, we provide a concise summarization of previous findings regarding the effects of the BCG vaccine on innate immune memory and heterologous immunity, supplemented with clinical evidence of the non-specific effects of this vaccine on non-mycobacterial infections, cancer and autoimmunity. This interpretative synthesis aims at providing a plausible immunological and immunogenetic model by which BCG vaccination may, in fact, be beneficial for the current efforts in combating COVID-19.

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Avoiding COVID-19 Complications with Diabetic Patients Could Be Achieved by Multi-Dose Bacillus Calmette–Guérin Vaccine: A Case Study of Beta Cells Regeneration by Serendipity

10.20944/preprints202004.0134.v1 ◽

2020 ◽

Author(s):

Bassam M. Ayoub ◽

Eman Ramadan ◽

Nermeen Ashoush ◽

Mariam M. Tadros ◽

Moataz S. Hendy ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Study ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Aerobic Glycolysis ◽

Bcg Vaccine ◽

Diabetic Patients ◽

Bcg Vaccination ◽

Significant Difference

Diabetes mellitus (DM) is one of the major risk factors for COVID-19 complications as it is one of the chronic immune-compromising conditions especially if patients have uncontrolled diabetes, poor HbA1c &/or irregular blood glucose levels. Diabetic patient’s mortality rates with COVID-19 are higher than cardiovascular or cancer patients. Recently Bacillus Calmette–Guérin (BCG) has shown successful results in reversing diabetes in both rats and clinical trials based on different mechanisms from aerobic glycolysis to Beta cells regeneration. BCG is a multi-face vaccine that has been used extensively in protection from TB and leprosy and has been repositioned for treatment of bladder cancer, diabetes & multiple sclerosis. Recently, the COVID-19 epidemiological study confirmed that universal BCG vaccination reduced morbidity and mortality in certain geographical areas. Countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies that have shown low numbers of reported COVID-19 cases. Some countries have started clinical trials that included a single dose BCG vaccine as prophylaxis from COVID-19 or an attempt to minimize its side effects. This proposed research aims to use BCG vaccine as a double-edged weapon countering both COVID-19 & diabetes, not only as protection but also as therapeutic vaccination. The work includes a case study of regenerated pancreatic beta cells based on improved C-peptide & PCPRI laboratory findings after BCG vaccination for a 9 years’ patient. The patient was re-vaccinated based on a negative tuberculin test & no scar at the site of injection of the 1st BCG vaccination at birth. Furthermore, the authors in the present article described a prospective BCG multi-dose clinical study in full details that they will apply in case of acceptance of their submitted grant & the ethical committee approval. The aim of the clinical study is to check if double dose BCG (4 weeks apart) will show a significant difference in the protection of health care professionals in Egypt. The authors suggest and invite the scientific community to take into consideration the concept of direct BCG re-vaccination (after 4 weeks) because of the reported gene expressions & exaggerated innate immunity consequently. As the diabetic MODY-5 patient (mutation of HNF1B, Val2Leu) was on low dose Riomet® while eliminating insulin gradually, a simple analytical method for metformin assay was recommended to ensure its concentration before use as it is not approved yet by the Egyptian QC labs.

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COVID-19 vaccination clinical trials should consider multiple doses of BCG

10.31219/osf.io/h24bj ◽

2020 ◽

Cited By ~ 2

Author(s):

Bassam Ayoub

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Type 1 Diabetes ◽

Immune Cells ◽

Multiple Dose ◽

Innate Immune ◽

Bcg Vaccine ◽

Innate Immune Cells ◽

Multiple Doses

Vaccine repositioning is a hot research topic as an alternative to the traditional vaccine approach, which is a costly and time-consuming process due to the availability of previous safety and toxicology data. Multiple-dose BCG vaccine repurposing for COVID-19 will be an uprising breakthrough of vaccine discovery with safer outcomes. BCG induces cross-protection that might not be related to the target disease as innate immune cells, including monocytes and natural killer cells, contribute to this immune protection as known as “trained immunity” [1]. BCG had multifaceted protection against TB, Leprosy & heterogeneous pathogens [2]. Moreover, it was repositioned as a treatment for type-1 diabetes, many types of cancer & multiple sclerosis [2]. BCG vaccine accelerates the “resetting” of the immune system [3] or “turn on” immunity mechanism that agrees with its pleiotropic repurposing for many diseases. Multiple-dose BCG vaccine was used for reversing type-1 diabetes & for treating bladder cancer [4-5]. While intravesical multiple doses of BCG for bladder cancer showed many complications [6-7], intradermal multiple doses of BCG for diabetes showed high safety profile [4]. As recent studies have shown that upon certain vaccinations, human innate immune cells can undergo extensive metabolic and epigenetic reprogramming, which results in enhanced immune responses upon heterologous re-infection, a process termed trained immunity [8]; The author recommends that COVID-19 vaccination clinical trials should consider multiple doses of BCG. After reviewing the recent COVID-19 literature, although some preliminary studies suggested BCG to fight COVID-19 [9-12], they did not consider the use of multiple intradermal BCG vaccination (at least 2 doses, 4 weeks apart [4]) for the prophylaxis of COVID-19 outbreak. I do recommend that diabetic patients should participate in clinical trials to benefit from the reported BCG anti-hyperglycemic effect [4]. What if safe multiple doses of BCG turned on the immunity and protected people from COVID-19 more efficiently than a single dose?

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