Vaccine Info

Bacille Calmette-Guerin (BCG) Vaccine

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August 11, 2022
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BCG Vaccine Description 2022

The Mycobacterium Bovis Bacille Calmette-Guerin (BCG) vaccine is an attenuated, live culture preparation of the BCG strain of Mycobacterium Bovis. Mycobacterium tuberculosis (Mtb) is the ethiological agent of tuberculosis (TB). The biological interaction between Mtb and the human host is complex and only partially understood, says the WHO.

As of August 2022, the U.S. FDA had issued Organon Teknika Corp., LLC Approvals for two BCG vaccines: BCG Live, STN: 103050, and TICE BCG, STN: 102821. In its thirteenth report, the formulation of international requirements for the manufacture and control of the BCG vaccine was first considered by the WHO Expert Committee on Biological Standardization. The WHO adopted requirements for the BCG vaccine in 1965, and these were updated in 1978 to reflect the increased knowledge concerning the dose of vaccine to administer and the change to freeze-dried preparations. These were modified in 1985 to amend requirements concerning the expiry date. 

The initial BCG vaccine was developed in 1921 by French scientists Albert Calmette and Camille Guérin. The BCG vaccine was designed to protect cattle from bovine tuberculosis and was administered for the first time to a newborn baby in Paris in 1921, as reported by The Lancet. The BCG vaccine was initially targeted against tuberculosis, tuberculosis meningitis, and nonspecific protective effects against other respiratory tract infections. The U.K. Health Security Agency also says BCG vaccine-related tuberculosis morbidity and mortality reductions are as high as 70%.

Furthermore, decades of research suggest that BCG has nonspecific benefits against non-tuberculous infections in newborn babies and older adults, and offers immunotherapeutic benefits in certain malignancies such as non-muscle-invasive bladder cancer, reported The Lancet on Sept. 7, 2021. For example, India introduced BCG in mass immunization with its highest T.B. burden in 1948. In addition, the U.S. NIH says the BCG vaccine is relatively safe and not associated with severe complications.

 A 2004 study in the United Kingdom showed that an mRNA vaccine had "modest but significant protection" against Mycobacterium tuberculosis in mice. 'Some vaccines, especially those derived from live attenuated microorganisms, also have essential beneficial heterologous effects outside the target disease, wrote researchers in a study published by The Lancet on July 5, 2021. And BMC - Gene Biology published a study on Sept. 22, 2021, that showed the variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which affect or produce metabolites in circulation. In addition, Roseburia is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity.

Additionally, CELL Reports published a study on Nov. 16, 2021, linking in vivo BCG administration to single-cell transcriptomic changes, validated in human genetics experiments, and highlighting genes that are putatively responsible for nonspecific protective effects of BCG. And on May 2, 2022, Cell Reports published a study that found the BCG vaccine induces specific changes in metabolites and lipids that correlate with innate immune system responses. 

The BCG Atlas is an open-source database of global BCG vaccination policies and practices founded in 2011. Many foreign-born persons in the USA have been BCG-vaccinated. Newborns and infants have realized health benefits from BCG vaccination. However, the U.S. CDC says the BCG vaccine is not generally recommended for use in the USA because of the low risk of infection with Mycobacterium tuberculosis.

On August 5, 2022, new research (MIS BAIR) led by the Murdoch Children’s Research Institute in Australia and published in the peer-review Science Advances journal showed how BCG vaccination produces ‘trained immunity responses’ lasting more than 14 months after the vaccine is administered.

As of August 11, 2022, the BCG vaccine is available in countries such as the U.S., Canada, ChinaCuba, EthiopiaJamaciaJapan, GermanyUK, Mexico, Europe, Brazil, Korea, Russia, SpainSouth Africa, QuebecIndia, New Zealand, Australia, Venezuela, and Nigeria. The global Tuberculosis Vaccine revenue was about $7 Million in 2020 and is expected to increase over 3% per year to 2027, based on the Report Ocean report.

BCG Vaccine Versions

As of August 2022, over 14 sub-strains of BCG have evolved and used BCG vaccines in different laboratories worldwide. The strain variation might contribute to BCG vaccines' highly variable protective efficacy. BCG vaccine versions with marked variability in the content of live mycobacteria include but are not limited to BCG-Denmark (Statens Serum Institute); BCG- Japan, BCG-India, BCG-Bulgaria. BCG-induced whole blood cytokines differed significantly by age, vaccine formulation, and concentration. In addition, BCG-induced cytokine production correlated with CFU, suggesting that mycobacterial viability may contribute to BCG-induced immune responses. The B.D. Commercial Middlebrook 7H11 medium was rated well. The BCG Vaccine AJV (A.J. Vaccines) is the only licensed BCG vaccine in the U.K.

The Serum Institute of India applied to the Drugs Controller General of India seeking emergency use authorization for its recombinant BCG (rBCG) vaccine TuberVac to prevent tuberculosis on March 22, 2022. On July 26, 2021, BioNTech announced clinical trial plans for its mRNA vaccine for T.B.

Merck's version of the TICE® BCG organism is grown to prepare the freeze-dried cake in agar composed of the following ingredients: glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, and iron ammonium citrate. The final preparation before freeze-drying also contains lactose. Merck's freeze-dried BCG preparation is delivered in vials containing 1 to 8 x 10^8 colony-forming BCG units, equivalent to approximately 50 mg of wet weight. Determination of in-vitro potency is achieved through colony counts derived from a serial dilution assay. Intradermal guinea pig testing is also used as an indirect measure of strength. Merck confirmed BCG vaccine production increase in January 2021.

And VPM1002 is a recombinant BCG that is the most widely used vaccine globally. The vaccine developed in Germany has the genetic code of the BCG edited to lead to better availability of the T.B. antigens, thus training the immune system to fight tuberculosis better. VPM1002 is a recombinant BCG (rBCG) in which the listeriolysin O encoding gene has replaced the urease C gene from Listeria monocytogenes. Urease C drives the neutralization of phagosomes containing mycobacteria by generating ammonia, thereby inhibiting phagolysosomal maturation and contributing to the survival of mycobacteria inside the macrophage. Its depletion allows for rapid phagosome acidification.

Since Aug. 2018, the U.K. has been using the BCG vaccine manufactured in Denmark by A.J. Vaccines. Before this, the U.K. used an alternative BCG vaccine manufactured by InterVax. The WHO reference materials for the BCG vaccine and BCG vaccine substrains (Tokyo 17, Danish 1331, and Russian BCG-I) are available to qualified applicants in the International Reference Preparations Catalogue. In addition, on July 19, 2021, the Indian Council of Medical Research posted an online symposium on BCG Centenary Vaccine.

Drugbanks Accession Number is DB12768; UNII: 8VJE55B0VG, 5H5854UBMZ; ATC code: J07AN01; KEGG: D03063D06466 CMS billing code: J9030 BCG LIVE INTRAVESICAL INSTILLATION, 1 MG.

BCG Vaccine Indication

The BCG vaccine is used in many countries (U.K.) to prevent childhood tuberculous, meningitis, bladder cancer, and other diseases. Those born on or after September 2021 will follow the new schedule in the U.K. The BCG vaccine should be given to eligible babies within 28 days or soon after. 

The BCG vaccine also helps fight other viruses, such as respiratory infections. For example, one study conducted in West Africa found that vaccinated children with BCG had about a 50% reduction in overall mortality, primarily because it reduced respiratory infections, sepsis, or blood poisoning.

A study published on May 2, 2019, reported that BCG vaccination is mediated via the induction of innate immune memory and heterologous lymphocyte activation, resulting in enhanced cytokine production, macrophage activity, T-cell responses, and antibody titers. In addition, a 2019 observational study reported that the vaccine is related to fewer deaths from certain infections other than T.B. in low-income countries.

The WHO 2021 Report recommends routine neonatal BCG vaccination in countries with moderate to severe tuberculosis prevalence. The reduction in childhood mortality may be due to epigenetic reprogramming of the nucleotide-binding oligomerization domain receptor. BCG vaccination prevents disseminated diseases, including tuberculous meningitis and miliary tuberculosis, associated with high mortality in infants and young children. However, its preventive efficacy against pulmonary tuberculosis, which varies among populations, is only about 50%. The WHO says BCG vaccination should continue for all infants soon after birth except for those with HIV living in high tuberculosis prevalence settings.

Public Health England (PHE) announced on July 27, 2021, beginning September 2021, that eligible babies born on or after this date should be offered the BCG vaccine at 28 days or soon after. BCG vaccination is recommended for babies up to 1-year-old, and BCG vaccination may also be recommended for older children who have an increased risk of developing TB. And providers are required to check the record for a negative SCID result or confirm that the child was not offered SCID screening before administering the BCG vaccine. On September 15, 2021, the U.K.'s PHE updated its fact sheet.

BCG Vaccine and Tuberculosis 

Tuberculosis (TB) is a vaccine-preventable disease, reported in The Lancet on September 7, 2021. TB is the leading cause of death from infectious disease worldwide, causing about 1.3 million deaths per year, mainly in the developing world. The respiratory virus M tuberculosis is spread via airborne transmission and more often affects men, who account for 60% of all cases, according to a study published by the CDC in May 2020.

The Lancet published an early-release study on August 10, 2022 - Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis. Interpretation: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is also ineffective in adolescents and adults. Immunoprotection, therefore, needs to be boosted in older populations.

In the USA, BCG vaccination should be considered for select persons who meet specific criteria and consult with a TB expert, says the CDC. Also, BCG vaccination should not be given to immunosuppressed persons (e.g., HIV infected) or persons likely to become immunocompromised (e.g., organ transplant). And, BCG vaccination of health care workers should be considered individually in settings where a high percentage of TB patients are infected with M. tuberculosis strains resistant. A new CDC report indicates that the average number of TB cases in the USA has decreased by about 2% to 3% annually over the past ten years.

BCG vaccination should only be considered for children who have a negative tuberculin skin test and are continually exposed. It cannot be separated from untreated or ineffectively treated adults for TB disease or TB caused by strains resistant to isoniazid and rifampin. When used to protect against TB, BCG is injected into the skin. Keep the vaccination area dry for 24 hours after receiving the vaccine, and keep the area clean until you cannot tell the vaccination area from the skin around it.

BCG vaccination may also be recommended for older children who have an increased risk of developing TB, such as children who have recently arrived from countries with high levels of TB, including those in Africa, the Indian subcontinent, parts of southeast Asia, parts of South and Central America, and parts of the Middle East, and children who have come into close contact with somebody infected with respiratory T.B.

Beginning September 2021, eligible babies born in the U.K. were offered the BCG vaccine at 28 days or soon after. However, it is 70-80% effective against the most severe forms of T.B., such as TB meningitis. Furthermore, it is less effective in preventing the formation of TB that affects the lungs. This includes babies who live in an area with high rates of T.B. or babies with parents or grandparents from a country with increased rates of T.B. On July 4, 2022, India's National Institute for Research in Tuberculosis launched a study to provide BCG revaccination to 9,000 children who are household contacts of tuberculosis patients to gauge whether a booster BCG would help prevent the disease.

The WHO released its Global T.B. Report 2021, which provides a comprehensive and up-to-date assessment of the TB epidemic and progress in its prevention, diagnosis, and treatment at global, regional, and country levels. The WHO recommends neonatal BCG vaccination in countries or settings with a high incidence of tuberculosis. Global spending on TB in 2020 fell to $5.3 billion, less than half of the global annual target of $13 billion by 2022. And World Tuberculosis Day is held on March 24 annually to raise public awareness about TB The date marks the day in 1882 when Dr. Robert Koch announced that he had discovered the bacterium that causes TB.

Tuberculosis Infection Tests

According to a Quest Diagnostics Health Trends® study published in the Journal of Public Health Management & Practice on July 25, 2022, conducted by Quest, Stanford University School of Medicine, and the Veterans Affairs Palo Alto Health Care System in Palo Alto, Calif. Among the study's most significant findings are that 32.3% of patients who tested positive for latent TB were also tested for HBV infection. Among patients tested for both infections, 19.6% with chronic hepatitis B also have latent TB, more than twice the TB positivity of patients without chronic hepatitis B (7.3%). 

On September 6, 2021, The Lancet reported three tests are used in the U.S. to identify latent tuberculosis infection: the tuberculin skin test and two IFN-γ release assays (T-SPOT.TB and QuantiFERON). And on July 20, 2022, the journal Nature published a study: Evaluation of early innate and adaptive immune responses to the TB vaccine Mycobacterium bovis BCG and vaccine candidate BCGΔBCG1419c - that concluded the use of BCGΔBCG1419c may be advantageous as an alternative TB vaccine candidate.

The Lancet published on August 4, 2022: Donor-derived transmission of M tuberculosis via bone allograft in 2021 resulted in substantial morbidity and mortality. Eight product recipients died 8–99 days after product implantation (three deaths were attributed to tuberculosis after recognition of the outbreak). All 105 living recipients started treatment for tuberculosis disease at a median of 69 days (IQR 56–81) after product implantation. Conclusion: All prospective tissue and organ donors should be routinely assessed for tuberculosis risk factors and clinical findings. 

BCG Vaccine and Alzheimer's Disease

The peer-reviewed journal MDPI published Evaluation of BCG Vaccination and Plasma Amyloid: A Prospective, Pilot Study with Implications for Alzheimer's Disease on Feb. 12, 2022 - both the favorable direction of change after BCG as well as the utility of the APS—a valuable surrogate A.D. biomarker—may prompt a definitive large-scale multicenter investigation of BCG and A.D. risk as determined by plasma amyloid peptide ratios and APS.

A study by Montefiore-Einstein researchers published by Clinical Genitourinary Cancer in May 2021 supports earlier findings that BCG therapy correlated with a lowered risk for developing Alzheimer's disease. For example, about 25% of patients who received BCG treatment for non-muscle-invasive bladder cancer had a 60% reduced risk of developing Alzheimer's disease or other dementias compared with those who did not receive BCG. In addition, the analysis suggested that BCG's possibly protective effect against dementia may be more robust in men. However, the authors note that more extensive studies involving more patients are needed to corroborate their findings.

BCG Vaccine and Bladder Cancer

Bacillus Calmette-Guerin is the most common intravesical immunotherapy for treating early-stage bladder cancer. It's used to help keep cancer from growing and help keep it from coming back, says Cancer.org. BCG has been one of the most successful immunotherapies and has been the "standard of care for patients with bladder cancer" since 1977. An abstract presented at the European Association of Urology 2022 Annual Meeting in July 2022 reported BCG vaccination nearly halved the risk of progression among patients with non–muscle invasive bladder cancer compared with transurethral resection of the bladder, but only among those with very high-risk disease.

ImmunityBio, Inc. announced on July 28, 2022, that the FDA accepted for review a Biologics License Application from ImmunityBio, Inc. (NASDAQ: IBRX) for its antibody cytokine fusion protein as a treatment for patients with BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ with or without Ta or T1 disease. If approved, N-803 plus BCG would be the first immunotherapy combination for this indication in 23 years that can be delivered directly intravesically to the bladder to induce natural killer cells and T cells. It represents an essential step in the clinical demonstration of the Nant Cancer Vaccine hypothesis proposed by ImmunityBio’s founder, Patrick Soon-Shiong, M.D.

On December 8, 2021, the journal Vaccine published a study: A BCG success story: From tuberculosis prevention to optimal bladder cancer treatment. This abstract concluded by saying, 'Recombinant technology is expected to improve both the efficacy and production of BCG, hopefully expanding BCG availability and relieving the recurring supply shortage for both vaccination and cancer therapy.'

Verity Pharmaceuticals Inc. announced on September 9, 2021, that it had received approval to begin distributing VERITY-BCG™ (Bacillus Calmette-Guérin [BCG]: Strain Russian BCG-I). This approval means that hospitals and clinics across Canada will no longer see shortages of this critical drug.

On September 13, 2021, ImmunityBio, Inc. announced updated data from an ongoing bladder cancer trial showing sustained complete response rates in patients with BCG-unresponsive non-muscle-invasive carcinoma in situ (CIS) bladder cancer (Cohort A). Of the 81 patients in the QUILT 3.032 study, 58 patients (72%) had a complete response at any time (three or six months) to intravesical BCG plus N-803 (Anktiva) with a median duration of C.R. of 19.9 months. And the U.S. Patent & Trademark Office has recently allowed ImmunityBio's patent application for a method of treating cancer, including non-muscle invasive bladder cancer, using Anktiva (N-803) in combination with Bacillus Calmette-Guerin (BCG). The new patent will extend the patent life on the N-803/BCG combination therapy for bladder cancer to at least 2035.

On September 9, 2021Canada approved the distribution of VERITY-BCG™ (Bacillus Calmette-Guérin [BCG]: Strain Russian BCG-I). VERITY-BCG™ is an adjuvant therapy after transurethral resection (TUR) of a primary or relapsing superficial papillary urothelial cell carcinoma of the bladder stage Ta (grade 2 or 3) or T1 (grade 1, 2, or 3), without concomitant carcinoma in situ. It is only recommended for stage Ta grade 1 papillary tumors when there is a high risk (>50%) of tumor recurrence.

In 2009, a study reported anti-tumor responses induced by recombinant BCG vaccines based on different tandem repeats of MUC1 and GM-CSF. A single dose of M. Bovis bacillus Calmette-Guérin immunotherapy has a therapeutic benefit in treating a non-invasive form of bladder cancer. It is administered intravesically, and proven benefits include the malignancy's delay and prevention of progression.

BCG Vaccine and COVID-19

A randomized phase 4 clinical trial of BCG vaccine in patients with convalescent COVID-19: Clinical evolution, adverse events, and humoral immune response, published on May 22, 2022, concluded that the 'BCG vaccine is safe and offers cross-protection against COVID-19 with potential humoral response modulation.' The Lancet - eClinicalMedicine published results from a phase 3 study conducted in South Africa on May 12, 2022, that concluded the BCG vaccine did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalization.

A peer-reviewed phase 3 clinical study published on April 22, 2022, concluded that 'we found that BCG vaccination has off-target effects on innate and adaptive immune responses to SARS-CoV-2. The immunomodulatory signature of BCG's off-target effects on SARS-CoV-2 responses is distinct from that observed for bacterial and fungal stimuli. Moreover, the BCG-induced changes in SARS-CoV-2 immunity directly contrast to immune signatures of severe COVID-19. These (BRACE study) findings support the hypothesis that BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and activation of eosinophils in response to SARS-CoV-2.

On November 20, 2020, a study by Cedars-Sinai in Los Angeles, CA, raised the possibility that the BCG vaccine may help prevent coronavirus infections or reduce the disease's severity. In the new study, published in The Journal of Clinical Investigation, investigators tested the blood of more than 6,000 healthcare workers in the Cedars-Sinai Health System for evidence of antibodies to SARS-CoV-2, the virus that causes COVID-19, and also asked them about their medical and vaccination histories. The study found that workers who had received BCG vaccinations in the past—nearly 30% of those studied—were significantly less likely to test positive for SARS-CoV-2 antibodies in their blood or to report having had infections with coronavirus or coronavirus-associated symptoms over the prior six months. Texas A&M University, Baylor College of Medicine, MD. Anderson Cancer Center, Cedars-Sinai Medical Center, and Harvard University conducted a late-stage, phase 4 clinical trial of Merck's TICE version of the BCG vaccine. ClinicalTrials.gov Identifier: NCT04348370 was first posted on April 16, 2020, and was last updated on October 6, 2021, with a completion date of May 31, 2022. 

On January 13, 2022, frontiers in Immunology published a peer-reviewed study that concluded saying 'Our study expands the list of BCG peptides potentially involved in T cell cross-reactivity with SARS-CoV-2-derived peptides and identifies multiple high-density "neighborhoods" of cross-reactive peptides which could be driving heterologous immunity induced by BCG vaccination, therefore providing insights for future vaccine development efforts.'

BCG Vaccine and Diabetes

Massachusetts General Hospital, in partnership with NYU Langone Health, launched a multi-center phase 2 clinical trial, "Repeat BCG Vaccinations for The Treatment of Pediatric Type 1 Diabetes," which will enroll 150 patients aged 12 to 17 in a placebo-controlled study of two injections of BCG spaced four weeks apart. On June 25, 2021, researchers from MGH presented positive updates on their trials of the BCG vaccine to safely and significantly lower blood sugars. Key findings include a new understanding of how the response to BCG vaccination differs depending on a patient's age of onset and additional support for the role of BCG vaccination in altering glucose transport and changing Tregs.

On February 27, 2020, the Journal of Internal Medicine published a study that concluded 'New findings of immune and metabolic defects in type 1 diabetes that can be corrected with repeat BCG vaccination suggest that this therapeutic strategy may be applicable in other diseases with inadequate aerobic glycolysis, including Parkinson's disease, dementia, depression and other disorders affecting the nervous system.'

On May 22, 2020Science Direct published: BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes. This is the first documentation of BCG induction of Myc and its association with systemic blood sugar control in a chronic disease like diabetes.

On June 21, 2018, the journal Nature published 'Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations.' This report is on a randomized 8-year-long prospective examination of type 1 diabetic subjects with the long-term disease who received two doses of the BCG vaccine. After year 3, BCG lowered hemoglobin A1c to near-normal levels for the next five years. These findings set the stage for further testing a known safe vaccine therapy for improved blood sugar control through changes in metabolism and durability with epigenetic changes even in advanced Type 1 diabetes.

BCG Vaccine and Eczema

A study published in the journal Allergy showed that the BCG vaccine had a modest beneficial effect in preventing eczema in high-risk infants. The benefit was greater in infants with two atopic parents, meaning those who have hay fever, asthma, or eczema. In these infants, a single dose of BCG soon after birth reduced the incidence of eczema by 25%. However, the authors noted insufficient evidence to recommend neonatal BCG vaccination for all infants to prevent eczema in the first year of life.

BCG Vaccine and HIV

Co-infection with Mtb and HIV is a lethal combination, says the WHO. In sub-Saharan Africa, where HIV is most prevalent, the annual incidence of T.B. has risen to more than 300 cases per 100 000 inhabitants. In some of these places, nearly 50% of the HIV-infected population is co-infected with T.B., and more than two-thirds of T.B. patients are infected with HIV. The lifetime risk of developing T.B. disease is as high as 30-50% for HIV-infected persons. In some parts of southeast Asia, an estimated 20-25% of T.B. cases will be directly attributable to HIV.

On June 27, 2022, The Lancet Infectious Disease published the results from a phase 2 study on HIV-infected children in South Africa. The researchers' Interpretation: The VPM1002 vaccine candidate was less reactogenic than BCG and was not associated with any serious safety concerns. Both vaccines were immunogenic, although responses were higher with the BCG vaccine.

In October 2020, the journal Nature published a BCG vaccine review that stated 'the (i) potential T.B. vaccine candidates that can be exploited for use as a dual vaccine against TB/HIV copandemic (ii) progress made in the realm of TB/HIV dual vaccine candidates in a small animal model, NHP model, and human clinical trials (iii) the failures and promising targets for a successful vaccine strategy while delineating the correlates of vaccine-induced protection.'

On November 17, 2021, The Lancet published a study: Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis. Interpretation - C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, the WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications.

BCG Vaccine and Multiple Sclerosis

The European Journal of Neurology published an Original Article on February 15, 2022 - Bacillus Calmette-Guerin vaccination and multiple sclerosis: a population-based birth cohort study in Quebec, Canada, focusing on relapsing-remitting M.S. (RRMS). The study's findings suggest that BCG vaccination does not decrease the risk of RRMS and that future studies should consider phenotypes of M.S.

A 2017 review published in the journal of frontiers in Neurology - Conflicting Role of Mycobacterium Species in Multiple Sclerosis - found BCG vaccination may be an effective therapy for slowing the progression of M.S. The researchers also noted that other studies suggest that the BCG vaccination may help with preventing M.S. in people at risk. A study published in 2021 found BCG vaccination may restore normal Notch signaling, which is disrupted in M.S., possibly due to infection by Epstein-Barr virus causing auto-immunity.

BCG Vaccine and Pregnancy

The BCG vaccination should not be given during pregnancy. No harmful effects of BCG vaccination on the fetus have been observed, and further studies are needed to prove its safety.

BCG Vaccine and Yellow Fever

The study demonstrated the effects of BCG vaccination on genome-wide histone modifications induced in trained monocytes, which are associated with reduced levels of yellow fever virus viremia due to increased IL-1β production and release. These cross-protection effects of BCG against YFV infection confirm the nonspecific effects of the BCG vaccine.

BCG Vaccine Dosage

The WHO Expert Committee first considered forming international requirements to manufacture and control the BCG vaccine on Biological Standardization in its thirteenth report. Approved dose: BCG vaccine can be given either cutaneously or intradermally. Research is currently being conducted on respiratory administration since humans' natural infection and sensitization to Mycobacterium tuberculosis occur in the respiratory system. The timing and dose of BCG vaccination assessed by vaccination tuberculin sensitivity (1995); US FDA; Medline.gov; U.K. - 2020; WHO. The intact vials of BCG VACCINE should be stored refrigerated at 2–8°C (36–46°F). This agent contains live bacteria and should be protected from direct exposure.

BCG Vaccine Side Effects

Tell your health care provider promptly about any unusual or severe symptoms after receiving this vaccine or directly to the Vaccine Adverse Event Reporting System - www.vaers.hhs.gov.

BCG Vaccine News For 1994 - 2022

August 9, 2022 - A new study led by a BU School of Public Health researcher suggests BCG vaccine protection may begin to wane as children get older and, thus, adults should receive a booster BCG vaccine.

August 5, 2022 - The immune-boosting benefits of a tuberculosis vaccine can be seen in infants more than one year after vaccination, according to results from 130 children in a new study.

July 9, 2022 - Dr. Subhash Babu, scientific director at India's NIH-International Centers for Excellence in Research stated in an article, “We have found in our study that in the elderly, BCG somehow reduces the exaggerated immune response that leads to adverse Covid outcomes.”

June 24, 2022 - The BCG vaccine market is expanding due to an increase in the number of TB cases worldwide, rapid advancements in technology in the field of medical research on vaccines, and favorable government policies with increased funding. And the prevalence of bladder cancer is resulting in an increase in demand for the BCG vaccine. According to the CDC, around 12,000 men and 5,000 women die from bladder cancer annually.

May 28, 2022 - FrontPage Africa discovered that the BCG vaccine inventory, which is compulsorily given together with the Oral Polio Vaccine, has been depleted in Liberia.

May 26, 2022 - GAVI wrote: Pakistan's National T.B. Control Programme, run with the support of The Global Fund and others, has made significant strides in establishing a strong care and surveillance network to treat T.B. patients.

May 23, 2022 - ImmunityBio, Inc. stated if approved by the U.S. FDA, N-803 plus BCG would be the first new immunotherapy for this indication in 23 years that can be delivered directly to the bladder (intravesically) to induce natural killer cells and T cells, providing a new treatment option for patients with this form of bladder cancer.

May 22, 2022 - The results from a phase 4 clinical study in Brazil published by a peer-review journal concluded that 'The BCG vaccine offers cross-protection against COVID-19 with potential humoral response modulation. Limitations: No severely ill patients were included in this study.

May 6, 2022 - The U.K. announced changes to the NHS neonatal BCG immunization program. The BCG vaccine is not given as part of the routine vaccination schedule but only when a child is at increased risk of coming into contact with T.B.

May 3, 2022 - The T.B. Alliance applauds the new guidelines for treating drug-resistant tuberculosis released by the WHO.

April 14, 2022 - According to Rutgers University researchers, a study found two strains of the bacterium causing tuberculosis have only minor genetic differences but attack the lungs in a completely different fashion.

April 7, 2022 - The joint IAVI-Moderna programs for T.B. vaccine collaboration will advance research on a set of promising antigens that the partners hope will bring much-needed diversity to the global preclinical T.B. vaccine pipeline.

March 16, 2022 - According to a recent study, the BCG vaccine does not decrease a person's risk of developing multiple sclerosis. Statistical analyses broadly showed no links, across several time points, between BCG vaccination and the risk of relapsing-remitting M.S. Also, age at vaccination had no apparent effect on M.S. risk.

March 10, 2022 - The NEJM published an ORIGINAL ARTICLE: Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. CONCLUSIONS - Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis in the SHINE Study.

March 1, 2022 - Massachusetts General Hospital, in partnership with NYU Langone Health, launched a phase 2 clinical trial to investigate a BCG vaccination treatment for pediatric type 1 diabetes even in subjects with established disease.

January 20, 2022 - The T.B. Alliance announced that it has received funding up to $30 million over 5 years from the United States Agency for International Development to jumpstart the search for new tuberculosis treatments and optimize current treatments.

January 10, 2022 - A study in the Proceedings of the National Academy of Sciences, crystallizes decades of evidence suggesting that the generalized immune-boosting properties of many vaccines can cross-protect patients against multiple pathogens.

December 10, 2021 - The Lancet published a study by eBioMedicine: CD4+CCR6+ T cells that dominate the BCG-induced transcriptional signature. Interpretation: This detailed characterization of BCG-induced immune responses and TCR clonotypes improves our understanding of the immune response triggered by BCG, and provides evidence for an important role for CCR6+ CD4 T cells.

September 28, 2021 - The Stop T.B. Partnership today released new data showing how the COVID-19 pandemic and low levels of funding represent the main barriers to achieving the United Nations Sustainable Development Goals of ending T.B. by 2030.

September 27, 2021 - The journal Vaccine published: Recombinant BCGs for tuberculosis and bladder cancer. This review discusses the development of second-generation, genetically modified BCG candidates as T.B. vaccines and as anti-tumor adjuvant therapy for NMIBC.

September 23, 2021 - The Lancet Infections Disease published a new study. Interpretation: As countries refine national tuberculosis programs and strategies to end the tuberculosis epidemic, the excess burden experienced by males is important. Interventions are needed to actively communicate, especially to men, the importance of early diagnosis and treatment.

September 22, 2021 - BMC Gene Biology published 'The influence of the gut microbiome on BCG-induced trained immunity. Variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which in turn affect or produce metabolites in circulation. Roseburia is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.'

August 24, 2021 - The Murdoch Children's Research Institute reported initial study findings published in the journal Allergy, which showed that the BCG vaccine had a modest beneficial effect in preventing eczema in high-risk infants.

August 5, 2021 - The Weather Channel published an article that stated: A team of researchers from the CMR-National Institute for Research in Tuberculosis and the ICMR-National Institute of Epidemiology, both based in India, has found that the BCG vaccine used to reduce the threat of tuberculosis may provide older people with some protection against COVID-19. Analysis of the samples revealed a significant decrease in several cytokines (small proteins that control immune system cell activity) among these vaccinated individuals like IL-6, type 1 interferons, interleukin-2 (IL-2), and TNF-alpha GM-CSF.

August 4, 2021 - A new study published by Science Advances stated, 'Our results demonstrated that BCG vaccination resulted in diminished plasma levels of types 1, 2, and 17 and other proinflammatory cytokines and type 1 interferon. BCG vaccination also decreased plasma levels of CC, CXC chemokines, APPs, MMPs, and growth factors. Furthermore, plasma levels of the aforementioned parameters were significantly lower in vaccinated individuals when compared to unvaccinated control individuals.

July 5, 2021 - The Lancet published: Assessing the effect of BCG revaccination on long-term mortality. Increasing evidence accumulated since the mass vaccination programs of the 20th century suggests that some vaccines, especially those derived from live attenuated microorganisms, also have important beneficial heterologous effects outside the target disease. Probably the vaccine that has been most studied concerning its protective heterologous effects is BCG.

July 5, 2021 - The Lancet published: The effect of BCG revaccination on all-cause mortality beyond infancy: 30-year follow-up of a population-based, double-blind, randomized placebo-controlled trial in Malawi. We found little evidence of any beneficial effect of BCG revaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, might obscure any benefits.

June 9, 2021 - An Australian-led BRACE trial is now the world's largest study on the off-target effects of the BCG vaccine. Since the trial launched in March 2020, more than 6,800 healthcare workers have enrolled across 36 sites in Australia, Brazil, the Netherlands, Spain, and the U.K.

May 7, 2021 - The WHO convenes a Guideline Development Group to advise on updates to its recommendations on managing tuberculosis in children and adolescents.

April 12, 2021 - The American Journal of Preventive Medicine published a new study: Childhood Bacillus Calmette–Guérin Vaccination and Its Association With Less Severe COVID-19 Pneumonia. Conclusions: BCG vaccination received in childhood is associated with less severe COVID-19 pneumonia (p=0.028) and milder liver function deficiency, in addition to a lower death rate in BCG-vaccinated patients versus non-vaccinated individuals. Overall, the death rate was significantly lower in the BCG-vaccinated group (4.2%, 5/118) than in the unvaccinated group (19.0%, 55/290. Another unexpected finding is less liver dysfunction in COVID-19 patients with BCG immunization history, which is likely associated with metabolic reprogramming that alters certain metabolites that can function as cofactors in some liver enzymes. However, definitive proof of the BCG vaccine's benefit must validate this broad approach, which remains lacking.

April 7, 2021 - The WHO stated, 'Those in the highest economic quintile are five times more likely to deliver their babies in health facilities and have their babies vaccinated with BCG than those in the lowest quintile.'

March 23, 2021 - Study: BCG Vaccine-Induced Trained Immunity and COVID-19: Protective or Bystander? This review focuses on BCG-related cross-protection and acquisition of trained immunity, as well as the correlation between BCG vaccination and COVID-19 incidence and mortality.

February 23, 2021 - The Lancet article: Quantifying the global number of tuberculosis survivors: a modeling study. The number of tuberculosis survivors alive in 2020 is more than ten times the estimated annual tuberculosis incidence. Therefore, interventions to alleviate respiratory morbidity, screen for and prevent recurrent tuberculosis, and reduce stigma should be immediately prioritized for recently treated tuberculosis survivors.

February 17, 2021 - The Lancet published a new 'BCG-induced nonspecific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomized controlled trial.' This study investigated whether BCG altered all-cause infectious disease morbidity in healthy infants in a different high-mortality setting (west Africa) and explored whether the changes are mediated via trained innate immunity. Study Interpretation: BCG vaccination protects against non-tuberculous infectious diseases during the neonatal period, in addition to having tuberculosis-specific effects. Prioritizing BCG on the first day of life in high-mortality settings might significantly benefit public health by reducing all-cause infectious morbidity and mortality.

February 17, 2021 - In The Lancet Infectious Diseases, Sarah Prentice and colleagues report that BCG's tuberculosis vaccine protects against non-tuberculous infectious diseases. Trials on infants with low birthweight in West Africa suggest that BCG vaccination reduces all-cause mortality in the neonatal period, probably because of heterologous protection against non-tuberculous infections. This study investigated whether BCG altered all-cause infectious disease morbidity in healthy infants in a different high-mortality setting and explored whether the changes are mediated via trained innate immunity.

January 19, 2021 - According to Dr. Camille Locht, research director of Inserm at the Institut Pasteur de Lille, stated, "The BCG can train the cells of the innate immune system to make them more fit and active to fight against other diseases. This is why we think that training the immune system with BCG will have a protective effect against organisms that have nothing to do with tuberculosis or BCG."

December 9, 2020 - Based on the capacity of BCG to (1) reduce the incidence of respiratory tract infections in children and adults; (2) exert antiviral effects in experimental models; and (3) reduce viremia in an experimental human model of viral infection, we hypothesize that BCG vaccination may induce (partial) protection against the susceptibility to and/or severity of SARS-CoV-2 infection.

December 9, 2020 - Study: These data show BCG vaccination is safe and can protect the elderly against infections.

December 4, 2020 - Study: Unlike many adjuvants, BCG decreases the incidence of lymphoid malignancies, and its effect on various autoimmunopathies is different, not necessarily harmful. The peculiar BCG vaccination effect may be related to its early impact on immature immune systems and host-BCG interactions' symbiotic character. Geo-epidemiological data on the relationship between the historical practice of using BCG vaccination in different countries and the current incidence of new coronavirus infection and mortality are presented. Historically, the medical and social reasons for the different national policies of health authorities regarding using the BCG vaccine are considered.'

November 20, 2020 - A widely used tuberculosis vaccine is associated with a reduced likelihood of contracting COVID-19 (coronavirus). The findings raise the possibility that a vaccine already approved by the U.S. Food and Drug Administration may help prevent coronavirus infections or reduce the disease's severity. The vaccine, known as Bacillus Calmette-Guérin (BCG), was developed between1908 and 1921 and is administered to more than 100 million children worldwide every year. It is FDA-approved as a drug to treat bladder cancer and as a vaccine for people at high risk of contracting T.B. The BCG vaccine is currently being tested in multiple clinical trials worldwide for effectiveness against COVID-19.

November 19, 2020 -  The Journal of Clinical Investigation published a Cedars-Sinai Health System study for evidence of antibodies to SARS-CoV-2 and found that workers who had received BCG vaccinations in the past—nearly 30% of those studied—were significantly less likely to test positive for SARS-CoV-2 antibodies in their blood or to report having had infections with coronavirus or coronavirus-associated symptoms over the prior 6-months than those who had not received the BCG vaccine. "It appears that BCG-vaccinated individuals either may have been less sick and therefore produced fewer anti-SARS-CoV-2 antibodies, or they may have mounted a more efficient cellular immune response against the virus," said Arditi, professor of Pediatrics and Biomedical Sciences. "We were interested in studying the BCG vaccine because it has long been known to have a general protective effect against a range of bacterial and viral diseases other than T.B., including neonatal sepsis and respiratory infections."

November 17, 2020 - A new study published by The Lancet found 'Patients with high-risk non–muscle-invasive tumors that do not respond to adjuvant therapy with the standard-of-care immunotherapy, Bacille Calmette-Guérin (BCG), constitute a challenging patient population to manage and many alternative therapies are being studied. While intravesical BCG has remained the mainstay of therapy for intermediate and high-risk non–muscle-invasive bladder cancer, the therapeutic options for the muscle-invasive and advanced disease have expanded to include immunotherapy with checkpoint inhibition, targeted therapies, and antibody-drug conjugates.'

November 5, 2020 - Researchers of a trial by Parel's Haffkine Research Institute and B.J. Medical College, Pune, conducted on 60 Covid patients hospitalized with breathlessness and pneumonia claimed to have found a reduction in oxygen requirement from the third or fourth day and improved x-rays and C.T. scan from day 7-15. No deaths in the arm got the BCG shot, while two deaths in a group got a standard line of care.

October 11, 2020 - The University of Exeter is leading the U.K. arm of the trial, called the BCG vaccination to Reduce the impact of COVID-19 in healthcare workers' (BRACE) Trial. The U.K. joins study centers in Australia, the Netherlands, Spain, South Africa, and Brazil in the largest trial. "BCG has been shown to boost immunity in a generalized way, which may offer some protection against COVID-19," stated Professor John Campbell of the University of Exeter Medical School. 

October 3, 2020 - Texas A&M researchers are looking into a potential vaccine that may help COVID-19. In addition to the medical professionals who participated in the BCG vaccine study, more first responders such as firefighters and police officers can now see if they are eligible for the study.

September 24, 2020 - The BCG vaccine may be a potential, safe, affordable, and readily available candidate intervention to decrease the high burden of disease associated with HSV infection and recurrences, but properly controlled randomized trials are required. BCG administration led to a 1.9 to 5.5‐fold increase in survival rate following the HSV challenge (vaginal, corneal, or intraperitoneal inoculation).

September 24, 2020 - Fiocruz and the Murdoch Children's Research Institute in Australia announced they would begin testing the BCG vaccine on 3,000 healthcare professionals to verify the immunizer's protection against Covid-19. The trial, which was initially expected to be carried out only in Mato Grosso do Sul, will be expanded to Rio de Janeiro. Coordinated in Brazil by Fiocruz researchers Julio Croda and Margareth Dalcolmo, the National Committee approved Ethics in Research.

August 31, 2021 - A study published by Cell: Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Data show that BCG vaccination is safe and can protect the elderly against infections.

August 19, 2020 - In this issue of the JCI, Koeken and de Bree et al. report that BCG reduces circulating inflammatory markers in males but not in females, while de Bree and Mouritis et al. describe how diurnal rhythms affect the degree of BCG-induced innate memory. These studies further delineate factors that influence the magnitude of responses to BCG and may be crucial to harnessing its potential benefits.

August 17, 2020 - "It has been known for years that some vaccines can offer protection against diseases that they're not targeting. The best example is the BCG vaccine used to prevent tuberculosis. In addition, it can prevent people from acquiring malaria," said Andrew Bradley, the Mayo Clinic COVID Research Task Force Chair.

August 5, 2020 - A new analysis suggests that mandated BCG vaccination can effectively fight against COVID-19.

July 28, 2020 - This epidemiological study assessed the global linkage between BCG vaccination and COVID-19 mortality. In various European countries, BCG vaccination indicated that every 10% increase in the BCG index was associated with a 10.4% reduction in COVID-19 mortality. However, these results fail to confirm the null hypothesis of no association between BCG vaccination and COVID-19 mortality and suggest that BCG could have a protective effect. 

July 14, 2020 - Based on the ACTIVATE study's interim analysis, findings show a 53% decrease in the incidence of all new infections with BCG vaccination.

July 9, 2020 - Researchers at the National Institute of Allergy and Infectious Diseases identified an 'associated' linkage between BCG vaccination and the reduction in COVID-19 disease

July 3, 2020 - Researchers at the University of Sydney and Centenary Institute are repurposing a BCG vaccine, with major components SARS-CoV-2 virus, creating a new vaccine candidate called BCG: CoVac.

May 26, 2020 - The NIH published a Bacillus Calmette Guerin (BCG) summary by Chika N. Okafor, Ayesan Rewane; Ifeanyi I. Momodu.

April 6, 2020 - Researchers at the Johns Hopkins Bloomberg College of Public Well discovered that COVID-19 mortality amongst countries offering BCG vaccination was eight instances lower.

May 2, 2019 - The discovery of innate immune memory has greatly improved our understanding of the mechanisms underlying the nonspecific effects induced by BCG vaccination. 

December 29, 2018:  In T1D, BCG vaccination restored blood sugars to near normal, even in patients with advanced disease of >20 years duration. This clinically important effect may be driven by the immune system's resetting and shifting glucose metabolism from overactive oxidative phosphorylation, a state of minimal sugar utilization, aerobic glycolysis, and high glucose utilization for energy production.

September 1995 This CDC updated previous recommendations regarding the use of the BCG vaccine for controlling T.B. in the United States (MMWR 1988;37:663-4, 669-75). 

1995 - The generation of nitric oxide and interferon-gamma clearance after BCG infection is impaired in mice lacking the interferon-gamma receptor.

1994 - Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-analysis of the Published Literature.

BCG Vaccine Clinical Trials

BCG is currently involved in active clinical trials covering various conditions. Click here to review the various ongoing clinical trials. 

An India-based clinical trial CTRI/2020/06/025854 [Registered on: 13/06/2020] - Study to Evaluate the Effectiveness of BCG vaccine in Reducing Morbidity and Mortality in Elderly individuals in COVID-19 Hotspots in India - Department of Clinical Research ICMR-National Institute for Research in Tuberculosis No.1, Satyamoorthy Road Chetput, Chennai. According to Babu in July 2022, multiple studies by his department — some of them published — have established a definite role of BCG in calming the dreaded cytokine storm that has often been the reason for Covid deaths.

On December 3, 2020, Review Article was published in the New England Journal of Medicine stated that: 'cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.'

April 28, 2020 - Dr. Jeffrey Cirillo at the Texas A&M Health Science Center leads a group of institutions in a vaccine clinical trial to prevent COVID-19 disease cases in just six months. This phase 4 vaccine study will include 1,800 participants and researchers from Harvard's School of Public Health, the University of Texas MD Anderson Cancer Center in Houston, Cedars Sinai Medical Center in Los Angeles, and the Baylor College Medicine in Houston. On December 11, 2020JCI published Rivas et al. add to these arguments by showing that BCG-vaccinated healthcare providers from a Los Angeles healthcare organization had less COVID-19 diagnosis and serology than unvaccinated individuals. Prospective clinical trials are thus warranted to explore BCG effects in COVID-19. We posit that beyond COVID-19, vaccines that elicit trained immunity, such as the BCG, may mitigate the impact of emerging pathogens in future pandemics. Almost one-third of the volunteers participating in the study had received earlier BCG vaccination, accompanied by a marked decrease (by approximately 30-40%) of self-reported COVID-19 diagnoses, self-reported positive COVID19 RT-PCR tests, and anti-SARS-CoV-2 specific serology. BCG vaccinations were associated with lower COVID-19 incidence, although the vaccinated group was slightly older and had more co-morbidities.

Clinical Trials