BCG Vaccine Description
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 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.
BCG-induced whole blood cytokines differ 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 BCG vaccine was initially targeted against TB, tuberculosis meningitis, and nonspecific protective effects against other respiratory tract infections.
As of January 2023, the biological interaction between Mtb and the human host is complex and only partially understood, says the World Health Organization (WHO). The WHO adopted requirements for the BCG vaccine in 1965, and these were updated in 1978 to reflect the increased knowledge of vaccinations and the change to freeze-dried preparations. These were modified in 1985 to amend requirements concerning the expiry date. In its thirteenth report, the WHO Expert Committee on Biological Standardization considered the formulation of international requirements for the manufacture and control of the BCG vaccine. On September 30, 2022, the WHO published consolidated guidelines on TB: module #3.
On January 17, 2022, the WHO director Dr. Tedros Adhanom Ghebreyesus, led the 'Ending Tuberculosis: How Do We Get There' discussion and announced plans to establish a new TB Vaccine Accelerator Council that will facilitate the licensing and use of effective novel TB vaccines. The WHO published, on December 8, 2022, an investment case for new tuberculosis vaccines.
The U.S. National Institutes of Health (NIH) says the BCG vaccine is safe and not associated with severe complications. However, 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. And on August 15, 2022, research findings published by the Cell Reports Medicine journal suggested BCG platform protection against infectious diseases and vaccine efficacy takes 1-2 years to manifest, but the protection may last decades.
The Rockefeller Foundation announced on September 20, 2022, it would commit US$15 million to the Global Fund to Fight AIDS, TB, and malaria.
As of January 29, 2023, the BCG vaccine is U.S. Food and Drug Administration (FDA)-approved and available in countries such as the U.S., Canada, China, Cuba, Ethiopia, Jamacia, Japan, Germany, UK, Mexico, Europe, Brazil, Korea, Russia, Spain, South Africa, Quebec, India (1948), New Zealand, Australia, Venezuela, and Nigeria. However, the U.S. Centers for Disease Control and Prevention (CDC) says the BCG vaccine is not generally recommended for use in the U.S. because of the minimal risk of infection with Mycobacterium tuberculosis.
The BCG Atlas is an open-source database of global BCG vaccination policies and practices founded in 2011.
BCG Vaccine Versions
As of January 28, 2023, there are various BCG vaccines and candidates under development. There are about 14 sub-strains of BCG that have evolved. 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, and BCG-Bulgaria. The B.D. Commercial Middlebrook 7H11 medium was rated well.
Since August 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. And the Serum Institute of India recombinant BCG (rBCG) vaccine TUBERVAC-rBCG is approved in India to prevent TB in adults and younger people.
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.
Verity Pharmaceuticals Inc. announced on September 9, 2021, that it received approval to begin distributing VERITY-BCG™ (Bacillus Calmette-Guérin [BCG]: Strain Russian BCG-I).
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. Drugbanks Accession Number is DB12768; UNII: 8VJE55B0VG, 5H5854UBMZ; ATC code: J07AN01; KEGG: D03063, D06466 CMS billing code: J9030 BCG LIVE INTRAVESICAL INSTILLATION, 1 MG.
BCG Vaccine Price
The UNICEF data shows the awarded price of BCG vaccine per dose is nominal. The U.S. CDC Vaccine Price List was last updated in December 2022. Many U.S. pharmacies price BCG vaccines over $100.00 for one vial. The global TB Vaccine revenue is expected to increase by over 3% per year to 2027, based on various Reports. Additional BCG vaccine prices and discount information are posted at InstantRx™.
The BCG vaccine is used in many countries (U.K.) to prevent TB, TB meningitis, to treat bladder cancer, and other diseases. The U.K. Health Security Agency also says BCG vaccine-related TB morbidity and mortality reductions are as high as 70%. 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.
In the UK and various countries, BCG vaccination is administered to newborn infants at risk of TB. The WHO suggests BCG programs for different age groups are equally effective against TB during puberty. BCG vaccines have been found effective in protecting children against the more rare severe forms of TB, such as TB meningitis. The Lancet Global Health published a study in September 2022, that found BCG vaccination at birth does provide significant protection against TB disease among children under 5 years old.
Public Health England (PHE) announced on July 27, 2021, that eligible babies 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. On September 15, 2021, the U.K.'s PHE updated its fact sheet.
The WHO 2022 Report recommends routine neonatal BCG vaccination in countries with moderate to severe tuberculosis prevalence. The WHO says BCG vaccination should continue for all infants soon after birth except for those with HIV living in high tuberculosis prevalence settings.
Furthermore, recent research suggests that BCG vaccination has nonspecific benefits against non-TB 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, and Cancer Immunology on June 24, 2022. Epidemiologist Christine Stabell Benn and colleagues found (Mar. 2012) that BCG administered to children with low birth weight reduced all-cause mortality in these children by about 40% in the first year of life.
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. 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. The Stop TB Partnership and Treatment Action Group review published on December 6, 2022, found the annual funding for TB research reached $1 billion for the first time in 2021.
The Lancet published an early-release study on August 10, 2022 - Infant BCG vaccination and risk of pulmonary and extrapulmonary TB 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.
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 TB. The Do More by 2024 initiative in Georgia has reduced the incidence of both TB and drug-resistant TB by 50% since 2015.
BCG 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 (A.D.) 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 of developing A.D. However, the authors note that more extensive studies involving more patients are needed to corroborate their findings.
BCG Bladder Cancer
BCG is the most common intravesical immunotherapy for treating early-stage bladder cancer 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.
On September 20, 2022, Ludwig Enterprises announced that it had started discussions regarding the initiation of a clinical study to evaluate the response of bladder cancer patients to BCG immunotherapy.
ImmunityBio, Inc. announced on July 28, 2022, 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.
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.'
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.
Massachusetts General Hospital (MGH) published results from a study led by Denise Faustman in the peer-review journal Cell Reports on August 15, 2022, that found people with type 1 diabetes vaccinated with 3-doses of BCG displayed fewer infectious disease symptoms and lesser severity and fewer infectious disease events per patient. On June 25, 2021, researchers from MGH presented positive updates on their trials of the BCG vaccine to safely and significantly lower blood sugars, which showed the effect takes years to manifest.
On May 2022, the National Institute of Scientific Research in Quebec researchers found that early-life BCG vaccination did not reduce the risk of diabetes in adolescence, but by the time those children were adults older than age 30, their risk of type 1 diabetes was 35% lower.
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, 2020, Science 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. 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.
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. The Murdoch Children's Research Institute's initial study findings were published in the journal Allergy on August 24, 2021, which showed that the BCG vaccine had a modest beneficial effect in preventing eczema in high-risk infants. But a single dose of BCG-Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents.
Coinfection with Mtb and HIV is a lethal combination, says the WHO. In sub-Saharan Africa, where HIV is most prevalent, the annual incidence of TB has risen to more than 300 cases per 100,000 inhabitants. In some of these places, nearly 50% of the HIV-infected population is coinfected with TB, and more than two-thirds of TB patients are infected with HIV. The lifetime risk of developing TB disease is as high as 30-50% for HIV-infected persons. In some parts of southeast Asia, an estimated 20-25% of TB cases will be directly attributable to HIV, confirms the WHO.
For neonates born to mothers with an unknown HIV status and neonates with an unknown HIV status born to HIV-infected mothers (regardless of their ART status), the WHO recommends BCG vaccination, as the benefits outweigh the risks. For a neonate confirmed by virologic testing to be positive for HIV, it is recommended that BCG vaccination be delayed until ART has been started.
Experts at Fred Hutchinson Cancer Center suggested in a study published in The Lancet HIV on October 11, 2022, future TB vaccine development clinical trials should ensure people living with HIV have access to safe and effective TB vaccines.
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 TB 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.'
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 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.
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 Side Effects
Tell your healthcare 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 - 2023
January 9, 2023 - ImmunityBio is studying N-803 plus TICE® BCG vaccine in adults with non-muscle invasive bladder cancer (NMIBC) CIS with or without Ta/T1 papillary disease in a phase 2/3 clinical trial. On November 10, 2022, the NEJM Evidence published results from ImmunityBio's QUILT 3.032 trial. N-803 has been studied in more than 700 patients in multiple clinical trials in liquid and solid tumors. The FDA is currently reviewing the Biologics License Application for N-803 plus BCG for the treatment of NMIBC CIS with a Prescription Drug User Fee Act date of May 23, 2023.
November 3, 2022 - The peer-review journal Nature published a study that demonstrates inflammation and immune activation are associated with the risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb, and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN-αα2, TNF-αα, CXCL10 (IP-10), and complement C2 are also higher in infants that were subsequently infected with M.tb.
October 23, 2022 - BMC Public Health published a retrospective review of vaccine wastage and associated risk factors that found BCG was the vaccine most wasted (32.19%).
September 1, 2022 - The Lancet Global Health published a study that found that BCG vaccination at birth does provide significant protection against TB disease. And Immunoprotection needs to be boosted in older populations.
August 22, 2022 - A modified TB vaccine (BCG) developed at Texas Biomed could help treat non-muscle invasive bladder cancer without strong side effects. Results in mouse models and human cells show promising results (June 2022) and pave the way for human clinical trials.
August 15, 2022 - Researchers at Massachusetts General Hospital published a new paper in Cell Reports Medicine demonstrating the protective potential of multiple doses of the BCG vaccine against infectious diseases.
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 age 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.
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.
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 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 22, 2021 - BMC Gene Biology published 'The influence of the gut microbiome on BCG-induced trained immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.'
February 17, 2021 - In The Lancet Infectious Diseases, Sarah Prentice and colleagues report that BCG's tuberculosis vaccine protects against non-tuberculous infectious diseases.
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."
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.
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. study describe how diurnal rhythms affect the degree of BCG-induced innate memory.
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.
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 U.S.
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.
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, 2020, JCI 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.