BCG Vaccine (Tuberculosis)
Tuberculosis or TB (short for tubercle bacillus) is a common, and in many cases a lethal, infection caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough or sneeze. Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected.
The classic symptoms of active TB infection are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss (the latter giving rise to the formerly prevalent term "consumption"). Infection of other organs causes a wide range of symptoms. Diagnosis of active TB relies on radiology (commonly chest X-rays), as well as microscopic examination and microbiological culture of body fluids.
BCG Vaccine The only current vaccine available against tuberculosis (TB), Bacille Calmette-Guérin (BCG), created in 1921. According to the WHO, the vaccine has “variable protective efficacy.” Even thought BCG is unreliable in protecting against pulmonary TB, which accounts for most of the disease burden worldwide, this vaccine is given at birth to infants in most countries 'around the world. WHO recommends vaccinating infants with BCG as it provides protection against severe extra-pulmonary (non-lung) forms of pediatric TB, a rare and unusual form of the infection. "Further work is needed on the cost-benefit ratio of BCG as opposed to that of other approaches to control. One argument favoring the discontinuation of BCG is based on the advantages of testing pregnant women."
CDC Publications TB tests (pdf) - "Mantoux Tuberculin Skin Test. TST is administered by injection. Tuberculin is made from proteins derived from inactive tubercle bacilli •Most people who have TB infection will have a reaction at the injection site. Syringe being filled with 0.1 ml of liquid tuberculin are injected between the layers of skin on the forearm.
September 30, 2019 – Clinical trials with GMO-containing vaccines in Europe: Status and regulatory framework “The possibility to genetically modify micro-organisms to bring immunogenic material (antigens/epitopes) to the human (or animal) immune system to provoke an immune response, provides new hope to producing prophylactic vaccines against HIV, malaria and tuberculosis and emerging diseases. Regulatory requirements associated with the development of genetically-modified organism (GMO)-containing vaccines in Europe add an additional burden to the clinical trial application procedure and to the preparation and initiation of a clinical trial of such vaccines.”
April 11, 2017 - Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomized clinical trial (full text) "In conclusion, 'we did not find an overall effect of BCG vaccination on antibody levels after pentavalent vaccines given 'during the first year of life. Age at BCG vaccination may be a modifying factor, as BCG vaccination 2 to 7 days after birth might have an enhancing effect on antibody responses. This would be important to assess in future studies of possible non-specific effects of BCG on antibody responses. This study adds to a growing number of studies showing that 'girls mount higher antibody responses than boys.
March 14, 2017 - Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two-phase I dose escalation trials (full text) "Four SAEs were reported: mental status changes (50/0 one dose regimen); mesenteric lymphadenitis (50/500 two-dose regimen); ileus (50/500 two-dose regimen); and subdural hemorrhage (placebo).
October 13, 2016 - Association of BCG, DTP, and measles-containing vaccines with childhood mortality: systematic review "Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all-cause mortality on average from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys."
August 17, 2016 - Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial "This study did not find a non-specific public health benefit of BCG on parent-reported infections. BCG may have reduced the incidence of infections in children of BCG-vaccinated mothers during the first 3 mo."
May 11, 2016 - Adverse reactions to the Bacillus Calmette–Guérin (BCG) vaccine in new-born infants—an evaluation of the Danish strain 1331 SSI in a randomized clinical trial (full text) "The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine."
March 18, 2016 – Adverse events following immunization in patients with primary immunodeficiencies “Evidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients.”
March 7, 2016 - Interferon-Gamma-Dependent Immunity in Bacillus Calmette- Guerin Vaccine Osteitis Survivors. "Background: Inborn errors of interferon-gamma (IFN-[gamma]) -mediated immunity underlie disseminated disease caused by Mycobacterium bovis (BCG) live vaccines."
August 14, 2015 -Investigation of Tuberculosis in a High School — San Antonio, Texas, 2012 "IGRA tests can provide additional evidence of infection to encourage acceptance and adherence of foreign-born patients who believe their positive TB test is attributable to 'Bacille Calmette-Guerin vaccination and might also prompt greater acceptance of treatment for latent TB infection compared with a positive TST alone."
October 7, 2014 - Investigations into an outbreak of suppurative lymphadenitis with BCG vaccine SSI in Singapore "We identified 283 cases of lymphadenitis, of which 76% were suppurative. A spike in suppurative lymphadenitis cases was seen in the 2011 vaccinated cohort, with an incidence rate of 3.16 per 1000 vaccines, as compared to 0.71 to 0.85 per 1000 in the 2009, 2010 and 2012 cohorts. Our investigations identified the likely cause of the outbreak to be batch-related, arising from manufacturing issues encountered by the manufacturer, after ruling out vaccine administration-related and host-related factors."
July 7, 2014 - Stool Microbiota and Vaccine Responses of Infants "Actinobacteria abundance was positively associated with T-cell responses to BCG, OPV, and TT; with the delayed-type hypersensitivity response; with immunoglobulin G responses; and with TI. B longum subspecies infantis correlated positively with TI and several vaccine responses. Bacterial diversity and abundance of Enterobacteriales, Pseudomonadales, and Clostridiales were associated with neutrophilia and lower vaccine responses."
July 2014 - Injection site abscess due to Mycobacterium tuberculosis following DPT vaccination. "Injection site abscesses are not so uncommon and usually bacterial in origin. Very occasionally, these are due to mycobacteria, particularly rapidly growing non-tuberculous mycobacteria."
December 13, 2013 - Protection by BCG against tuberculosis: a systematic review of randomized controlled trials "Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects."
October 18, 2013 - Costal BCG osteomyelitis developing 1 year after BCG vaccination "Reported here is the case of a 15-month-old boy with costal osteomyelitis due to the (BCG) vaccine against tuberculosis. Mild complications of this vaccine, such as localized abscess and regional lymphadenitis, are occasionally recognized, but its association with osteomyelitis is 'extremely rare."
September 30, 2013 - Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta-analysis"There were 1608 participants in the final MANCAS analysis. The 12-month prevalence of wheeze was 15.1%. There was no difference in prevalence between those who were and were not BCG vaccinated (15.8% vs 14.3%; relative risk, 1.05; 95% CI, 0.94-1.19). The updated meta-analysis incorporated 4 new studies: this showed that the protective effect of BCG vaccination against the development of asthma identified in our previous meta-analysis was attenuated (odds ratio, 0.95; 95% CI, 0.89-1.00). No protective effect of BCG was seen for sensitization, eczema/atopic dermatitis, rhinoconjunctivitis, or allergy in general."
August 19, 2013 - Mucosal Vaccination against TB Using Inert Bioparticles "Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract."
June 29, 2013 - Tuberculosis vaccine trials "Three of these four endpoints showed a similar trend (table). Endpoint 1 deviated in the other direction because the placebo group (see full study) had nearly twice as many microbiologically negative cases (19) as the vaccine group (ten). Comment: The placebo group received Candida skin test antigen (Candin, AllerMed, USA). Ingredients here: Candida albicans Skin Test Antigen should be administered intradermally according to the directions included under Dosage and Administration of this package insert. Candin is made from the culture filtrate and cells of two strains of Candida albicans. The fungi are propagated in a chemically defined medium consisting of inorganic salts, biotin and sucrose.
June 7, 2013 - Tuberculosis vaccines: time to reset the paradigm? "Progress will require appraisal of the gaps in our understanding of protective immunity and appropriate use and interpretation of the available animal models. Identifying correlates of protection by dissecting immune responses induced by existing partially effective vaccines may be a good place to focus renewed efforts."
May 21, 2013 - Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction "This study enlightens the possible benefits of adding vitamin C to an anti-tuberculosis regimen and suggests that the development of drugs that generate high oxidative burst could be of great use in tuberculosis treatment."
February 8, 2013 - A systematic review of safety data reporting in clinical trials of vaccines against malaria, tuberculosis, and human immunodeficiency virus "The review demonstrated lack of standardized safety data reporting in trials for vaccines against malaria, TB and HIV. Standardization of safety data collection and reporting should be encouraged to improve data quality and comparability."
February 6, 2013 - Ahead of WHO meeting, experts clash over tuberculosis targets "The tuberculosis drug Sirturo (bedaquiline) hit the US market in late December, and analysts expect another, delamanid, to gain regulatory approval in the EU this year. However, both are reserved for drug-resistant tuberculosis, which accounts for just 5% of new cases. And, optimistically speaking, the approval date for two leading tuberculosis vaccines now in mid-stage clinical trials is 2021 at the earliest, according to some in the field."
February 4, 2013 - Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial "In our double-blind, randomized, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4—6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as a placebo at a clinical facility in a rural region near Cape Town, South Africa"
February 4, 2013 - Lymph node targeting of BCG vaccines amplifies CD4 and CD8 T-cell responses and protection against Mycobacterium tuberculosis "Most importantly, intralymphatic vaccination with 2 × 103 CFU BCG induced sustained protection against M. tuberculosis in intratracheally challenged C57BL/6 mice, whereas subcutaneous vaccination with 2 × 105 CFU BCG conferred only a transient protection. Hence, direct administration of M. bovis BCG to lymph nodes demonstrates that efficient targeting to lymph nodes may help to overcome the efficacy problems of vaccination with BCG."
December 2012 - A rational vaccine pipeline for tuberculosis [State of the art series. New tools. Number 5 in the series] "A major challenge for TB vaccines is to establish a correlate of vaccine immunity which would greatly facilitate bridging studies needed to approve, license and distribute new TB vaccines in all areas endemic for TB. This will require TB vaccines that are both safe and effective in all populations. It cannot be accomplished without hard work as well as additional resources that match the ambitious goals of the TB community. "
July 2012 - Bacille Calmette-Guerin disease following Bacille Calmette-Guerin vaccination of an HIV-infected health-care worker "This case highlights the potential risks of BCG and clearly demonstrates the need to consider HIV testing in all patients prior to BCG vaccination."
June 7, 2012- Drug-resistant TB studies show burden in China, new antibiotic results "The authors wrote that the findings confirm that China has a serious drug-resistant TB problem, and that, based on World Health Organization (WHO) MDR-TB estimates, China has the highest annual number of MDR-TB cases each year in the world."
May 10, 2012 - Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go? (full text) "Whatever the explanation for its inadequacy, BCG vaccine is clearly insufficient for worldwide TB control. Thus, there is a strong need to develop vaccines that can either boost BCG's initial priming and protective effects or replace BCG by superior vaccines. Both strategies and approaches will be discussed below, after a short introduction to the key immunological features of TB."
April 30, 2012 - Testing for TB Infection - A little-known, rarely-used blood test is available to determine if a person is actively infected with M. tuberculosis. Called QuantiFERON-TB (QFT), the test was approved for use by the FDA in 2001 to identify active tuberculosis infections. The test involves drawing a blood sample, mixing it with PPD and incubating the solution for up to 24 hours. If the patient's sample releases a larger proportion of IFN-g (interferon gamma) than the control sample, this is a marker of active disease. As of December 2005, CDC guidelines approved the use of the QuantiFERON TB Gold test (QFT-G) to screen for active tuberculosis. REF: MMWR 2005;54(RR- 15):49-55.
April 2012 - Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomized trial "The overall vaccine effectiveness of a first BCG vaccination at school age was 25% (3—43%). In Salvador, where vaccine effectiveness was 34% (8—53%), vaccination of 381 children would prevent one case of tuberculosis and was 'cheaper than treatment."
March 5, 2012 - A Vaccine against Tuberculosis Infections "Currently the only vaccine used for human immunization against tuberculosis is the BCG vaccine. The BCG vaccine is developed from an attenuated strain of Mycobacterium bovis. An attenuated vaccine contains live bacteria that have lost their ability to cause infection in humans. Although there is widespread use of the BCG vaccine, it has several shortcomings which need to be addressed in order to try to reduce the impact of TB, particularly in less economically developed areas where TB is endemic. The BCG vaccine is mostly considered to be effective against TB in children with its impact on adult TB being less marked. This is partly due to the decreased effectiveness of the vaccine when there has been previous exposure to mycobacteria and partly because of the poor performance of the BCG vaccine against latent infections. On top of this, many studies have indicated that BCG loses its effectiveness with time, giving protection for as little as 10-20 years. Since adult infections with TB are the primary cause of new mycobacterial infections in a population, and since they account for the majority of cases of TB, these inefficiencies of the BCG vaccine need to be addressed."
January 2012 - Osteomyelitis following Bacille Calmette-Guerin vaccination. "The real-time polymerase chain reaction has an essential role to confirm the diagnosis of BCG osteomyelitis. With proper surgical intervention and chemotherapy, the prognosis is usually good."
January 23, 2011 - A multistage tuberculosis vaccine that confers efficient protection before and after exposure "H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG."
March 2009 - Risk of sensitization in healthy adults following repeated administration of rdESAT-6 skin test reagent by the Mantoux injection technique. "Local adverse reactions at the injection site and adverse events were recorded. One out of 31 (3%) volunteers showed a positive skin reaction (sensitization) upon a second injection of rdESAT-6 after 28days and an increased IFN-gamma response to ESAT-6. For 7 (23%) of the volunteers, local adverse reactions related to the product were registered, but all reactions were mild and predictable."
November 17, 2008 - Osteomyelitis due to BCG Vaccination (pdf) "Timely diagnosis of BCG osteomyelitis is important since therapy is effective when initiated early in the course of disease. But several factors may delay prompt diagnosis. The lesions may be overlooked due to their rarity. The symptoms tend to develop slowly, and the primary course is fairly benign. The chest radiological changes (when detectable) are not diagnostic, and blood tests in BCG related bone disease often show low-grade inflammation, as seen in this case."
October 8, 2007 - Differential productions of lipid virulence factors among BCG vaccine strains and implications on BCG safety "We found that there is a good correlation between the ability of BCG strains to produce these two lipids and the propensity of BCG to induce complications following vaccination in children, which provides a partial explanation for the molecular mechanisms of BCG reactogenicity."
April 8, 2005 - BCG vaccine-associated suppurative lymphadenitis "Clusters of BCG vaccine-associated suppurative lymphadenitis (BCG-ASLD) have been reported in many countries. We have observed an increase in BCG-ASLD following the change from the percutaneous Evans vaccine to the intradermal BCG Statens Serum Institute (SSI) vaccine."
March 2005 - CDC Issues Guidelines on Use of QuantiFERON TB Gold Test (free registration) "For persons with recent contact with persons who have infectious TB, negative QFT-G results should be confirmed with a repeat test performed 8 - 10 weeks after the end of exposure, as is recommended for a negative TST result," the authors conclude. "Studies to determine the best time to retest contacts with negative QFT-G results have not been reported. Until more information is available, the timing of QFT-G testing should be the same as that used for the TST."
September 2004 - Potential Public Health Impact of New Tuberculosis Vaccines "Although BCG is the most widely used vaccine in the world, its efficacy in preventing adult forms of TB is relatively poor, with an average efficacy ≈50%. A new, more effective vaccine would be expected to improve TB control substantially, and therefore, vaccine development is one of the highest priorities in TB research. The Gates Foundation recently provided nearly $83 million in grants to boost TB vaccine research.
March 2002 - BCG — different strains, different vaccines? "After nearly a century of use, BCG vaccines continue to generate controversy and confusion. Their ability to prevent tuberculosis in studies has been inconsistent'. When they have been protective, no clear mechanism of action has been established. Furthermore, the existence of different BCG strains has been described since the 1940s. These strains vary according to several laboratory properties, which may or may not translate into a discernible effect on vaccination.
September 1, 1999 - Mycobacterium bovis Osteomyelitis as a Complication of Bacille Calmette-Guérin (BCG) Vaccination: Rapid Diagnosis with Use of DNA Sequencing Analysis. A Case Report (full text) "Only after two months did both the pathogen grown on culture and its biochemical characteristics reveal that an acid-fast rod identical to the strain used for the BCG vaccine was responsible for the problem. The radiograph that had been made four months after treatment showed a so-called head-within-a-head appearance, formation of callus, and periosteal reaction (Fig. 4). The medications were given for a full year."
June 6, 1997 - Disseminated Bacille Calmette-Gue´rin Disease After Vaccination: Case Report and Review (pdf) "Cases also occur after revaccination of individuals who were anergic following the initial administration of BCG vaccine. Disseminated BCG disease is an uncommon but devastating complication of vaccination that should be considered in the appropriate clinical setting. "
August 1996 - Adverse local reactions from accidental BCG overdose in infants (pdf) "In one report 158 of 403 children vaccinated by a doctor developed adverse local reactions; this was attributed to faulty technique.
February 1995 - Relationship of Secretion Pattern and MPB70 Homology with Osteoblast-Specific Factor 2 to Osteitis following Mycobacterium bovis BCG Vaccination (pdf) "A literature search concerning osteitis after Mycobacterium bovis BCG vaccination in neonates revealed that MPB70-high-producer substrains were associated with an increased incidence of osteitis following vaccination. These observations indicate that the function of MPB70 is related to the interaction between bacilli and the host following vaccination or infection with mycobacteria.