Discovery Of M Tuberculosis
The discovery of the etiologic agent of TB by Robert Koch formed the basis for rational understanding of the disease and served as a platform for design of novel intervention measures including diagnostics, vaccines and therapeutics. In his groundbreaking description of the etiology of TB, first orally on March 24, 1882, at a meeting of the Physiological Society in Berlin and less than 3 weeks thereafter in written form in the Berlin Clinical Weekly published April 10, Koch carefully described his work . His strategy later led to the formulation of the so-called Kochs postulates by Friedrich Loeffler which comprise :
Constant presence of the microbe in question in diseased tissue
Isolation and growth on solid culture of the responsible microbe
Experimental induction of a similar disease by the isolated microbe from pure culture.
Figure 1. Description of the etiology of TB by Robert Koch. Agenda of the meeting of the Physiological Society in Berlin, where Robert Koch for the first time presented his data on March 24, 1882 and first page of the publication on this topic in the Berlin Clinical Weekly, April 10, 1882 . Figure also includes photo of Robert Koch from 1883 .
Figure 2. Kochs postulates, based on Robert Kochs lecture on the etiology of TB and phrased in general terms by F. Loeffler .
A Look At Each Vaccine: Tuberculosis Vaccine
The tuberculosis vaccine is rarely used in the United States. It is only recommended for children living with someone who is actively infected with TB who either cannot take antibiotics to treat the infection or is infected with a strain of TB that is highly resistant to all antibiotics. Decisions regarding this vaccine are typically made in consultation with a local TB control program. The TB vaccine is given as a single shot.
In most other countries, the vaccine for tuberculosis, known as the BCG vaccine, is used more commonly because of the frequency of tuberculosis.
How Is The Tuberculosis Vaccine Made
Known as BCG, the TB vaccine has been around since the early 1920s. It is made by weakening a strain of bacteria similar to tuberculosis that was first isolated in cows. This strain of bacteria, called Mycobacterium bovis, is similar enough to the human strain that vaccination with the bovine strain protects against disease caused by the human strain.
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Named After The French Scientists Who Developed It The Bcg Vaccine Is Usually Given In Infancy And Provides Protection In Childhood Against Pulmonary Tb That Affects The Lungs And A High Degree Of Protection Against Other Fatal Forms Of The Disease In Children
Despite universal vaccination of neonates and infants in TB-endemic countries, Mycobacterium tuberculosis still kills more people worldwide than any other infectious pathogen approximately 1.4 million deaths each year. Approximately a quarter of the worlds population is infected with it, of whom 5-10% will develop TB disease during their lifetimes. TB is also a major driver of antimicrobial resistance an estimated 3.3% of new TB cases and 17.7% of previously treated cases in 2019 were drug-resistant. Although improved diagnosis and treatments are helping to reduce deaths, TB remains a major economic burden and a key driver of global inequity not to mention causing immense human suffering.
Simultaneous Administration With Other Vaccines
BCG vaccine may be administered concomitantly with inactivated vaccines and live vaccines at different injection sites using separate syringes and needles. In a blinded, randomized trial, neonates experienced less pain when the BCG vaccine was administered prior to concurrent intramuscular hepatitis B vaccine. If not given concomitantly, a minimum interval of 4 weeks is recommended between administration of two live parenteral vaccines to reduce or eliminate potential interference from the vaccine given first on the vaccine given later. Live oral and nasal vaccines, like rotavirus vaccine and live attenuated influenza vaccine , may be given concomitantly with, or at any time before or after, live parenteral vaccines, such as BCG vaccine. Refer to Timing of Vaccine Administration in Part 1 for additional general information.
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Tb Vaccines In Clinical Trials
There are nearly 15 Tb vaccines in clinical trials. There are six vaccines including AdAg85A, MTBVAC, ID93+GLA-SE, Crucell Ad35/MVA85A, DAR 901 and TB/FLU-04L in phase I trials, six vaccines including VPM 1002, H1/H56/H4+IC3 and Crucell Ad35/AERAS-402 in phase II trials while two vaccines including MVA85A and M72+AS01E are in phase IIb trials and one vaccine M. vaccae is in a phase III clinical trial.
Recombinant Bcg As A New Vaccine Against Tb
Recombinant BCG techniques may be useful for the development of a more effective mycobacterial vaccine than the parental BCG now in use. Various strategies have been used to develop rBCG against mycobacteral diseases. One is based on rBCG producing large amounts of autologous protective antigens these supplementary antigens are designed to enhance immunity to other BCG antigens by increasing the expression of their genes, as is the case for the immunodominant TB antigens. Recombinant BCG vaccine expressing and secreting the 30-kDa, major secreted protein of M. tuberculosis, also referred to as -antigen and antigen Ag85B , is associated with better host survival after challenge than parental BCG in the highly demanding guinea pig model of pulmonary TB. Animals immunised with rBCG30 and then challenged with an aerosol of a highly virulent strain of M. tuberculosis survived significantly longer than animals immunised with conventional BCG .
Alternatively, BCG genes that have been lost by deletion from parental M. bovis strain and that are important antigens can be restored. An example is the case of ESAT-6 deleted from region RD1 of BCG . Both these approaches are attractive for improving or adding antigens to BCG and could be important in conferring immunity against TB.
In another approach rBCG have been constructed secreting diverse cytokines, including IL-2, IFN- and others, in an attempt to enhance the immuno-stimulatory properties of BCG .
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Tuberculosis Vaccines In The Pipeline
There are more than a dozen TB vaccines in clinical trials. While new TB vaccines may not prevent a person from ever getting infected, some have shown signs that they could stop infected people from progressing to disease. Stopping infection would be the Holy Grail, but it is a really, really high bar, acknowledges Gordon. Stopping people latently infected from progressing to disease would be a game changer. In nearly all TB vaccine trials, volunteers had latent TB infection and prior BCG immunization.
Two vaccines, MTBVAC in Phase 2a and VPM1002 in Phase 3, are being trialed in adults as well as infants and neonates, which could be especially useful for immunocompromised children with HIV. This is noteworthy because most TB vaccine candidates are being trialed in adolescents and adults. If we can stop adolescents and adults from getting TB, then we wouldnt worry about children needing vaccines for TB, says Scriba.
The candidate that seems to be on everyones lips is M72, a protein subunit vaccine being developed by GlaxoSmithKline . The vaccine includes a fusion of two proteins from M. tuberculosis and an adjuvant, AS01, which GSK uses in its blockbuster shingles vaccine and its leading malaria vaccine candidate. Although the M72 vaccine had not looked so promising in nonhuman primates, it lowered the incidence of pulmonary TB by 54 percent over three years in a recent trial involving more than 3,000 adults in Kenya, South Africa, and Zambia.
The Impact Of Tuberculosis
Tuberculosis kills more people in the world than any other infection. Each year about 10 million people are infected with TB and about 1.8 million die. Cases of TB occur in the United States each year, but most are diagnosed in people not born in the U.S. In 2018, less than 10,000 cases of TB and fewer than 500 deaths were caused by TB.
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Symptoms And Causative Agent
Tuberculosis is a disease caused by the tuberculosis bacteria, Mycobacterium tuberculosis.
Symptoms of active tuberculosis infection include cough lasting several weeks, coughing up sputum or blood, fever, night sweats, fever, and pain in the chest.
Some people may be infected with tuberculosis bacteria but have no symptoms. This is called latent tuberculosis. Latent tuberculosis may lead to active disease. Some people with latent tuberculosis may never become ill.
Different Approaches Toward Development Of A Tuberculosis Vaccine
The 30 years between 1890, when Koch had first announced his vaccine against TB, and 1921, when Albert Calmette and Camille Guérin administered BCG to a human neonate for the first time, were characterized by the development and clinical testing of different vaccine types including subunit vaccines, inactivated vaccines and live whole-cell vaccines with only one final success: BCG . This vaccine was created following the principles of Pasteur to attenuate the causative agent of disease by culture conditions which caused loss of virulence factors. This was not the only approach based on live vaccines. Other attempts employed minute doses of M. bovis or M. tuberculosis themselves to immunize cattle or humans, respectively . They followed the concept of variolation widely used on the Asian continent and propagated by Lady Montagu in Western Europe prior to the introduction of Jenners cowpox .
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Common And Local Adverse Events
Intradermal administration of BCG vaccine usually results in the development of erythema and either a papule or ulceration , followed by a scar at the immunization site. Keloid formation occurs in 2% to 4% of vaccine recipients. Non-suppurative regional lymphadenopathy occurs in 1% to 10%. Most reactions are generally mild and do not require treatment.
The Immune Response Against Tb
The lung is the portal of entry of M. tuberculosis in most human infections and provides a suitable environment for this slowly replicating pathogen. The infection is established in alveolar macrophages of the distal alveoli before it is recognised by the adaptive immune response 56 weeks later. CD4+ and CD8+ T cells are recruited through the lung, inducing protective immunity.
Both CD4+ and CD8+ T cells are essential for protective immunity against M. tuberculosis. Resistance to M. tuberculosis involves the activation of mycobacterial-specific CD4+ and CD8+ T cells by dendritic cells , which migrate from the site of the infection in the alveoli to the draining lymph nodes. The development of interferon –secreting CD4 T cells is dependent on the secretion of interleukin -12 by infected DC. Subjects deficient in receptors for IFN- and IL-12 are extremely susceptible to mycobacterial infections, confirming the absolute requirement for T-helper cell type 1 -like T cells for host immunity .
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Guidance On Reporting Adverse Events Following Immunization
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to immunization, or to a change in the frequency of a known AEFI. Refer to Adverse events following immunization in Part 2 and other guidance for additional information about AEFI reporting.
Challenges For Tb Vaccine Development
There are a number of substantial underlying problems to be faced in developing vaccines with enhanced protective efficacy against TB. In contrast to a classical vaccine-preventable disease such as smallpox, recovery from infection with M. tuberculosis is not associated with sterilising immunity against reinfection after clearance of the original infection with antibiotics. Studies of the molecular epidemiology of TB indicate that reinfection with new strains of TB is more frequent than previously believed . Therefore, vaccines need to be more effective than infection with M. tuberculosis itself.
One-third of the population worldwide is estimated to be infected with M. tuberculosis, and therefore any new TB vaccine should be suitable for use in subjects pre-exposure, to prevent infection, but also post-exposure, to prevent the development of disease or as an immuno-therapeutic agent to act with antimicrobials to increase the rate of clearance of M. tuberculosis.
An additional challenge is that as a large percentage of the human population has already been immunised with BCG, and so any new generation vaccines against TB must also be able to protect the population that has already been vaccinated with BCG. Obviously, new vaccines must also be safe enough to be used in HIV-infected individuals .
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The Covid Pandemic Must Lead To Tuberculosis Vaccines
A tuberculosis patient consults with their doctor in Indonesia. Diagnosis and treatment of the disease has been severely affected by the COVID-19 pandemic.Credit: Jefri Tarigan/Anadolu Agency/Getty
Researchers and clinicians are upset and frustrated that decades of work in diagnosing, treating and researching tuberculosis have massively stalled. The slowdown means the world is losing ground against a disease that kills 1.5 million people every year.
As the International Union Against Tuberculosis and Lung Disease held its annual conference online last week, Guy Marks, the unions president, spoke for many when, comparing efforts against COVID-19, he said: Many of us who work in the field feel robbed that equivalent efforts to develop a TB vaccine have never been as well committed or funded.
Researchers are again urging decision-makers to revive diagnosis, treatment and research programmes for TB and other infectious diseases, such as malaria. And they are saying that much can be learnt from how the creation of COVID-19 vaccines was fast-tracked.
Researchers have been warning that even more people will die from TB and other infectious diseases, such as malaria and HIV, if health systems continue to neglect these infections because of the continuing focus on coronavirus . And they are pleading with funders and governments not to drop the ball on TB work.
Side Effects Of The Bcg Vaccine
Like all vaccines, the BCG vaccine can cause side effects, but they’re uncommon and generally mild.
Some common side effects may include:
- soreness or discharge from where the injection was given
- a high temperature
- swollen glands under the armpit in the arm where the injection was given
More serious complications, such as abscesses, bone inflammation and widespread TB are rare.
Most children develop a sore at the injection site. Once healed, the sore may leave a small scar. This is normal and nothing to worry about.
Serious side effects from the BCG vaccine, such as a severe allergic reaction , are very rare.
The Yellow Card Scheme allows you to report suspected side effects from a vaccine. It’s run by the medicines safety watchdog, the Medicines and Healthcare products Regulatory Agency .
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Specific Features Of Tuberculosis As They Relate To Vaccination Strategies
Mycobacterium tuberculosis causes a chronic infection which can, but need not, result in a chronic disease with high lethality if untreated . M. tuberculosis is transmitted in aerosols and the lung is the major port of entry, the prime site of disease symptoms and the main source of transmission. Infection induces an acquired immune response composed of antibodies and T cells . General assumption considers T lymphocytes as major mediators of protective immunity. Soon after infection, phagocytes, notably mononuclear phagocytes and neutrophils, enter the site of bacterial growth, where they engulf the mycobacteria. Some microorganisms are killed, whereas others survive persisting inside mononuclear phagocytes. Granulomas are formed which in their well-structured solid stage contain M. tuberculosis under the direction of T lymphocytes . CD4+ helper-1 T cells are considered critical for protective immunity, notably after maturation into memory T cells . Increasing evidence suggests a role for TH17 cells and for CD8+ cytolytic T lymphocytes . Also, a role of B lymphocytes and antibodies in TB control, long considered of low to no relevance, has been reinvigorated .
Next generation vaccines must be better than BCG and need to achieve one or more of the following criteria :
Prevention of infection : Such a vaccine does not allow M. tuberculosis to stably establish itself in the host, but most likely permits short-term infection which is rapidly terminated.
The Current Vaccine Against Tb: Bcg
The current TB vaccine, bacillus Calmette-Guérin , is a live vaccine that protects against severe childhood forms of disease, including milliary and extrapulmonary TB and the often fatal TB meningitis. It also confers protection against leprosy. The World Health Organization recommends BCG vaccination in areas of high TB prevalence and incidence. BCG vaccination is currently compulsory in 64 countries and administered in > 167 countries , . Indeed, BCG remains the most widely used vaccine in the world.
BCG is an inexpensive vaccine that has been given to > 2.5 billion people since 1948. It has a long-established safety profile and has outstanding adjuvant activity, eliciting both humoral and cell-mediated immune responses. It can be given at birth or any time thereafter and a single dose can produce long-lasting immunity. It has also been licensed as a treatment for bladder cancer.
Recently, an investigation of the long-term efficacy of BCG vaccine, a 60-yr follow-up study in American Indians and Alaska natives, has shown remarkable results that the efficacy of BCG vaccine persists for 5060yrs, suggesting that a single dose of BCG vaccine can give life-long protection .
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Do The Benefits Of The Tuberculosis Vaccine Outweigh Its Risks
The tuberculosis vaccine is not highly effective at preventing lung infections caused by the tuberculosis bacteria. For this reason, the vaccine is only recommended for a small subset of those in contact with someone infected with tuberculosis specifically someone in constant contact with a person infected with TB who either refuses to take antibiotics or is infected with a strain that is resistant to all antibiotics. On the other hand, the tuberculosis vaccine has no serious side effects. Therefore, in the small subset of people who should use the vaccine, the benefits clearly outweigh the risks.