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- Macrophages produce 2 cytokines in the case of M.tuberculosis: IL-1 & TNF-alpha
- CD4 T cells can recognise mycobacterial antigens if processed & presented by macrophages in the context of major histocompatibility complex class II proteins
- Tubercles (granuloma) formation

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Definition of TB: is an infectious disease that is caused by mycobacterium tuberculosis affecting especially the lungs

Strong reaction to the mycobacterium: spread in the body
No reaction: limited to the lungs

Tuberculosis is highly aerobic (needs oxygen to survive), therefore the apices of the lungs (the oxygen concentration is higher there) is mainly affected

Symptoms of TB: weight loss, fever (cytokines are released), strong cough, haemorrhaging (due to rupture and erosion of blood vessels)

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Epidemiology of TB
- Endemic: found among people in a certain area
- Epidemic: wide spread of the disease at a particular time i.e. Hannah's school
- Pandemic: prevalent in the whole world / multiple regions (widespread)

HIV infected people are also more likely to be infected by tuberculosis: diminished CD4 T cells

In Africa: 30% - 40% of the HIV patients die because of tuberculosis

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How it enters the body
- rapid spread required, it has to be crowded, airborne droplet nuclei, sneezing, coughing

Primary tuberculosis: once bacteria is in the lungs
1. airborne nuclei
2. reach the alveoli of the lung
3. 1st response: alveolar macrophages ingest the bacteria
- lymph node: Ghon complex (calcification)
4. TB still multiple and destroy the macrophage
5. facultative intracellular pathogen: multiply in and out of the cell
6. infected macrophage are carried by the lymphatic and regional nodes
7. cellular immunity or immune response is not effective

Secondary infection: 2 to 3 years after the infection
What factors can make this possible:
- malnutrition
- immunosuppressive drugs
Gets reactivated, reactivation is mostly affect the apex of the lung
- a place for mycobacteria to multiply and escape
What is the immune response involved in this secondary infection?
- alveoli material is deliquified & necrosis
Bacteria into the alveoli: moist environment & high oxygen levels

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Diagnosis

Initial test - Microscopic examination of smear such as sputum/sputum smear positivity

Early morning spata in most reliable because pulmonary secretions accumulate over night

Acid fast staining of sputum culture

Challenge: slow due to slow growth rate of the bacteria (3 to 6 weeks for a colony to form)

Delayed type hypersensitivity and Tuberculin skin test:

Involves injection of purified protein derivative (PPD) from bacteria into the skin.

It takes advantage of cell mediated immunity against the bacterium involving sensitised T cells since the pathogen is located on macrophages.

Positive test: sensitised T cells react with TB proteins in the case of past infection causing a delayed hypersensitivity reaction in 48 hours which results in hardening(induration) and reddening of the area=>Mantoux test

Positive test in young people=active infection, in old people=hypersensitivity from previous infection in most cases.

A positive test is usually an indication that X-ray or CT examination is needed to detect lung lesions and to isolate the bacterium.

TB blood test

Measures release of TNF gamma from WBCS after exposure to mycobacterial antigen=>preferred for people who have received BCG vaccinations.

Interferon gamma release assays: Can be used under every circumstance under which the tuberculin test would be used.

Nucleic acid amplification tests (NAAT)-detects bacteria 1-2 weeks sooner, can be used to test resistance to TB antibiotic, rifampin.

Rapid tests have higher sensitivity and less cross reactivity to BCG  vaccine than skin tests.

Imaging: CT is more sensitive than x-rays is identifying TB lesions

- skin test: purified protein derivative
positive reaction: thickening of the skin (phagocytes in the T cell) --> Hannah can u add?:)
- initial test: acid fast staining --> Cristina can u add?:)
sputum cells
- blood test: release of interferon gamma, cytokines are released when the T cells encounter the antigen
- amplification test: test antibiotic resistance

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1. Drug resistance: mainly to first line drugs
2. Immunocompromised individuals: HIV patients

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Prevention
- Vaccines: BCG (bacille Calmette-Guérin)
- negative skin test before vaccine!
- drug susceptibility

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Characteristics of the mycobacterium
- very resistant to drying (bcs of waxy coat made out of a mycolic acid) --> facilitate airborne transmission
- mycobacteria: because waxy barrier
- "myco": similar to fungus, clusters over liquid surfaces
-  slow growth: the mycobacterium goes "undetected", can delay diagnosis & delay tests for drug susceptibility
- slow growth is a mechanism for survival

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https://www.nature.com/articles/nrmicro749

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Additional access options:

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We thank one of the referees for their stimulating and useful comments.

Affiliations

Centre for Molecular Microbiology and Infection, Imperial College London, London, SW7 2AZ, UK

Graham R. Stewart, Brian D. Robertson & Douglas B. Young

Corresponding author

Correspondence to Douglas B. Young.

MACROPHAGE

Cell of the mononuclear phagocyte system that can phagocytose foreign particulate material. Macrophages are present in many tissues and are important for nonspecific immune reactions.

PHAGOSOME

A membrane-bounded cytoplasmic vacuole formed around a particle ingested by phagocytosis.

DENDRITIC CELLS

Professional antigen-presenting cells that take up proteins and present peptide antigens to T cells in conjunction with accessory molecules that stimulate T-cell activation. Characterized by many long thin processes extending from them.

T CELLS

Lymphocytes that undergo maturation and differentiation in the thymus. They are responsible for immune reactions that involve cell-cell interactions.

FOAMY GIANT CELL

A giant, multinucleate macrophage loaded with lipid.

BCG

Bacille Calmette-Guérin, the attenuated M. bovis live vaccine.

CASEOUS GRANULOMAS

An encapsulated lesion, known as caseous owing to a supposed resemblance to crumbly cheese. The underlying cells and tissue are totally destroyed in the process of caseous necrosis.

HYPOXIA

A condition in which the concentration of oxygen is greater than 0% but less than 20%.

WHOLE-GENOME PROFILING

The use of microarrays to obtain a snapshot of an organism's response to stimuli in terms of gene expression or genetic recombination.

SIGMA FACTOR

A subunit of bacterial RNA polymerase that is required for initiation of transcription. Some sigma factors confer the ability to recognize and bind to a particular promoter, thereby changing the pattern of gene expression.

PERFORIN

A pore-forming protein present in the granules of cytotoxic T cells.

TOLL-LIKE RECEPTOR

A family of mammalian transmembrane receptors related to the Toll protein of Drosophila. They are involved in the recognition of pathogens and microbial products and activate antimicrobial effector pathways in phagocytes.

Cite this article

Stewart, G., Robertson, B. & Young, D. Tuberculosis: a problem with persistence. Nat Rev Microbiol 1, 97-105 (2003). https://doi.org/10.1038/nrmicro749
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# data[].attributes.attachment_link.title
Tuberculosis: a problem with persistence

# data[].attributes.attachment_link.description
Mycobacterium tuberculosis is one of most successful pathogens of mankind, infecting one-third of the global population and claiming two million lives every year. The ability of the bacteria to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis, is central to the biology of the disease.

# data[].attributes.body
https://www.nature.com/articles/nri1666

# data[].attributes.attachment_link.readable_text
Abstract

Tuberculosis is out of control in developing countries, where it is killing millions of people every year. In these areas, the present vaccine - Mycobacterium bovis bacillus Calmette-Guérin (BCG) - is failing. Progressive tuberculosis occurs because the potentially protective T helper 1 (T H1)-cell response is converted to an immunopathological response that fails to eliminate the bacteria. Here, we discuss the data indicating that the problem in developing countries is not a lack of adequate T H1-cell responses but, instead, an exaggerated tendency to switch to immunopathological responses. We propose that a successful vaccine needs to block this immunopathology, because it is not the quantity of T H 1-cell activity that matters but, rather, its context.

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14. Grode, L. et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants secreting listeriolysin. J. Clin. Invest. (in the press).

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Acknowledgements

We are grateful to the European Union International Cooperation with Developing Countries (INCO-DEV) Fifth Framework Programme for supporting this work. K.D. was supported by a grant from the British Lung Foundation.

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Affiliations

the Centre for Infectious Diseases and International Health, Windeyer Institute for Medical Sciences, University College London, London, W1T 4JF, UK

Graham A. W. Rook, Keertan Dheda & Alimuddin Zumla

Corresponding author

Correspondence to Graham A. W. Rook.

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Competing interests

Graham Rook is a shareholder in SR Pharma plc (United Kingdom), which owns intellectual property relating to Mycobacterium vaccae.

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Rook, G., Dheda, K. & Zumla, A. Immune responses to tuberculosis in developing countries: implications for new vaccines. Nat Rev Immunol 5, 661-667 (2005). https://doi.org/10.1038/nri1666
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# data[].attributes.attachment_link.title
Immune responses to tuberculosis in developing countries: implications for new vaccines - Nature Reviews Immunology

# data[].attributes.attachment_link.description
Tuberculosis is out of control in developing countries, where it is killing millions of people every year. In these areas, the present vaccine - Mycobacterium bovis bacillus Calmette-Guérin (BCG) - is failing. Progressive tuberculosis occurs because the potentially protective T helper 1 (TH1)-cell response is converted to an immunopathological response that fails to eliminate the bacteria.

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Almost all tuberculous infections result from
inhaling infectious particles that were
aerosolized by coughing, sneezing, or
talking. The initial source of infection is the
lung in almost all cases. These so-called
droplet nuclei dry while airborne, can
remain suspended for hours, and when
inhaled can reach the terminal air passages
(Fig. 23-3). A cough or sneeze can produce
thousands of droplet nuclei, as can talking
for several minutes. Accordingly, the air in a
room occupied by a person with
pulmonary TB may remain infectious even
after the person has left the room.
Fortunately, prolonged exposure and
multiple aerosol inocula are generally
required to establish infection. Brief contact
carries little risk, and infection rarely occurs
outdoors because ultraviolet light kills M.
tuberculosis. Large drops of respiratory
secretions or contaminated inanimate
objects infrequently result in transmission. In the past, TB of the intestine or the tonsils was
common from ingestion of contaminated milk. This form of TB was caused by M. bovis, an
organism that is genetically similar to M. tuberculosis and causes infection in cattle.
Airborne spread of TB is efficient for several reasons. In source cases, the host inflammatory
response to TB creates open lung lesions (pulmonary cavities) that contain huge numbers
of organisms. Coughing spreads the organisms from such lesions into the air.
Contagiousness roughly correlates with the number of acid-fast bacilli visible by microscopy
of sputum. Patients who are acid-fast smear-positive are more contagious than those who
are acid-fast smear negative but culture positive. However, many new infections are acquired
from smear-negative but culture-positive patients, reflecting the limited sensitivity of acid-fast
staining. The small size of droplet nuclei is also ideal for bypassing the mucociliary lining of
large airways to reach the alveoli.
Tubercle bacilli do not produce exotoxins or endotoxin. Instead, the clinical manifestations
of TB result largely from the host immune response. Damage is caused by chronic
inflammation and survival of organisms within macrophages.
In primary infection, airborne droplet nuclei reach the alveoli where multiplication begins.
This primary infection usually involves the middle lung zone, where airflow is greatest. There,
the bacteria are ingested by alveolar macrophages, which may eliminate small numbers of
bacilli. However, M. tuberculosis multiplies mostly unimpeded, destroying the macrophage
(Fig. 23-4). Its capacity to multiply both inside and outside cells makes M. tuberculosis a
facultative intracellular pathogen. Lymphocytes and monocytes are attracted from the bloodstream, the latter differentiating into
macrophages, which ingest bacilli released from
dying cells. Infected macrophages are carried by
lymphatics to regional lymph nodes. Some
individuals develop the so-called Ghon complex,
in which an area of lung inflammation is
associated with enlarged hilar lymph nodes
draining the area. In the nonimmune host,
organisms may spread hematogenously
throughout the body. During this early
lymphohematogenous dissemination, the
organisms preferentially localize in certain
tissues, including lymph nodes, vertebral
bodies, and meninges but most importantly the
apices (upper parts) of the lungs. During the
days and weeks before an effective cellular
immune response develops, the organisms grow uninhibited in the initial pulmonary focus
and the additional sites.
Primary infection can have various outcomes (Fig. 23-5). Cellular immunity and tissue
hypersensitivity usually appear 3 to 8 weeks after infection and are marked by a positive
tuberculin skin test (discussed later in the chapter). In most affected individuals, this response
controls infection (although viable organisms may persist in the tissues), no symptoms
develop, and the only evidence of infection is a positive tuberculin skin test. However, in
some cases, the immune response does not control the primary infection, and progressive
primary TB develops. This manifestation usually affects the very young, the elderly, and
persons with advanced AIDS. In such individuals, the primary focus directly progresses to
worsening pneumonia, and the very young may develop tuberculous meningitis. The most
important consequence of lymphohematogenous dissemination is seeding of the lung
apices, where either progressive primary or secondary disease can occur.

In persons with immunity from previous
exposure to M. tuberculosis, organisms
in newly inhaled droplet nuclei are
destroyed before significant
multiplication occurs. Nearly all TB in
previously infected patients is the result of
endogenous reactivation. However, when
the airborne inoculum is large, or when
host defenses are compromised,
exogenous reinfection can occur.
Age influences the course of infection.
Infants and children younger than 5 years
of age who become infected are at high
risk for developing progressive primary
disease. In contrast, from age 5 to puberty
is a period of relative resistance to
progressive disease, although not to
infection. From puberty until young
adulthood, formation of apical cavities
soon after primary infection is common.
Most disease in this age group is caused by relatively recent infection rather than reactivation of childhood infection. Infection in mid-adulthood has a much better immediate and
probably long-term prognosis, presumably because of a reduced tendency to develop tissue
necrosis. In the elderly, infection acquired years earlier can progress as age compromises
immunity, leading to production of apical pulmonary cavities. In elderly persons who lack
preexisting immunity to TB, new infection can cause progressive primary disease resem-
bling primary infection in children, with involvement of lower or middle lobes and often
without cavities.
Endogenous Reactivation (Secondary Tuberculosis)
Endogenous reactivation usually occurs within 2 years after initial infection but can occur at
any time thereafter (see Fig. 23-5). Clearly, any impairment of the cellular immune system
can render a person vulnerable to reactivation of latent mycobacteria. Subtle depression
of the immune system resulting from stress or hormonal factors may go undetected. Other
factors include malnutrition, therapy with corticosteroids or other immunosuppressive drugs,
malignancy, and end-stage renal disease. Worldwide, the most important cause of
reactivation is coinfection with HIV. The higher frequency of certain histocompatibility types
(i.e., human leukocyte antigen or HLA) in persons who develop active TB suggests a genetic
predisposition. The disease may reactivate in the elderly because of a poorly understood
loss of immune competence that can occur with aging. In addition, local physical
disturbances at the site of a latent focus can alter the balance between host and pathogen.
For example, lung surgery can disturb quiescent pulmonary foci and cause active TB at that
site.
The most common site of reactivation is the apex of the lung. Lesions slowly become
necrotic, undergo caseous necrosis (named for its cheesy appearance), and eventually
merge into larger lesions. With time, the caseous lesions liquefy and discharge their contents
into bronchi. This event has several major consequences. It creates a well-aerated cavity in
which the organisms proliferate. The discharge of caseous material also distributes the
organisms to other sites in the lung, which can lead to a rapidly progressive tuberculous
pneumonia. In addition, the bacteria-laden contents of caseous lesions are coughed up and
become infectious droplet nuclei. Although the reason for the apical pulmonary localization
is not known with certainty, it is likely that deficient lymphatic flow at the apices, where the
pumping effect of respiratory motion is minimal, favors retention of organisms. When
hypersensitivity develops, tissue damage creates apical cavities characteristic of pulmonary
TB in adults.
Immune Response
TB requires a cellular immune response for control, with antibodies playing no apparent role.
In the first few weeks after exposure, the host has almost no immune defense against M.
tuberculosis, and small inhaled inocula multiply freely in alveolar spaces or within alveolar
macrophages. Once inside the cell, mycobacteria increase their chance of survival by
preventing acidification of the phagolysosome. Unrestrained replication proceeds for
weeks, both in the initial focus and in metastatic foci, until tissue hypersensitivity and cellular
immunity supervene. This tissue hypersensitivity is florid compared with other intracellular
infections.
All persons have CD4+ T lymphocytes that can recognize mycobacterial antigens if
processed and presented by macrophages in the context of major histocompatibility
complex class II proteins. When lymphocytes encounter antigen in this manner, they are
activated and proliferate, producing clones of similarly reactive lymphocytes. These in turn
produce many distinct lymphokines that attract, retain, and activate macrophages at the site
of antigen exposure. Activated macrophages accumulate lytic enzymes and reactive metabolites that increase their capacity to kill mycobacteria, but if released into surrounding
tissues, these macrophage products can cause necrosis.
When the population of activated lymphocytes reaches a certain size, cutaneous delayed-
type hypersensitivity to tuberculin becomes manifest. This response generally takes 3 to 8
weeks. At the same time, enhanced macrophage microbicidal activity, or cellular immunity,
appears.
The pathologic features of TB are the result of hypersensitivity to mycobacterial antigens.
Sustained immunity to new infection that follows natural infection is likely the result of
persistent viable tubercle bacilli in the tissues with in vivo boosting. Although activated
macrophages usually kill intracellular bacteria, intracellular mycobacteria may persist. An
uneasy equilibrium is reached; some macrophages kill the organisms, others are themselves
killed and release their bacterial contents, and still others harbor dormant bacteria for long
periods. Proteolytic processing of killed bacteria leads to continued immunological
stimulation. Immunocompromised persons may not contain the primary infection, and organisms may
invade the bloodstream and disseminate to cause a life-threatening infection known as
miliary tuberculosis. The term miliary is derived from the resemblance of the tubercles to
millet seeds (bird seed). Characteristic of the disease are tubercles found in many organs,
including the liver, spleen, kidneys, brain, and meninges. Caseation and cavitation are less
frequent than in secondary TB.
The involvement of macrophages in the containment of M. tuberculosis comes at a price.
Two cytokines produced by these cells, IL-1 and TNF-alpha (see Chapter 6), contribute to
symptoms of the disease. Among their various activities, these cytokines mediate fever,
weight loss, and night sweats. In response to the carbohydrates, lipids, and proteins of the
tubercle bacilli, macrophages also produce many other cytokines that modulate the immune
response. In particular, increased production of IL-10 may suppress the immune response
and promote disease progression. The net effects of these complex events are the local
pathological manifestations of TB, including caseous necrosis and fibrosis with
calcification.

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Treatment

Multiple-drug therapy is needed to minimise the emergency of resistant strains (usually isoniazid, rifampin, ethambutol and pyrazinamide =>first line drugs)

Usually involves 130 doses-may lead to cure or resistance in case of poor adherence

Second-line drugs: Usually involving aminoglycosides, fluoroquinolones, streptomycin and para-aminosalicylic acid (PAS)=>usually have toxic side effects.

Prolonged treatment: important because the tubercle bacillus grows very slowly or is only dormant. (the bacillus may be hidden for long periods in macrophages or other locations that are difficult to reach with antibiotics)

Pyrazinamide-effective for dormant bacillus

Multidrug resistant (MDR) strains: Strains that are resistant to isoniazid and rifampin (first line drugs)

Resistance can either be primary (infection with drug strain) or secondary (associated with treatment non adherence in people who have received TB therapy)

Extensively drug-resistant (XDR): Strains that are resistant to second line drugs such as fluoroquinolone, aminoglycosides amikacin or kanamycin as well as polypeptide capreomycin - these are usually non treatable

HIV patients + XDR tuberculosis died within 3 months.

- medication
- antibiotics: isoniazid, rifampin, pyrazinamide, ethambutol
- other medication --> margrate :))
- because slow growth, you need to take medication for a long time

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People infected with tuberculosis respond with cell-mediated immunity against the
bacterium. This form of immune response, rather than humoral immunity, develops because
the pathogen is located mostly within macrophages. This immunity, involving sensitized T
cells, is the basis for the tuberculin skin test, a screening test for infection. A positive test
does not necessarily indicate active disease. In this test, a purified protein derivative of the
tuberculosis bacterium, derived by precipitation from broth cultures, is injected cutaneously.
If the injected person has been infected with TB in the past, sensitized T cells react with these
proteins, and a delayed hypersensitivity reaction occurs in about 48 hours. This reaction
appears as an induration (hardening) and reddening of the area around the injection site. In
this test, known as the Mantoux test, dilutions of 0.1 ml of antigen are injected and the
reacting area of the skin is measured.
A positive tuberculin test in the very young is a probable indication of an active case of TB.
In older individuals, it might indicate only hypersensitivity resulting from a previous infection
or vaccination, not a current active case. Nonetheless, it is an indication that further
examination is needed, such as a chest X-ray or CT examination to detect lung lesions and
attempts to isolate the bacterium.
The initial step in laboratory diagnosis of active cases is a microscopic examination of
smears, such as sputum. According to recent medical opinion, the commonly used 125-
year-old microscopic exam routinely misses half of all cases. Confirming a diagnosis of TB
by isolating the bacterium poses difficulties because the pathogen grows very slowly. A
colony might take 3 to 6 weeks to form, and completing a reliable identification series may
add another 3 to 6 weeks.
Blood tests measure release of IFN-γ from white blood cells after exposure to mycobacterial
antigen in a test tube. They are the preferred tests for a person who has received BCG
vaccinations.
Nucleic acid amplification tests (NAATs), such as PCR, can detect M. tuberculosis 1 to 2 weeks
sooner than cultures and at the same time can determine resistance to a major TB antibiotic,
rifampin. Evidence indicates that, compared to the skin test, these rapid tests have higher
specificity and less cross-reactivity with BCG vaccination (see the discussion of TB
vaccines, following). They do not distinguish latent from active infection. These assays seem
likely to replace the tuberculin skin test for many uses, especially where cross-reactivity with BCG vaccination is a problem. If they could be adopted worldwide at centers for TB
treatment, they would help avert millions of TB-related deaths.
BCG vaccination is a problem. If they could be adopted worldwide at centers for TB
treatment, they would help avert millions of TB-related deaths.

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Excellent drugs are available for treating TB. These include isoniazid (INH), rifampin,
pyrazinamide (PZA), and ethambutol. Persons with pulmonary TB usually become
noncontagious within 2 weeks of therapy if the organisms are sensitive to the drugs
administered. Unlike most bacterial infections that can be cured with a single drug, active
TB requires multiple drugs for cure because of the remarkable propensity of the organism
to develop resistance. In any population of tubercle bacilli, chromosomal mutations
associated with resistance to any single drug are already present in about one of every 106 to
107 bacteria, even though the organisms have never been exposed to the drug. Because
tuberculous cavities can contain in excess of 1011 organisms, many of the bacteria present
will be resistant to any single drug, even before treatment is begun. In fact, some organisms
will be resistant to drugs that are yet to be developed.
Fortunately, the chance that one organism will become resistant to two drugs
simultaneously is small. Therefore, prescribing multiple drugs in combination prevents
resistance. Unfortunately, adherence with complex and prolonged treatment regimens is
difficult. If treatment is sporadic, multidrug-resistant strains can emerge, making treatment
more difficult or impossible. Spread of such strains to other individuals can be catastrophic.
For this reason, directly observed therapy for TB has become the standard of care, with every
dose directly administered by a health care provider, usually a public health worker.
Prescribing multiple drugs also allows for a shorter duration of therapy. In cases of drug-
sensitive TB, 18 months of INH plus ethambutol was once required for cure. In the 1970s, it
was discovered that including rifampin in the regimen allowed therapy to be shortened to 9
months. Later, it was discovered that adding PZA allowed cure in 6 months. In the United
States, individuals at risk for exposure to TB (e.g., health care professionals as well as medical
students and residents) are routinely screened for tuberculin conversion. INH is administered
to persons who convert to a positive reaction, which indicates recent infection. Such
treatment of latent infection is called chemoprophylaxis. Unlike treating active TB,
chemoprophylaxis requires only a single drug (e.g., INH) because there are so few organisms
that it is highly unlikely that resistant organisms will be present.
Drug-Resistant Tuberculosis
Drug-resistant TB is a major challenge to TB control worldwide. Resistance can be either
primary, as is the case when a person becomes infected with a drug-resistant strain, or
secondary, which arises in a person who has received TB therapy and is often associated
with treatment nonadherence. Mycobacterial strains that are resistant to INH and rifampin
are designated multidrug resistant, or MDR TB. Strains resistant to INH, rifampin, and
second-line agents such as fluoroquinolones and aminoglycosides are designated
extensively drug resistant, or XDR TB. Approximately 7% of TB cases worldwide are
multidrug resistant. Drug-resistant TB is associated with decreased cure, increased morbidity
and mortality, and can be disseminated to susceptible persons.
Prevention
The history of TB suggests that improving the standard of living decreases rates of disease.
In many resource-limited countries, that is unfortunately not a reality. Currently, an effective
vaccine made from killed M. tuberculosis does not exist. The immunology of TB tells us why:
killed vaccines may generate antibodies, but humoral immunity does not protect against TB. Cell-mediated immune responses are best elicited when antigens are presented by live
organisms.
The bacille Calmette-Guérin (BCG) vaccine is a strain of M. bovis made relatively avirulent
(attenuated) by multiple passages in culture. It is routinely given to newborns and young
children in many countries, including those with limited resources. Administering BCG
vaccine causes tuberculin skin test positivity, a criterion for a successful “take” of the
immunization. Long-term persistence of tuberculin positivity varies depending on the
patient’s age at BCG vaccination; the earlier the vaccination, the less durable the skin test
positivity. Because BCG-induced tuberculin positivity would decrease the value of tuberculin
skin testing to diagnose new infections, BCG is not used in the United States. The safety and
immunogenicity of BCG also make it a potential vector to deliver protective antigens from
other pathogenic organisms. Genes encoding such antigens have been introduced into BCG
to generate “multivaccines” that might protect against multiple pathogens.

Another argument against the universal administration of BCG vaccine is its very uneven
effectiveness. Experience has shown that it is fairly effective when given to young children,
but for adolescents and adults it sometimes has an effectiveness approaching zero. Worse,
it has been found that HIV-infected children, who need it most, frequently will develop a fatal
infection from the BCG vaccine. Recent work indicates that exposure to members of the M.
avium-intracellulare complex that is often encountered in the environment may interfere with
the effectiveness of the BCG vaccine—which might explain why the vaccine is more effective
early in life, before much exposure to such environmental mycobacteria. A number of new
vaccines are in the experimental pipeline, but they will require large numbers of human
samples and several years of follow-up to evaluate.

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https://www.nature.com/articles/nrdp201676.pdf