Tuberculosis

Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains ofmycobacteria, usually Mycobacterium tuberculosis.[1] Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air hen people ho have an active T! infection cough, snee"e, or other ise transmit their saliva through the air. #ost infections areasymptomatic and latent, but about one in ten latent infections eventually progresses to active disease hich, if left untreated, kills more than $%& of those so infected. 'ne third of the orld(s population is thought to have been infected ith M. tuberculosis,[)] ith ne infections occurring at a rate of about one per second. In *%%+, there ere an estimated 1).+ million chronic active cases globally, hile in *%1%, there ere an estimated ,., million ne cases and 1.$ million associated deaths, mostly occurring in developing countries. The absolute number of tuberculosis cases has been decreasing since *%%-, and ne cases have decreased since *%%*.[$] The distribution of tuberculosis is not uniform across the globe. about ,%& of the population in many /sian and /frican countries test positive in tuberculin tests, hile only $01%& of the 1nited 2tates population tests positive. [1] #ore people in the developing orld contract tuberculosis because of compromised immunity, largely due to high rates of 3I4 infection and the corresponding development of /I52.

Signs and symptoms

The main symptoms of variants and stages of tuberculosis are given, ith many symptoms overlapping ith other variants, hile others are more (but not entirely) specific for certain variants. #ultiple variants may be present simultaneously. /bout $01%& of those ithout 3I4, infected ith tuberculosis, develop active disease during their lifetimes. In contrast, )%& of those coinfected ith 3I4 develop active disease. Tuberculosis may infect any part of the body, but commonly occurs in the lungs(kno n as pulmonary tuberculosis).

67trapulmonary T! occurs hen tuberculosis develops outside of the lungs. 67trapulmonary T! may coe7ist ith pulmonary T! as ell.8eneral signs and symptoms include fever, chills, night s eats, loss of appetite, eight loss, and fatigue,and significant finger clubbing may also occur.

Pulmonary If a tuberculosis infection does become active, it most commonly involves the lungs (in about 9%& of cases). 2ymptoms may include chest painand a prolonged cough producing sputum. /bout *$& of people may not have any symptoms (i.e. they remain :asymptomatic:). 'ccasionally, people may cough up blood in small amounts, and in very rare cases, the infection may erode into the pulmonary artery, resulting in massive bleeding (;asmussen(s aneurysm).
Tuberculosis may become a chronic illness and cause e7tensive scarring in the upper lobes of the lungs. The upper lung lobes are more fre<uently affected by tuberculosis than the lo er ones. The reason for this difference is not entirely clear. [1] It may be due either to better air flo ,or to poor lymph drainage ithin the upper lungs.

Extrapulmonary
In 1$0*%& of active cases, the infection spreads outside the respiratory organs, causing other kinds of T!. These are collectively denoted as :e7trapulmonary tuberculosis:. 67trapulmonary T! occurs more commonly in immunosuppressed persons and young children. In those ith 3I4, this occurs in more than $%& of cases. =otable e7trapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and >oints (in ?ott(s disease of the spine), among others. @hen it spreads to the bones, it is also kno n as :osseous tuberculosis:.a form of osteomyelitis. / potentially more serious, idespread form of T! is called :disseminated: T!, commonly kno n as miliary tuberculosis. #iliary T! makes up about 1%& of e7trapulmonary cases.

Causes
#ycobacteria

2canning electron micrograph of #ycobacterium tuberculosis The main cause of T! is #ycobacterium tuberculosis, a small, aerobic, nonmotile bacillus. The high lipid content of this pathogen accounts for many of its uni<ue clinical characteristics. It divides every 1- to *% hours, hich is an e7tremely slo rate compared ith other bacteria, hich usually divide in less than an hour. #ycobacteria have an outer membrane lipid bilayer. If a 8ram stain is performed, #T! either stains very eakly :8ramApositive: or does not retain dye as a result of the high lipid and mycolic acid content of its cell all. #T! can ithstand eak disinfectants and survive in a dry state for eeks. In nature, the bacterium can gro only ithin the cells of a host organism, but #. tuberculosis can be cultured in the laboratory. 1sing histological stains on e7pectorated samples from phlegm (also called :sputum:), scientists can identify #T! under a regular (light) microscope. 2ince #T! retains certain stains even after being treated ith acidic solution, it is classified as an acidAfast bacillus (/B!).The most common acidAfast staining techni<ues are the Ciehl0=eelsen stain, hich dyes /B!s a bright red that stands out clearly against a blue background,and the auramineArhodamine stain follo ed by fluorescence microscopy. The #. tuberculosis comple7 (#T!D) includes four other T!Acausing mycobacteriaE #. bovis, #. africanum, #. canetti, and #. microti. #. africanum is not idespread, but it is a significant cause of tuberculosis in parts of /frica. #. bovis as once a common cause of tuberculosis, but the introduction of pasteuri"ed milk has largely eliminated this as a public health problem in developed countries. #. canetti is rare and seems to be limited to the 3orn of /frica, although a fe cases have been seen in /frican emigrants. #. microti is also rare and is mostly seen in immunodeficient people, although the prevalence of this pathogen has possibly been significantly underestimated. 'ther kno n pathogenic mycobacteria include #. leprae, #. avium, and #. kansasii. The latter t o species are classified as :nontuberculous mycobacteria: (=T#). =T# cause neither T! nor leprosy, but they do cause pulmonary diseases that resemble T!.

Risk factors

/ number of factors make people more susceptible to T! infections. The most important risk factor globally is 3I4. 1)& of all T! cases are infected by the virus.This is a particular problem in subA2aharan /frica, here rates of 3I4 are high. Tuberculosis is closely linked to both overcro ding and malnutrition, making it one of the principal diseases of poverty. Those at high risk thus includeE people ho in>ect illicit drugs, inhabitants and employees of locales here vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resourceApoor communities, highArisk ethnic minorities, children in close contact ith highArisk category patients and health care providers serving these clients.Dhronic lung disease is another significant risk factor A ith silicosis increasing the risk about )%Afold. Those ho smoke cigarettes have nearly t ice the risk of T! than nonsmokers.'ther disease states can also increase the risk of developing tuberculosis, including alcoholism and diabetes mellitus (threefold increase). Dertain medications, such as corticosteroids and infli7imab (an antiAFT=B monoclonal antibody) are becoming increasingly important risk factors, especially in the developed orld. There is also a genetic susceptibility for hich overall importance is still undefined.

Transmission
@hen people ith active pulmonary T! cough, snee"e, speak, sing, or spit, they e7pel infectious aerosol droplets %.$ to $.% Gm in diameter. / single snee"e can release up to H%,%%% droplets.6ach one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very lo (the inhalation of fe er than 1% bacteria may cause an infection). ?eople ith prolonged, fre<uent, or close contact ith people ith T! are at particularly high risk of becoming infected, ith an estimated **& infection rate. / person ith active but untreated tuberculosis may infect 1%01$ (or more) other people per year. Transmission should only occur from people ith active T! A those ith latent infection are not thought to be contagious.The probability of transmission from one person to another depends upon several factors, including the number of infectious droplets e7pelled by the carrier, the effectiveness of ventilation, the duration of e7posure, the virulence of the #. tuberculosis strain, the level of immunity in the uninfected person, and others. The cascade of personA toAperson spread can be circumvented by effectively segregating those ith active (:overt:) T! and putting them on antiAT! drug regimens. /fter about t o eeks of effective treatment, sub>ects ith nonresistant active infections generally do not remain contagious to others. If someone does become infected, it typically takes three to four eeks before the ne ly infected person becomes infectious enough to transmit the disease to others.

Pathogenesis
/bout 9%& of those infected ith #. tuberculosis have asymptomatic, latent T! infections (sometimes called IT!I), ith only a 1%& lifetime chance that the latent infection ill progress to overt, active tuberculous disease. In those ith 3I4, the risk of developing active T! increases to nearly 1%& a year. If effective treatment is not given, the death rate for active T! cases is up to --&. T! infection begins hen the mycobacteria reach the pulmonary alveoli, here they invade and replicate ithin endosomes of alveolar macrophages. The primary site of infection in the lungs, kno n as the :8hon focus:, is generally located in either the upper part of the lo er lobe, or the lo er part of the upper lobe. Tuberculosis of the lungs may also occur via infection from the blood stream. This is kno n as a 2imon focus and is typically found in the top of the lung.This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones. /ll parts of the body can be affected by the disease, though for unkno n reasons it rarely affects the heart, skeletal muscles, pancreas, or thyroid. Tuberculosis is classified as one of the granulomatous inflammatory diseases. #acrophages, T lymphocytes, ! lymphocytes, and fibroblasts are among the cells that aggregate to form granulomas, ith lymphocytes surrounding the infected macrophages. The granuloma prevents dissemination of the mycobacteria and provides a local environment for interaction of cells of the immune system. !acteria inside the granuloma can become dormant, resulting in latent infection. /nother feature of the granulomas is the development of abnormal cell death (necrosis) in the center of tubercles. To the naked eye, this has the te7ture of soft, hite cheese and is termed caseous necrosis. If T! bacteria gain entry to the bloodstream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, hite tubercles in the tissues. This severe form of T! disease, most common in young children and those ith 3I4, is called miliary tuberculosis. ?eople ith this disseminated T! have a high fatality rate even ith treatment (about )%&). In many people, the infection a7es and anes. Tissue destruction and necrosis are often balanced by healing and fibrosis. /ffected tissue is replaced by scarring and cavities filled ith caseous necrotic material. 5uring active disease, some of these cavities are >oined to the air passages bronchi and this material can be coughed up. It contains living bacteria, and so can spread the infection. Treatment ith appropriate antibiotics kills bacteria and allo s healing to take place. 1pon cure, affected areas are eventually replaced by scar tissue.[H,]

Diagnosis
5iagnosing active tuberculosis based merely on signs and symptoms is difficult.as is diagnosing the disease in those ho are immunosuppressed. / diagnosis of T! should, ho ever, be considered in those ith signs of lung disease or constitutional symptoms lasting longer than t o eeks. / chest JAray and multiple sputum cultures for acidAfast bacilli are typically part of the initial evaluation. InterferonAK release assays and tuberculin skin tests are of little use in the developing orld.I8;/ have similar limitations in those ith 3I4. / definitive diagnosis of T! is made by identifying #. tuberculosis in a clinical sample (e.g. sputum, pus, or a tissue biopsy). 3o ever, the difficult culture process for this slo Agro ing organism can take t o to si7 eeks for blood or sputum culture.Thus, treatment is often begun before cultures are confirmed. =ucleic acid amplification tests and adenosine deaminase testing may allo rapid diagnosis of T!.These tests, ho ever, are not routinely recommended, as they rarely alter ho a person is treated.!lood tests to detect antibodies are not specific or sensitive, so they are not recommended. The #antou7 tuberculin skin test is often used to screen people at high risk for T!. Those ho have been previously immuni"ed may have a falseApositive test result. The test may be falsely negative in those ith sarcoidosis, 3odgkin(s lymphoma, malnutrition, or most notably, in those ho truly do have active tuberculosis.Interferon gamma release assays (I8;/s), on a blood sample, are recommended in those ho are positive to the #antou7 test. These are not affected by immuni"ation or most environmental mycobacteria, so they generate fe er falseApositive results. 3o ever they are affected by #. s"ulgai, #. marinum and #. kansasii. I8;/s may increase sensitivity hen used in addition to the skin test but may be less sensitive than the skin test hen used alone.

Prevention
Tuberculosis prevention and control efforts primarily rely on the vaccination of infants and the detection and appropriate treatment of active cases. The @orld 3ealth 'rgani"ation has achieved some success ith improved treatment regimens, and a small decrease in case numbers.

Vaccines
The only currently available vaccine as of *%11 is bacillus Dalmette08uLrin (!D8) hich, hile it is effective against disseminated disease in childhood,

confers inconsistent protection against contracting pulmonary T!. =evertheless, it is the most idely used vaccine orld ide, ith more than 9%& of all children being vaccinated. 3o ever, the immunity it induces decreases after about ten years./s tuberculosis is uncommon in most of Danada, the 1nited Mingdom, and the 1nited 2tates, !D8 is only administered to people at high risk. ?art of the reasoning arguing against the use of the vaccine is that it makes the tuberculin skin test falsely positive, and therefore, of no use in screening. / number of ne vaccines are currently in development. The @orld 3ealth 'rgani"ation declared T! a :global health emergency: in 199),and in *%%-, the 2top T! ?artnership developed a 8lobal ?lan to 2top Tuberculosis that aims to save 1H million lives bet een its launch and *%1$./ number of targets they have set are not likely to be achieved by *%1$, mostly due to the increase in 3I4Aassociated tuberculosis and the emergence of multiple drugA resistant tuberculosis (#5;AT!). / tuberculosis classification system developed by the /merican Thoracic 2ociety is used primarily in public health programs.

Management
Treatment of T! uses antibiotics to kill the bacteria. 6ffective T! treatment is difficult, due to the unusual structure and chemical composition of the mycobacterial cell all, hich hinders the entry of drugs and makes many antibiotics ineffective. The t o antibiotics most commonly used are isonia"id and rifampicin, and treatments can be prolonged, taking several months. Iatent T! treatment usually employs a single antibiotic, hile active T! disease is best treated ith combinations of several antibiotics to reduce the risk of the bacteria developing antibiotic resistance.?eople ith latent infections are also treated to prevent them from progressing to active T! disease later in life. 5irectly observed therapy, i.e. having a health care provider atch the person take their medications, is recommended by the @3' in an effort to reduce the number of people not appropriately taking antibiotics. The evidence to support this practice over people simply taking their medications independently is poor.#ethods to remind people of the importance of treatment do ho ever appear effective. The recommended treatment of ne Aonset pulmonary tuberculosis, as of *%1%, is si7 months of a combination of antibiotics containing rifampicin, isonia"id, pyra"inamide and ethambutol for the first t o months, and only rifampicin and isonia"id for the last four months. @here resistance to isonia"id is high, ethambutol may be added for the last four months as an alternative. ;ecurrent disease If tuberculosis recurs, testing to determine to hich antibiotics it is sensitive is important before determining treatment. If multiple drugAresistant T! (#5;A

T!) is detected, treatment ith at least four effective antibiotics for 1, to *H months is recommended.

Medication resistance
?rimary resistance occurs hen a person becomes infected ith a resistant strain of T!. / person ith fully susceptible T! may develop secondary (ac<uired) resistance during therapy because of inade<uate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using lo A<uality medication. 5rugAresistant T! is a serious public health issue in many developing countries, as its treatment is longer and re<uires more e7pensive drugs. #5;AT! is defined as resistance to the t o most effective firstAline T! drugsE rifampicin and isonia"id. 67tensively drugAresistant T! is also resistant to three or more of the si7 classes of secondAline drugs. Totally drugAresistant T!, hich as first observed in *%%) in Italy, but not idely reported until *%1*, is resistant to all currently used drugs.

Prognosis
?rogression from T! infection to overt T! disease occurs hen the bacilli overcome the immune system defenses and begin to multiply. In primary T! disease (some 10$& of cases), this occurs soon after the initial infection.3o ever, in the ma>ority of cases, a latent infection occurs ith no obvious symptoms. These dormant bacilli produce active tuberculosis in $01%& of these latent cases, often many years after infection. The risk of reactivation increases ith immunosuppression, such as that caused by infection ith 3I4. In people coinfected ith #. tuberculosis and 3I4, the risk of reactivation increases to 1%& per year. 2tudies using 5=/ fingerprinting of #. tuberculosis strains have sho n reinfection contributes more substantially to recurrent T! than previously thought, ith estimates that it might account for more than $%& of reactivated cases in areas here T! is common. The chance of death from a case of tuberculosis is about H& as of *%%,, do n from ,& in 199$.

Epidemiology
In *%%+, the prevalence of T! per 1%%,%%% people as highest in subA 2aharan /frica, and as also relatively high in /sia. ;oughly oneAthird of the orld(s population has been infected ith #. tuberculosis, and ne infections occur at a rate of one per second on a global scale. 3o ever, most infections ith #. tuberculosis do not cause T! disease,and 9%0

9$& of infections remain asymptomatic. In *%%+, there ere an estimated 1).+ million chronic active cases. In *%1%, there ere ,., million ne cases of T! diagnosed, and 1.H$ million deaths, most of these occurring in developing countries.'f these 1.H$ million deaths, about %.)$ million occur in those coinfected ith 3I4. Tuberculosis is the second most common cause of death from infectious disease (after those due to 3I4N/I52). The absolute number of tuberculosis cases (:prevalence:) has been decreasing since *%%$, hile ne cases (:incidence:) have decreased since *%%*.[$] Dhina has achieved particularly dramatic progress, ith an appro7imate ,%& reduction in its T! mortality rate bet een 199% and *%1%. Tuberculosis is more common in developing countries. about ,%& of the population in many /sian and /frican countries test positive in tuberculin tests, hile only $01%& of the 12 population test positive. 3opes of totally controlling the disease have been dramatically dampened because of a number of factors, including the difficulty of developing an effective vaccine, the e7pensive and timeA consuming diagnostic process, the necessity of many months of treatment, the increase in 3I4Aassociated tuberculosis, and the emergence of drugAresistant cases in the 19,%s. In *%%+, the country ith the highest estimated incidence rate of T! as 2 a"iland, ith 1,*%% cases per 1%%,%%% people. India had the largest total incidence, ith an estimated *.% million ne cases. In developed countries, tuberculosis is less common and is found mainly in urban areas. ;ates per 1%%,%%% people in different areas of the orld hereE globally 1+,, /frica ))*, the /mericas )-, 6astern #editerranean 1+), 6urope -), 2outheast /sia *+,, and @estern ?acific 1)9 in *%1%.In Danada and /ustralia, tuberculosis is many times more common among the aboriginal peoples, especially in remote areas. In the 1nited 2tates the /borigines have a fivefold greater mortality from T!. The incidence of T! varies ith age. In /frica, it primarily affects adolescents and young adults. 3o ever, in countries here incidence rates have declined dramatically (such as the 1nited 2tates), T! is mainly a disease of older people and the immunocompromised.

Main article:

istory of tuberculosis

6gyptian mummy in the !ritish #useum A tubercular decay has been found in the spines of 6gyptian mummies. Tuberculosis has been present in humans since anti<uity at the latest. The earliest unambiguous detection of #. tuberculosis involves evidence of the disease

in the remains of bison dated to appro7imately 1+,%%% years ago. 3o ever, hether tuberculosis originated in bovines, then as transferred to humans, or hether it diverged from a common ancestor, is currently unclear. / comparison of the genes of #. tuberculosis comple7 (#T!D) in humans to #T!D in animals suggests humans did not ac<uire #T!D from animals during animal domestication, as as previously believed. !oth strains of the tuberculosis bacteria share a common ancestor, hich could have infected humans as early as the =eolithic ;evolution. 2keletal remains sho prehistoric humans (H%%% !D) had T!, and researchers have found tubercular decay in the spines of 6gyptian mummies dating from )%%%0*H%% !D.?hthisis is a 8reek ord for consumption, an old term for pulmonary tuberculosis. around H-% !D, 3ippocrates identified phthisis as the most idespread disease of the times. It as said to involve fever and the coughing up of blood, hich as almost al ays fatal.8enetic studies suggest T! as present in the /mericas from about the year 1%% /5. !efore the Industrial ;evolution, folklore often associated tuberculosis ith vampires. @hen one member of a family died from it, the other infected members ould lose their health slo ly. ?eople believed this as caused by the original person ith T! draining the life from the other family members. /lthough the pulmonary form associated ith tubercles as established as a pathology by 5r ;ichard #orton in 1-,9, due to the variety of its symptoms, T! as not identified as a single disease until the 1,*%s, and as not named tuberculosis until 1,)9 by O. I. 2chPnlein. 5uring the years 1,),01,H$, 5r. Oohn Droghan, the o ner of #ammoth Dave, brought a number of people ith tuberculosis into the cave in the hope of curing the disease ith the constant temperature and purity of the cave air. they died ithin a year. 3ermann !rehmer opened the first T! sanatorium in 1,$9 in 2okoQo sko, ?oland.

Dr! Robert "och discovered the tuberculosis bacillus!

The bacillus causing tuberculosis, #ycobacterium tuberculosis, as identified and described on *H #arch 1,,* by ;obert Moch. 3e received the =obel ?ri"e in physiology or medicine in 19%$ for this discovery. Moch did not believe the bovine (cattle) and human tuberculosis diseases ere similar, hich delayed the recognition of infected milk as a source of infection. Iater, the risk of transmission from this source as dramatically reduced by the invention of the pasteuri"ation process. Moch announced a glycerine e7tract of the tubercle bacilli as a :remedy: for tuberculosis in 1,9%, calling it (tuberculin(. @hile it as not

effective, it as later successfully adapted as a screening test for the presence of presymptomatic tuberculosis. /lbert Dalmette and Damille 8uLrin achieved the first genuine success in immuni"ation against tuberculosis in 19%-, using attenuated bovineAstrain tuberculosis. It as called bacillus of Dalmette and 8uLrin (!D8). The !D8 vaccine as first used on humans in 19*1 in Brance, but only received idespread acceptance in the 12/, 8reat !ritain, and 8ermany after @orld @ar II. Tuberculosis caused the most idespread public concern in the 19th and early *%th centuries as an endemic disease of the urban poor. In 1,1$, one in four deaths in 6ngland as due to :consumption:. !y 191,, one in si7 deaths in Brance as still caused by T!. /fter determining the disease as contagious in the 1,,%s, T! as put on a notifiable disease list in !ritain, campaigns ere started to stop people from spitting in public places, and the infected poor ere :encouraged: to enter sanatoria that resembled prisons (the sanatoria for the middle and upper classes offered e7cellent care and constant medical attention). @hatever the (purported) benefits of the :fresh air: and labor in the sanatoria, even under the best conditions, $%& of those ho entered died ithin five years (circa 191-). In 6urope, rates of tuberculosis began to rise in the early 1-%%s to a peak level in the 1,%%s, hen it caused nearly *$& of all deaths. #ortality then decreased nearly 9%& by the 19$%s. Improvements in public health began significantly reducing rates of tuberculosis even before the arrival of streptomycin and other antibiotics, although the disease remained a significant threat to public health such that hen the #edical ;esearch Douncil as formed in !ritain in 191), its initial focus as tuberculosis research. In 19H-, the development of the antibiotic streptomycin made effective treatment and cure of T! a reality. ?rior to the introduction of this drug, the only treatment (e7cept sanatoria) as surgical intervention, including the :pneumothora7 techni<ue:, hich involved collapsing an infected lung to :rest: it and allo tuberculous lesions to heal.The emergence of #5;AT! has again introduced surgery as an option ithin the generally accepted standard of care in treating T! infections. Durrent surgical interventions involve removal of pathological chest cavities (:bullae:) in the lungs to reduce the number of bacteria and to increase the e7posure of the remaining bacteria to drugs in the bloodstream, thereby simultaneously reducing the total bacterial load and increasing the effectiveness of systemic antibiotic therapy.3opes of completely eliminating T! (cf. smallpo7) ere dashed after the rise of drugAresistant strains in the 19,%s. The subse<uent resurgence of tuberculosis resulted in the declaration of a global health emergency by the @orld 3ealth 'rgani"ation in 199). 2ociety and culture

The @orld 3ealth 'rgani"ation and the !ill and #elinda 8ates Boundation are subsidi"ing a ne fastAacting diagnostic test for use in lo A and middleAincome countries. #any resourceApoor places as of *%11 still only have access to sputum microscopy. India had the highest total number of T! cases orld ide in *%1%, in part due to poor disease management ithin the private health care sector. ?rograms such as the ;evised =ational Tuberculosis Dontrol ?rogram are helping to reduce T! levels amongst people receiving public health care.

;esearch
The !D8 vaccine has limitations, and research to develop ne T! vaccines is ongoing. / number of potential candidates are currently in phase I and II clinical trials. T o main approaches are being used to attempt to improve the efficacy of available vaccines. 'ne approach involves adding a subunit vaccine to !D8, hile the other strategy is attempting to create ne and better live vaccines.#4/,$/, an e7ample of a subunit vaccine, currently in trials in 2outh /frica, is based on a genetically modified vaccinia virus. 4accines are hoped to play a significant role in treatment of both latent and active disease. To encourage further discovery, researchers and policymakers are promoting ne economic models of vaccine development, including pri"es, ta7 incentives, and advance market commitments. / number of groups, including the 2top T! ?artnership, the 2outh /frican Tuberculosis 4accine Initiative, and the /eras 8lobal T! 4accine Boundation, are involved ith research. /mong these, the /eras 8lobal T! 4accine Boundation received a gift of more than R*,% million (12) from the !ill and #elinda 8ates Boundation to develop and license an improved vaccine against tuberculosis for use in high burden countries.