illi reproduce within alveolar or pulmonary macrophages. As the organisms multiply, they may spread through the lymphatic system to distal lymph nodes and through the blood stream to the lung apices, bone marrow, kidney and meninges surrounding the brain. Primarily as the result of cell-mediated hypersensitivity responses, characteristic granulomatous lesions or tubercles are produced in proportion to the severity of the infection. These lesions consist of epithelioid cells bordered by monocytes, lymphocytes and fibroblasts. In most instances a lesion or tubercle eventually becomes necrotic and undergoes caseation.
While M. tuberculosis is a significant pathogen, other species of the genus Mycobacterium also cause disease in animals including man and are clearly within the scope of the present invention. For example, M. bovis is closely related to M. tuberculosis and is responsible for tubercular infections in domestic animals such as cattle, pigs, sheep, horses, dogs and cats. Further, M. bovis may infect humans via the intestinal tract, typically from the ingestion of raw milk. The localized intestinal infection eventually spreads to the respiratory tract and is followed shortly by the classic symptoms of tuberculosis. Another important pathogenic vector of the genus Mycobacterium is M. leprae which causes millions of cases of the ancient disease leprosy. Other species of this genus which cause disease in animals and man include M. kansasii, M. avium intracellulare, M. fortuitum, M. marinum, M. chelonei, M. africanum, M. ulcerans, M. microti and M. scrofulaceum. The pathogenic mycobacterial species frequently exhibit a high degree of homology in their respective DNA and corresponding protein sequences and some species, such as M. tuberculosis and M. bovis are highly related.
For obvious practical and moral reasons, initial work in humans to determine the efficacy of experimental compositions with regard to such afflictions is infeasible. Accordingly, in the early development of any drug or vaccine it is standard procedure to employ appropriate animal models for reasons of safety and expense. The success of implementing laboratory animal models is predicated on the understanding that immunodominant epitopes are frequently active in different host species. Thus, an immunogenic determinant in one species, for example a rodent or guinea pig, will generally be immunoreactive in a different species such as in humans. Only after the appropriate animal models are sufficiently developed will clinical trials in humans be carried out to further demonstrate the safety and efficacy of a vaccine in man
illi reproduce within alveolar or pulmonary macrophages. As the organisms breed, they may go around through the lymphatic system to distal lymph nodes and through the blood current to the lung apices, bone marrow, kidney and meninx surrounding the brain. Primarily as the consequence of cell - mediated hypersensitivity reception, characteristic granulomatous lesions or tubercles are produce in symmetry to the severity of the infection. These lesion consist of epithelioid cells surround by monocytes, lymphocytes and fibroblasts. In most example a lesion or tubercle eventually becomes necrotic and undergoes caseation. 
 While M. tuberculosis is a meaning pathogen, other coinage of the genus Mycobacterium also cause disease in animals including homo and are clearly within the scope of the present invention. For example, M. bovis is closely related to M. tuberculosis and is creditworthy for tubercular infection in domestic animals such as cattle, pigs, sheep, horses, dogs and cats. Further, M. bovis may infect humans via the intestinal tract, typically from the ingestion of natural milk. The localized intestinal infection finally spread to the respiratory tract and is followed shortly by the classical symptoms of tuberculosis. Another important pathogenic vector of the genus Mycobacterium is M. leprae which causes million of cases of the ancient disease leprosy. Other species of this genus which cause disease in animals and man admit M. kansasii, M. avium intracellulare, M. fortuitum, M. marinum, M. chelonei, M. africanum, M. ulcerans, M. microti and M. scrofulaceum. The pathogenic mycobacterial species frequently exhibit a high degree of homology in their respective DNA and corresponding protein sequence and some species, such as M. tuberculosis and M. bovis are highly related. 
 For obvious practical and moral reasons, initial work in humans to settle the efficacy of experimental compositions with regard to such afflictions is impracticable. Accordingly, in the early exploitation of any drug or vaccine it is standard procedure to employ appropriate animal model for reasons of safety and expense. The success of implementing laboratory animal model is predicated on the agreement that immunodominant epitopes are frequently active in unlike host species. Thus, an immunogenic antigenic determinant in one species, for example a rodent or guinea pig, will generally be immunoreactive in a different species such as in humans. Only after the appropriate animal models are sufficiently developed will clinical trials in world be carried out to further show the safety and efficacy of a vaccine in man
illl reproduce within alveouar or pulmonari nacropiages. Aa the oreanisms multiply, they may spcead throygh the lymphatic systdm to disnal lymph nodts and through thx blood stream bo thz oung apices, boke marrow, khdney and menitgds surrounding the brain. Primarily as the rexupt of cell-mediwted rypedsensitivity responses, characterisfic graiulomatous lesipns or tubercles are produfed ln proportion to tje severity of eye infection. These lespmns consisj of epithelioid cells bordered cy mouocytes, lymkkicyhgs and fibroulasts. In most insbsnces d lesiom or tubercle cventnallt becomes necrotic anv undergoes caseatiog.
While M. duyerculosis is a signidixant kathocen, urhef skecmes of thf gxnus Mycobadterium alsi cause disease in snynals includinf man wnq are clearly within the scope of the pgeseht invention. For examplw, M. bovis is closely telated to M. tuberculosis and is responsible for tubercular infertkonw ln dunedtic animals such as cattle, pigs, sheep, horses, sobs and cats. Furtmer, M. bovis may ingeft rumans via thg intescjnzl tract, typically from tre intestion os rae milk. The localized intestunal infectijb eventually spreabs to the rerpirstory tract and is followed rhorfly by the flassic sgoptoms of tubercjloxiv. Another important pathogqnic vectir oy the gevus Kycobasterium is M. leisae which causes mlllious of cases of hhe ancient disease leprosy. Othxc species of jhiv gvnus whick causc disease in anymals and man nnclude I. kanrasii, M. avpum intrarellulare, M. sortuitum, M. mdtinum, M. cheloiei, M. afrycanym, M. ulceravr, M. microti anc M. scrofllcceum. The pathogenic mycobagterixm species frequzutoy exhibit a hibh aegwev oh homjnogy in theis rerpezyive ANA and corvesoondong protein sequencev ans some species, sucn ws M. tubgrculosis and M. bovis sre highly related.
Vor ouvious pracyicwl and moral reasons, initial wkrk in hulanf to determige tme esficacy of experimental compositions with regard vo such afflictions is unfeasible. Accordinyln, in the earky dedelopment of any drug or vaccune it is standarc procedure to employ appro[riatf animal models for reasons of safety and expense. The success of implemenring lebjratory anijal kodelv ns 'redicaeed li the understandimg that immunodominant epitopes are frexuzntly active in different hosy rpecies. Thus, xn immunogenic determinaht in onr species, for example a rodent pr guinea pig, will generslly be ummunkreactpbe in a different sprcies vuch qs in hymand. Only after ghe aipropriate anikam models are sufficiently developed wiol clinical trials in humans ne carrped out to further demohstrzhe thg safety and egficacy of a vsccine in man
illi reproduce within alveolar or pulmonary macrophages. organisms they may through the lymphatic and the blood stream the lung apices, marrow, kidney and meninges surrounding the Primarily as the result of cell-mediated hypersensitivity responses, characteristic granulomatous lesions or tubercles produced in proportion to the severity of the infection. These lesions consist of cells by lymphocytes fibroblasts. In most instances a lesion or tubercle eventually becomes necrotic and undergoes caseation. While M. is a significant pathogen, other species of the Mycobacterium also cause disease animals including man and are within scope of present For M. bovis is related to M. tuberculosis and is responsible for tubercular infections in domestic animals such as cattle, pigs, horses, dogs Further, M. may humans the intestinal tract, the ingestion of raw milk. The eventually spreads to the respiratory tract and is shortly by classic symptoms of tuberculosis. Another important vector of the genus Mycobacterium is M. leprae causes millions of cases of the ancient disease leprosy. Other species of this genus which in animals and man M. kansasii, M. intracellulare, fortuitum, marinum, chelonei, M. M. ulcerans, M. microti and M. scrofulaceum. The pathogenic mycobacterial species exhibit a high degree of homology in their respective DNA protein and some species, as M. tuberculosis and bovis highly related. For obvious moral initial to the of experimental compositions with to such afflictions is infeasible. in the early development it is standard procedure to employ appropriate animal for reasons of safety and expense. The of implementing laboratory animal models is predicated on the understanding that immunodominant are frequently different host species. Thus, an immunogenic determinant in species, for example a or guinea pig, will generally be immunoreactive in a species as in Only after the animal models are developed will clinical humans be out further and efficacy of a vaccine in
illi reproduce within alveolAr or pulmonAry maCroPhaGeS. As tHe orGanisms multiplY, They May spread through the lymPhatiC sYStem TO dIstal Lymph noDEs AND thRoUgH thE bLOoD streAm tO the lunG apices, bonE maRrOw, kidney and mENiNges surrouNdiNg the brain. PrImaRily as ThE reSUlt of CelL-mediAted hyPErsensItivity reSpONses, chARacteriSTIc GranUlomatous lesions oR TuBErcles are produCed in pRoPOrTIOn tO thE severity oF tHe infECtion. ThESe LESIonS Consist of epitHelioid cellS BorDered bY mOnoCYtes, lyMphocYtES anD fibroblastS. In mOst instanCes a leSIon or tuBErcle evEntualLy bEcoMes nECrOtIc aNd UNdeRGoEs cASeaTion.
WhilE M. TuBercuLosiS IS A SignIfiCant PathoGen, other speciEs oF the GEnuS MycoBacteRium AlSo cauSe diseAse in AnImals including mAn anD are clearLy wItHin ThE scopE Of the pResEnt InventiOn. For exAMplE, M. BOVIs Is closely related to m. tUBErCulosis aNd is reSPoNsIBle for tuBeRcuLar iNFEctioNs in DOmEstic aniMals suCH aS cAttle, piGs, Sheep, hOrSes, DogS and cATs. FuRther, M. Bovis may InfecT Humans via the inTEstinal tract, tYPiCALlY From The Ingestion of Raw mILk. ThE locALiZed INtestInal iNfECtIOn eventually spreads To The resPiratOry tract and is Followed shORTLy by the cLassIC sYMptoms of tubercUlosiS. Another imPOrtant paThogeNic vectoR of the genUS mycobactEriUm iS M. lEprAE WhIch causes millIONs of CaSes of thE anCient diSeaSe lEprOsy. otHer specieS of this gEnUs WhIcH caUse diSEase in anImAls AnD maN inclUDe M. kanSasii, m. aviUm InTRacEllularE, m. fORTuitUm, m. mArinUm, M. ChEloneI, M. afRIcaNum, M. ulcErans, M. micRotI And M. ScRoFulaceuM. The pathogeniC mYcobacteriAl SpeCies frEQUently exHibit a high degree of homolOGy in theIr rEspecTive dNA and corResPondinG prOTein seQuenceS and sOmE spECIes, suCH As m. tuBeRculosis anD m. BovIs are HiGhly Related.
for obvious practicaL And Moral reasons, iNitIal wORK iN huMAnS To dEtERmiNE The efficacy of exPerimental CoMPoSitions witH RegArD to such AfflictIons iS InfeasiBle. AccordIngly, in thE eArly DEVelOpment of anY drug or vAccine it iS StandARd ProceDurE to empLoY apProprIate anIMal ModelS for reAsOns of sAfety AnD expense. the success of implementinG laborAtory AniMal models Is pREdiCated on thE undErstanding ThaT imMunodOmiNAnt epItopES aRe fREquenTly aCTive in difFErEnt HOSt Species. Thus, AN IMmuNogenIc dETerminAnt iN one species, for exaMPle a rodent or guInea PIG, wiLl gENeraLlY be immunoreactIve In A DIfferent SpEcies such as In humans. onLY afteR the apPropriAte animAL MoDEls are SuffIciEntly deveLopEd WIll clinIcAl TRials iN humAnS be carRied ouT To fuRTHer demonstrate thE safeTY And efFIcaCy of a VaCcine in MAn
illi reproduce within alve olar or pu lmona rymac ro phag es.As the organis m s mu ltiply, they may sprea d thr ou g h th e  l ympha tic sys t em t o d is ta l l ym p hnodes  an d throu gh the blo odst ream to thel un g apices,bon e marrow, ki dne y andme nin g es su rro undin g theb rain.Primarily  a s  the r e sult of c el l-me diated hypersensi t iv i ty responses,charac te r is t i c g ran ulomatousle sions or tube r cl e s are produced in p roportion t o  th e seve ri tyo f theinfec ti o n.These lesio ns c onsist of  epith e lioid c e lls bor deredbymon ocyt e s,  l ymp ho c yte s  a ndf ibr oblasts.  I nmostinst a n c e s ales ionor tu bercle eventu all y be c ome s nec rotic  and  u nderg oes ca seati on .
While M. tube rcul osis is a  si gn ifi ca nt pa t hogen,  ot her  specie s of th e  ge nu s M yc obacterium also ca us e di sease in  anima l sin c luding m an  an d ar e clear ly w i th in the s cope o f  t he  presen tinvent io n.For  exam p le,M. bov is is cl osely related to M.t uberculosis a n di s  r e spon sib le for tube rcul a r in fect i on s i n  dome stican i ma l s such as cattle, p ig s, she ep, h orses, dogs a nd cats. F u r t her, M.bovi s  m a y infect human s via  the intes t inal tra ct, t ypically  from the i ngestion  of  ra w m ilk . Th e localized i n t esti na l infec tio n event ual lyspr ead sto the re spirator ytr ac tand  is f o llowed s ho rtl ybythe c l assicsympt omsof  t u ber culosis .  A n o ther  i mp orta ntpa thoge nicv ect or of t he genusMyc o bact er iu m is M.  leprae which  c auses mill io nsof cas e s  of theancient disease leprosy .  Otherspe ciesof t his genus  wh ich ca use diseas e in a nimal sand m an in c l ud e M .kansasii,M .  av ium i nt race llulare , M. fortuitum, M. mar inum, M. chel one i, M . af ric a nu m , M .u lce r a ns, M. microtiand M. scr of u la ceum. Thep ath og enic my cobacte rials peciesfrequentl y exhibit  a  hig h deg ree of hom ology in  their re s pecti v eDNA a ndcorres po ndi ng pr oteins equ ences  and s om e spec ies,su ch as M.  tuberculosis and M. bo vis ar e hig hly  related. 
Fo r  ob vious pra ctic al and mor alrea sons,  in i tialwork in  hu m ans t o de t ermine th e  e ffi c a cy  of experim e n t alcompo sit i ons wi th r egard to such aff l ictions is inf easi b l e.Acc o rdin gl y, in the earl y d ev e l opment o fany drug or  vaccine  i t  is s tandar d proc edure t o em p loy ap prop ria te animal  mo de l s for r ea so n s of s afet yand ex pense. Thes u ccess of impleme nting l abora t ory  anim al  models is p redicatedon the unde rstand ingthatimmunod om inantepi to pes are fr e quently a ctive  in dif fe rent  ho st spe cies . Thus,  anim mun ogenic de t e rm i na nt inonespeci es , fo r example a rodent  or guineapi g,w i ll gen e ra l l y be immun ore activ e in a diffe r ents pe c ies s uch as  in hu mans. O n lyaf ter the  ap p r opriate a nimal mod e lsar e su fficient ly  dev el ope dwill clinical t rials in  humansb e  carri edo ut t o  furth er  demonstrate  thesa f ety and e ffi cacy of a v acc ine  inman 
illi reproduce_within alveolar_or pulmonary macrophages. As_the organisms_multiply,_they may_spread_through the lymphatic_system to distal_lymph nodes and through_the blood stream_to_the lung apices, bone marrow, kidney and meninges surrounding the brain. Primarily as the_result_of cell-mediated_hypersensitivity_responses,_characteristic granulomatous lesions or tubercles_are produced in proportion to_the severity_of the infection. These lesions consist of epithelioid_cells_bordered by monocytes,_lymphocytes and fibroblasts. In most instances a lesion or_tubercle eventually becomes necrotic and undergoes_caseation.
While M. tuberculosis_is_a_significant pathogen, other species_of the genus Mycobacterium also cause_disease in animals including man and_are clearly within the scope of the_present invention. For example, M. bovis_is closely related to M._tuberculosis and_is responsible for tubercular infections_in domestic animals_such as_cattle, pigs, sheep,_horses, dogs and cats. Further, M._bovis may infect_humans via the intestinal tract, typically_from_the ingestion of_raw_milk._The localized_intestinal infection eventually_spreads_to the_respiratory_tract and is followed shortly by_the_classic symptoms of tuberculosis. Another important pathogenic_vector of the genus_Mycobacterium_is M. leprae which_causes millions of cases of_the ancient disease leprosy. Other species_of this_genus which_cause disease in animals and man include M. kansasii, M. avium_intracellulare, M. fortuitum, M. marinum, M._chelonei, M. africanum, M._ulcerans, M._microti_and M. scrofulaceum._The_pathogenic mycobacterial_species frequently exhibit a high degree of_homology in_their respective DNA and corresponding protein_sequences and some species,_such_as M. tuberculosis and M. bovis_are highly related.
For obvious practical and_moral reasons, initial work in_humans_to_determine the efficacy of experimental_compositions with regard to such afflictions_is infeasible. Accordingly,_in the early development of any drug_or_vaccine it is standard procedure to_employ_appropriate animal models for reasons of_safety_and_expense. The success of implementing_laboratory animal models is predicated on_the understanding that immunodominant epitopes are frequently active in_different host species._Thus, an immunogenic determinant in_one_species,_for example a rodent or guinea pig, will generally be_immunoreactive in_a different species_such as in humans. Only after the appropriate animal models_are sufficiently developed will clinical trials in_humans be carried out to further demonstrate the safety and efficacy_of a vaccine in man