Will we ever eradicate animal tuberculosis?

Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 h ps://doi.o g/10.1186/s13620-023-00254-9 COMMENTARY Open Access © The Au ho (s) 2023. Open Access This a icle is licensed unde a C ea i e Commons A ibu ion 4.0 In e na ional License, which pe mi s use, sha ing, adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons licence, and indica e i changes we e made. The images o o he hi d pa y ma e ial in his a icle a e included in he a icle’s C ea i e Commons licence, unless indica ed o he wise in a c edi line o he ma e ial. I ma e ial is no included in he a icle’s C ea i e Commons licence and you in ended use is no pe mi ed by s a u o y egula ion o exceeds he pe mi ed use, you will need o ob ain pe mission di ec ly om he copy igh holde . To iew a copy o his licence, isi h p://c ea i ecommons.o g/licenses/by/4.0/. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecom- mons.o g/publicdomain/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed in a c edi line o he da a. I ish Ve e ina y Jou nal Will we e e e adica e animal ube culosis? Ch is ian Go áza 1*, José de la Fuen e1,2, Albe o Pe elló1,3 and Lucas Domínguez4 F om Se en h In e na ional Con e ence on Mycobac e ium bo is Galway, I eland. 7-10 June 2022. h ps://www.mbo is2022.com Abs ac Two cha ac e is ics o he Mycobac e ium ube culosis complex (MTC) a e pa icula ly ele an o ube culo- sis (TB) epidemiology and con ol, namely he abili y o his g oup o pa hogens o su i e in he en i onmen and he eby acili a e indi ec ansmission ia wa e o eed, and he capaci y o in ec mul iple hos species includ- ing human beings, ca le, wildli e, and domes ic animals o he han ca le. As a consequence, a he han keeping he ocus on ce ain animal species ega ded as main enance hos s, we pos ula e ha i is ime o hink o complex and dynamic mul i-hos MTC main enance communi ies whe e se e al wild and domes ic species and he en i on- men con ibu e o pa hogen main enance. Rega ding he global si ua ion o animal TB, many indus ialized coun ies ha e eached he O icially Tube culosis F ee s a us. Howe e , in ec ion o ca le wi h M. bo is s ill occu s in mos coun- ies a ound he wo ld. In low- and middle-income coun ies, human and animal TB in ec ion is endemic and bo ine TB con ol p og ams a e o en no implemen ed because s anda d TB con ol h ough es ing and culling, mo emen con ol and slaugh e house inspec ion is oo expensi e o e hically unaccep able. In acing inc easingly complex epi- demiological scena ios, mode n in eg a ed disease con ol should ely on h ee main pilla s: (1) a close in ol emen o a me s including collabo a i e decision making, (2) expanding he su eillance and con ol a ge s o all h ee hos ca ego ies, he en i onmen , and hei in e ac ions, and (3) se ing up new con ol schemes o upg ading es ablished ones swi ching om single ool es and cull app oaches o in eg a ed ones including a m biosa e y and accina ion. Keywo ds Accep abili y o con ol op ions, Fa m biosa e y, In eg a ed disease con ol, Main enance hos communi y, Tes and cull, Vaccina ion In oduc ion Animal ube culosis (animal TB) is he disease caused by in ec ion o wild and domes ic animals wi h Myco- bac e ium bo is and closely ela ed membe s o he Mycobac e ium ube culosis complex (MTC). The in ec- ion o human beings wi h MTC membe s o he han M. ube culosis is known as zoono ic TB. Despi e eno mous e o s and cos s, comple e e adica ion o he causa i e agen s o animal TB has so a only been achie ed in Aus- alia, a coun y wi h no ele an non-bo ine MTC main- enance hos s [1, 2]. This o e iew p oposes a c i ical look in o he u u e o animal TB con ol. The i s sec ion add esses he epidemiology o animal TB wi h a ocus on se e al impo an bu s ill neglec ed aspec s such as he mul i- hos na u e o he pa hogen, pa hogen gene ic di e si y, and i s equen indi ec ansmission. The second one add esses eme ging ools wi h a signi ican impac on *Co espondence: Ch is ian Go áza Ch is ian.Go [email p o ec ed] 1 SaBio Ins i u o de In es igación en Recu sos Cinegé icos IREC (UCLM & CSIC), Ciudad Real, Spain 2 Depa men o Ve e ina y Pa hobiology, Cen e o Ve e ina y Heal h Sciences, Oklahoma S a e Uni e si y, S illwa e , OK, USA 3 Sabio ec, Camino de Moledo es s/n. 13003, Ciudad Real 13071, Spain 4 VISAVET and Depa men o Animal Heal h-Facul y o Ve e ina y Medicine, Uni e sidad Complu ense Mad id, Mad id, Spain Page 2 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 unde s anding TB epidemiology. The hi d sec ion b ie ly desc ibes he global si ua ion o animal TB om a one heal h pe spec i e, i.e., no only in ca le, bu also in wild- li e and in domes ic animals di e en om ca le which a e o en neglec ed ega ding TB con ol. The ou h and inal sec ion deals wi h he ools a ailable o TB con- ol in ca le and in o he hos s and he oppo uni ies o upg ade he cu en TB con ol s a egies based on be e s akeholde in ol emen and he concep o in eg a ed disease con ol. Di e si y in hehos species, genome and ansmission inanimal ube culosis Two cha ac e is ics o he MTC a e ex emely ele an o animal TB epidemiology and con ol, namely hei abili y o su i e in he en i onmen and hei capaci y o in ec mul iple hos species. Rega ding he o me , mycobac e ia e ol ed om, and many species a e, en i- onmen al o ganisms. E en he species which e ol ed o adap o mammalian hos s, such as he membe s o he MTC, a e s ill able o su i e in he en i onmen [3–6]. This means ha one cha ac e is ic o M. bo is is he abil- i y o indi ec ansmission media ed by subs a es such as wa e o eed. This has ob ious implica ions o a m biosa e y and p e en i e medicine, o ins ance, by conside ing eed- o wa e -media ed c oss species ansmission [4, 7], bu also o he slaugh e house inspec ion o ca le, since gas oin es inal ansmission has been shown o p oduce di e en lesion se e i y and dis ibu ion bo h a e expe - imen al in ec ions [8] and in na u al se ings [9]. Rega ding he la e , some mycobac e ia became spe- cialized in pa asi izing mammals, and so he MTC e ol ed, including M. bo is, possibly he MTC membe wi h he b oades hos ange [10, 11]. Mycobac e ium bo is can in ec se e al di e en wild and domes ic hos species, and he mo e hos s a e pa o a gi en sys em, he mo e likely i is ha TB is main ained h ough ime in his sys em [12]. Fu he mo e, in ec ions wi h membe s o he MTC a e gene ally ch onic and debili a ing, lead- ing o p olonged oppo uni ies o ansmission and o con amina ing he en i onmen [13]. In ac , i is ime o o ge he classical single o wo- hos sys em iews, whe e only ce ain species we e ega ded as main enance hos s [14] and hink o complex and dynamic mul i-hos MTC main enance communi- ies whe e se e al di e en wild and domes ic species and he en i onmen con ibu e o build a ne wo k ha acili a es pa hogen su i al (Fig.1). The success ul New Zealand example o p og essi e M. bo is e adica ion a - ge s an almos comple e hos communi y including ca - le, wildli e (b ush ail possums, T ichosu us ulpecula) and domes ic animals o he han ca le ( a med dee ) and is now aiming a TB eedom in ca le and a med dee by 2026, TB eedom in possums by 2040, and biological e adica ion o Mycobac e ium bo is by 2055. Ano he aspec ele an o pa hogen ansmission is associa ed wi h i s gene ic di e si y and he di e se species-speci ic hos esponses o in ec ion. Rega ding he human pa hogen M. ube culosis, gene ic he e oge- nei y includes egion- and hos -speci ic a ia ions ha may a ec pa hogen ansmission, p e alence, suscep- ibili y o d ug ea men s and accine de elopmen [15–18]. Some species o clones o he MTC demons a e ex ao dina ily li le i ulence o ce ain hos s, such as Eu opean badge s (Meles meles) o ins ance. In some popula ions, mos o he in ec ed badge s ha e no isible lesions and appea appa en ly heal hy indi iduals [19]. By con as , in ec ed Eu asian wild boa (Sus sco a) a e mo e likely o de elop gene alized TB in Medi e anean Ibe ia han in A lan ic habi a s [20]. Among he possible explana ions, i could be ha he se e e d ough pe iods cha ac e is ic o he Medi e anean summe con ib- u e o igge clinical TB h ough an e ec on hos con- di ion and immuni y, h ough inc eased exposu e and ein ec ion a wa e holes, o h ough a combina ion o bo h mechanisms [21–23]. In ec ions wi h no signi ican lesion de elopmen (non- isible lesions, NVL) can las o long pe iods o ime (yea s) bu may e en ually e e o clinical disease leading o pa hogen shedding as soon as he e is a change in he immune s a us o he in ec ed indi idual [13, 19]. Wha e e he cause, a iabili y in bo h pa hogens and hos s ep esen s an addi ional chal- lenge o TB con ol [24]. Eme ging echnologies and hei impac onTB epidemiology andcon ol Two new echnologies al eady con ibu e signi ican ly o ou unde s anding o indi ec MTC ansmission, pa ho- gen gene ic di e si y, and complex hos and pa hogen ne wo ks: whole genome sequencing (WGS) and en i- onmen al DNA. The i s one, WGS, is inc easingly used o es ablish he sou ce o ou b eaks and unde s and how in ec ion sp eads, i.e., he di ec ionali y o ansmission [25]. I also allows deep insigh s in o he phylogene ics and e olu ion o MTC membe s and he possible mecha- nisms o local adap a ion, pa hogenici y, and p o ec i e immuni y [26]. Al e na i ely, acking di e en species wi h GPS de ices o came a apping can be help ul in iden i ying isk ho spo s and quan i ying c oss-species in e ac ions in complex hos communi ies [27–30]. Fu he mo e, he p esence o MTC in he en i onmen opens he possibili y o non-in asi e MTC moni o - ing and e-DNA-based isk analyses [31]. En i onmen- al DNA has been ins umen al o unde s anding MTC shedding pa e ns [6] and iden i ying en i onmen al Page 3 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 isk ho spo s [4, 32]. Simple e-DNA echnology such as sponge sampling has he po en ial o signi ican ly con- ibu e o on- a m isk iden i ica ion and isk-mi iga ion [31, 33]. This echnology shows ea ly p omise and migh soon become deployable as a ield ool. O he new echnologies anging om selec i e b eed- ing [34] o a i icial in elligence (AI) and machine lea n- ing (ML) also ha e he po en ial o con ibu e o he u u e animal TB con ol [35, 36]. Howe e , much needed b eak h oughs in TB diagnosis a e s ill pending, meaning ha in- i o TB diagnosis in all hos species s ill elies on me hods wi h a ela i ely poo sensi i i y and a iable speci ici y [24]. A global pe spec i e onanimal ube culosis Animal TB ep esen s a global challenge o heal h and economy [37]. Success ul animal TB con ol, up o he le el o being decla ed O icially Tube culosis F ee (OTF), has been achie ed in many indus ialized coun- ies including he USA and Canada in No h Ame ica, mos membe s o he Eu opean Union, and Aus alia, among o he s. Howe e , in ec ion o ca le wi h M. bo is is epo ed in 44% o 188 WOAH e i o ies om Janua y Fig. 1 The main enance communi y concep . The uppe panel ep esen s 7 Mycobac e ium ube culosis complex (MTC) hos species including ca le, domes ic animals o he han ca le (sheep, goa ), and wildli e ( ed and allow dee , wild boa , badge ) and hei space- ime coincidence ( ep esen ed by he line hickness) in he Ibe ian Peninsula, as assessed h ough came a ap ne wo ks. The lowe panel shows how he compe ence o a hos communi y o main ain MTC ci cula ion o e ime is la ge in mul i-hos sys ems (a highe hos species ichness) han in single- o wo-hos ones. (modi ied om e e ences [6] and [9]) Page 4 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 2017 o June 2018 [38] and is likely o occu in mos coun ies a ound he wo ld, including mos OTF ones. In many o hese, ca le TB occu s a e y low p e alence due o he implemen a ion o con ol o e adica ion p o- g ams o e long pe iods o ime [39]. In he UK, cu en bo ine TB (bTB) he d p e alence le els o 6–14% a e below he es ima ed 20–40% p e alence p e-compulso y con ols in he 1940s-50s bu s ill a away om e adica- ion [39]. In he EU, he Membe S a es a e esponsible o he e adica ion o bTB and may ecei e communi y inancial suppo o he e adica ion p og am. Howe e , unding o bTB con ol schemes is being phased ou in EU. To mee he unding c i e ia, Membe S a es mus s a e e adica ion o bo ine TB as he inal a ge o hei p og am [40]. Howe e , comple e e adica ion o bTB is no only di icul o achie e in high p e alence coun ies, bu also in coun ies wi h low p opo ions o TB-in ec ed he ds including some OTF coun ies whe e TB p e a- lence is cu en ly ising [41]. Figu e2 compa es he ime ends in ca le TB he d p e alence in he EU and in New Zealand. In con as wi h indus ialized coun ies, in de elop- ing low- and middle-income coun ies (LMIC) whe e human and animal TB in ec ion is endemic and bo ine TB con ol p og ams a e no implemen ed, he si ua ion is like ha desc ibed a he beginning o he 20 h cen u y when one ou o nine human dea hs we e due o TB and 10–20% o hem had an animal o igin [42, 43]. In Uganda, 7.5% o he annual 559/100,000 pop o al TB cases a e due o zoono ic TB [44] and he ca le he d p e alence is as high as 28% [45]. In Nepal, young women who a e mo e in ol ed in handling wi h li es ock o milking a e mo e likely o su e ex apulmona y TB [46], and 18% o ca le and 32% o wa e bu alo es TB posi i e [41]. In LMICs, s anda d TB con ol h ough es ing and culling, mo emen con ol and slaugh e house inspec ion a e o en oo expensi e o jus unaccep able due o economic o eligious easons, and he TB si ua ion in domes ic animals o he han ca le emains la gely unexplo ed (Fig. 3). Conside ing ha o many LMICs he e a e bigge challenges ega ding animal heal h, accina ion eme ges as he only po en ially accep able in e en ion. One majo complica ing ac o p e en ing animal TB e adica ion is i s occu ence in wild mammal spe- cies [39]. This is he case o whi e- ailed dee (Odocoi- leus i ginianus) in Michigan, he b ush ail possum in New Zealand, o di e en wildli e hos s in se e al pa s o Eu ope. In many o he egions wo ldwide, he ole o wildli e MTC main enance hos s, o e en hei e y exis - ence, emains unexplo ed [47]. E en wo se, while i is well es ablished ha se e al domes ic animals o he han ca le such as sheep, goa s, pigs, o camelids can con ib- u e o MTC main enance, he si ua ion o TB in domes ic hos s o he han ca le emains la gely unknown in mos egions o he wo ld. The Wo ld Bank (2011; h ps:// docum en s1. wo ld bank . o g/ cu a ed/ en/ 32367 14681 79364 909/ pd / 66859 0WP00 PUBL0 0Li e s ock 0A la s0web. pd ) lis ed TB among he op en mos impo an animal diseases no only in ca le bu also in wa e bu - alo, pigs, and camelids – a clea hin o he global el- e ance o domes ic animals o he han ca le o MTC main enance. This is c i ical because in ce ain egions i has been es ima ed ha domes ic animals o he han ca - le ep esen abou 50% o he o al in ec ed animals, and ha he sum o in ec ed wildli e and in ec ed domes ic hos s o he han ca le comple ely ou numbe s in ec ed ca le [48]. The way o wa d: omsingle ool oin eg a ed disease con ol As s a ed abo e, MTC is likely o pe sis in complex mul i-hos communi ies a he han in ela i ely sim- ple one- o wo-hos sys ems. Howe e , knowing which hos s a e mos ele an in a speci ic sys em as well as hei abundance, dis ibu ion and in e ac ion is no easy. In I eland o ins ance, es ima ing he badge popula ion size was highly challenging [49] and e ealed a a he small numbe (63,188; 5–95 h pe cen ile 48,037–79,315) as compa ed o 7.3 million ca le, 5.5 million sheep, and 1.6 million pigs. The I ish TB hos sys em migh be locally mo e complex and include sika dee (Ce us nip- pon), oo [25, 50]. In A gen ina, open-ai domes ic pigs and in asi e e al pigs (wild suids) con ibu e o MTC main enance along wi h ca le [51] and he hos commu- ni y migh also include o he wildli e [52]. Thus, he i s equi emen when aced an endemic animal TB si ua ion is unning an epidemiological diagnosis, i.e., desc ib- ing which species, bo h domes ic and wild, a e locally Fig. 2 Mean annual ca le ube culosis he d p e alence in he Eu opean Union (EU, blue) and in New Zealand (yellow) om 2004 o 2021. The dashed line indica es EU da a excluding he UK a e B exi . Con ol a ge s all h ee hos ca ego ies in New Zealand bu almos only ca le in he EU Page 5 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 in ol ed in MTC main enance, hei numbe s, and how hey a e connec ed o each o he [31]. O e ime, ce ain egions epea edly show high ca le TB incidences and alloca ion o mo e esou ces o hese a eas may be needed o comba he disease [53]. Al e na- i ely, p oblem egions migh hypo he ically be excluded om he gene al con ol p og am o g an ed ce ain excep ions o cope wi h pa icula ly challenging isk ac- o s. Bo h op ions would imply a geog aphical zoning o disease con ol. Beyond zoning, he classic con ol measu es o ca - le TB con ol a e diagnos ic es ing and slaugh e o es -posi i e animals, combined wi h mo emen con ol o in ec ed he ds and pos -mo em inspec ion o ca le a he aba oi o p esence o ypical issue lesions [39, 54]. Age culling was epo edly one o he ing edien s o he success ul e adica ion in Aus alia [1] bu is no com- monly lis ed among he TB con ol ools in ca le. In wildli e, he op ions o dealing wi h TB a e gene ally limi ed o seg ega ion o domes ic animals om wildli e, which is a ge ing ca le TB con ol a he han wildli e TB ( a m biosa e y; [33]), wildli e-o ien ed biosa e y and hygiene (e.g., sa e ca cass disposal; [55]), andom o a - ge ed culling o he wildli e hos s [56, 57], o accina ion [58]. Inno a i e and p omising combined app oaches include a badge es and accina e o emo e ial in No he n I eland [57]. The hi d ele an hos g oup howe e , namely he TB-suscep ible domes ic animals o he han ca le, is o en neglec ed ega ding TB con ol. Se e al o he abo e-men ioned ools can possibly be applied o mo e han one hos ca ego y (Fig.4). The ca le TB con ol oolbox includes he well-es ab- lished es and cull, bu also he equally aluable a m Fig. 3 Challenges o global animal ube culosis e adica ion. A In many low- and middle-income coun ies (LMIC), culling as a means o disease con ol is unaccep able o economic o eligious easons. B The ole o domes ic animals o he han ca le in in ec ion main enance is unknown and o en neglec ed, bo h in LMIC and in indus ialized coun ies. C Many coun ies lack su icien knowledge on he Mycobac e ium ube culosis complex main enance communi y. This gap hinde s imp o emen s in ube culosis con ol by a ge ing he whole hos communi y. D Close in e ac ions be ween hos ca ego ies e idence he need o add ess all ele an hos s a he same ime o success ul ube culosis con ol Page 6 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 biosa e y and accina ion. These eme ging ools dese e sho commen s as hey a e expec ed o g ow in ele- ance o e his decade. Fa m biosa e y consis s o he managemen and physi- cal measu es designed o educe he isk o in oduc- ion, es ablishmen and sp ead o in ec ions (biosecu i y measu es, BSMs). I is a key disease con ol ool, espe- cially whe e no accine is a ailable no au ho ized and when mul i-hos communi ies inc ease he isks, like o animal TB [59]. Biosecu i y challenges a y g ea ly among p oduc ion sys ems, and hei managemen is in luenced by nume ous geog aphic, en i onmen al, eco- nomic, socio-cul u al, and poli ical ac o s. In Medi e a- nean bee ca le a ms, BSMs such as seg ega ing wildli e and ca le a wa e holes had an e ec in e ms o educ- ing ca le TB incidence [60]. O he po en ial isk poin s, wa e e s, sp ings, and wa e holes we e he mos com- mon ones, and BSMs ela ed o wa e managemen we e iden i ied as essen ial on mos a ms, along wi h BSMs ega ding wildli e managemen . Fa me s p io i ized low-cos BSMs bu 75% o he a me s adop ed he p o- posed plans o some ex en indica ing ha on- a m isk mi iga ion p o ocols a e p ac ical and easible [33]. Spain, whe e wildli e is egionally ega ded as an impo an ba - ie o TB con ol in ca le, has egula ed wildli e man- agemen and biosa e y in game species in an a emp o lessen his isk (h ps:// www. boe. es/ busca / doc. php? id= BOE-A- 2020- 2109). Rega ding accina ion, he las 10 yea s ha e wi nessed eno mous p og ess in wildli e, ca le, and li es ock o he han ca le. Badge accina ion wi h BCG has been p o en o con ibu e o TB con ol unde ield condi- ions and hus badge accina ion is now in eg a ed in o na ional con ol p og ams in he EU Membe S a e I e- land and in he UK [61–64]. The e ec i eness o ca le accina ion wi h BCG was ecen ly e iewed and se e al new ield ials we e published, indica ing a 28–85% e i- cacy unde ield condi ions [65–67] and es ima ing ha , insi ua ions o low o mode a e p e alence (< 15%), using BCG could lead o an OTF si ua ion in 10 yea s [67]. In he UK, ca le accina ion wi h BCG is expec ed o become in eg a ed in o he na ional TB con ol p og am a e de eloping a DIVA es and gaining WOAH accep - ance o suppo he UK’s ade ag eemen s [68]. Hea -inac i a ed mycobac e ia a e sa e, ha e less logis- ic cons ain s han li e accines, and a e al eady used in comme cial pa a ube culosis (Johne’s disease) accines such as Sili um™ (CZ Vaccines, Po iño, Spain). Hea inac i a ed M. bo is is based on he same p inciple and has been shown o p oduce immuni y agains MTC in wild boa and domes ic pigs [69–71], badge s [72], goa s [73], ed dee [74], ca le [75], zeb a ish [76, 77], and A i- can bu alo (Synce us ca i ) (P o . Ani a Michel, pe sonal communica ion). Fu he mo e, hea inac i a ed myco- bac e ia con e c oss-p o ec ion agains a b oad ange o pa hogens including Salmonella in pigs [78]. Two suc- cess ul ield ials ha e been un in wild boa [70, 79], bu no licensing has aken place so a . P o ec i e mecha- nisms ha e been associa ed wi h ac i a ion o inna e immune esponse h ough he complemen C3 pa hway in esponse o biomolecules such as mycobac e ial p o- eins and glycans such as Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) p esen in glycop o eins and glycolipids [80]. Fu - he mo e, he immune esponse o hea -inac i a ed M. bo is has ansla ed in o adju an applica ions o boos immune esponse o he con ol o ca le ick in es a- ions [81, 82]. The challenge o animal TB con ol policies is no only he unce ain y associa ed wi h epidemiological mechanisms d i ing he disease p ocess, bu also he geog aphical and empo al a ia ion in public and s ake- holde pe cep ion abou he accep abili y and e ec i e- ness o he a ailable con ol op ions [83, 84]. Wo ldwide, changes in he human demog aphic cha ac e is ics and social a i udes a e unde way, which a e likely o o ce a c i ical ee alua ion o he TB con ol s a egies [85]. The success o any in e en ion is p edica ed on he abil- i y and willingness o ele an human ac o s o ou inely implemen hem. This migh be shaped by he pe cep- ions and subjec i e expe iences o a me s and o he ac o s. S anda d es and cull disease con ol s a egies, o ins ance, ha e signi ican impac s on he sus ainabil- i y o a ming, especially in small holdings [86] and his can a ec a me a i udes owa ds disease con ol. In he Fig. 4 Animal ube culosis con ol ools. In eg a ed schemes should conside all h ee hos ca ego ies, ca le, domes ic animals o he han ca le, and wildli e (le ). In e en ion op ions ( igh ) should ideally be combined and a ge mo e han one hos ca ego y whene e possible. Solid lines indica e egula use (in some coun ies), dashed lines indica e possible o occasional use Page 7 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 wo s -case scena io, he dis us can pe mea e poli ics and hinde he con inua ion o success ul schemes. Social science insigh s a e needed o unde s and how indi id- ual, sys emic, and mo e- han-human ac o s in e sec and in luence one ano he and a e c ucial o e ec i ely engage all ele an s akeholde s [39, 87]. In his ega d, New Zealand is a showcase whe e li es ock a me s a e e ec i ely in ol ed in he na ional animal TB con ol s a egy h ough he Animal Heal h Boa d. This kind o public-p i a e pa ne ship app oach could be u he explo ed o s eng hen animal disease con ol. In mos pa s o he globe, a comple e e adica ion o M. bo is is unlikely o be achie ed in he sho o medium e m. E en wo se, a his global scale, animal TB p e a- lence igu es a e no imp o ing ecen ly o any o he h ee hos ca ego ies excep o e y speci ic se ings. This causes signi ican and p olonged cos s and c ea es inc easing dis us among he a me s and he ield e - e ina ians abou he p ac icali y o ongoing TB con ol schemes. Hence, i he scien i ic communi y and he ani- mal heal h manage s wan o make signi ican p og ess, we need o go beyond he pa ed oads. In on o inc easingly complex epidemiological sce- na ios, success ul animal TB con ol equi es i s and o emos a clea ision and objec i es and he willing- ness o hold i m [2]. Once he ision is clea , he s a - ing poin is a comp ehensi e assessmen o he in ol ed hos species, en i onmen al ac o s, and social con ex : he epidemiological diagnosis [31]. One example (in Spanish) is he Plan de Ac uación sob e TUBe culosis en Especies Sil es es (PATUBES, h ps:// www. mapa. gob. es/ es/ g anad e ia/ emas/ sanid ad- animal- higie ne- g anad e a/ pa ub es2017_ 3_ cm30- 378321. pd ). Exis ing p o- g ammes in I eland and New Zealand ep esen ongoing examples o mul iple hos managemen when a emp ing o con ol animal TB. A e his comp ehensi e assess- men o he epidemiological si ua ion, an in eg a ed dis- ease con ol scheme can be se up based on h ee pilla s: (1) a close in ol emen o he a me s including collabo- a i e decision making, (2) expanding he con ol a ge o he en i onmen and all h ee hos ca ego ies and hei in e ac ions, and (3) upg ading es ablished con ol schemes om single- ool o in eg a ed ones including a m biosa e y and he s a egic use o accina ion along wi h bols e ing he exis ing es and cull schemes (Fig.5). Abb e ia ions AI A i icial in elligence BCG Bacille Calme e Gue in BSM Biosecu i y measu e bTB Bo ine ube culosis DIVA Di e en ia ing in ec ed om accina ed animals e-DNA En i onmen al DNA LMIC Low- and middle-income coun ies M. bo is Mycobac e ium bo is ML Machine lea ning MTC Mycobac e ium ube culosis complex OTF O icially Tube culosis F ee PATUBES Plan de Ac uación sob e TUBe culosis en Especies Sil es es TB Tube culosis WGS Whole genome sequencing WOAH Wo ld O ganiza ion o Animal Heal h Acknowledgemen s The co esponding au ho acknowledges he kind in i a ion o a end and p esen a plena y alk a he Mbo is 2022 con e ence in Galway, I eland. Abou his supplemen This a icle has been published as pa o I ish Ve e ina y Jou nal Volume 76 Supplemen 1, 2023: Se en h In e na ional Con e ence on Mycobac e ium bo is. The ull con en s o he supplemen a e a ailable online a h ps:// i ish e jo u nal. biome dcen al. com/ a ic les/ suppl emen s/ olume- 76- suppl emen -1. Au ho s’ con ibu ions CG planned he e iew and w o e he i s manusc ip d a . JdF, AP and LD we e majo con ibu o s o he planning and edi ing o he manusc ip . All au ho s ead and app o ed he inal manusc ip . Funding This e iew is a con ibu ion o p ojec MYCOTRAINING (SBPLY/19/180501/000174) unded by Jun a de Comunidades de Cas illa-La Mancha, Spain and EU-FEDER. A ailabili y o da a and ma e ials No applicable. Decla a ions E hics app o al and consen o pa icipa e No applicable. Consen o publica ion No applicable. Compe ing in e es s The au ho s decla e ha hey ha e no compe ing in e es s. Fig. 5 A schema ic ision o in eg a ed animal ube culosis con ol. A e de ining he in ol ed hos species and hei (en i onmen media ed) in e ac ions, an in eg a ed scheme should a ge all ele an hos s and make use o all a ailable con ol ools while in ol ing he a me s and o he ele an ac o s in decision making Page 8 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 Recei ed: 26 Sep embe 2022 Accep ed: 13 Sep embe 2023 Re e ences 1. Cousins DV, Robe s JL. Aus alia’s campaign o e adica e bo ine ube cu- losis: he ba le o eedom and beyond. Tube culosis. 2001;81(1–2):5–15. 2. Glan ille RJ. Aus alia’s colou ul pa h o ube culosis eedom. I Ve J. 2023;76(Suppl 1):15. h ps:// doi. o g/ 10. 1186/ s13620- 023- 00244-x. 3. Allen AR, Fo d T, Skuce RA. Does Mycobac e ium ube culosis a . bo is Su i al in he en i onmen con ound bo ine ube culosis con ol and e adica ion? A li e a u e e iew. Ve e ina y Med In . 2021;8812898. h ps:// doi. o g/ 10. 1155/ 2021/ 88128 98. 4. Ba asona JA, Vicen e J, Díez-Delgado I, Azna J, Go áza C, To es MJ. En i onmen al p esence o Mycobac e ium ube culosis complex in agg ega ion poin s a he wildli e/li es ock in e ace. T ansbound Eme g Dis. 2017;64(4):1148–58. h ps:// doi. o g/ 10. 1111/ bed. 12480. 5. Cou enay O, Reilly LA, Sweeney FP, Hibbe d V, B yan S, Ul-Hassan A, Newman C, Macdonald DW, Delahay RJ, Wilson GJ, Welling on EMH. Is Mycobac e ium bo is in he en i onmen impo an o he pe sis ence o bo ine ube culosis? Biol Le . 2006;2(3):460–2. h ps:// doi. o g/ 10. 1098/ sbl. 2006. 0468. 6. San os N, San os C, Valen e T, Go áza C, Almeida V, Co eia-Ne es M. Widesp ead en i onmen al con amina ion wi h Mycobac e ium ube - culosis Complex e ealed by a molecula de ec ion p o ocol. PLoS ONE. 2015a;10(11):e0142079. h ps:// doi. o g/ 10. 1371/ jou n al. pone. 01420 79. 7. Palme MV, Wa e s WR, Whipple DL. Sha ed eed as a means o dee - o- dee ansmission o Mycobac e ium bo is. J Wildl Dis. 2004;40(1):87–91. h ps:// doi. o g/ 10. 7589/ 0090- 3558- 40.1. 87. 8. Se ano M, Se illa IA, Fue es M, Geijo M, Risalde MÁ, Ruiz-Fons JF, Go - aza C, Jus e RA, Domínguez L, Elguezabal N, Ga ido JM. Di e en lesion dis ibu ion in cal es o ally o in a acheally challenged wi h Mycobac e- ium bo is: implica ions o diagnosis. Ve Res. 2018;49:74. h ps:// doi. o g/ 10. 1186/ s13567- 018- 0566-2. 9. Xu F, Tian L, Li Y, Zhang X, Qi Y, Jing Z, Pan Y, Zhang L, Wang XFM, Zeng Q, Weixing Fan. High p e alence o ex apulmona y ube culosis in dai y a ms: e idence o possible gas oin es inal ansmission. PLoS ONE. 2021;16:e0249341. h ps:// doi. o g/ 10. 1371/ jou n al. pone. 02493 41. 10. Galagan JE. Genomic insigh s in o ube culosis. Na Re Gene . 2014;15:307–20. h ps:// doi. o g/ 10. 1038/ n g36 64. 11. Gonzalo-Asensio J, Malaga W, Pawlik A, As a ie-Dequeke C, Passema C, Mo eau F, La al F, Da é M, Ma in C, B osch R, Guilho C. E olu iona y his o y o ube culosis shaped by conse ed mu a ions in he PhoPR i u- lence egula o . P oc Na l Acad Sci U S A. 2014;111(31):11491–6. h ps:// doi. o g/ 10. 1073/ pnas. 14066 93111. 12. Ba asona JA, Go áza C, de la Fuen e J, Vicen e J. Hos ichness inc eases ube culosis disease isk in game-managed a eas. Mic oo ganisms. 2019;7(6):182. h ps:// doi. o g/ 10. 3390/ mic o o gan isms7 060182. 13. Esmail H, Ba y 3 dCE, Young DB, Wilkinson RJ. The ongoing challenge o la en ube culosis. Phil. T ans. R. Soc. B. 2014;369: 20130437. h ps:// doi. o g/ 10. 1098/ s b. 2013. 0437. 14. Nugen G. Main enance, spillo e and spillback ansmission o bo ine ube culosis in mul i-hos wildli e complexes: a New Zealand case s udy. Ve Mic obiol. 2011;151(1–2):34–42. h ps:// doi. o g/ 10. 1016/j. e mic. 2011. 02. 023. 15. Ad ani J, Ve ma R, Cha e jee O, Pachou i PK, Upadhyay P, Singh R, Yada J, Naaz F, Ra ikuma R, Buggi S, Sua M, Gup a UD, Pandey A, Chauhan DS, T ipa hy SP, Gowda H, P asad TSK. Whole genome sequencing o Mycobac e ium ube culosis Clinical isola es om India e eals gene ic he e ogenei y and egion-speci ic Va ia ions ha migh a ec d ug sus- cep ibili y. F on Mic obiol. 2019;10:309. h ps:// doi. o g/ 10. 3389/ micb. 2019. 00309. 16. Ba aglia S, Spi ale i A, Cabibbe AM, Meehan CJ, U pa el C, Ismail N, Tah- seen S, Sk ahina A, Alikhano a N, Mos o a Kamal SM, Ba bo a A, Niemann S, G oenhei R, Dean AS, Zignol M, Rigou s L, Ci illo DM. Cha ac e iza- ion o genomic Va ian s Associa ed wi h Resis ance o Bedaquiline and Delamanid in Nai e Mycobac e ium ube culosis clinical s ains. J Clin Mic obiol. 2020;58(11):e01304–20. 17. Chae H, Shin SJ. Impo ance o di e en ial iden i ica ion o Myco- bac e ium ube culosis s ains o unde s anding di e ences in hei p e alence, ea men e icacy, and accine de elopmen . J Mic obiol. 2018;56(5):300–11. 18. Smi h CM, Bake RE, P oulx MK, Mish a BB, Long JE, Woong Pa k S, Lee HN, Ki i sy MC, Belle ose MM, Oli e AJ, Mu phy KC, Papa inasasunda am K, Boehm FJ, Reames CJ, Meade RK, Hamp on BK, Linne z CL, Shaw GD, Hock P, Bell TA, Eh S, Schnappinge D, Fe is F, Ioe ge MT, Sasse i TR. Hos -pa hogen gene ic in e ac ions unde lie ube culosis suscep ibili y in gene ically di e se mice. Eli e. 2022;11:e74419. 19. Ga ie -Widen D, Cooke MM, Gallaghe J, Chambe s MA, Go áza C. A e iew o in ec ion o wildli e hos s wi h Mycobac e ium bo is and he diagnos ic di icul ies o he no isible lesion p esen a ion. N Z Ve J. 2009;57:122–31. 20. Muñóz-Mendoza M, Ma e os N, Boadella M, Go aza C, Menéndez S, de Juan L, Bezos J, Rome o B, Copano MF, Amado J, Sáez JL, Mou elo J, Bal- sei o A. Wild boa ube culosis in Ibe ian A lan ic Spain: a di e en pic u e om Medi e anean habi a s. BMC Ve Res. 2013;9:176. 21. Ba oso P, Se ano E, Ca pio AJ, Ace edo P, Vicen e J, Go áza C. Low impac o ube culosis se e i y on wild boa body condi ion. Res Ve Sci. 2023b;155:161–7. h ps:// doi. o g/ 10. 1016/j. sc. 2023. 01. 014. 22. Ma ín-He nando MP, Hö le U, Vicen e J, Ruiz-Fons F, Vidal D, Ba al M, Ga ido JM, de la Fuen e J, Go aza C. Lesions associa ed wi h Myco- bac e ium ube culosis complex in ec ion in he eu opean wild boa . Tube culosis. 2007;87(4):360–7. 23. Vicen e J, Ba asona JA, Ace edo P, Ruiz-Fons JF, Boadella M, Diez-Delgado I, Bel an-Beck B, González-Ba io D, Quei ós J, Mon o o V, de la Fuen e J, Go aza C. Tempo al end o ube culosis in wild ungula es om medi- e anean Spain. T ansbound Eme g Dis. 2013;60(SUPPL1):92–103. h ps:// doi. o g/ 10. 1111/ bed. 12167. 24. Thomas J, Balsei o A, Go áza C, Risalde MA. Diagnosis o ube culosis in wildli e: a sys ema ic e iew. Ve Res. 2021;52:31. h ps:// doi. o g/ 10. 1186/ s13567- 020- 00881-y. 25. C ispell J, Cassidy S, Kenny K, McG a h G, Wa de S, Came on H, Rossi G, Macwhi e T, Whi e PCL, Lyce S, Kao RR, Mo ia y J, Go don SV. Mycobac- e ium bo is genomics e eals ansmission o in ec ion be ween ca le and dee in I eland. Mic ob Genomics. 2020;6(8):1–8. 26. B i es D, Gagneux S. Co-e olu ion o Mycobac e ium ube culosis and Homo sapiens. Immunol Re . 2015;264:6–24. 27. Cowie CE, Hu chings MR, Ba asona JA, Go áza C, Vicen e J, Whi e PCL. In e ac ions be ween ou species in a complex wildli e: li es ock disease communi y: implica ions o Mycobac e ium bo is main enance and ansmission. Eu J Wildl Res. 2016;62:51–64. 28. Kukielka E, Ba asona JA, Cowie CE, D ewe JA, Go áza C, Co a elo I, Vicen e J. Spa ial and empo al in e ac ions be ween li es ock and wildli e in Sou h Cen al Spain assessed by came a aps. P e Ve Med. 2013;112(3–4):213–21. h ps:// doi. o g/ 10. 1016/j. p e e med. 2013. 08. 008. 29. T igue o-Ocaña R, Laguna E, Jiménez-Ruiz S, Fe nández-López J, Ga cía- Bocaneg a I, Ba asona JA, Risalde MA, Mon o o V, Vicen e J, Ace edo P. The wildli e-li es ock in e ace on ex ensi e ee- anging pig a ms in cen al Spain du ing he mon ane a pe iod. T ansbound Eme g Dis. 2021;68(4):2066–78. 30. T igue o-Ocaña R, Vicen e J, Palencia P, Laguna E, Ace edo P. Quan i ying wildli e-li es ock in e ac ions and hei spa io- empo al pa e ns: is egu- la g id came a apping a sui able app oach? Ecol Ind. 2020;117:106565. h ps:// doi. o g/ 10. 1016/j. ecoli nd. 2020. 106565. 31. Ma ínez-Guijosa J, Rome o B, In an es-Lo enzo JA, Díez E, Boadella M, Balsei o A, Veiga M, Na a o D, Mo eno I, Fe e es J, Domínguez M, Fe nández C, Domínguez L, Go áza C. En i onmen al DNA: a p omising ac o o ube culosis isk assessmen in mul i-hos se ings. PLoS ONE. 2020;15(5). h ps:// doi. o g/ 10. 1371/ jou n al. pone. 02338 37. 32. San os N, Almeida V, Go áza C, Co eia-Ne es M. Pa e ns o Mycobac e- ium ube culosis-complex exc e ion and cha ac e iza ion o supe -shed- de s in na u ally-in ec ed wild boa and ed dee . Ve Res. 2015b;46:129. h ps:// doi. o g/ 10. 1186/ s13567- 015- 0270-4. 33. Ma ínez-Guijosa J, Lima-Ba be o JF, Ace edo P, Cano-Te iza D, Jiménez- Ruiz S, Ba asona JA, Boadella M, Ga cía-Bocaneg a I, Go áza C, Vicen e J. Desc ip ion and implemen a ion o an On- a m Wildli e Risk Mi iga ion P o ocol a he wildli e-li es ock in e ace: ube culosis in Medi e anean en i onmen s. P e Ve Med. 2021;191. h ps:// doi. o g/ 10. 1016/j. p e e med. 2021. 105346. 34. Ring SC, Pu ield DC, Good M, B eslin P, Ryan E, Blom A, E ans RD, Dohe y ML, B adley DG, Be y DP. Va iance componen s o bo ine ube culosis Page 9 o 10 Go áza e al. I ish Ve e ina y Jou nal (2023) 76:24 in ec ion and mul i-b eed genome-wide associa ion analysis using impu ed whole genome sequence da a. PLoS ONE. 2019;14:e0212067. h ps:// doi. o g/ 10. 1371/ jou n al. pone. 02120 67. 35. Rome o MP, Chang YM, B un on L, P osse A, Up on P, Rees E, Tea ne O, A nold M, S e ens K, D ewe JA. A compa ison o he alue o wo machine lea ning p edic i e models o suppo bo ine ube culosis disease con ol in England. P e Ve Med. 2021;188. h ps:// doi. o g/ 10. 1016/j. p e e med. 2021. 105264. 36. S anski K, Lyce S, Po phy e T, de B ons oo BM. Using machine lea n- ing imp o es p edic ions o he d-le el bo ine ube culosis b eak- downs in G ea B i ain. Sci Rep. 2021;11:2208. h ps:// doi. o g/ 10. 1038/ s41598- 021- 81716-4. 37. Olea-Popelka F, Muwonge A, Pe e a A, Dean AS, Mum o d E, E lache -Vin- del E, Fo cella S, Silk BJ, Di iu L, El Id issi A, Ra iglione M, Cosi i O, LoBue P, Fujiwa a PI. Zoono ic ube culosis in human beings caused by Myco- bac e ium bo is—a call o ac ion. Lance In ec Dis. 2017;17(1):e21–5. h ps:// doi. o g/ 10. 1016/ S1473- 3099(16) 30139-6. 38. Mu ai K, Tizzani P, Awada L, Mu L, Mapi se NJ, Cace es P. Con olling Bo ine Tube culosis: a One Heal h Challenge. OIE Pano ama Bulle in. 2019. h ps:// doi. o g/ 10. 20506/ bull. 2019.1. 2909. 39. P ei e DU. Epidemiology caugh in he causal web o bo ine ube culo- sis. T ansbound Eme g Dis. 2013;60:104–10. h ps:// doi. o g/ 10. 1111/ bed. 12105. 40. Re i iego Go dejo FJ, Ve mee sch JP. Towa ds e adica ion o bo ine ube - culosis in he Eu opean Union. Ve Mic obiol. 2006;112:101–9. 41. Bhanda i M, Thoen CO. Zoono ic ube culosis in humans, elephan s, and o he animals in Nepal. Chap e 16 in Cha les O. Thoen, James H. S eele, John B. Kaneene, edi o s Zoono ic Tube culosis: Mycobac e ium bo is and o he pa hogenic mycobac e ia. Whiley, N.Y. 2014; h ps:// doi. o g/ 10. 1002/ 97811 18474 310. 42. Mulle B, Du S, Alonso S, Ha endo J, Laisse CJ, Pa sons SD, an Helden PD, Zinss ag J. Zoono ic Mycobac e ium bo is-induced ube culosis in humans. Eme g In ec Dis. 2013;19(6):899–908. 43. Olms ead LA, Rhode PW. An impossible unde aking: he e adica ion o bo ine ube culosis in he Uni ed S a es. J Econ His . 2004;64:1–39. h ps:// doi. o g/ 10. 1017/ S0022 05070 40029 55. 44. Bya ugaba F, E e EMC, God euil S, G imaud P. Pulmona y ube culosis and Mycobac e ium bo is, Uganda. Eme g In ec Dis. 2009;15(1):124–5. 45. Sichewo P, E e E, Michel A. P e alence o Mycobac e ium bo is in ec- ion in adi ionally managed ca le a he wildli e-li es ock in e ace in Sou h A ica in he absence o con ol measu es. Ve Res Commun. 2019;43(3):155–64. 46. S ee ama eddy C, Pandu u K, Ve ma S, Joshi H, Ba es M. Compa ison o pulmona y and ex apulmona y ube culosis in Nepal – A hospi al-based e ospec i e s udy. BMC In ec Dis. 2008;8. h p:// www. biome dcen al. com/ 1471- 2334/8/8. 47. Go áza C, Che Ama A, O’B ien DJ. Open ques ions and ecen ad ances in he con ol o a mul i-hos in ec ious disease: animal ube culosis. Mammal Re . 2015;45:160–75. h ps:// doi. o g/ 10. 1111/ mam. 12042. 48. San os N, Richomme C, Nunes T, Vicen e J, Al es PC, de la Fuen e J, Co eia-Ne es M, Boschi oli ML, Delahay R, Go áza C. Quan i ica ion o he animal ube culosis Mul i-Hos Communi y o e s insigh s o con ol. Pa hogens. 2020;9:421. h ps:// doi. o g/ 10. 3390/ pa ho gens9 060421. 49. By ne A, Pa nell A, O’Kee e J, Madden JM. The challenge o es ima ing wildli e popula ions a scale: he case o he eu opean badge (Meles meles) in I eland. Eu J Wildl Res. 2021;67:85. h ps:// doi. o g/ 10. 1007/ s10344- 021- 01528-9. 50. Kelly DJ, Mullen E, Good M. Bo ine ube culosis: he eme gence o a New Wildli e main enance hos in I eland. F on Ve e ina y Sci. 2021. h ps:// doi. o g/ 10. 3389/ e s. 2021. 632525. 51. Ba andia an S, Ma il MJ, Capobianco G, Pé ez Agui ebu ualde MS, Zumá aga MJ, Ei in ME, Cue da MX, Win e M, Ma ínez Vi o M, Pe ez AM, La Sala LF. Epidemiology o Pig Tube culosis in A gen ina. F on Ve e ina y Sci. 2021;8. h ps:// doi. o g/ 10. 3389/ e s. 2021. 693082. 52. Abdala A, Ga baccio S, Zumá aga M, Ta abla HD. Mycobac e ium bo is en auna sil es e de la cuenca leche a de San a Fe, A gen ina. Re is a A gen ina de Mic obiología. 2015;47:174–82. h ps:// doi. o g/ 10. 1016/j. am. 2015. 04. 005. 53. Madden JM, McG a h G, Sweeney J, Mu ay G, T a alos JA, Mo e SJ. Spa- io- empo al models o bo ine ube culosis in he i ish ca le popula ion, 2012–2019. Spa ial and spa io- empo al epidemiology. 2021;39. h ps:// doi. o g/ 10. 1016/j. ss e. 2021. 100441. 54. Pozo P, Cespedes Ca denas N, Bezos J, Rome o B, G au A, Naca J, Saez JL, Minguez O, Al a ez J. E alua ion o he pe o mance o slaugh e house su eillance o bo ine ube culosis de ec ion in Cas illa y Leon, Spain. P e Ve Med. 2021;189. h ps:// doi. o g/ 10. 1016/j. p e e med. 2021. 105307. 55. Cano-Te iza D, Risalde MA, Jiménez-Ruiz S, Vicen e J, Isla J, Paniagua J, Mo eno I, Go áza C, In an es-Lo enzo JA, Ga cía-Bocaneg a I. Manage- men o hun ing was e as con ol measu e o ube culosis in wild ungu- la es in sou h-cen al Spain. T ansbound Eme g Dis. 2018;65(5):1190–6. 56. Boadella M, Vicen e J, Ruiz-Fons J, de la Fuen e J, Go áza C. E ec s o culling eu asian wild boa on he p e alence o Mycobac e ium bo is and Aujeszky’s disease i us. P e Ve Med. 2012;107(3–4):214–21. 57. Menzies FD, McCo mick CM, O’Hagan MJH, Collins SF, McEwan J, McGeown CF, McHugh GE, Ha CD, S inge LA, Molloy C, Bu ns G, McB ide SJ, Doyle LP, Cou cie MA, McB ide KR, McNai J, Thompson S, Co be DM, Ha wood RG, T imble NA. Tes and accina e o emo e: Me hodology and p elimina y esul s om a badge in e en ion esea ch p ojec . Ve Rec. 2021;189:11–8. h ps:// doi. o g/ 10. 1002/ e . 248. 58. Go mley E, Co ne LAL. Con ol s a egies o wildli e ube culosis in I eland. T ansbound Eme g Dis. 2013;60:128–35. h ps:// doi. o g/ 10. 1111/ bed. 12095. 59. Wal e D, Ande son CW, Smi h R, Vande klok M, A e ill JJ, Ve cau e en KC. On- a m mi iga ion o ansmission o ube culosis om whi e- ailed dee o ca le: li e a u e e iew and ecommenda ions. Ve e ina y Med In . 2012;616318. h ps:// doi. o g/ 10. 1155/ 2012/ 616318. 60. Ba asona JA, Ve Cau e en KC, Saklou N, Go aza C, Vicen e J. E ec i e- ness o ca le ope a ed bump ga es and exclusion ences in p e en ing ungula e mul i-hos sani a y in e ac ion. P e Ve Med. 2013;111:42–50. 61. Ca e SP, Chambe s MA, Rush on SP, Shi ley MDF, Schuche P, Pie a alle S, Mu ay A, Roge s F, Ge inby G, Smi h GC, Delahay RJ, Hewinson RG, McDonald RA. BCG accina ion educes isk o ube culosis in ec ion in accina ed badge s and un accina ed badge cubs. PLoS ONE. 2012;e49833. h ps:// doi. o g/ 10. 1371/ jou n al. pone. 00498 33. 62. Chambe s MA, Roge s F, Delahay RJ, Lesellie S, Ash o d R, Dalley D, Gow age S, Da é D, Palme S, B ewe J, C awshaw T, Cli on-Hadley R, Ca e S, Cheeseman C, Hanks C, Mu ay A, Palph amand K, Pie a alle S, Smi h GC, Tomlinson A, Walke NJ, Wilson GJ, Co ne LAL, Rush on SP, Shi ley MDF, Ge inby G, McDonald RA, Hewinson RG. Bacillus Calme e- Gué in accina ion educes he se e i y and p og ession o ube culosis in badge s. P oc. R. Soc. B. 2011;278:1913–1920. h ps:// doi. o g/ 10. 1098/ spb. 2010. 1953. 63. Go mley E, Ní Bhuachalla D, Fi zsimons T, O’Kee e J, McG a h G, Mad- den JM, Foga y N, Kenny K, Messan L, Mu phy D, Co ne LAL. P o ec- i e immuni y agains ube culosis in a ee-li ing badge popula ion accina ed o ally wi h Mycobac e ium bo is Bacille Calme e–Gué in. T ansbound Eme g Dis. 2021. h ps:// doi. o g/ 10. 1111/ bed. 14254. 64. Go mley E, Ní Bhuachalla D, O’Kee e J, Mu phy D, Aldwell FE, Fi zsimons T, S anley P, T a alos JA, McG a h G, Foga y N, Kenny K, Mo e SJ, Messam LLM, Co ne LAL. O al accina ion o ee-li ing badge s (Meles meles) wi h Bacille Calme e Gué in (BCG) accine con e s p o ec ion agains ube culosis. PLoS ONE. 2017. h ps:// doi. o g/ 10. 1371/ jou n al. pone. 01688 51. A icle e0168851. 65. Bayissa B, Si ak A, Wo ku A, Zewude A, Zeleke Y, Chanyalew M, Gumi B, Be g S, Conlan A, Hewinson RG, Wood J, Vo de meie HM, Ameni G. E alu- a ion o he e icacy o BCG in p o ec ing agains con ac challenge wi h bo ine ube culosis in Hols ein-F iesian and Zebu C ossb ed Cal es in E hiopia. F on Ve e ina y Sci. 2021;822:702402. h ps:// doi. o g/ 10. 3389/ e s. 2021. 702402. 66. Re amal P, Ábalos P, Aleg ía-Mo án R, Valdi ieso N, Vo de meie M, Jones G, Saadi K, Pe ez Wa C, Salinas C, Á ila C, Padilla V, Bena ides B, O ellana R. Vaccina ion o Hols ein hei e s wi h Mycobac e ium bo is BCG s ain induces p o ec ion agains bo ine ube culosis and highe milk p oduc- ion yields in a na u al ansmission se ing. T ansbound Eme g Dis. 2022;69(3):1419–25. h ps:// doi. o g/ 10. 1111/ bed. 14108. 67. S ini asan S, Conlan AJK, Eas e ling LA, He e a C, Dandapa P, Vee asami M, Ameni G, Jindal N, Raj GD, Wood J, Jule N, Bakke D, Vo de meie M, Kapu V. A Me a-analysis o he e ec o Bacillus Calme e-Gué in accina- ion agains bo ine ube culosis: is Pe ec he enemy o good? F on Ve Sci. 2021;18:8:637580. h ps:// doi. o g/ 10. 3389/ e s. 2021. 637580.