In Focus History and eradication of smallpox in Turkey Osman §adi Yenen isanbul Universiy Istanbul Medial Faculty Department of Medical Microbiology » (Capa, isanbul, Turkey / El: yeren@istanal edu. ‘Turkey has played a prominent role for the Western World in the prevention of disease from two different angles. The first is the istanbul connection from where the variolation orig- inated. The Ankara connection, on the other hand, provided the source for the modified Vaccinia Virus Ankara (MIVA) as both the third generation smallpox vaccine and the recom- binant vector for modern day vaccine development. In this article, the history of disease and eradication efforts both in the Ottoman Empireand inthe Republic era of Turkey will be discussed with an emphasis on the worldwide significance of istanbul and Ankara connections in the history of sinallpox. Dring the 600 years of Ottoman history smallpox was ever-present alongside other epidemics such as plague and cholera. The prox: imity ofthe Anatolian plateau to South-western Ask and major trade routes where itisbeleved to have originated from was probably the reason for its presence in Asia Minor since ancient times, Written revons before the 15th Centuryare scarce and details ofthe disease in the impiee remain underlocumented. Fven after the 15th Century, reconb-keeping was inadequate due to a lack of under standing oF infectious disease contol hi tional Sanitary Conference in Paris (1851), which ended without 1 ts importance in public Ith. The Ortoman Empire was represented atthe First Interna any successful resolution to disease control, At the 13th Intema: tional Sanitary Conference (1926), smallpox and typhus were recox, nived as diseases to be controlled with quarantine measures! Mest documents related to the di ase in the empire date hack to 19th Century. While disease prevention and Jenner type vaccination started during the collapse of the empire, full eradication occurred, only alter the foundation of the Republic of Turkey, Causative agent and short history The usative agent of smallpox is the varioa views (Orthopensvirus) within the family Posriridae. Genomic studies indicate the presence of two or three different clades of the vin, The date of origin ofthe virus is unknown, Although disease indicating scars ‘were detected on Egyptian mummies, thevirus itself has neverbeen iclentiie?, So far the only molecular evidence for the existence of the virus was detected in 300 year-old Siberian mummies, Further analysis indicated the oots of the virus date back 10 928 AD however, some historians take the origin back t 10,000 BC, speculating on its possible re ionship with the compox vies? On ‘the other hand, Gubser and Smith’, following their studies on the DNA analysis ofthe virus, revealed relationship between the virus and the camelpox virus: possibly these two vinuses originated from the same ancestor. Babin and Babkina’ suggested that the tater. pox, camelpox and varioka viruses originated from the same an {cestor around the Horn of Afica andl spreatl to Bast Afi through ‘camel movements dating back 3500 years ‘Manifesting itself wth fever and flaky skin, the disease has four lfferent clinical types: ordinary; (vaccine) modified; flat and hem Corthagic smallpox’. Strains resulting in varying degrees of manifes: tation have been identified as (2) the vaiola major resulting in 10-30% in death and! (i) the variola minor that results in <1% in death, Historical records show diseases similar to smallpeax were transmitted yan ne Bayt Iran (430 BC), to Sicily (395 AD) andl to China (48-49 AD), from ina to Korea (583 AD) and finally from Korea to Japan in 585 AD", However, cifficulies sto Hittites (1350 BC), from thereto Mesopotamia to Rome (165 AD) and from ‘encountered in those days in distinguishing between diseases showing sim relation to symptoms render the recorus¥ smallpor. The first clinically valid record for distinguishing berween, smallpox and measles was achieved by the Iranian physician EbRa7i (010 AD)? ox 1), who considered smallpox as a form of coagu lation in children’s blood, Smallpox repeatedly arrived in. Anatolia through the crusades (2096-1291) and spread through trade routes crossing the great Sahara and reaching East and West African ports! In the early 16th ‘Century, ithecame widespread in most European etiesand with the first explorers it spread to Americas, Australia and Africa With the Spanish congquistacors it was transmitted tothe native population of ‘Cuba and Hispaniola (today’s Dominican Republic) resulting in the extermination of the Azecs and Incas. These epidemics also resulted in the loss of workforce and subsequent introduction of African slaves in Americas", The Spanish and Portuguese, respec tively, introduced dhe disease to Chile in 1554nd to Bevin 1555. Itin Focus 0.29 on 1. Excerpts fram Rhazes’ Smaps and Medsles Treatise? [Now tbe Small-Pox arises when the blood purefies ond ferments so that the superfluous vapoursare thrown out of, anit is ‘hxarged froma te blooelof infants, which is like mus, nto the blood of yonung men, which slike wine perfectly ripened and the Sinai Pas tself may he compeareto the fermentation ana the bissing noise which take place in musta atime. Anal hiss te reason why children, especially males, rarely escape being seed with this disease, becanse it is impossible o prevent the blood’ schanging from thisstate into itssecond tate, just ast tsimpossibleto prevent must (whose natreitisto mathe a hissing: noise cl to ferment, from changing into the sate which happens to itafter its malking a bissing noise and its fermentation. Yon shonl now that the Measlestwhich are ofa deep redand violetcolowurare ofa bad and fatal bind and thatthe Small Pose in which the pustulesare yellow, bard, close toetber, confluent, numerous, and of a deep red or violet cofour, and that kind which spreads ike berpes, and gives the surface ofthe bol the appearance of vibices, are all had andl mortal. (p. 94) was introduced 10 North Americaby the British in 1617 with serious, consequences 9 American Indian populations. The disease was reported in South Africa in 1713, in Australia in 1872, New Zealand ‘and Pacific Islands from 1872 onwards, thus becoming a problem worldwide’, Following the 1953 proposal of Dr Brock Chisholm, General Sec retary, WHO and the 1958 call by USSR delegation member Victor ‘Aedtanov, WHO initiated a global eradication campaign in 1967. With the las ease reported in October 1977 it was elared eradicated, (reviewed in Fenneret af.*and Henderson) anel the final report of the Global Commision, WHO for the Certification of Si smaller Eradication confirmed these results (1979). ‘The final declaration ‘was made by the World Health Assembly at the Geneva Mecting (1980) to the health ministers of all participant countries. Today limited amounts of variol stuns are kept in two different WHO collaborative reference centees: () Centre for Disea olan Prevention (Atlanta, GA, USA);andl (ji) "The State Research Centre of sesCon Virology and Biotechnology (moved from Moscow to Novosibirsk, Russia after 199)", ‘Smallpox prevention: variolation and vaccination Varoltion (or inoculation; ding dhe 80h Gentry these ew terms were ised interchanges) technique was Ise on the cixervation that the pate had and mini against second infection, In ancient China, powdered vara criss were used to ine heathy nvidia nexus o inslacons, tn ancient India ntraermal inoculations of lesion material were practise A information prior to 1550 was reported to be speculative by Boylston", in the Ottoman Empire similar practices tw these in India were used (see below), Vaecination, on the other ‘band, was desved from the observation that human beings sulned immunity against smallpex after exposure to cowpo. Materials taken from cowpox lesion were inoculated intradermally to healthy people. Similar administrations were carried out in England on a popular level, which was later given a scientific basis by Edward Jenner in 1796 (reviewed in Boston" and Buin"). ‘Smallpox and variolation in Ottoman times the evidence of disease existence near Anatolia dates back vo the ‘Blephant War (570 AD). "The arrival ofthe disease in Constantinople dates ack to 12th Century and important evidence can be found in the poem of Theodore Prodromos: ‘The body ix beated violently through with extraordinary torches from: the fever... lle by lide (the pimples) grade ally on the seventh day become murderous pustules. Have lyon ever seen a violent shower of rain coming down on a Take, bow the entire surface of the lake swells up on account of te closely packed bubble? (ct in Hopkins", p.27) Evidence of the application of inoculation technique in Ottoman, Empire can be found in the leters of two Greck Physicians, These two leters written by Emanuel Timonis (bom in Chios, Greece of Italian parents; family physician to the British Ambassador to the Porte, Sir Robert Sut on Exbward Wortley 1) and Jacob Pylarini a native of Cephalonia anda graduate on, and to his successor, Monta ‘of Pacha in both law and medicine, previously, physician to Tsar Peter the Great in Russia, practised in istanbul and served as Venetian Consul at Smyrna) were presented! to the British Roval Society”. Hoth physicians witnessed the application of inoculation technique, ancl also-administereditthemselves during the smallpox ‘outbreak in Constantinople in 1701, Also, ‘Timonis later sent a ‘communication to the Koval Society for the meeting in May 1714, desenbing in detail how to collect variolacrust, when tosample, how vo preserve and apply (Box 2) Acconting to Pylatni, the inoculation technique was intrexluced 10 ‘Constantinople by a Greek lady in 1660 thar was welcomed by the Christan population, yet declined by the Moslem population of the city due to their belie ‘The Turks alone, so addicted are they to their predesinarian ‘notions, andso riveted ioancient prejudices, neglectto reap any adveantange ow tein Focus ox 2. Excerpts from Emanuel Timonis’ Communication read bry Joba Woodward? ‘The writer of this ingenious discourse observes, in the frst place, that the Circassians, Georgians, and other Asiates, have introduced tbispractice of procuring tbe maallpex hy asort of inoculation, for about the space of forty years, among the Turks ‘an otbers at Constantinople ‘That although atfirst the more prudentwere very cautions in tbe use ofthis practice; yet the happy success thas found to have in thousands of subject or these eight years past, bas put itout ofall suspicion andl doubt; since the operation, baring heen performedon personsofallages sexes, anc different remperamentsand even inthe worst constitution ofteair, yet none have been found to die ofthe smalls, when at the same time it was very mortal when it seized the putient the common way, of which half the affected dyed. This be attests pon bis on obsereeation. Neu he observes they that have this inoculation practised upon them are subject to very slight symploms, some being scarce sensible they are il or sick; and what is valued by the fair, i never leaves any scars oF pis tn the face. The method ofthe operation isthus. Choice beingmade. proper contagion, the matter ofthe pustulesisto be communicated to the person propused to take the injection; whence it has metaphorically, the name of incision or inoculation. Kor thi purpose they makechotce ofsome boy, or yountglady, ofa found bealtby temperament, that sseized with the common smallpox (ofthe distinct, not fluc ford) on the tefl or thirteenth dary from the beginning of ks sickness they with a needle prick the tubercles (chiefly those on the shins and hams) and press out the matter coming from them into some convenient vessel of glass, OF the like, to receiveit;itisconvenient to wash and clean the vese first wilh warm water: aconvenien! quantityof bis mater being, thuscollected,istole stopped close, and kept warm inthe xnsomof the person that carries it, and, assonon as may be, brought the place ofthe expecting future patient. {The patient therefore being in a warm chamber, the operator is to matke several little wounds with a needle. in one. neo.or ‘more placesoftbe skin, illsomedtropsofbiood follow, and immediately dropout some drops ofthe mater tate glass, andl it well with the blood issuing out; one drop of the mater is suficient for each place pricked. These punctures are made inaierenaty ir any ofthe fleshy parts, bud succeed best in the muscles ofthe arm or radius... Box 3. Excerpts from Patrick Russes communication’? Aboutnineorten yearsagn, while on avisivata Turkish larem, alady happenedto Expressmuchanxietyforanonty child, ‘who had not yet bad the Smallpox: tbe distemper at that tine being frequent in the city: None ofthe ladies in the company bad ever beardofinoculation; so that, havingonce mentioned it, found myself obliged o enter into addetailofthe operation and Of the peculiar advantages of t. Among the female servants in the chamber was an old Bedouin, who buaving beard me with great autention, assured the ladies, hat my account was upon the whole a jus one, onty that I did not seem 9 well to understand the way of performing the operation, which she asserted should be done not with lancet, but with a needle, she herself bad received the disease in that matter, when a ebild: bad in ber time inoculated many; adding moreover, that the practice was weil known to the Arabs, and that tex termed it buying the Smailpor. or these several years past, ver few slaves have heen brought from Georgia. From what i could collectamong those already ere, who remember anything of their own country, inoculation was well known there: I bave seen several old Georgian ‘women, wbo ad been inoculated, when children, in their father’s houses. ImArmenia, the Turcoman tribes, aswell as the Armenian Christians, have practised inoculation since the memory of man; brut, like the Arabs, are able o give no account of ts first introduction among them. Itbasalreadybeen mentioned, that the Turksat Bagdad and Mousu! make no scruple wo inocatate their children. Lave seen dase seme Turkish strangersbere, who baud been inoculated a Erzeronm. Hence iis probable thatthe Turks, in ober partsof the Ottoman empire, do not merely, as fataliss, reject inoculation; but that orber considerations, which bave influence in countries where fataliss are ridiculed or anatbematized, concur likewise in Turkey, to oppose the reception of a practice to beneficial to mankind. Despite these carly communications, European interest in the ingculation technique in Otdoman Empire was achieved after the efforts of Lady Montagu, Dr Charles Maidand and Sir Hans Sloanein Britain (see below). On the other hand, the technique was used 19 apply parly i the Empire by the Moslem population® (Box 3). ‘The Ottoman Courtalso endured the disease including the sultans ‘themselves as did their children and wives, Sultans Ahmet 1 (1604), Ahmet IIL (1708) and AbdImecie (before 1839) all had te dis exe”*, Daughters of Murad Il (1599) and Abdolhamid (1782) and the sons of Mustafa I (1771) and Mahmut (1825) both died of the disease although the sons of Abdilhamidl 1 andl Mahmut both survived the infection (including the crown prince MehmetIn Focus Figure 1. (@) Vaccinator's bag of collection for vaccine material, rosewater bottle and walrut shalls used to hydrate dred vaccine material) ivory vaccination needle, or vaccine pen (18th Century) (Courtesy of Prot. Dr ter Uze) Nusret)"***, Such information indicates the lack of any inocula tion practice the Ottoman Courtalthough twas practivedin other pars ofthe Empire. Smallpox was experiencea in istanbul as aa epidemic in 1701, 1706, 1825 (extension of the European pandemic between 1824-1829), 1845, 1871 and 1577-1878 as wells small outbreaks of 1881, 1887, 1890, 1891, 1894, 1908, 1809 and 1925. Itanbulhad always been the comics hit this city most crowded city of the Empire and most epi firs, although outbreaks occurred haphazardly in provincial towns from time to time (e.g. 1847-1887)", The firs reconts of inocula tion practice the Ottoman Court derives from the palace physician ismail Pasha’s lithographic book Menafil ef (Benefits for Chil dren)? Inthisbook, an Anatol ankvalin 1679 ‘The inoculation technique spread with the Seljuks (1055) from the Caucasus region 10 Asi Minor and subsoquently passed on to COrromans, The technique was mostly applicd by house women who dri samples of varolacrustsinsde walnutsills, which were applied (© healthy individuals interclecmally after resuspension using mse water in May (Figure 1). Inoculation needles andl imple ments have also heen through series of changes, userl also for vaccination, and the current design bifurcated needle was ints duced in 1965 (reviewed in Baxby", The Istanbul Connection British interest in che inoculation technique dates back 10 the appointment of Lord Kdward Wortley Montagu as the Extraordinary Ambassador to Ci is wi rastantinople in 1716, Lady Montag was ictim and carried scars onherface (1715)-shehadalsolost his brother to the disease (1713). keen observer andavwriter, Lady Montagu first mentioned the inoculation technique to her fiend Sarah Chiswell (ho later died ofthe disease in 1726), in her letter posted from Adrianople on the way to Constantinople (1717)!%" (Box 4). Following her observations in Constantinople, she gor her S:ycar-old son inoculated with the support of the imbassy doctor Maitland! (1718). On her return 10 England, shealso got her3-year (od daughter inoculated during the 1721 epidemic in England. This application was the first example of the inoculation technique in Britain, generating interest widely among, aristoceats, ‘To test the safety of the inoculation technique before it was given 10 the daughter of Prince of Wales, Princess Caroline, sx prisoners from Newgite were inoculated with the virus and the success of the application le to the release Of these prisoners? Upon these trials, and several others in private families, the late queen, then princess of Wales... sent for me to ask my ‘pinion of he inoculation of the princess: Itold her Royal Dighness, that by whut appeared in the several assays, t seemed to be a method to secure people from the great dangers attending, that distemper in the natural wa (GSloaine and Birch") Princess Caroline, following her suecessful inoculation also had her 11. (Ams andl 9- (Caroline) year-old daughters inoculated ‘Smallpox and vaccination in Ottoman and Republic era of Turkey Duc to lack of interes inthe inoculation technique atthe Otoman, Courtapplic ener’ slefinition Hons were conducted regionally. vaccination (An inquiry into the Causes and lifects ofthe Variolae Vaccintae, or Cow-po, 1798") was generated in the western medical environment of inoculation", Lis book titled Jngatiry ‘was printed England in multiple copies from 1798and new copies ‘were also produced in Geneva, Hannoverand Wien. Reprints ofthein Focus ox 4. Excerpts from Lady Montagu’ letter” ToSarab Ciswel, Adrianople, LApPILITIT Aproposofdistempers lam goingto tell yowa thing that lam sure will make you wish yourselfhere. Thesmailpex, so fatal and sogeneralamongstus.ishere entirely barmlesshy the invention to engrafting, which isthe orm theygiveit Thereisasctofold women who make t their husinessto perform the operation. Esery autumn in the month of September when the great beat & ‘abated, perople endl ome cnotber to krone if any of thetr family basse mind to bave the smalipexe. They male peartis for this urposcand when hey aremet commonly fiteenor sixteen toyether)theold.womancomeswitha nutshell fullofthe mater of the hestsort ofsmailpax, and asksthal veins you please to have opened. She immediately rips open that you offer to ber witha large needle which givesyoumo more pain than acommonseratch) and putsinto the nein asmuch venomascan liewpon the ‘ead of ber needle, and after binds up te litte wound with a bollow bitof shell andin this manner opens for or five veins. The Grecians have commonty the superstition of openingyone inthe middleofthe forebead, n each arm anddon the breastio marl the sign ofthe eross, but this has avery ill effect, allthis wounds leaving Mle scars, and is not done hy those that are not superstitious, who choos to have thentin the legs or that partofthe arm that isconcealed. The cbildren or young patients play together all be rest ofthe day, and are in perfect bealth tat the eight, Then the fever begins to setze them and they keep their beds neo days, very seldom three. They have very rarely above twenty or thirty in thetr faces, which never mark, and in eight days time they are as well as before thetr illness Whore they are wounded there remains ranninas sores dering the distemper which don’ tdoublisagreat relief to it Every year thousands undergo thisoperation, and the French Amnbassadlor says pleasantly that they take the smallpox: bere hy way of diversion, as they take the waters in other countries. There is m0 example ofantyone thathasdied init, and you may believe Lam well satisfied of le safety of the experiment, since lintendtotry item mydear tle son. lam patriot enotaghto tale paint bring tbisusepul invention into fashion in loigland and Isbondd not fail o write to some of our doctors very particularly about it enew anyone of them tbat | thought bad virtue enouth to destroy sucha considerable branch oftheir revenue for thegood of mankind. But hau distemper istoo beneficial to them M010 expose to all their resentment the hardy weight that should undertake to putan end tot. Perbaps, if] ve to return, Hay, enever, bave courage to wear wil them. Upon this occasion admire the heroism in the beat of your friend, ete ToWontey, Constantinople, 23 March 1718 ‘The boy wees engrafted last Tuesday, cane is at this time singing ana playing ana very impatient for bis supper. cannot engraft the girl ber nurse beas not baad the smallpas. ToWortey, Constantinople, 1 rit 1718 Your son is as well as can be expected, and I bope past all manner of danger ‘original article were in fce circulation as wel trinslationsin va iron. In fact, the fist vaccination took languages allowing the method to be intexuced in many coun tries". ‘The Ottomans fist read Pnguizy in 1801, as Giuseppe Marchal's Kalan text was translated into Turkish by Mustafa Hebget fendi with the ttle Risaled Telkih- Bakari™™™, Subseq 1811, Sanizade Atallah Embassy in istanbul, as a Swiss man, Jean dle Carmo, hac secured a small amount of Italian vaccination material, which ws taken t0 istanbul by some fiends of the British Ambassador (Ihomas Bruce; Lond Elgin) and administered to the childrea at the Embassy in di conducted a series of tests on his evember 100°", Vaccination materia supplied by dle Carmo farm animalsat Avasaziand madesanumberofrecommendationsto reached a faras Bombay via Greece ancl Baga” Sultan Mahmut IL such as a new vaccination centre and mass ‘vaccinations while dedicating chapterofhis book to this practice ‘The first imperial decree regarding smallpox vaccine was issued on Vaccination might have been known to the Ottomans since 1810, 20M however, Sultan Abdlilmecid (bom 1823, died 1861) had caught 1840". Religious concerns expressed in Burope earlier?” ‘were also voiced in istanbul at this time and only after fatwa by the smallpox in infaney and this was probably the reason why caution ‘was exercised in his administration, Accoling to Walsh, the first instance of vaccination at the time of Sultan Mahmut I, who allowed ito be aelministered to his children (bya rench physician) after the death of his the eklest son in 1825, henceits acceptance by the rest of his subjects. Iniually, imported vaccines were used throughout the empire however small amounts from Europe were insufficient to meet the demand nd vaccination teams preserved ‘quality lesion material afer successfl vaccinations of upper class Seyhilisam declaring vaccination permissible according 10 the Islamic lw, lnge-scae vaccination campaigns started at no cost 10 ‘the public, Reganless, vaccine production di not startunsil 1872, and imported vaccine material was administered oniy on critical Population segments such as military cadets or in eases of emer: gency, by vaccination teams from istanbul?®, Vaccination profes sionals were tranedat the Schoolfor Vaceinators within the vaccine production centre from 17 May 1898, which graduated 319 profes. Sonal vaccinators until 1903, By 1910 village schoo! teachers andIn Focus midwives were also admitted to this school and its name was later changed! to Minor Health Officers School as minor surgery oper tions also became part of the school's curriculum, Despite iter ruptions 1 the program, the school stayed in exstence until 1950s and truined countless waccinators The Otoman Empire made itan obligatory vaccine for children of school age and the Regulation on Smallpox: Vaccination of 8 July 1885 denied school registration to those 1 able te» prodlace any proof of vaccination. The seconel Regulation om Smallpas Vacet nation of 21 July 1894 also dictated that newhoms be waeeinated Within six months of bith’®, Updates to the regulation were incor porated in 1904 and 1915 increasing the numberof vaccinations for an individual t0 3 by age 19."The common practice of human to human vaccination (variolation) also became strictly prohibited? Despite regulary effort, the administration of smallpox vieeine han reached all comers of the empire, anda repo udded Recon: struction in Turkey by the American Committee of Armenian and in 1918 confirms the lack of systematic camp ign ation is practised in langer towns and cities and in the army. ‘Only in the army is it systematically carried out." (cited in Ore sn p.224)Aherthe foundation ofthe Republi, the Pubic Bill came into force (24 April 1930) and made smallpox vaccination obligatory forall citizens The Ottoman production of siallpox vaceine stated with the reopening of The Imperial Vaccine Production Centre (Telkibane) In 1892in 1892 and domestic production was distributed allover the ‘country bringing an end to imported vaccines”. An inspectorate way established in 1890-1891 and Colonel Hseyin Rahmi Bey bec he first vaccine inspector (Figure 2). Later in 1894, the vaccine proxluction centre wi located a proper building during, senior Inspector Remi Bey"s time (1895-97). After his death in 1896, the production centre directors were Dr Hasan Zhe) Nui Bey (1896-1897) and Dr Rifat Hlisamettin Pasha (1897-1913) respectively After the Young Turk Revolution of 1908, it became the ‘Ottoman Vaccination Centre" nthe years following, the centre directors were De Kemal Muhtar Bey (1913-1920), De fa Hisamettin Pasha ‘aguin (1920-1922), Dr Kemal Mu Bey again (February 1922 10 September 1922), Dr Serafetin Mustaft (in the Republican era Dr Serafettin Mustafa Kam) (1923-194). Berween 1892 and 1913, 4 total of 7,260,784 tues; and between 1914 and 1919 a total number of 27,688,449 tubes of vaccine were produced at this centre. During the War of Independence, ‘he Red Crescent transported vaccines from this production centre to Anatolia 366,000 in 1920, 1,770,000 in 1921 and 1,283,000 tubes ia 192 respectively. Bermeen 1892 and 1923 inoculation viruses for Figure 2. Cover page of the Servet Funun magazine published on 17 November 1892. Haseyin Remzi Bey (n the middle) and Telknane staff are seen together with he calf used a the cere for vaccine production (courtesy of Vokan Gulpok imported from Paris” even though information lable standardisation until the 1960 was unknown and in this period, regarding the doses contained is unava vaccine 2Oddosecubes oF 250 (5 ml) and 500 (OmL) dose boules were in circulation”. ‘The Vaevine Proxluction Centre moved to Ankara in 1934 and the production continued under supervsions of Dr Serafettin Mustafa Kam (1934-1936), De Niyazi Erzin (1936-19 (1942-1947), Prof DeZihul Berke (1947-1962) (1962-197) ), Dr Nusret Figek ye Hthan Selita 1d virologist Gigidem Artal until the production ended in 1981 (Mustafa Hacvmeroiiu, personal communication, 200)" Vaccine production oceurtedako ebewhere in the empire such as Mecea, Basra, Sana’a, Bagdad andl Da and in Sivas, pprocluction centre for rabies ancl smallpox vaccine was also estab lished, However, these centres were shortived an the main ‘cent forproduction remained istanbul Afterthe foundauion ofthe Republic in 1923, records regarding smallpox improved consider ably: the official number of infected cases and resulting deaths are provided iTable 1in Focus ‘Table 1. The umber of infected cases and resulting deaths during Republican Era 6 1925 29 "7 1927 2 6 1928 a 8 1929 1746 870 1930 30 160 1931-1939 2524 ma 1940 958 130 1942 1871 174 1943 12905, 1380 1944 6093 078 1851 152 a 1957" 128 7 "the lst smatipox outreak. ‘Asa result, berween 1925-1957 total of 27,755 infected cases and 4039 deaths were reported", Nosmallpoxinfection was eenin ‘Turkey after 1957anel the vaccine production cametoan endin 1981 (Cijdem Antuk, personal communication, 2004), The Ankara Connection As mentioned above, folowing the eradication of smallpox, ony collaborative reference centres recognised by WHO are offically ‘entitled toholdlive variola strains, however tis not known whether unauthorised laboratories have any holdings, Sinee the 1980s, smallpox vaccination has come «0 a stop but the majority of the ‘world population is not immune tosmallpex, nor to crossinfection ‘with animal orthopoxviruses and concerted efforts to specifically develop vaecin ist smallpox an all poxviruses ave inten fd, Limitations of space do not allow further details here bus the Moaified Vaccinia Virus Ankara (MYA), which fe 1 the devel opment of (imvamune”), a thie generation vaccine will be ‘explained, The origin oF MVA dates hack to the CVA dermovaccini strain, which was the cross strain of those obtained from donkeys and caves. Dr Serafettin Mustafa (Kamm) claimed to have produced use specific strains (maintained between donkeys and calves) frst at istanbul Vaccine Production Centre in 1932", Kor the mainte nanceof the vaccine strain donkeysanel calves were used ancl uring, the eradication campaigns seed cultures were obtained from WHO (Gahan Saltanda, perwnal communication, 205). Renner et a indicates the useofthe strain for vaccine proxhicton in Turkey between 1968 10 1971, German researchers took the CVA dermo- vaccinia strain to Germany and started its passaue in 1958 using chicken embryo fibroblast cutures™™®, After 300 passages changes in the pl e observed and at its 516th passage it vas named MVA to differentiate que moxphology of the strain we from other attenuated vaccine strains, The strain MVA was created ay result of 574 dhuion passage ofthe attenuated strain ‘Complete genomic sequence analysis ofthe strain has hen carrie ‘out revealing cic 15% gene Hoss compared to the original ge -MVA falls to replicate in human cells, which sets it apart from vaccinia vinss. Thus, t poses no risk oF spreading in or among, ‘the carmers, and gains importance in vaccine research as well as vector delivery system In the 1970s, MVA was used! in clinical Ualsand regardless of minor local or general reactions, theresulting dard vaccinia virus reduced the diameter ofskin lesions proving it should be stressed that this vaccine has not heen tested against major outbreak of smallpox so far, Aeconting to some weiter” MVA vaccine was tested on over 100,000 individuals in Germany and in Turkey without any compl: cations, yet Information about its use in Turkey is awaiting contr mation (Ethan Grldarca, personal communication, 2005), in on the administration Bayem, Germany, Gemer et al also me Of this vaccine t around 140,000 children in the midh1970s but there is no confirmation that this vaccine, producedby the Bavarian Vaccine Insitute, reached Turkey. Conclusions {In her review of the Ottoman Physicians and Medical Sciences, Historian of Medicine, San mentions the lad of data on the ‘capabilities ofthe Ottomans in generating theory nel thei interest in the generation of new knowledge via research” Most medica reports produced in the Ottoman ent were based on medica pictice rather than the philosophical hckground or clinical obser ‘ations, which was aso the casein lealng with smallpothroxghout ‘the empire. Oroman medical circles had ao irerest, even a the level of intellectual curiosity, in inoculation that was applied widely among the Sultan's subjects, Necessity led them to resort 10 vaccination as a novel technique in the 19th Century. Finally, due to the global quest fora cr understanuing of the nature oF what ‘causes the disease, they distanced themselves from Islamic ta tons (Divine Wisdom) and Galenie understanding of diseases and forthe first time in 1885 the vaccine was only applied to children®® ‘whereas it was compulsory in many other countries long before it yenmar, 1810, ‘was applied in the Ortomaa Empire (avaria, 1807;in Focus Norway, 1811; Russia 1812)" Although itis stil unclear how ‘German scientists obtained the strain that resulted in the cevelop- mentof the MVA, the Republican ext. of Turkey used contemporary scientific principles for disease prevention and eradication Acknowledgements The author thanks Prof. Dr Zayre uran (stanbal University, istanbul Medical Faculty, Department of Medical Microbiology) for teanstaons from German to Turkish, References 1. Scan 0.. a Yeah, WV. 191 dnertional Quran ss from Rossi by Be Merona V. Bite), Connecti, craton Une vers Pres, Ihe pp 1 3 2. Das, LE. (2015) Pres Kap, DAM aa Towle, PM, Fede Vida, 6c Pakula, Lppcoa Wins 8 Wis, pp. 2160-2194 4. McC 8. (197) Anolon oldelscs:-slp ane nor MUG and Brown, PJ (0): The Anrep of Pcs Dae Inaerational Health Porgeecies. Nest, Gone ae Brech Pbtshes, moan 4. agi etal 2012) Yl vi na year Sen my. Bal J Me. 367, 2057-29. 10 1OENTIMGI O26 5. MeN. (958) Magen pes (Tec) New Yr, Ate ks Dosey, p35 3. 6 Gute, C andsnith G22) Thesequenccufcamepaevinnshowsitienent ‘hcl sled he cause fran jae Vid 83,855 72 7. abl, LV and Babin LN. 2012) A remap say ofthe obese rmccea ein. ect Gon. Bk 12, 1997-1604 01S} mcd A ennes, Fal. 19) Smalpar and ws erdcaon. Genes, Wort Heath Onto, 209266 9. Rl (Ans Matas ZararraArRas (1) ATi Srl ‘roc and Maes. (Tarte fom the Origa Aric Will Akane ‘Gren, Logon Prine or The senha Soke 1988 rept 201), 29,98 10, Okdwone, MLA. (198) Vrs, Mags, 6 Hry. Ose, On Usberity ress pp 27-44 11 tas $1997) Addon ad ory. san, Parad pedal, Newt aes, Ye very Pres, 412 12 Barge, and Dosing, (1987 Smaps: the tamper the mont erie ff the mine of death. Am fer. Mad 127, 635.612. do0.7826/ (os 819-1278 fa 4997101500000 13 Un, 2001 Sap es hsonpan emeg avamcapen flag erie Sami Pea Ifo. 12,71 80d 0058p 200121555 14 Menderion,D A (200 Smaller The PeabofADbee Now Yr, Pers owks. on 1 8 15, sate of Medeine 2008 ine Varia Vs Constdeatons for Comin esearch. Washi, DC The Kaen Aedes resp. 1-151 16. Bovisnn, AW 12) Dane Providence Smale coud te Fonte 18 antary Medal Reon Noh Charen, SC, Crate Space see Pub Fader, pp 282 17 in 1. in) The Bracken alc Ford anne and Te Fitand (Only Bradcation ofa Human Ifo Dias Yond Avani PSs pre. 1% Hopkins, BR. QU) The ate Kile: Smaps Hy. ica ae arden The Univer of Chica Pr, pe 1 30 (Onignly pbs Princenaond Peasants Srl sory by Te Une Chic Prosi v8) 19, Podakws Reba, and ear, J (2005) ena Tin, Jas lina and inocu. J Md eg 4, 81-12 2s 2 2 % Pa 6 6 x. 8 » Tons and Woon. (1714) An acon orion pute sal by sono cen as has fest heen ped a Constantinople Heng the cue of eer fo Ean! Tanonis, Oset ‘a ALD. SR Shel Const Decca, 713. Fl Tras 29,72 2 ae 10.10 1714.0010 er J.1716) Awa safe mad if communicating te sale iy ‘serie ely cated and agit to use. Tae alae fem {he ain, Ph Trams Sc Zon. ath commerce 165, {he year 18, Ald Vo Vn 1713 172. london, L810 ‘ese aad asl A (1758) An acre can in Ai, eter ‘om Dr Parick Rs nse at Aleppo, wo Alder Ruse, MD. FIRS. roca ter fom De Alor assliothe lf Morin PRS Pa Trans $8, 1-190, 105017 (OY “Yk, N10) A Hisar of Hhcare by Haan. Dicy Meas, Un, EK 9A) Cxmands imperacrnds Baber ve Ving Inna Oderien CeratpnaTyp Paks Vata al 17-30. ‘over 8.948) An oko the hry fea Yi age tat entry a alin Turkey ad the wee work Cer A.C) Tarheel A veer cnc he sry of sal occ erste Tip Tas Esti Ya Yann er 38 tab, ‘iy, D. QC} Seals varcnatim enim Aries ae inks ccs and pi. Vaecine 20, 2180-219, 10 1DIGSIRG4AL2)000282 Mea, MW. (1717 Toe Tr masters nero: Desa Aaa Testebenlarwastl lace Vg Pr don 2011 (LSet 1994 cao), pp 190 ethchars, AM. (198) The salpon son Me aed doh of a od dice Meola 47,455 50. ah. 2005) Quasar crdencelerplgmentoathe cx ican forts procul lp: Ean and New gd inthe 170 Se Ma 99, 252-266, 101258995202 Sven, AML (291) A Hsry of mano. (Secnl sh). Le, Ae dame Pres pp 29 308 San, ad De, T. (1755-1755) A acct cation By Sr Has Src Bart Gen 1 Me Raby, be publish, Ane 1736, Comms Dy Themas ich, DD. Soo RS PAE Trans 49, 516-520. 10.1057 sul 798.0075 em (19%) gr tt Cases na ctf the arlene, (Come 798s Jer, (Bl) Vacation gis Snail. Now York, Frome Ros Gat Min Sei, pp 13- Toyeon, A 2015) The rg of cnn. yan JER Se Med 106, 395-9980. 77/OIOTEBIHOS295 Dog. an, (2007) Teint caro AL Teenie Wet by ley Mary Montag snl Tarky's contin to ths. acne 25, 261-265, de10.1164 acne 20702075 {Wao (1836) A Resena a Cnstaniople. Vol H, Ob Xtal, ety, a Das, AH, 00-92 akin, (1999) tao andthe Sa in Baro 1830130, Candie mbes Unies Pr 246 394 Sore, AFM and Stone, WD. 22) Lady May Wortley Montagu: medica ‘elo controncry lowing rine felt Md gr 10, 282286 dani, 208) The oma Army 1911918 Disa & Daa om the aud Sa Le i, The Davey Uh es, p27 Giant #92) Geka sande alan yet ea ar ak eis gence hss Tar Tc Do 23, 246218 nN (1952) Tne gc, Tr Mi Ter go. ey. 12, 138-142 Gulia, E a. (1965) Memleketimtae 196 yds yaa sce har ede amas vec ale sa. Park 1 Tec. ed De 23, 179-20 ert, PH. fa. 202) A oe vm ems: new ri an theese es er sale elion. me Vac mamaber 951-97, dot04161- 21060In Focus 6 semen Varia Sumas MVA infection 3, 6 U4. Pasage history, papers sn pat fh act si VA, OE POVGAL272 Masai, $0988) jum aarti teltsanesn, hie: Cave A. is Take de Giga Ag we Tri fn oak te bry of smal vaccination". nln rivets Typ Ta Rein Yay, Yan No In pp, 190-205, Me, A CON5) Sato vata an Herman wih pe nes amps Imai Merb Info Die 26,28 430 WONG 9571 0025.0 Meyer, HE otal (91) Mapping of deetons in dhe gemme of the aes vet vrs MVA ae teh: on rece J Gam Vir 7210S 1 de 107} 0022 15177251051 awit (1998 Thecompletcgenonicsoqunccoltbe med ait ‘har rin: corparion with hr eons, Vinay 264,365 206 he 00 19989125 stalpoe cine: Cli Ie. 38, 179-1758. do DOS 1256 (im 8a 2015) Cnc apponns fatwa MVA pon sn apt Ro Yates 12,1595 1416 a ISSA ASHES) Se 1 eal (1979 MIVA Suen en Pace. Kine Eben, cher 98, 236-2892. [NVA vacation rt see: cial es wh eae ve vac ran (M)| 1 LOS OLS anc a (998) Mid vaccinia vs Ankara andes it ths hres a man vain. J Gan Vo. 79, 159-1167 Rencthat Seta 2001) Dewi new sapmacenen ma fed Dic eit, RY. 205 Sap apn agent ficken, AiR $7 7-12 dao 10160166 3512(02)00195 (On (9A ste alla Ana ier Tp abies Ye, 55. Un, AC (19) Tp Matron Vr Deh Vaya Ian 56 Geom, Fe a2) Die chen. Proven, eo ud Tepe ener nant Bankr Manatee dnb 11,993 07 (Sao. Freer, ag are anagemont of ences sed 107 soanizo0sarss0 57 San, (995) Osa heami ve Up It (ORaN Me ‘Sen, Md Tp Tar Ararat 8, 16 (Te New Hs Stats sie aa Biography Prof. Osman Sadi Yenen (MD) sayraduatcofsanbul Universi, Medical Faculty (1974). Un 1997 he served as medal personnel inthe Turkish Naval Forces, at Gihune Military Medial Acad (GMMA), Ankara and at GMMA Teachin ospital in istanbul ses and clinical mice respectively as an expert of Infectious di Diology. He was appointed as a full profassor at the istanbul University, Medical Faculeyin 1997 and currently serves as teaching, cae the Department of Microbiology, Virology and Ke has over 100 peer-reviewed! pub lications both in Turkish and! English, He served ay the secretary sand the president of the Turkish Society for Clinical Microbiology and Infectious Diseases (KLIMIK) and was the co-convener of the {th European Congress on Clinical Microbiology and Infectious Diseases held in istanbul (BOMID 1-4 Apeil 2001) as well as being, part of the onginisation of many intemational conferences 100k place in Turkey including the 1UMS in 2008, The Australian Society "Microbiology bringing Microbiologists together Not a member? Join now! www.theasm.org.au