CHEMICAL, CLINICAL, AND IMMUNOLOGICAL STUDIES ON THE PRODUCTS OF HUMAN PLASMA FRACTIONATION. XII. THE USE OF CONCENTRATED NORMAL HUMAN SERUM GAMMA GLOBULIN (HUMAN IMMUNE SERUM GLOBULIN) IN THE PREVENTION AND ATTENUATION OF MEASLES'2 BY C. W. ORDMAN, C. G. JENNINGS, JR., AND C. A. JANEWAY (From the Deprtments of Bcteriology nd Immunology, nd Peditrics, Hrvrd Medicl School nd School of Public Helh, nd the Children's nd the Infnts' Hospitls, Boston) The prevention or modifiction of mesles by mens of pssive trnsfer of humn ntibodies is well-estblished procedure. Convlescent mesles serum, pooled dult serum, nd globulin derived from humn plcents hve ll proved effective. Convlescent serum hs probbly given the best results, wheres pooled dult serum hs been the lest stisfctory. The following dt, compiled from the literture by McKhnn (1), indicte the comprtive vlue of these preprtions: Preprtion Number Prote- Attenu- Filure of Cses tion tion per cen Per cent Per cent Convlescent serum 1627 75 17 8 Adult serum 584 56 24 20 Plcentl extrct 2740 64.3 30.4 5.3 This mteril ws unselected, no djustment being mde for dosge, exposure-injection intervl, ge, or degree of exposure. The following communiction presents the results of studies on the vlue of Frction II (Humn Immune Serum Globulin) s prophylctic gent ginst mesles. Frction II is serum gmm globulin concentrte derived from pooled norml humn plsm by the methods of Cohn, Oncley, Strong, Hughes, nd Armstrong (2). l This work hs been crried out under contrct, recommended by the Committee on Medicl Reserch, between the Office of Scientific Reserch nd Development nd Hrvrd University. 2This pper is Number 19 in the series "Studies on Plsm Proteins" from the Hrvrd Medicl School, Boston, Msschusetts, on products developed by the Deprtment of Physicl Chemistry from blood collected by the Americn Red Cross. (Received for publiction Februry 17, 1944) Since, s hs been demonstrted by Enders (3), the ntibodies ginst certin viruses, such s those of mumps nd influenz A, re concentrted mny times in this frction, it ws felt tht it should constitute n effective prophylctic gent ginst mesles, s originlly suggested by Robinson.' These studies were begun somewht lter, but crried on t the sme time s those of Stokes, Mris, nd Gellis (4), reported in the preceding pper. During the winter nd spring of 1942-43, limited epidemic of mesles occurred in nd round Boston. This ws complicited by contemporneous nd much more extensive epidemic of Germn mesles. Those cses lone hve been included in the survey in which the dignosis of true mesles ws unequivocl. Four groups of persons served s subjects during the course of the study: children of fmilies under the cre of city physicins, students t severl privte schools, cses encountered in privte prctice, nd individuls exposed in the wrds of hospitl. CONTROLLED FAMILY STUDY Most of the primry cses occurred in fmilies in the lower income groups living in crowded qurters, nd, ccordingly, the exposure of the other children of the fmily ws, in ll but few instnces, intimte.4 Ech primry cse ws ' See J.A.C.S., 1940, 62, footnote on pge 3398. 4 We wish to cknowledge our indebtedness to the lte Dr. Hrry Goldmn, Deputy Helth Commissioner, City of Boston, nd his office ssocites, nd to Dr. Joseph Rosenthl nd his ssocites of the District Medicl Service, Boston Dispensry, for their invluble ssistnce in reporting to us cses of mesles with home contcts. 541
542 C. W. ORDMAN, C. G. JENNINGS, JR., AND C. A. JANEWAY investigted s soon s possible fter it ws reported to us. If the ptient ws found to hve true mesles, those siblings who hd no history of mesles were used in the study, provided the time reltions were pproprite. The first prt of the work comprised n ttempt to scertin, under crefully controlled conditions, the cpcity of Frction JI to prevent mesles. A single preprtion (A66) ws used. The dosge ws rbitrrily selected s 5.0 cc. for children over 5 yers, nd 2.5 cc. for children under this ge, with the exception of infnts between 6 months nd 1 yer, who were given 2.0 cc. Those under 6 months were presumed to be immune nd were not inoculted. When there were 2 or more susceptible contcts in fmily, they were divided into 2 groups composed of persons s nerly like s possible with respect to ge nd degree of exposure. Children over 15 yers of ge were plced in the control group in order to minimize the effects of the greter immunity which hs been found to chrcterize older persons. The globulin ws injected intrmusculrly in the glutel region into the members of one group. The other group received no injection nd served s control of the vlidity of the exposure. The globulin ws dministered s erly s possible fter exposure, usully on the fourth or fifth dy. The fmily ws visited by one of us t 2- nd 3-week intervls fter inocultion, or when we hd been informed by the fmily of the first sign of illness in ny of the children. At ech visit, ll children were exmined for coryz, Koplik spots, rsh, nd fever, nd inquiries were mde of prents nd children concerning symptoms nd signs which menwhile might hve occurred in ny of the contcts. The second prt of the fmily study consisted of n ttempt to ttenute the disese rther thn completely to prevent it. The sme dosge ws used s in the first phse of the study, but the injection of Frction II ws withheld until bout the 9th dy fter exposure. A different preprtion (D26) ws used in ll but 3 cses, in which A35 ws used. Return visits were mde every 2 dys until 3 weeks fter injection. The sme exmintions were crried out nd history obtined s in the previous series. The results of the study re shown in Tble I nd Figure 1. Tble I includes ll cses. In 3 fmilies, the dequcy of exposure of the contcts ws questioned t the time they were first seen. The fct tht subsequently no dditionl cses developed in the controls or in the inoculted children indictes tht either exposure ws TABLE I Results in controued fmily study (Crude figures) Results Results Totl Uninocu- Aim no. Inoculted lted cses No Mild Typicl controls No Mild Typicl mesles mesles mesles mesles mesles mesles Protection 74 45 40 (89 5 (11 0 29 7 (24 2 (7 20 (69 per cent) per cent) per cent) per cent) per cent) Attenution 65 40 27 (67.5 12 (30 1 (2.5 25 4 (16 0 21 (84 per cent) per cent) per cent) per cent) per cent) Totl 139 85 67 (78.5 17 (20 1 (1.5 54 11(20 2 (4 41 (76 per cent) per cent) per cent) per cent) per cent) per cent) (Corrected figures) Protection 54 31 26 (84 5 (16 0 23 1 (4 2 (8 20 (88 per cent) per cent) per cent) per cent) per cent) Attenution 54 31 18 (58 12 (39 1 (3 23 2 (9 0 21(91 per cent) per cent) per cent) per cent) per cent) Totl 108 62 44 (71 17 (27 1 (2 46 3 (7 2 (4 41 (89 per cent) per cent) per cent) per cent) per cent) per cent)
USE OF GLOBULIN IN PREVENTION AND ATTENUATION OF MEASLES 543 FIG. 1. CONTROLLED FAMLY STUDY indequte or immunity ws present. In Tble I nd Figure 1 re presented the dt obtined only in those fmilies in which one or more controls developed mesles, or in which one of the inoculted children developed modified or typicl mesles. It should be emphsized, however, tht mong 85 susceptibles inoculted with Frction II, only 1 cse of typicl mesles developed, nd, in this instnce, the child ws ccidentlly given only 1.5 cc. of preprtion D26 on the tenth dy fter exposure. Of 54 controls, 41 developed typicl mesles which ws of verge or severe intensity. Moreover, no complictions were observed mong the 17 children who contrcted mesles in mrkedly ttenuted form fter inocultion, wheres, of the controls who got mesles, 4 subsequently developed otitis medi nd 2 developed pneumoni. EPIDEMICS IN PRIVATE SCHOOLS An opportunity to observe smll or potentil epidemics of mesles in 3 privte schools ws fforded us through the courtesy of the school physicins, Dr. J. R. Gllgher of Phillips Acdemy, Andover, Mss., nd Dr. R. K. Byers of Milton Acdemy (Boy's nd Girl's Bording Schools), Milton, Mss. We re indebted to both of these men for their ssistnce in following the subsequent course of the ptients in these groups. In the Andover epidemic, 70 presumbly susceptible boys, rnging from 13 to 18 yers of ge, were exposed to 19 cses of mesles between Jnury 15, 1943, nd Februry 9, 1943. On Februry 10, 28 of these boys were inoculted intrglutelly, ech with 5.0 cc. of A66. Also, on Februry 10, 7 dditionl susceptibles, who were lredy ptients in the Infirmry with the questionble dignosis of mesles in the preeruptive stge, were given similr inocultions of the globulin. Thirty-five of the boys who denied hving hd mesles were not inoculted, nd thus served s controls. The degree of exposure in ech cse ws virtully impossible to scertin nd the exposure-injection intervl eqully difficult to determine becuse of the widespred nd irregulr distribution of the disese throughout the school. The sudden cesstion of this epidemic mkes the results hrd to interpret. Of the 35 students
544 C. W. ORDMAN, C. G. JENNINGS, JR., AND C. A. JANEWAY inoculted, 9 developed mesles within 3 dys of injection, suggesting tht exposure hd occurred some 10 dys before inocultion. Five boys developed mesles more thn 3 dys fter inocultion, but ll these cses were extremely mild in chrcter. Of the 35 controls, 11 developed mesles within the first 3 dys of our study. Four only cme down 3 or more dys lter, ll with disese of t lest verge severity. Thus, some 21 inoculted students nd 20 controls, ll of whom were presumbly susceptible, filed to develop mesles. It ws the impression of the school physicin tht the disese mong the inoculted students, even those who developed mesles shortly fter injection, ws less severe in generl thn mong the controls, nd tht the incidence of complictions ws less. Only cse of otitis medi developed in the former group in contrst to 6 cses in the ltter group. Moreover, 2 susceptible students, who hd been dmitted to the Infirmry for illnesses other thn mesles nd hd been indvertently plced in mesles wrds in close contct with ctive cses, were inoculted nd filed to develop the disese. In Milton Acdemy Boy's Bording School, the study begn on Februry 25, 1943. Two of the students hd come down with mesles on Februry 16 nd 17, respectively, nd third hd developed the disese on Februry 23. All of them were t lrge in the school for dy or two, crrying on their norml ctivities, before the rsh ws noticed. There were, in the bording school, 26 presumbly susceptible students rnging from 12 to 19 yers of ge. Twenty-four of these were inoculted intrglutelly, ech with 5.0 cc. of A66, on Februry 25, 1943. Two boys, one of whom filed to pper for inocultion nd nother, who supposedly hd hd mesles previously, becme, indvertently, controls. Of the 24 inoculted students, 20 did not come down with mesles, nd 3 developed definitely modified mesles. One inoculted boy nd both uninoculted controls developed mesles of verge severity. It is of interest tht 7 inoculted students developed symptoms of upper respirtory infection bout 2 weeks fter injection, but hd no other signs of mesles. An opportunity to determine, in prt, the length of immunity conferred by the globulin ws fforded when one of the group who hd been inoculted on Februry 25, developed typicl mesles rsh on April 16. Subsequently, 11 of the previously inoculted group developed mesles within the next month. Of these, 4 exhibited very mild form of the disese, wheres the remining 7 hd mesles of verge severity. Six of these were boys who hd hd symptoms of upper respirtory infection 2 weeks fter their originl exposure, indicting tht they either hd hd no mesles t tht time or else the ttck ws so mild s to hve induced no immunity. At Milton Acdemy Girl's Bording School, 2 cses of mesles developed on My 2, 1943. Fourteen girls, rnging in ge from 15 to 18 yers, were presumbly susceptible. All of this group hd hd intimte contct with the primry cses nd were injected intrglutelly with D26, 5 dys fter exposure. Seven girls were ech inoculted with 5.0 cc. nd 7 were given 1.5 cc. Of the 7 girls who hd received 5.0 cc. of globulin ech, 1 developed no disese, 5 hd very mild mesles, nd 1 hd n verge cse. Of the 7 who received 1.5 cc. of globulin, 4 were pprently protected, 1 developed mild mesles, nd the other 2 hd verge severe cses. The higher incidence of disese mong those who received the lrger dose cn probbly be ccounted for by the smll number of cses in ech group nd the pprent indequte selection of cses for ech group. Tble II includes the totl uncorrected figures for ll schools, nd shows the results obtined when correction is mde for the sudden cesstion of the Andover epidemic by eliminting tht group of cses. CASES ENCOUNTERED IN PRIVATE PRACTICE A number of physicins in Boston nd its vicinity were given certin of the preprtions for use in their privte prctices. Their coopertion, interest, nd creful observtion of their ptients hve been very helpful in this study. Most of these physicins hd hd considerble previous experience with the use of plcentl extrct. One hundred nd ninety-six supposedly susceptible individuls were inoculted with one or nother preprtion of Frction II. The dosge nd exposure-injection intervl were left to the discretion of the individul physicin, so tht these fctors, s well s degree of exposure, ge
USE OF GLOBULIN IN PREVENTION AND ATTENUATION OF MEASLES 545 TABLE II Results in school epidemics (Crude figures) (Corrected figures) 40138125 1 66 9 231 4 1ll1 21 0 101 2 100 of contct, nd use of controls vried considerbly. A stndrd report form ws returned by the physicin fter period of from 3 to 4 weeks. Only 8 uninoculted controls were noted in this group of reports. TABLE III Results in cses in privte prctice (Crude figures). No. cses No Per Mild Per Typicl Per inoculted mesles cent mesles cent mesles cent 196 99 51 87 45 10 4 (Corrected figures) 164 71 43 83 o50 10 7 The dt presented in Tble III show tht the percentge of individuls protected ws smller thn in the controlled fmily group. The totl number of cses, however, in which it cn be firly stted tht the globulin exerted modifying effect on the disese represents 96 per cent of the whole number of the presumbly susceptible children who were inoculted within 11 dys fter their initil exposure. When those with less thn intimte exposure, those who might in ll probbility hve been immune before injection, those on whom dt ws indequte, or those who were inoculted fter the ninth postexposure dy re excluded, 93 per cent of the presumbly susceptible children either did not contrct mesles or hd the disese in mild form. INDIVIDUALS EXPOSED IN A HOSPITAL During the course of our study, number of cses of mesles developed mong ptients on the wrds of hospitl. In ech cse, most of the presumbly susceptible children on the wrd where the disese occurred, regrdless of intimcy of contct with the primry cse, were inoculted intrglutelly with one of the preprtions of Frction II, the dosge being set t 2.5 cc. for children under 5 yers nd t 5.0 cc. for those over tht ge. The exposure-injection intervl vried from 0 to 11 dys, lthough in most cses globulin ws given within 5 dys of exposure. Of the 82 children inoculted, 77 ppered to be protected nd 5 hd definitely modified mesles. However, mong 18 presumbly susceptible uninoculted children, only 2 known cses of mesles developed. Thus, it is pprent tht the degree of exposure encountered in well-run hospitl wrd is miniml nd evlution of the efficcy of n nti-mesles preprtion of this sort under these conditions is impossible without dequte controls nd stisfctorily high morbidity rte in the control group.4 DISCUSSION AND SUMMARY The evidence derived from the controlled study in fmilies indictes tht Frction II is good source of mesles ntibody. Moreover, this evidence is supported by the results of the trils of the mteril which were crried out under other conditions. From the stndpoint of protection, the product ppers to be t lest s effective s convlescent serum or plcentl extrct, nd probbly superior to norml humn serum in 4 By the time of publiction, Frction II hd been given to 350 susceptible children exposed in 35 seprte outbreks of mesles on the wrds of vrious hospitls. Of these, 95 were not followed, 241 did not develop mesles, 13 developed mild mesles, nd 1 typicl mesles.
546 C. W. ORDMAN, C. G. JENNINGS, JR., AND C. A. JANEWAY mounts usully dministered (1, 5, 6). In view of the finding of Enders (3), tht the concentrtions of ntibodies in Frction II recting with certin viruses, bcteri, nd bcteril toxins re from 10 to 40 times s gret s those in the plsm from which the prticulr preprtion ws derived, it is not surprising tht mesles ntibodies should be present in dequte concentrtion. This concentrtion of ntibody is mde pprent by the dose pprently necessry for protection. Although no set figures cn be rbitrrily stted, the consensus of most uthors ppers to be tht from 5 cc. to 20 cc. of convlescent serum, from 10 cc. to 80 cc. of pooled dult serum, nd from 1 cc. to 4 cc. of plcentl extrct re necessry to fford complete protection in the lrge mjority of cses. Dosge. Although we hve not ccurtely determined the minimum effective dose of Frction II, it is pprent tht 5 cc. ws dequte for protection in most of our cses, nd in the smller children, 2.5 cc. gve eqully good results. It is lso pprent tht the exposure-injection intervl plys r8le in determining whether protection or ttenution is to result from tretment. Approximtely the sme proportion of individuls ws protected if the injection ws given in ny one of the first 5 dys, but from the sixth dy onwrd, the percentge of ttenuted cses nd filures incresed. In Figure 2 re plotted the doses per pound of body weight s ordintes, nd s bscisse, the dys which elpsed between first exposure nd injection. This chrt includes dt from ll of our groups of cses, but no cses 00625 x O NO MEASLES * MLD MEASLES X MODERATE OR AVERAGE MEASLES 3: 00125 * U x U Li 0025 * * ** _X_ o0 X * XU 02 No "0 x 0 O 8 x Goo 0 0o ~ 0 o x O * n X 1000 * U * O* *0000 0o s g 80g0n gog 113 *0 0 Io.. 02, x 1 2 3 4 5 6 7 8 9 K) 11 12 13 14 BYE; AFTER FnRST PROBAB F EXPO6URE FIG. 2. RELATION OF RESULTS OBTANED FOLLOWING INJECTION OF NoRnAw HUMAN SERUM GAmMA GLOBULIN TO DOSAGE ON A WEIGHT BASIS AND TO ExPOSURE-INJECTION INTERVAL. Dt obtined from 222 cses with intimte exposure nd dequte follow-up.
USE OF GLOBULIN IN PREVENTION AND ATTENUATION OF MEASLES hve been included in which there ws not intimte exposure for resonble period of time, resonble evidence of susceptibility, or dequte dt upon the results of injection. The gret mjority of the 222 cses recorded in Figure 2 were children under 10 yers of ge. Whether results obtined in this ge group my be crried over to dolescents nd dults by clculting the dose on weight bsis is not definitely known. It is pprent from the figure tht, with 3 exceptions, ll those individuls receiving 0.1 cc. per pound of body weight or more within the first 5 dys fter exposure were protected. When the dose ws less thn 0.1 cc. per pound of body weight or the intervl fter exposure longer thn 5 dys, there ws decrese in the number of cses protected nd n increse in the number of cses developing mild (modified) mesles. A dose of pproximtely 0.025 cc. per pound in the first 5 dys resulted in the development of mild mesles in most cses, but the numbers re too smll for definitive conclusions. Finlly, when very smll doses were employed or the exposure-injection intervl prolonged beyond 9 dys, no effect on the disese ws usully obtined. Further investigtion is plnned which, it is hoped, will more ccurtely estblish the reltionship between time nd dosge., Durtion of immunity. The fmily study yielded some informtion on the durtion of the pssive immunity produced by Frction II, since in ll fmilies where the controls cme down with mesles, the inoculted children were thus subjected to new nd intimte exposure within 5 to 14 dys fter injection. In no cse did the inoculted nd re-exposed children develop recognizble mesles. This suggests tht n effective immunity lsts for t lest 2 weeks fter the injection of dose of the size used. It is of interest tht one nephrotic boy, who received wht should hve been protective dose, developed typicl mesles, suggesting tht the ntibody my hve been rpidly lost due to the proteinuri. The results in the Milton Acdemy Boy's School sug- ' Studies crried out in 1944 in much lrger series of cses nd with lrge number of preprtions hve confirmed the vlidity of these recommendtions s to dosge. It is now cler tht in order to chieve protection or ttenution the physicin should vry the dose rther thn the intervl between exposure nd injection. 547 gest tht the immunity produced by the injection of 5 cc. does not lst for 7 to 10 weeks, since the mjority of previously inoculted boys, reexposed t this time, developed verge mesles. McKhnn (1) hs emphsized the prolongtion of the incubtion period in cses of modified mesles, but in most of our modified cses, the rsh ppered 10 to 15 dys fter tht of the primry cse. In few ptients, symptoms were observed only during the third week, so tht 3-week period of observtion for inoculted cses is probbly dvisble. Rections. In spite of the estblished vlue of convlescent serum, plcentl extrct, nd dult serum, certin disdvntges re ssocited with ech preprtion. Convlescent serum is vilble in reltively limited quntities. Norml pooled dult serum is redily vilble, but its low potency necessittes the injection of lrge volumes, which is undesirble, prticulrly in smll children. However, 2- to 4-fold concentrtion of serum hs been chieved by the process of desicction from the frozen stte, the resulting dried powder being reconstituted with smller volume of wter thn ws present in the originl mteril. Such concentrted serum hs proved both sfe nd effective for the prophylxis of mesles (7). Plcentl extrct, lthough vilble in quntities nd requiring only smll inoculum, cuses locl nd systemic rections of vrying severity in considerble number of inoculted individuls. Frction II, in contrst, offers definite dvntges. It is redily produced from n bundnt source of supply. In smll doses, it hs proved to be s effective s the best of the stndrd preprtions. No severe rections hve been observed in the severl hundred individuls inoculted with it. In less thn 5 per cent of these, mild rections occurred. With single exception, the rections consisted of slight feeling of stiffness in the muscle injected or little locl erythem nd indurtion. In one cse, the individul hd rise in temperture to 102 F. 2 dys fter inocultion but no other systemic or locl mnifesttion. Whether or not this febrile rection ws due to the globulin cnnot be stted. So fr no untowrd sequele hve been observed, following the use of Frction II intr-
548 C. W. ORDMAN, C. G. JENNINGS, JR., AND C. A. JANEWAY musculrly, but the possibility tht viruses present in the pooled plsm from which Frction II is obtined might be crried over in the process of seprtion cnnot be entirely neglected. Homologous serum jundice, which hs been described following the injection of humn serum in yellow fever immuniztion (8) nd in pssive protection ginst mesles nd mumps (9), hs n incubtion period of 1 to 4 months. As mny cses s could be followed were visited or questioned by letter 3 to 6 months fter inocultion. Of 400 cses so followed, one cse of typicl ctrrhl jundice ws noted just 3 months fter n injection of 5 cc. of globulin. Tht this ws pure coincidence is suggested by the fct tht lthough 74 others re known to hve received this preprtion, no other cses of jundice hve been reported to us. It is hoped tht nswers to these nd other problems will be forthcoming s result of work now in progress. The necessity for observing certin precutions in survey of this sort is brought out very clerly in severl of our studies. One must eliminte the possibilities, in so fr s possible, of insufficient exposure, previous unrecognized clinicl ttcks, nd unrecognized modified ttcks t the time of investigtion. In number of infectious diseses, lbortory tests exist which cn, with some certinty, eliminte vrious of these fctors, while others my often be excluded by creful histories nd physicl exmintions. In the cse of mesles, we re, s yet, entirely dependent on the ltter methods nd n evlution of the results of study must be crried out with the fctors mentioned bove clerly in mind. The nturl secondry ttck rte of mesles in n urbn community hs been estblished t bout 75 per cent for ll ges, rising to 85 to 90 per cent for children between 1 nd 10 yers of ge nd dropping shrply fter 10 to between 15 nd 40 per cent (10). In our investigtion, by fr the gretest number of inoculted individuls were in the 1- to 10-yer ge group. In ddition to ge, intensity of exposure is of gret importnce in determining the secondry ttck rte. In our hospitl wrd cses, for exmple, exposure ws pprently entirely indequte nd no fir ssumption my be mde therefrom. It hs been shown (6, 10) tht prolongtion or repetition of exposures is of no significnce, providing the originl exposure is sufficiently intimte. One cnnot ssume tht exposures in schools, hospitls, or on the plyground re dequte. On the other hnd, exposures within the fmily, of children within the sme ge group, re usully intimte. We hve included in our corrected tbles (excluding those in the school epidemics) only such cses, together with few others where dequte proof of close exposure existed. Even under such conditions, there my be some doubt s to the dequcy of the exposure or bout other fctors such s pre-existing immunity. Accordingly, in order to obtin results of the gretest relibility possible, it is wise to hve controls such s were demnded in our fmily study. The corrected tbles in tht study include dt only from those cses in which one or more controls cme down with mesles or where the inoculted individul developed the disese. Stillermn, Mrks, nd Thlhimer (5) hve emphsized the necessity of creful observtion of inoculted persons in order to detect the mildest cses of mesles, which might escpe ny but trined nd experienced observers. Undoubtedly, number of individuls who might ordinrily be clssified s hving been completely protected exhibit, t one time or nother, one or more of the stigmt of mesles in very mild or bizrre form, nd unless dily observtions re mde of ech person, these might redily be missed. Their totl of 77 per cent complete protection or very mild mesles corresponds closely, s they note, with the figures given by most uthors for complete protection lone with convlescent serum nd with the 71 per cent protection obtined by us in our fmily survey. It is possible tht the percentge of protection recorded by us my include some cses of very mild unrecognized mesles. CONCLUSIONS 1. The humn serum gmm globulin (Frction II), seprted nd concentrted by chemicl frctiontion of norml humn blood, is very stisfctory prophylctic gent ginst mesles. 2. A controlled group of cses with exposure within the fmily fforded rte of 71 per cent protection, 27 per cent modifiction nd only 2 per cent filure, mong 62 inoculted children.
USE OF GLOBULIN IN PREVENTION AND ATTENUATION OF MEASLES Of 46 uninoculted controls, only 7 per cent filed to contrct mesles, while 4 per cent got mild mesles, nd 89 per cent developed mesles of verge severity. 3. In children, n intrmusculr dose of 0.1 cc. per pound of body weight within the first 5 dys fter exposure ppers to be dequte for complete protection in lrge mjority of cses, with the present methods of preprtion. In order to produce ttenution of the disese, it would seem tht bout one qurter this dose should be dministered during the first 5 dys fter exposure. After this, somewht lrger doses my be necessry. 4. No significnt untowrd rections were observed in ny of the inoculted cses. 5. The importnce of dequte controls, iritimte exposure, nd creful observtion of inoculted individuls in evluting the efficcy of prophylctic gent ginst mesles is emphsized. This work ws crried out with the technicl ssistnce of Miss Virgini S. Poole, BA. BIBLIOGRAPHY 1. McKhnn, C. F., The prevention nd modifiction of mesles. J. A. M. A., 1937, 109, 2034. 2. Cohn, E. J., Ondey, J. L., Strong, L. E., Hughes, W. L., Jr., nd Armstrong, S. H., Jr., Chemicl, clinicl, nd immunologicl studies on the products of plsm frctiontion. I. The chrcteriztion of 549 the protein-frctions of humn plsm. J. Clin. Invest., 1944, 23, 417. 3. Enders, J. F., Chemicl, clinicl, nd immunologicl studies on the products of plsm frctiontion. X. The concentrtions of certin ntibodies in globulin frctions derived from humn blood plsm. J. Clin. Invest., 1944, 23, 510. 4. Stokes, J., Jr., Mris, E. P., nd Gellis, S. S., Chemicl, clinicl, nd immunologicl studies on the products of plsm frctiontion. XI. The use of concentrted norml humn serum gmm globulin (humn immune serum globulin) in the prophylxis nd tretment of mesles. J. Clin. Invest., 1944, 23, 531. 5. Stillermn, M., Mrks, H. H., nd Thlhimer, W., Prophylxis of mesles with convlescent serum. Am. J. Dis. Child., 1944, 67, 1. 6. Gunn, W., Mesles: Report of the Medicl Officer of Helth nd School Medicl Officer on the Mesles Epidemic-1931-32, 1933-34, 1935-36. London County Council, P. S. King & Son, Ltd., 1933, 1936, 1938. 7. McGuiness, A. C., Stokes, J., Jr., nd Armstrong, J. G., Vcuum dried humn serum in prevention nd tretment of certin of the common communicble diseses; n 8-yer study. Am. J. M. Sc., 1943, 205, 826. 8. Oliphnt, J. W., Gillim, A. G., nd Lrson, C. L., Jundice following dministrtion of humn serum. Pub. Helth Rep., 1943, 58, 1233. 9. Memorndum prepred by Medicl Officers of the Ministry of Helth, Homologous serum jundice. Lncet, 1943, 1, 83. 10. Stillermn, M., nd Thlhimer, W., Attck rte nd incubtion period of mesles. Am. J. Dis. Child., 1944, 67, 15.