Tecncal Report on Poliomyelitis

N .June 10. 1955, the Puiblic Health Service tories whiclh might wish to manufacture and sent a Teclhniical Report on the Salk store vaccine intended for commercial use pend- l'oliomiivelitis Vaccine to the Secretary of ing decision to license the product. Whlen the Healtlh, Education, anid Welfare. Publislhed success of the field trial was reported April 12, below are the sumnmary. the report on epi- 1955. official minimum requirements were is- deemiological experience and new developments sued. Six manufacturers, each of which had in biologrics, and an expan(ledl calendar of eveents. produced vaccine under the provisional require- Copies of the r-eport were inade available to all ments, were granted licenses. State an(l local lhealtlh departments. Since only Records and samples of vaccine lots had been a limite(ld unuber of copiesare available throllugh submitted to the Public Healtlh Service Labora- the Puiblic Ilealtlh Service, it is recommenided tory of Biologics Control prior to April 12, and, that initerestedl lhealth departtment employees witlhin the next few davs, tlhose which were con- obtain a copy in their own agency. sidered acceptable, were released. Most bio- logical products for commercial distribution are released on the basis of an examination of Summary the detailed record of events in maniufacture The report presenits the teelhnical problems ani(l testingc, (known as a protocol), with or involve(d in the product ion, testinl, anid safety witlhout futrther testing by the Laboratory of of Salk polioiimvelitis vaccine. It also describes Biologics Cointrol. Release of most of the lots the responsibilities of tlhe lPublic Health Serv- of polionmyvelitis vaccine was based on review ice in control of the mianuflachitue of the vaccine of the manufacturing, protocols. Tissue cul- as a biologrical produlct. tuire tests for the presence of live were The vaccine as preplare(l for the 1954 field comipleted prior to release by the Laboratory of trial was ani experimiienital lprodtlct mn-ade by Biolog,ics Control on abotut lhalf of these lots comiimercial producers for the National Foun- aniid monkey tests were completed on 6 lots in- dationi for Infanitile Paral sis. After somie ini- volvingr at least 1 lot from eaclh of 5 manu- tial (lifficliltv, the indutstrial firms were able to facturers. turln ott a goo(l l)rodluct, an1(d the field( triial was On April 26, six cases of poliomyelitis 'were carried out successftlly. V'acciie l)production reported anmong chlildren who lhad received vanc- for the field trial l)ermiuittedl tlhe laboratories of cinie mi-ianuiifactured by the Cuitter Laboratories. industry and the Puiblic Health Service to ac- Att the request of the Public Health Service, quirie ex-perience in testino . this firmi imml--e(liately recalled all of its vaccine. As a, i estilt of its stuidies over a l)period of 2 The entsuting inivestigation of the Cutter Labora- yelars, -whiclh included particip-ation witlh iniidus- tolries was lalter extended to the entire industry tiry land withi I). Jonias Salk in testingr of vac- aiid le(d to a temporary suspension of the cinie for the field( trial, the I'iublic Healtfi Serv- nationwid(le prog0ram. ice planned to act quickly oni licenssiii if the The Puiblic Ihealthl Service on April 28 estab- an.alysis of the field trial (lata show\ed thlat the lislhed a l'olioinyelitis Suirveillance Unit witlhin vaccilne w.as safe and effective. It hasltd issule(d its Comnilnicable Disease Center in Atlanta, prospective minin nun irequiremiienits in May Ga. Thtis unlit is investigating all reported 195.4. as a(lvisorv for pliarmaceutical labora- cases of poliomnvelitis, wlhetler or not asso-

738 Public Health Reports ciated with vaccine. Sixteeni virus labora- senisitive tlhain the monikey test. It mulst be per- tories, througlhout the Nation, are cooperatingc, fornmed witlh a lar-ge enouglh sanll)le of vacciine in examininig and reportingc upon specimnenis aind unider closely controlled coiiditioiis if it collected from cases and suspected cases. The is to lhave the milaxiimumu value. The tlheoreti- epidemiological data so far obtained clearly cal considerations wlich govern inactivation define the Cutter incident as ain outbreak with and testing, lhave been analyzed in the light of characteristics of a common source epidemic. inforimiation (leveloped dluiig,c this inquiry. The cases of poliomyelitis following, use of vac- As a result of the inquiry anid of analysis cines made by the other manufacturers have not of the manufacturers' experience aind records, beein inore numerous than would be expected at clhangres vere imade in processing, control and this season except for a few cases wlhichl sug- safety testing. Revised requiireenieits in the gested (but were too few to be conclusive) an testing, procedures were establislhed ainid the association with one lot of vaccine produced by release of vaccine was resumiied. The modifica- Laboratories. That firmn has witlh- tions provide greater assurance of safety. As drawn the unused portion of this lot. a result of the review and the institution of The Salk vaccine is a suspension of poliomye- revised requirements, the production and avail- litis virus inactivated by formaldelhyde to make ability of vaccine has been delayed. the virus harmless but still capable of inducing The Salk vaccine applies new practices in the the production of antibodies. The vaccine con- production of viral . The vaccine has tainis inactivated virus of eaclh of the three progressed from the experimnental level to large- types. The original concept of vaccine prepa- scale production with unprecedeented rapidity. ration was that the process itself assured a wide This speed, reflecting the increased tempo of margin of safety. Safety tests for thle vaccine all medical research, created problems in bi- were conceived to detect botlh mass contamina- ologics control amenable to solution only with tion resulting from accidents in manufacture tlle accumulation of knowledge and experience. and residual live virus which the process was It is likely that otlher problems of equal com- intended to eliminate. plexity will be raised by the development of The intenisive investigations of the past 5 otlher new viral vaccines. Action taken by the weeks indicate that the records manufacturers Public I-Iealth Service for dealing witlh botlh the were required to subimit did not include certain current and the long,-ranige problems include: data which are essential for ani adequate assess- 1. Amenidment of minimum requiremenits for ment of consistency in performance. The the production and testing of poliomyelitis protocols submitted related only to lots of vac- vaccine. cine proposed for clearance and gave no infor- 2. Incorporation of minimum requirements in mation concerninig lots discarded in the course official regulations as manldatory stanidards. of mianufacture. Furtlher, the inforiiation re- 3. Creation of a Technical Conmmittee on quested did not bring out certain data on proc- Poliomnyelitis Vaccine. essing and testingc no+\- known to be important. 4. Creation of a Division of Biolog,ics Stand- The total experience of the man-ufaetuirers ards, witl strengthened staff anid facilities. now reveals that the process of inactivation did 5. Increased onsite plant surveillance and not always follow the predicted course, sinlce consultation. positive tissue culture tests not inffrequently 6. Reoriented testing anid researelh prog,ram. occurred after the expected completion of the 7. Establishment of a Poliomyelitis Suirveil- inactivation process. Greater depenldence, lanice 'Unit. tlherefore, nmust be placed on sensitive tests for S. Review of legrislative autlhoritv. v-ery smnall quantities of residuial live virus as part of process control. Two types of tests are uised to determnine thle Epidemiological Experience presence or absence of live virus in the vaccine: Investig,ation of reports of p-aralytic - the nmonkey test and the tissue culture test. The mnvelitis occurrince in association with inijections tissue culture test hias been found to be miore of vaccinie was assioned to the Comimuililnicable

Vol. 70, No. 8, August 195.5 739 D)isealse (Ceniter. The niewly established Polio- orator ies, to extenid surveillance over poliomye- mvelitis Surv\eillalnce Uniiit has operated to yield litis this seasoni. 'I'lhis surveillaince was hiighly precise fieldl infoimnation oni the ocenii-leiice of lesirable to studyv the durability of iiimuility poliomyelitis throughotut the couniitry. As a re- ill the lhalf a illioni clhil(lreni whio lhad beeim stilt of this activity the Cuttter incident was iiimminiize(d (iring the field trials in 1954, and elelarly (lefined as Can outbreak with claracteris- eveni more desirable if the results of the field ties of a commiiiioni sourlce epidemic. tr ial le(I to a geieral imniuiitiizatioli program in 19-55. IP'oUio yelUtbs' 8te rvedila ie 'rog iant Wlheni the first occurrenice of poliomiiyelitis The Public Health Service coniduicts a stir- cases in vaccinated clild-ein was reported, this -eillmice programli throutgIh its Conuinuniiiiicable program was quickly brought inlto play to col- Disease Ceniter to lhell) the States in ral)i(l rec- lect and evalutate field and laboratory data whiclh ogiitioni, stu(lv, and conitrol of stuch diseases as nihlit inidicate the nature anid siginificance of malaria, tyv)lms, smallp)ox, diplhtlheria, psitta- the disease ouitbreak. Altlhouhli some cases of cosis, aind rabies. In 1954, CDC personnel col- poliomyvelitis could be expected to occur by co- laborate(d in the poliomvelitis field trial evalua- inceidence followiiug vaccination, eaclh reported tioni, udler the (lirectioni of 1)r. Tlhomas Francis. calse deserved thorongrh inivestioationi. 'I'lTe P'tublic I-lealtlh Seirvice lhad prepared, witl On April 25, 195.5, the Public. Health Service State health departments ani(l cooperating lab- receive(l a repor-t of poliomiiyelitis in a Clhicago

Poliomyelitis Vaccine Distribution

Plamns for the voluntaiiry eontrI l Tile P1mublic Healthl Service respon- vately (l)erate(l hospitals, etc. The ani(l distribuition of o)(liomyelitis vac- sibilities for allocanting vaccine equi- lproportion of linilunization:s pro- this autmiin rest -at present on the Sttates are (lescribed -ided ly pliublic a1gelicies ill ea2Cll ('ie talIlyaniong how tw-o cofdl(litions: chart. State xvill vary, dellending oil in this much 1. The elmlpletioi of the pr4g,ram Fo'r listance.lilll(elr Stel 1, the Na- vaccinie the State (leci(les to plis the amount, if any, of the National Foundation for In- onllolio- purchaise, tiommil Advlisory Co'(11mi1ttee other fantile Paralysis to provi(le vaccine \Vc('('illn etrellomllellned( that purichased by flliunds. chil- myelitis (Oice the Public Health Service for first and secl(d grade schiool va(i'cine illitially be given to (hildeln (li-en. Wheni thisoccix vnrs. ai a-ree(l- has advised the State of the amiount (f , thri'ough 9. As iln('reIs-ed :msystem of v(liuiutary controls stilp- (If vaccwin axvailalble to it. and(I haas up1 (If become available. will go inito effect. Vaccine wvill be plies vaccine a(lvise(I the nianufctuirers; If the sh;ipped ilito each State by the imlanii- wldl(itl(Ilnil aige groiupls Xvill be in- S;t4ate's ailloca-tions to piublic ageicies facturers under a plan thaltxt ill as- c'llde(d. In Step 2, a Staite's shlare (Steps 3 through 7), the task (If als- suire equitable (listribultion amoing of this child polplilationl will (leter- suring fair (listribtutioni withini the the States. aind wlhich will take into main(e its shaire (If vaccine. Thius, if Staite wvill be borne by the State accOlunt the (lesiles of States as be- a IStaite lihas 2 per''ent (of time NationI's aiithzzl ity. tweenl pulblic va'cillatioln prl)grams plm,laltimi> of chlildrlenl Di tle periority The key to intirastate distribution and(I distribiuti ni in normal drug g-roup, it ivill be enititled to 2 iercent is the quality of planning in the ehl.anlnels. (If tile ava;iliable supplIly of va(chlne. S t a t e itself. Throuigh regionial 2. The asslllumptioln that the vac- The ((tiler steps describe the pro- miieetings all(l individual consultation cine wvill still be in slhort siupply. ('c(lures developedl to assuim'e a proper the Public Health Service has it will de- If this condition prevails, (livisioli of va(ccile, as (leteiiiiled( worked with all States and Terri- mantid strenuous; efforts to assure by each State attuthlrity between tories in (levising the. basic elemnenits that available siupplies are (listril- 11mlbli(ic a-encies and private (listribli- (If intrastate plliis. Obviously, no uited equitably amiionig the States andI visefl thtt W-ulid aioniig (clildren in the priority age tiIl (litlet;s. Public agenc'ies ill- siIngle plan ('anllIe (le of all grimp in aill palrts (f the States. ('clde il( llealtha (delpartlllem'lts, tit tile nee(ls tind res(Iur('es Stalte ('linics, plublic iIspIital.;s. all(l States. The Executive (Conimmittee ainy(Itilem facilities wxllose services (f the State and Teiritoriail Health crsot, A.s- Nt(lt(atcl(flt by Otis L. A alie pIrovided throughi tax fnids; pri- ()ffi(ers' Assoc((iation collaborated xixtatit Sury'oit(fIctieril, aidi chief, vate clhannxels (If distribution inelilude wvithl the Public Hletilth Serviee in Bwtciuo f Stt(tt *'c'ici('(c'. (lrig stores, Ilhyslicils, ain(d pri- the (leveloplilent (f suggested prinei-

740 Public Health Reports child who became paralyzed approximately one On April 27, the Surgeon General requested week after injection of vaccine manufactured the Cutter Laboratories to recall all of its ppod- by the Cutter l,aboratories. uct pending a complete investigation. On On April 26, at nioon, illness suspected to be April 28 he directed that the surveillance pro- poliomyelitis was reported from the Napa Val- gram be expanded to aid in evaluation, by epi- ley, Calif., in a child who also had received demiological observations, of the occurrence of Cutter vaccine about one week previously. On poliomyelitis in relation to vaccination. The the evening of April 26, four other cases of ill- data presented here are derived from reports of ness following injection of Cutter vaccine were the Poliomyelitis Surveillance Unit through reported from widely separated areas in Cali- May 27,1955, and constitute the field data which fornia. California State health authorities im- the Public Health Service has considered in de- mediately started investigation of the cases. termining actions since April 26. The absence of other knowni poliomyelitis in some of these areas at the time, the interval be- Poliomyelitis Associated TVith Vaceination tween vaccinatioin anid onset of the disease, and A total of 113 poliomyelitis cases, with-' correlation between site of injection and site of deaths, were recognized among nearly 51/2 mil- paralysis created sufficient presumptive evidence -lion individuals within onie month after injec- of association witlh the vaccine to cause the tion of poliomyelitis vaccille (table 1). The Public Healtlh Service to take action. greatest number of cases associated with the

ples of initrastate distribution. In- 3. Acceptance of and adherence to stocks in solme areas and conisequent cluded in this material are the fol- program principles by physicians, lo- deprivation in others.) lowing suggested objectives: cal health officers, pharmacists, and The manufacturers have cooper- 1. Equitable distribution of vac- other related professional groups. ated fully in setting up their part of cine to eligible persons-the priority (Accurate records and either a plan the voluntary control system. The age group-in all areas throughout for screening orders in advance or a public health profession has the job the State. "post-audit" system will be neces- of planning its corollary organiza- 2. Public acceptance of the vaccine sary to assure equitable distribu- tion and of making the whole system and the distribution plan. tion, and to prevent the piling up of function.

Vol. 70, No. 8, August 1955 741 Table 1. Poliomyelitis cases and attack rates in order to compute "expected" cases by compar- recipients of poliomyelitis vaccine, with onsets ison with 5-year trends based on State reports. between Apr. 20 and May 21, 1955 Cases associated with vaccine produced by other manufacturers include: 19 paralytic and Approx- Cases Total 10 nonparalytic Lilly-associated cases, largely inmatei attack Vaccine manu- number rates from southern States; 7 paralytic and 4 non- facturer of paralytic WVyeth-associated cases from the mid- vaccineles Pr-Non-P.pa-ilara- Total 100,000per00 ytc west and east; 2 paralytic Parke Davis-associ- month1 ated cases from Illinois; and 2 nonparalytic Pitman-Moore-associated cases from Nebraska. Total J5,__ 394, 0001 78 35 113 2 Type 1 poliomyelitis virus has been isolated Cutter-__-_- 409 000 59 10 69 17 from 17 Cutter-associated and 2 Wyeth-associ- Lilly _----__- 2, 514 000o 10 19 29 1 Parke Davis___ 1, 234, 000 2 0 2 <1 ated cases. One isolation of type 2 and one Pitrnan-Moore - 461, 000 0 2 2 <1 isolation of type 3 virus have been made from Wyeth-___-__ 776,000 7 1 11 1 two separate Lilly-associated cases. 1 These attack rates are of limited significance in themsElves, since vaccines of some manufacturers were Ca.ses Reported and Number Expected used in areas in which the seasonal rise in incidence already had begun. It was only among first and second grade chil- dren wlho received vaccine that age is known product of anv one manufacturer was 69-59 of with sufficient accuracy to calculate expected them paralytic. These cases occurred among numbers of cases. It is not possible to compare approximately 409,000 recipients of vaccine pre- the vaccinated group with a nonvaccinated pared bv the Cutter L.aboratories. The attack group in the same areas because a very high rate in this group was 17 per 100,000 in 1 month. proportion of the children of this age received AMost of these cases were reported from Cali- vaccine. The method used in computing ex- fornia and Idaho where the National Founda- tion for Infantile Paralysis provided Cutter Table 2. Comparison of reported and expected vaccine for school clinics, but a scattering of numbers of poliomyelitis cases in children re- ceiving poliomyelitis vaccine in National Foun- cases occurred in other parts of the country dation for Infantile Paralysis clinics, Apr. where the vaccine had been released in small 15-May 7, 1955 quantities through conmercial channels. Cut- ter vaccine was used for school clinics in Ari- Approxi- Poliomyelitis caseF;, zona and New AMexico; but no cases have been mate with onset from number of Apr. 20-May 21 reported among vaccinated children from these Vaccine vaccinees States. manufacturer (NFIP - clinics Reported' Expected Among approximately 4,985,000 persons who only) number 1 number 2 received the products of four other manufac-

turers, a total of 44 cases was reported, only 19 Total_ - 4, 844, 000 79 36 of wlichl were paralytic. The attack rate in Cutter - 309, 000 35 1 5 this group was less thani 1 per 100,000 in 1 Lilly _ -2, 514, 000 29 24 month. The nonparalytic cases are of epidemi- Parke Davis- 834, 000 2 3 Pitman-Moore_ 411, 000 21 2 ological significance but of little clinical or Wyeth 776, 000 11, 2 social importance. The reporting of nonpara- . lytic poliomyelitis depends upon diagnostic 1 Reported cases aged 6-8 years with onset between w Apr. 20 and May 21. Includes both paralytic and practices, lhich vary from place to place; 12 of nonparalytic cases since expected numbers for com- the 25 noinparalvtic cases were reported from parison are based on crude rates which include all cases reported as poliomyelitis in previous years. Texas. Sinice, however, official weekly morbid- 2 Expected cases if the estimated, age-adjusted, ity reports from States do not always dis- median attack rate for the previous 5 years had per- tingistish betweeii and nonparalytic tained in the vaccinees of 1955. paralytic NOTE: These rates are specific for geographic areas cases, the latter are included in this analysis in where the various poliomyelitis vaccines were used.

742 Public Health Reports pected cases has been to apply the median at- Table 3. Paralytic poliomyelitis cases by inter- tack rate for the past 5 years in each geographic val between poliomyelitis vaccine inocula- area to the number of children wlio were vacci- tion and onset of paralysis, Apr. 20-May 21, nated. This is a crude measure, since polio- 1955 myelitis incidence undergoes wide and unpre- Paralytic poliomyelitis dictable variation in successive years, but it cases in vaccinees inocu- provides the best available tool to determine lated with material pro- Experi- Interval duced mental whether cases among children vaccinated are by- data on (days) mon- more commoni than would be expected by coin- I Cut- Parke keys cidence (table 2). ter Lilly Dai IWyeth The difference between the numbers observed I_. and expected (35 and 5) is significant in the Total 2_.__ 50 9 1 6 32 case of those receiving Cutter vaccine and dem- 5-7- 8 2 0 0 3 onstrates an association between the Cutter 8-10 22 4 0 1 12 product and an increased poliomyelitis inci- 11-13 8 0 0 1 9 14-16 - 9 1 1 0 3 dence. The excess of reported cases over the 17-19 - 2 1 0 1 3 -- expected number vaccinated with the Wyeth 20-22 1 1 0 1 1 product (11 and 2) may be significant, but the 23-25 -- -- - 0 2 1 numbers are too small to permit firm interpre- 1 Data abstracted from David Bodian: Vireimia in tation of such crude data. experimental poliomyelitis. Am. J. Hyg. 60:358, November 1954. Mahoney virus was injected into Among the children who received vaccines the right calf of 32 cynomolgus macaques and the made by Lilly, Parke Davis, and Pitman-AMoore, interval between inoculation and paralysis recorded. 2 Data not available on interval for 9 Cutter cases the numbers of cases reported are within the and 1 each of Lilly, Parke Davis, and Wyeth. range expected by chance occurrence. Yet, the distributions of cases following vacci- Evidence of Infectious Virus in Vaccine nation in these two areas show marked simi- Evidence supports the hypothesis that the ex- larity when adjusted for time differences. cess cases among individuals receiving Cutter 2. Cutter-associated cases show a high degree vaccine may have resulted from the use of vac- of correlation between the extremity injected cine containing infectious virus. This evidence witlh vaccine and the extremity wlhich was first falls into three categories: paralyzed; 43 of 55 cases (78 percent) on whom 1. The interval between injection of vaccine records are complete showed this relationship and first paralysis in Cutter-associated cases (table 4). This finding is strikingly similar ranged from 5 to 20 days -(table 3). The me- to the e7xperimental experience in monkeys. dian case occurred on the ninth day and the In contrast to this high degree of correlation spread of the mid three-quarters was from 6 for Cutter-associated cases, only 1 of 10 Lilly- to 14 days. This finding parallels the fre- associated cases showed this relationship. quency distribution of incubation periods in Paralytic cases associated witlh Wyetli and monkeys infected by intramuscular injection Parke Davis vaccine, althouglh consistent with of virus. Moreover, the tenmporal distribution this observation on correlation, are too few to of cases following injection of Cutter vaccine warrant conclusion. is the expected distribution in a common source 3. A number of poliomyelitis cases have oc- outbreak resulting from a single exposure to curred among lhousehold associates of vaccinated the infectious agent. children (table 5). A total of 47 such cases (39 Additional significance attaches to these find- paralytic and 8 nonparalytic) had been recog- ings wlhen comparison of the intervals between nized by AMay 27. These were distributed about inoculation and first paralysis is made specific equially betweeni parents and clhildren. Of the for geographic area and calendar time. Large 47 cases among houselhold associates, 35 (29 nuimbers of clhildren received Cutter vaccine in paralytic and 6 nonparalytic) were associated clinics in California and Idaho, the California witlh Cutter-vaccinated clhildren; 9 (7 paralytic clinics being held slightly before those in Idaho. and 2 nonparalytic) were associated with

Vol. 70, No. 8, August 1955 743 Table 4. Comparison of paralytic poliomyelitis c ases in vaccinees by site of inoculation and site of first paralysis

P'aralytic p)olionivselitis cas;es inl vacciiiees iiioctilatesd NNith Experimnental data mnaterial produiced by- oII ionoikevs I

Sites of iniocuilationi anid first C'utter (utter_ ,illhillyyeth [lare \WvtliX paralysis I~~ IJa-IS '

______tum ber . Perceint ______i- Number Percenit, N uimiiber Percent N umtiber Ntiumber

'I'ot al 2 5r)5 100 10 100 2 7 32 100

Same - 43 78 1 10 1 3 23 72 Different - 12 22 9 90 1 4 9 28 iI lodiaii, I). Unpublished data fromn experimiienit cited in table 3. 2 Data niot available oni site of first l)aralvsis for 4 Ctutter anid 1 Lillv cases.

WIvetli-vtcciiiate(l cliil(lr-eii znd 2) (lall patttit- I9^oc1 (Yt;o n IN-tic) wvere aissociaite(l witl Lilly--vaccinated Another lhyV)otlhesis consii(lere(l in the inuvesti- clildlr eni. Abmot miie-tlii ( otf the vaiccinizated gration of eases of p)aralvtic I)oliolnivelitis ill cliil(lrieii in these lhouiselholdts hla (levelod)eed cliil(lr eii following inijectioni of vaccine waIs that ujinor illness wvithin 2 Nv-eeks aifter inoctulation central nier-vouts svstenii ilivolveniienit nmav lhatve an(i prior to the onset of p)olioinvelitis iii the beei p)reci)itated by the intrainiusctlar inijec- hlouiseliol(l coiitacts. tioin of vaccine in individuals; whio wer-e alreadv Time interval I)etweein vatccinaition of clhildren infected witl p)olionivelitis virus. Ilala thtis beeni excess cases wotil(l be ex- and thte oniset of polionivielitis in tiheir l)plrents the case, tlhe to to (st1ii( il) ings )1)ixiniiites tw-o inc ubta:tioi pe- l)ected occur it aireas kniown be experi- eneing soniie One lhave ex- io(ls iii time L-) Clttei-aissociate(l in(d the 9 10olionivelitis. miiiglit naturally cases at this II'vethl-aissociated cses, as wsould I)e exl)ecte(d pectel occtirriing seaCtson in the sonitlherii States and1 in souitlheri (1ali- if the v-1cc1iiitte(l chil(l weie the souirce of in- fornia. The excess cases dli(l not adhere to this fectioni. 'T'lhe , Lillyv-issociated catses follove(d in Idaho in slioi tei inter-vazils. patterl lbu)t octiurred tniiexl)ectedly tissociatioii w-itlh Cutter vaccinie whier e nio other

p)oliomiiyelitis was Ibeing observed. Tlhey failed Table 5. Poliomyelitis cases in household con- to occur in the southern States whlere a very tacts of vaccinees with onset between Apr. 22 vaccilne and May 27, 1955 largre iiuinber of cliil(lreni receive(l ,illv in areais whlere poliollivelitis was know-n to be T'hese do the Vacecinees inioculated with p)resenit. (lata niot supl))ort p)rovo- Cases ini household coni- material inanatifactuired by- Cation hy1)otlhesis. tacts of vaccinees aml(l oniset interval Cutter Lillv Wveth Total Ic'wl/t of A total of 1 13 p)oliomiiyelitis cases ( 78 para-

3535 3 9 477 lxtit and.- had Total cases 3 .->IN-ti nonparalytic) (develop)ed by --- Maiv 21 among(r 11or)e than ., mliillioni ind(livi(duals Paralyfic Nollparalvtic 0 2 Vaccinated against l)olioninelitis siince April 14. = - -155is. ( Oli)iisOn of rel)opte(d and1(1 expected Sp)anl iln dlaysx)etwveen inoculation of vac- lillinubers of cases indlicate association between cimmee allil onset ill Cuttei( 1( iomilvel it is iCine aindl an iiicrlealse(I p)arent or sibling '9-33 8S 14 17-30 8-33 Median (lavs 9-14 19--3() 19. ilci(lelice of )olioniNelit is. 'I'lT e (Iistribiitioii of Cutter-associated cases bv interval betweei inoe-

I Excludes I case hlere interval was 2 olavs. illation a(ld (late of paralysis and tile correla-

744 Public Health Reports tioi b)etween sites of inoculation andt paralvsis of scientific and technic(al data nowN- av\aihlible. arle strikingly simtilar to exp)erilmenital (lata. The incealeclse iln scientific knowledgle fr-oin tlhis Tlhese finldlilngs ind(licate thlat at least somiie of the exl)erienice has been1 considerable. 'I'lme Ltil)lic Cuttter-associated cases dleveIol)ed fioimi usse of Healthl Serv%-ice is ill a pOsitioln to tuse tile ex- poliomiyelitis vlaccine conit aiiiit.r inifective virutis. perielnce of recenit imiouitlhs, suiper-imposed tupon Additional dataI relating cases to specific lots ex)peiieiiee of past years, as a b)asis for extend- of vaccine aire undi(ler analysis in coniiiectioii witlh inigc and improv-ing its bio(logics control ftunc- the study of the Cutter pllant priocesses, and will tionis. be iniclit(le(d ini a rel)ort to be madle wlieiu all The Putiblic Health Service's niew imeasuires hliases of this stud(ly are comp)leted. .alle (liscuisse(l b)elow : E vidlence is iiot conieltusiye blit su(rgests there _ ;m11c,dmelt of iLb0,,nmm Li,eqfiireeneu,fx lhave beeni a similtar association witlh a few itmay requiiremiienits for vaccine CaseS folloWillng tlle tuse of Wyetlh vaecinie. In T'he minimumiittl pr-o- contrast, the dlata inldicate tliat the inicidenice (hictioli anted testingr hlave leen rerise(l to providle of after Ilse of the prodluects; of a stubstantially grieater margin oof safety. Es- p)olionluyelitis these changes for1a re(lifired otlher

Vol. 70, No. 8, August 1955 74.. Joseph Smadel, with Dr. James A. Shannon, The change also removes the biologics control associate director of the National Institutes of activity from a framework in which emphasis Health, as chairman. The committee was made has been on research not primarily related to responsible for: (a) formulating recommenda- biologics control. As a separate division, the tions on measures to assure improved safeguards staff will have both a clearer mandate and a and greater effectiveness of the Salk vaccine, better opportunity to conduct such research as (b) recommending release of lots of vaccine, is essential to deal with trends, advances, and and (e) fostering collaborative research by in- problems in biologics. dustry, the National Institutes of Health, and The professional staff of the new division will university scientists on problems which must be be augmented. Broader professional cover- solved in connection with vaccination against age will be provided by the addition of senior poliomyelitis. members to the staff. The division will also be strengthened by additional facilities and Creation of a Division of Biologics Standards by augmented administrative and statistical The Puiblic Health Service biologics control services. program has operated heretofore as a constitu- ent laboratory within one of the large research Onsite Plant Surveillance and Consultation programs of the National Institutes of Health- Public Health Service staff members and ex- the National Microbiological Institute. Now pert part-time consultants drawn largely from the Surgeon General has requested authority to university research centers will conduct a pro- organize expanded biologics function, with the gram of surveillance and technical consultation status of a separate division in the National In- in the plants of the manufacturers while vaccine stitutes of Health, to be called the Division of is under production. These scientists will col- Biologics Standards. The Secretary of Health, lect information for the division and will foster Education, and Welfare has approved this collaborative work deemed essential by the Tech- request. nical Committee on Poliomyelitis Vaccine. This step is take-n as the culmination of de- Similar procedures will be followed as other velopments in medical research related to: (a) problems of biologics control arise in the future. the expanding range of diseases to wlhich bio- logical products may be applicable, (b) the Expanded Testing and Research Progranm kinds of new biologics whicih may be available, The testing program of the new division will particularly in the field of virology, and (c) be directed primarily toward determination of the compressed time interval between the dis- the exact significance of safety and potency covery of new biologics and their use. tests, and modification of tests and their inter- The principles utilized in the control of virus pretation to make test data yield more pene- infections successfully applied to the Salk vac- trating information. cine offer promise of solutions to a hitherto When an industrial product must meet highly baffling group of disease problems. The so- precise standards, whether the product be a called "wonder drugs"-antibiotics and sulfa jet engine or a biologic, primary dependence is compounds-have made little impression on the placed on "tests in process" rather than tests of problems of virus infection. We can expect the the final product. A final test must be made, development of potent new biologics which will it in no sense for the liave unprecedlented application, particularly but is a substitute many to control of virus diseases. tests conducted along the way. The fact that new products are developed, Great emphasis will not be placed on simple tested, and used over progressively shorter time repetition of the testing already done in in- periods is one of the boons of modern medical dustrial laboratories since this adds little to the research. Buit it creates an essentially new set safetv factor. The mechanism of onsite plant of tasks in the field of biologics control. The consultation, described above, will determine new tasks can be performed more effectively that such testing is well done, and will interpret unlider the new arrangremeent. critically the test results.

746 Public Health Reporits The development and interpretation of these current infor-mation on polioinyelitis cases, and tests is of paramount importance in controlling for obtaining, from collaborating university safety and potency. Much remains to be learned laboratories effective laboratory support for about their underlying significance. These epidemiological studies. The purpose is to questions, for example, are not now answerable: study vaccine performance. How long must a tissue culture be watched be- fore definitive readings can be taken? What is Review of Legislative Authority the effect of calf serum on virus growth in tissue The Biologics Control Act was passed in 1902, culture? I-ow can the monkey safety test be and amendments since then lhave not funda- made more sensitive? Resolution of questions mentally altered the basic act. The terms of of this sort is better calculated to insure the the act are being carefully reviewed in the light safety of virus vaccine than are any number of of the increasing complexity and scope of the repetitive tests. Working toward their solution biologics control function. If ainendments ap- will be a major responsibility of the new pear advisable, recommendations will be made division. to the Congress. In this connection, it is to be emphasized that industrial cooperation, par- Poliomyeltis Surveillance Unit ticularly in the course of the recent review of The Public hIealth Service has established a the processes of the six manufacturers, has been nationwide, network for supplying precise and excellent.

Calendar of Vaccine Standards and Distribution

July 1953. In preparation for the in the production of biological prod- be used in the field trial until poly- expected clinical trial of the polio- ucts, inviting them to make polio- valent pool material, taken prior to myelitis vaccine developed by Dr. myelitis vaccine for the field trial. division and final bottling, had been under the auspices of Two of these (Parke Davis and tested for safety in the manufac- the National Foundation for Infan- Lilly) had been in experimental pro- turer's laboratory, Dr. Salk's labora- tile Paralysis, Dr. William G. Work- duction since the fall of 1953, work- tory, and the Laboratory of Biologics man, chief of the Public Health ing collaboratively with Dr. Salk. Control and after approval by the Service Laboratory of Biologics Con- F i v e manufacturers responded, Vaccine Advisory Committee of the trol, visited the Connaught Labora- Parke Davis, Eli Lilly, Cutter, National Foundation for Infantile tories in Toronto, Canada, to discuss Wyeth, and Pitman-Moore. (Later, Paralysis. and observe techniques for growing Sharp and Dohme elected to enter March 1954. At the request of the a total of six man- bulk poliomyelitis virus. the field, making National Institutes of Healtlh, a vaccine were December 1953. Dr. Joseph Sma- ufacturers.) The they series of meetings was held with Na- on con- del, Army Medical Services Gradu- to produce was experimental, tional Foundation representatives, Foundation for ate School, and Dr. Workman con- tract to the National Dr. the Vaccine Com- and to be used Salk, Advisory sulted with the National Foundation Infantile Paralysis, mittee, and the manufacturers. Two for for Infantile Paralysis in the prep- only investigative purposes. out of the first 6 lots of experimental aration of provisional standards for February 1954. The Laboratory of vaccine tested in the Laboratory of the manufacture of poliomyelitis Biologics Control had agreed in late Biologics Control had failed in vaccine. These standards, derived 1953 to cooperate in testing the vac- safety tests, and an additional 2 had largely from the experience of Dr. cine, at the request of the National failed the manufacturer's tests, in- Salk in making an experimental Foundation. In February 1954, it dicating the presence of active polio- vaccine in his own laboratories, began participation in triplicate myelitis virus in the vaccine. The were designed as a guide for indus- safety testing of the experimental Vaccine Advisory Committee re- try in the preparation of vaccine vaccine, receiving large numbers of solved to delay the initiation of the for the field trial. test samples. This triplicate test- field trials for 4 weeks to permit a ing was done to gain experience in review of the vaccine tested during February 1954. The provisional safety testing and to take advantage the extra time and to enable Dr. Salk standards were sent by the National of the opportunity to further de- to complete inoculation studies on Foundation for Infantile Paralysis velopmental research on a biologi- some 7,500 children in the Pittsburgh to 10 manufacturers with demon- cal prodtuct. The National Founda- area who were given commercially strated competence and experience tion agreed that no vaccine would produced vaccine.

Vol. 70, No. 8, August 1955 7417 April 1954. The Vaccine Adlvisory August 1954. The National Fouin- ('himical dIata oni vaccine liiieliared Commiit tee of t le N ElP reconvened, (lati(in for Inifanitile Paraldysis, ctln- witiiout, iniethtliolate since it wvas in W~ashinltoii. IRejireszeiit1itives of tracted w%ithi hr. Thiomtas Francis, teeichi(aily a (liftel-emit limoduict froii the N;itionial Inistitutes, of Health .Jr., U'iiiversity o)f Mlichigan Sho thle ine uised ill thle field trial. I hata amd the iialiufacturers, were presenit. o)f Imlbuie Heatlthi, for amialysis o)f the suplilliedI on 6.(X00 chliildrein iinjected 'thie (iata oni the vaccines produeed (lata dlerived fronii the fieldi trial. It 1111(1 teste(i siIic'e thle March meeting wa-s iiii(Ier-st(io(l that htis re-sults catedl that the vaccine i%vithliot mier- 10 blIitclivs ill liib.iier') were, cotI- c(((11d niot lie expected biefore March thiolate wvas safe and po(tent, (Ani sidleredl, togethier withi Dr. Salk's oir Apr-il 11)5i5. The Puiblic Health a(d(iti(inal. 3,(WX) we-re r'elrt e(d hin- (lata coiiceriiiiig the 7,500 incwulated S'ervice pr(ividedl about 21) eiii(eniii- jectedl by- I )r. Salk, lbut no (lata %ver'e childreni. All resuilts were of ta neg- ologists and statisticians to assist suibmiittedl to the Laboraitory (if Bi- ative character'. anid the coiiiiiiittee D)r. FranMCIS 'vitli hiis stuidy. ologic's Control). revommiended that the fieldI trial August 1954. The National Fount- January 1955. The mianufa('tulrers piroceed. The statemeiit iss;uedl fol- dationl placedI orders with ttie five began to subimit to the Laboraitory 4if lowinig the meetinig,' which was cont- mnanufactuirers foi' the liurchiase (if Ihiologics Control pI't)oetocls mlnid slani- curredl iii by tihe Putblic Healthi upj to 27 mnhilhiomi cc. oif va('cine. This jIdes of their first, produetmomi 1(its of Service, conitaiiied the following x%va-s (loimie to encourage, tile inanufac- vac('iie, ii ailticipati(iii (if a favor'- stateniienit *. the possilbility of tur'ers. to stay iii producitioni after aItble relio)rt oni the results (if thle fieldI infectious- activity r-entaininig it aniy tue fieldI trial. trials. Thte Labom'atorny (if Iliologics vacci lie meetingf tile specifications September 1954. Beginning in. this Co(ntrol liegami review%% of lprotocols- .111(1 minhimail r-equiremienits hias beeni ani(l testing (if materials- %vell in a(d- redlucedl to- a point bielow which it iiiuintli, anad ('(titining thi'ouigh to J.January 1955, tile Laboratory uif 1Hi- vance (of tile expected (late o)f ac'tual ('illlot he miieasuredl by pracl(ti('iblle licemisinig amm(l (if tue o)fficial estabilish- lIftbora tory pirocedure." ()iligic-s C(ontrol inspectedi the plaiits of eac'li (if the six vac('iile llanulfac'- iiieiit (if mimhimiun staindar1ds for' p0- inio'lm that v-ac('-inle mighft be May 1954. Th'le fieldt trial wvas be- tlirers excelit for one thait lhad been temicy gun,sing. vaccine supplied by Parke inslIectedl hi July (Wyeth). These availabile for)t the snimimiier (if 11)55, Davis anidl Eli Lilly. Three othier wvere g-eiieral insp)ections m'equiired by should field tr'ial resuilts lie fav-or- urna tiufactuirers (Cuitter, Wyethi, and( i'egulations amidi( lilcilidedI attention abile. Pitnianm-Mo,ore) produced lots of iiia- topoliomniyelitis vac'imne PL-odlictionl April 1955. By April 12, 1955. a terial. wlichlipassed the tests,, hutt IdIans and facilities. total (if 40 protocols, withi samplAes tie National Fountdation's (lecision November 1954. Two imeetiiigs. at- hiad beemi suibunitted to~tile Labora- was to use the vaccinie froini the. twvo tory of Biologi(cs (' Silix regu- lar,gest p)roducers onily ill order to teii(le(I liy represemntatives oif tile Na- t ioimal F"ouindation. the nianufac- lar production lots- 111(1 hieen. fuilly redIuce varia-bility froiimiuliple tested in monkeys and in tissuie culi- man.-ufac-turer.s. The Public Healthi tuirers ( in('ludimng Shairp a(Id Dohiiiie, NXvhm(ch hadlii eniter'ed tile fieldt). tumie by tile Laboratory (if Biologics Service officially indicated -I belief NIH staff, anid representatives (if the Conitrol. with niegative result-s. Addi - in the sotunld jii(lgilieiet of the Vaccine tional. tissuie cuiltuire tests h11( bieeni Advisory Commilittee, iii its r'ecoiu- (Comniaught. Labioratories iii Toro)nto, Canada, wNere lieldI in Pittsbuirghi to ruin oni -somie other lots. Sterlity inienda.-tioni to the NFIP to Coiiduct tests were run oni all lots. lPritoicols tlhe field trial. (liscuss5 dleterioriIation iif po(tenc(y in suiliie lo)ts (of vaccinie. Thiis was on mill. lots were r'eviewe(I imid(epenid- May 1954. A. (loc.Ilmellt eiititle(l learn'med throughI tests mniaule oni vac- emitly by two or miioi'e Laboratory oif "Milliilktliii Itequireimets, P'olio- cinie left (iver' fromi the NFILI fieldi Bliol(igi('s C'mitrol scienltists to (leter- mnyelitis Vaccilne" was p)repare(I by trial, and( it wvas believed toi lie miimile 'onifoI'iiiity wVithl the mininiiitimI the Labioratoryv of P.iolog-ics (Coit.rol, (caiused biy mmier'tli(ilate %%vhichI wa-s m'e(liiirenlieilts. witlh thle a-dVice aiid cooperation of usedl as a P)reservative, in thte vac- April 5, 1955. The (Iiilectuir o)f the the man-ufacturers anid Dr. Salk. cine. This problemi wvas tiien initeni- National Instituites o)f Healtht amid TI'iis was to (distribuited vaccinle man-i- sively Stii(iie(l biy -IIIll((imcermiedl, ivNitli the ('hief (if the Lahioratory (if Bio- ufacturers and( ititerestedl parties as- ai view~toi preveiiting the (leleteriouis 1hu-igics Control visite(1 lir. Francis in a guide to prospective stadi(ards, if effe('t uif nier'tlliolate oi' selecting an- Anin Aribom', Mlich., to dlis('uss aniy the were to lie p)r(lunct later iicCisedl. itlier' Iim'eservative whtich (lidiinot pI'elinminary (lalta fro-m ti e a nahysis5 July 1954. 'ilie inloctilatioii phllise ha;ve tilis actioni. Tile nilanufa('- iif time field tm'ial whi('hi wv(iili(lihave oif the field trial was coniipletedl. The turei's hiad to dlisc'ard( sevem'al mui- a bear'ing uiponi thIe mlinimiiumii etluire- resuilts, which %vere ilot, available lios f (l(ises of vacc'(ine comitainimig miiemits an111d i'emnsimig. Time imiuinedli- unitil AXpril 121. 11)55, ind(ica-tedI tha,-t nierithiolate. I i(d(eiby t1imit tiime. aite mmee(l was for' (dathi ~iermittinig es- thiere wa-s no4 (vid(leice (if (disprolior- December 1954. The Labiom'atory taldishlmment (if criteria for acceptablhe tioilat e frequeiiev oif para-lytic poio- o)f Bi1(ilgics (Coitrol a(lvisedI time hi(tenc(y levels for- liolliIiny('hitis vac- miyelitis in viicciiiatedI chil(lreni up to nan-ufactur'er's, the Naitionail F1"oin- 'imie, somiie ho)ts (if whIic'h lia(l alreadly 4 weeks after inijection.iionol(f selec- da tioni. and hr. Salk tlint, before ii- hieemn subimitted for release. This in- live loca lizatmio of inaralysis. cemnsi mig, it wN-ouldl requiire ad(-lit ional fom'matioum fromi I)r. FrIhnc'is; wa-s sup)-

748 748 ~~~~~~~~~~~~~~~~~~~PubhicHealth Reports, April 27, 1955. By this (late, 40 Sturveillanice Ulinit w.vas directed to tions wvithliD. S'alk. lots of vacceine containiiiigr a total of mtake daily relxsrts to tlle- Surgeonvm April 7, 1955a. Newv dlraft r-equirie- 10.5 miillion cce. liala beeni released. Gleneral and State livlaItim and other umieiits fo)r potency stlnarioads wvere (This replresents volumeit irior to Ine(dicitl ili s tinaia bottling. rThere is 15- 20- transmiitted to time manamufacturers. to) April 28, 1955a. Thev Laboratory percent shrinkage in to oif tillillg duie Biologics, ( 'mltr(il (later April 12, 1955. At Anni Ar-bor, overtilling anid other Causes.) Of tu~gimnvntedl b)y I6 (oolieratinig laboratoriesl he- Mlich.. Dr. Franicis a mttlounce(d tile r-e- this totail, nearly 5 cc. were iiuilioii gaoi series tests all stilts of the anmlalysis of tlel(I trials uised tirst injections a- (If on Cuitter ini (apoi vac1cinle. seekimng to carrieod (ilt in 19~54 undi(er tile alis- nintely 412., iniillioii imioiler- the Na- dletermnlie Iv-iletlier- activ-e v-irus (011( lbe pices o)f the -Natiomnal Foundation. tion.al Fouindattioni prog~Irani aii(I dle- onie- tected. Meanmwhmile, testing (if vac- 1955. half miillioni by others withi vaccine April 12, Thie Laboratory of vine froit othier niiainiffactiirers coni- B'iologics (Control issuied the tirst offi- (list ri buted thirouighi commlercial timmuied. (.il mliniintit re(iiireiltemlts for po- chiailnels). April 29-30, 1955. Ani ad hoc liomiyelitis vaccinie, revisinlg tile pi'-o April 26, 1955. The Laboratory of gvroutij of a(dvisers, 11 (if the Nation's v.isional minininuin requirements is- Biologics Control received word of sue(1 inl Ma-y 19.i4 to inlcliude s-tand- five cases of paralytic poliomyelitis og~ists, was conivenied at tile ar(ds for potency ail(l a requiiremlent in California chiildr-en National. among whio Instituites of to review tlit. tile tmanutfactuirer shlow that had rec-eived Cutter HealOth tile vaccinie. There sitmation and make recomnniendations amny preservative added to tile tini- hiad been one earlier in case Chicago oill necessary actiomi. By this timie, islle(l vaccimne caus'es- 110 appreciable withini the previous 24 hiours. The there were 17 rep)orted (1tses of Para- loss oif potency witiliill the period inicidlence seemiedI to be above tile rate ly%tic polhiomlyelitis a iii aig ehlid(rell duirinig which tile va--ccine mlay b)e expevtedl fronii niatural infection, ali(1 iiljected witi vacit((i fronti the Cut- uise(l. there was correlationi be-tweeni the ter Labor-atories. The group) re- 1955. A site of inijectioni and( tile April 12, group ofspca paralysis. v-iewedI protocols submuitted on Cutter Oilsulitaltts imiiet wvitli tIme (Ilief of the April 27, 1955. Following a(lvice vaccine, (liscussed tile situiation with Laboratory of Biologics Control ill fromi the National Inistitutes of seniior tecihnical rep)resentatives Anni fromn Arlior. to review tile rep)ort (of Healthi staff, who hieldI a telephlone eaci of tile six vaiccine D)r. Francis ani(l tile niainufactur- iiliiiiiiunl y-e- conferenlce with at group) of advisers, eI.s. alnd submllittedl a tinlnaiiluis (luirieineilts 111t1(1 to imake recommnen- the Surgreon Genleral requested Cut- relxlrt. The 111(st inimlirtanmt finiitliigs dantionis -s to) the of licentsing Salk ter to withdraw its vaccine fromn use. wvere thlat :(ci the actiomi of the poliomnyelitis vaccine. Thley agrreedl The Cutter Laboratories agreed to Public Hlealthl Service in rectalling unianimminosly that the evi(dence ava-i- (l0 so, aii(l witiliin less thani ami houir tile (Ctitter vaccimie was juistifiedI;(b ;tble warrainted licensimlgj, of tile niotifiedI all their distributors to re- the conthimluation o)f wVithl vacdille. cover all of tiheir unuszed vaccine. tile prol(Iuict (If othier mlanuifac*turers April 12, 1955. Thte Secretary (of April 27, 1955. The National In- w;ts warrainte(I (c) careful epidem- H-ealIth. Education, and Welfare is- stitutes of Ilealti tsent two experts, lolo-gical1 and laborattory studIies stie(d to six vonlilitmiles~ Parike Davis, il. virology and in tile op)eration of sl1o111(1 li econtimitedl amiol extendted; (d it was probable tihat mIletliods Eli Lilly. Wyeth, (Cutter, Plitnilan- biologics pr(Kluetioli planlts to iiiake (If testing be Moore. and Sha:me aild 1Doinie) ii- ant examiinationl of tile Cuitter Lab- hiroduction itnd( c1011l(1 iun- ' ( c) a (eilses to Im1n1ifilufature oratories 'and rep)ort oni all (details of piroved and( smnall colnimlittee pioliomtyelitis oif extoer.ts 5110111(1 stud(y tile Itiiliinumin v1tccine. Tile Secretary took this tileir laboratory pirocessing and test- inig. A eng,inleer- requirenments to) deterinine.if chammges aictioni (il time recommtlemtdationm oif tile stanitary a.Sjsite(Iil s,onie of the later p)hases of the inl- wvere inmdicated. clilef oif t le Laboiratory oif Ihologics sletioni. ThIs teanit was, talso di- April 30, 1955. Based 0)1 thie C'ontrol, ttalnslinittC(d throuigh anld ap)- rec- recte(d to check tile recovery of all ommmmlemnda tiomns l isted almuve, tile chi1ef prove(d hiy tile Surlgeonl G.emlerail of tliiluse(1 Cutter vaccine. tile Public HealtIl Service. o)f tile Ltlo ratomvy of Bio 1logic-s C'll- April 28, 1955. The Pub)lic Health trodl conclumdedl thm.it hle (011I(j11(mt ap- April 12-13, 1955. The fir-st lots 'Service set tip.a special Poliomycl-eitis anovymm dadditional loits of vaccine oif poliomyelitis vaccimne were re- Sur11veillance Uinit ill tile CommunIIIica- umiitil thet review o,f thle ulimmimumummi mle- leasedl the of by Labormatory Biologics ble [)isease (Ceiter, Atlanta, Ga;.. olu1iremmemits omildo hoe comilofletedl. -Itnd( Control a-fter- bavinmIr iilet tile niew for rapid inves,tigationi of all case:s 50) adlvlsed time mmt:lmiufatcturers. At mnimininui requitiremients. Thiirteeni replortedl as poliomnyelilis. A ilation- this timtle, nmction Was1 beimmg, Witimhelod lots o)f 4 vaccine, (Cutter. 2 Eli Lilly, widle ep1idein1iolog"ical nietwvark was o utotalI o)f :1.9 mmmilhioin 4o.f vac-t : Parke I a avis, 1nd 2 Pitinm mm-Mioore) e,st;olislced thirough1 State an1d local vimme. fmr wvlmich smnlsando ol oII aplred wvere, Tis ralilld actionl heaNltll officials. Trhis was supple- lma(1 beemSibshmnitteod lint athooit whtioht wits po(ssilile wecause thet protocols uutentedl by~ cooperatingu. laboratories addloitionalt1 inmfo rnitimal Ii mtodl hieii m-e- and1( sampllles' had been received ini ohilesteod by the I.aloro;ttory o)f lbioi- v.tI I Ilice.I iiih- of v[iruses The Poliomyelitis 1oogics Cmllitrll. andmiono 330(.(MM) oc. stmib-

Vol. 70, No. 8, Aumgus-t 195574 7419 mitted for clearance a day before May 13, 1955. Based on the recom- These manufacturers were withhold- the meeting on requirements. mendations of the inspection team inlg request for clearance of a large May 5-6, 1955. A six-member sub- at Parke Davis, followed by a care- amount of vaccine pending a clari- committee of the April 29-30 ad hoc ful analysis of their protocols at the fication of this problemn. This fore- advisory group was convened at the National Institutes of Health, ap- cast production delays which would National Institutes of Health to con- proximately 41/2 million cc. of Parke require revision in the expected sider the adequacy of the minimum Davis vaccine already released were vaccine supply in the immediate requirements, including the precise recleared. Of this supply approxi- future. method of vaccine production and mately 1 million cc. remained un- May 16-20, 1955. A Public Health testing, the basis for decisions used. Clearance on one lot previ- Service team of scientists and ad- reached by review of protocols, and ously approved, but as yet unused, visers visited the Wyeth and Pit- related matters. Technical repre- was withheld. man-Moore plants. Although the sentatives of all six vaccine manu- May 15, 1955. A scientific review manufacturing techniques and pro- facturers attended part of the meet- panel meeting at the National Insti- fessional competence of the firms ing; they provided detailed data on tutes of Health, hearing the report were excellent, it was concluded that their total manufacturing experi- of the plant inspection and reap- no action would be taken on reclear- ence, including lots of material on praising the protocols on Eli Lilly ance of their vaccine until there which protocols had never been sub- vaccine, cleared approximately 31/2 could be an opportunity to assess all mitted for approval because of fail- million cc. of Lilly vaccine previ- the data from all the plants and ure to meet requirements during ously released; of this, only about reach conclusions on the factors that processing. The subcommittee: (a) 378,000 cc. remained unused. The should govern release of vaccine al- noted the accumulating epidemiologi- Parke Davis lot on which reclear- ready processed as well as steps that cal evidence of significant associa- ance was withheld on May 13 was might be built into the manufactur- tion between Cutter vaccine and the ordered withdrawn, and an addi- ing and testing processes as addi- occurrence of paralytic poliomyelitis tional Parke Davis lot was released. tional safeguards in the future. and the absence of evidence impli- The group also suggested modifica- May 20, 1955. A special advisory cating poliomyelitis vaccine pro- tions of the manufacturing and test- group met at the National Institutes ing processes of all manufacturers duced by the other manufacturers; of Health to consider questions of seeking to build in additional factors (b) stated the desirability of in- dosage and use of vaccine during creasing the margin of safety in the of safety. epidemics. The dosage question was vaccine (they prepared a tentative May 15, 1955. An ad hoc group of considered because of some experi- draft for revision of the minimum epidemiological advisers met at the mental evidence suggesting that in- requirements); and (c) believed it Institutes National of Health simul- jecting 0.1 cc. of vaccine intrader- might be well to withhold further taneously with the group on revi- mally instead of 1 cc. intramuscu- injections until a team of scientists sions of the minimum requirements. larly might be effective. The group, could visit each plant and study the At that time at least 54 cases of after reviewing all the data, recom- production processes, facilities, rec- paralytic poliomyelitis appeared to mended the following: (a) adher- ords, and protocols in the light of be associated with the Cutter vac- ence to the existing dosage and route what was now known about the ex- cine. The group felt: (a) that of injection, based on evidence of perience of the various manu- there might possibly be some corre- lation in a few children receiving the the vaccine's protective value during facturers. product of another manufacturer; the 1954 field trials; (b) approval May 7, 1955. The Surgeon General and (b) that the number of sibling of extension of time between first recommended to the medical and or parental contact cases following and second dosage of vaccine to 5-6 public health professions that vac- vaccination of a member of the weeks if necessary; and (c) caution cinations should be suspended pend- household warranted careful and concerning use of injections during ing completion of study of the continuing check. or near epidemic periods or in areas recommendations. May 16, 1955. The director of the of high prevalence, with decisions May 8, 1955. In a detailed state- National Institutes of Health re- made by local authorities. ment, the Surgeon General repeated ported to the Surgeon General that May 23, 1955. Members of the his recommendation that new vac- two manufacturers, after a long pe- Vaccine Advisory Committee of the cinations should not be given for the riod of producing consecutive lots National Foundation for Infantile time being and announced that the of vaccine that met all requirements, Paralysis, the American Medical As- manufacturers' production and test- had recently experienced difficulty sociation, and the Association of ing procedures and facilities would getting consistent results. Under State and Territorial Health Officers be inspected by a team of scientists the proposed revisions of the mini- met at the National Institutes of on a plant-by-plant basis, in the order mum requirements, which were un- Health and were given a review of of their entry into the poliomyelitis der consideration, sonme of these lots the poliomyelitis immunization and vaccine production field. of vaccine could not be approved. vaccine situation.

750 Public Health Reports May 25, 1955. AXri mIInendnient to once placed in use in ea(h plant; lplans, States sliould( take imlmmnie(liate the minimum requiiiremeints was de- anid that smsall amounits of vaccine aetion t) (develol) and(l ilhmplelmelt cided i11o1i anid( discussed in detail would prol)ably be maide1available lplanmis to a.sisre equmitaile distribu- with the vtacine manufaIcturers' bleginning early in the week of May tioni within their respective popula- technical representatives, vlio were 30 and progressiv ely thereafter. tiomIs; (4) In order to insure equita- also given summlillary informnation on June 1, 1955. The reclearance of ble distributioni, plains for intrastate the currenit epi(lemiological picture, 200,000 cc. of vaccine ianuafactured diistribution of the vaccine should in- the data derived from the five plant b)y Pitmnan-Moore and by Wyeth was clude a system for obtaiining reports inspections, and the arnalysis of tile a n n o u n c e d. Surgeon General of shilpiments from the manufac- sensitivity and reliability of the Scheele also stated that "no iml)or- turems anid reports of sales from re- safety tests as performed under the tant differences were found in the tail outlets; (3) A coordinated na- existing minimum requirements. quality of performance or the scien- tionwi(le educational c a ni p a i g n The executives of the manufacturing tific caliber of the manufacturers should be developed to assist health firms were asked to study the revised iowv releasing the vaccine for gen- departments and physicians in keep- standards further and be prepared eral use." ing the public informed about the to bring their teclhnical staff chiefs poliomyelitis vaccine program. June 9, 1955. A new Division of to a meeting the following d.ay for 1955. The Public final discussions. Biologic Standards was established July 8, Health at the National Institutes of Health. Service announced the release of May 26, 1955. A new, periimanient The biologics control program here- 300,000 cc. of Wyeth vaccine, making advisory group was established by tofore was the responsibility of a a total of about 1,837,000 cc. made the Surgeon General and held its laboratory of the National Micro- av-ailable since the revision of test- first meeting at the Nationial Insti- biological Institute. ing requirements on MIay 26. Since tutes of Health. Called the Teclh- April 12, the total released was ap- Increasingly nical Committee on1 Poliomyelitis complex problems in proximately 10,837,000 cc. The Di- the Vaccine, this group was asked to biologics field, aimong theim the vision of Biologic Standards as- perforin two functions: to advise on virus vaccines, made establishment signed 6 scientists to the plants of of newv the release of vaccine under the mini- time organization necessary, the 6 Ilianufacturers to serve as tech- I)r. Scheele stated. nium requirements as amended, and nical aides on production and testing to give continuing guidance in vac- June 10, 1955. A detailed technical procedures, and in research develop- cine production and testing with report [parts of wvhich are published ment. particular em)hasis on research in this issue-Ed. note] was pre- July 8, 1955. Surgeon General leading to iimprovements and refine- sented by Surgeon General Scheele Scheele announced the formulation ments in the vaccine. to Secretary Hobby and made public. of a tentative program for develop- May 27, 1955. The representatives June 22, 1955. The following rec- mental research aim-ed at discovering of all six firms declared their in- ommendations on vaccine distribu- new knowledge immediately appli- dividual support of the amended re- tion were made by the National Ad- c.able to further imiprovemnent of pro- quirements in the interest of making visory Committee on Poliomyelitis duction and testing of poliomyelitis a safer vaccine, and the Surgeon V'aecine (uunder the chairmanship of vaccine. The program will consider General made public announcement l)r. Chester S. Keefer, special as- otlier strains of poliomyelitis virus of this fact. Industry was asked to sistant to Secretary Hobby): for inclusion in the vaccine, im- provide the Public Health Service proved tests for po)tency, the im- with revised estiinates predicting the (1) Wlhen the available supply of provenmenit of monikey safety tests, amount of vaccine they might be able vaccine warrants changes in the des- the development of concentration to mnake available this summer under ignated age group to whom immuni- metho(ls for use both in safety test- the amended requirements. zation is limited, such adjustments ing anid in routine production proc- wvill be made by extending the exist- studies on May 27, 1955. Ia a press confer- esses, aind standardiza- in,g priority group so that it becomes tion of tissue culture ence at the National Instituites of susceptibility increasingly broader; (2') For the to The Health, Public Health Service offi- poliolllyelitlis viruis. research timue being, the 3 through 9 priority call for a cials made public the details of the plans positive, cooperative age group shouild be adhered to. As endeavor, in in- amendments to the miniiinummi re- wvhiell uniiversity, vaccine b)ecomes available, the com- and quirenments and their possible impli- dustrihl, governmenlt labora- nmittee wvill broadlen the age grouip to tories combine to cationis in regard to availability of concentrate their' inclu(le equal additionls below andn research resources. This vaccine. It was stated that there program albove this group to the exteimt that is expected to gear in Xvith programs wo uld be a net slowdown iimimie(li- pro(luetion of the vaccine indicates; supported by tie National Founda- ately; that the revisions did not (-) Since su(e5ess of the voluntary tionI for Infantile Paralysis an(l etitail ally consequiiential lengthening plan dtel)emmiis largely upon tile de- otilier organizations sponlsoring simi- of the total manufalcturing process, veloilinelit of effective int rastate ilar aml(l related research.

Vol. 70, No. 8, August 1955 75)1