active immunization

7/27/2019 Active Immunization

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1963;32;444PediatricsMargaret H. D. Smith

ACTIVE IMMUNIZATION: CURRENT CONSIDERATIONS

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ISSN: 0031-4005. Online ISSN: 1098-4275.

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AC T IVE IMMUN IZAT ION : CURRENT CONS IDERAT IONSM arg a re t H . D . S m ith , M .D .

D ep artm e n t o f P ed ia tr k and E pid em iok gy , T u la ne U n ive rsi ty Sch oo l o f M ed ic in e , a n ( iT he C har ity H o sp ita l o f L ou isa na a t N ew O rle ans

A i d e d in p art by G rant 2 E -207 o f th e N a tion al In sti tu te o f A llergy and Infect iou s D isea ses.B a sed u po n a ta lk en titled C u rre n t S tatu s o f O ld V acc ines p resen ted in a S ym po siu m at the 1 96 2

A n nua l M eeting of th e A m e ric an A cad em y o f P ed iatr ics C hicag o I llin o is O c tob er 31 19 62 . D r. G eoffreyE dsa lls ta lk o n Passive Im m u niza tion to th e sam e S ym posium is the b as is o f h is R ev iew w h ich w illappear in P E D I A T R I C S f or O ct ob er .

A DD RE SS : M .H .D .S . D e par tm e nt o f P edia trics Tu lan e U niv ers ity S ch ool of M e dic ine 1 4 :3 0 T ulaneA v e n u e N ew O rle ans 12 Louisiana.

P EDIATR IC S S eptem iw r 1 963

R E V IE W A R T IC L E

44 4

T H E P R A C 1IC A L A S P E C T S of im m un iza tionh av e ch an ged in the la st few yea rs an d

a re inev itab ly destined to ch an ge con tin u-o usly . N ot on ly does m odern sc ience keepp ro duc ing n ew er and m o re po ten t vaccin esb u t th e v acc ines them selv es alte r th e d is-tn ibu tion of d isease agen ts and the reby theep id em io lo g ic p atte rn of d isease . A s B a tsonan d C h ristie have expressed it: Im m u ni-za tion pro ced ure is a dyn am ic su b jec t inneed o f co nstan t eva lua tion .

D IP HT HE R IAN ow here d oes th is pheno m eno n seem

m ore c lea rcu t th an in th e case of d iph theria .W h e re a s 2 5 y ea rs ago a basic cou rse of im -m uniza tio n aga inst d iph th er ia w as essen tia lrepea ted na tu ra l ex posu re cou ld be re liedupo n to b oos t th at im m unity th rou gho u tla te r ch ildh ood and ado lescence . N ow adaysthe d isease itse lf has becom e so re la tive lyuncom m o n in m any areas tha t w e need tobe rem ind ed by artic les like th at o f D oegeH ea th and S herm an 2 in a recen t issu e ofP EDIATR IC S tha t 90 0 cases of d ip h the ria dooccur annu a lly in the U nited S tate s andtha t these cases tend to b e grou ped in sta tesw h ere im m u nizatio n program s lag . B ecauseof the ve ry sca rcity in m o st p laces o f op -pontun ity fo r na tu ra l expo sure the re is anap prec iab le nu m ber of ad o le scen ts andad u lts w ho ev en tho ugh im m un ized inch ild hood has ag ain becom e fu lly sus-cep tib le to in fec tion w ith C oryn eb acte r iu mdiph the riae . T h is fa lling off o f im m unityw ith inc reasin g ag e m ust acco un t fo r sm all

ou tb reaks o f d ip h the ria am ong o lden peop lein institu tions 3 and fo r cases in recen t yearsam o ng ce rta in sk id ro w group s.4 It is tilereason b eh ind the lon g schedu le of d iph-th en ia toxo id in ocu la tions recom m en ded inth e so-called R ed B ook of the A cadem y ofP ed ia tn ic s. T h a t the R ed B o ok schedu lem ay in a fu tu re ed ition requ ire m odifica -tio n w ith re spec t to the need fo r rep ea tedd iph th eria boo ste r stim u li is su ggested by arecen t ar tic le by V o lk an d co-w orke rs w h ore inocu la ted w ith D T toxo id a group ofyou ng su b jects inocu la ted 7 to 1 3 y ea rsp rev ious ly .6 T he bo oste r ino cu latio n con -tam ed 2 L f un its o f each to xo id ; no t on lyw ere goo d an tito x in leve ls ach ieved im -m edia te ly b u t th ey had 2 yea rs la te r n o tfa llen to preb ooste r leve ls .

E xp osure to live d iph th e ria b ac illi andpe rh ap s a lso repea ted in jec tion s of d iph -then ia tox o id b ring o n h ype rsen sitiv ity tothe d iph th eria b ac illus p ro te in con tain edin sub sequen t d oses o f d iph th e ria to xo id .H en ce the ad v isab ility o f a specia l to xo idto b e used in ad o le scen ts an d ad u lts w h ichw o uld con ta in on ly ve ry sm a ll am o unts o fd iph th eria toxo id to obv iate tile n ecessityotherw ise presen t fo r perfo rm ing a M o-loney or Z o elle r sk in tes t fo r hy pe rsens itiv -ity .7 E dsa ll and h is co llabora to rs fo llow ingthe p ion ee r o bse rv atio ns o f C anad ian andD anish w o rke rs have been la rg ely re spon -sib le fo r the deve lopm ent o f th e p repa ratio nlab e lled T D i.e . te tan us-d iph the ria tox o idad u lt type . T h is m a teria l co n ta ins theusu al am o unt o f te tanus toxo id con tain ed

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REV I EW A RT I CL E 44 5i n preparation recom mended f or basic im -munization of chi l dren. W hether one shouldstart employ ing thi s type of toxoid forbooster doses in chi l dren of 8 years, or 10years, or 12 years, i s di f f icul t to say . I t de-pends real l y on the am ount of experiencew hich a parti cular chi l d i s l i kel y to hav ehad w i th diphther ia; i f he has been broughtup in South L ouisiana, w here diphther iai s endem ic, or in most parts of L atin A men-i ca, or in the M iddle East, then 8 yearsw ould alm ost surel y be the upper age l im i tfor the saf e routine use of the more con-centrated type of diphther ia tox oid. I f , onthe other hand, the youngster i n questi onl i ves in one of the areas of the U ni ted Statesw here cl i ni cal diphther ia has not been seenf or m any years, than the age of 12 w ouldseem a l ogi cal time to start employ ing thedi l ute type of toxoid.

A gain in recent years the question off l uid toxoid v ersus toxoid w i th some f ormof alum inum adjuvant has been raised,ei ther w i th regard to a higher incidenceo f unpleasant si de reacti ons to alum inumadjuv ant in adolescents and adul ts, or be-cause the alum toxoids seem ed to prov okeparaly ti c pol i omyel i ti s m ore readi l y thantile f l uid toxoids. Studies f rom the M assa-chusetts Publ i c H eal th L aboratories hav eattem pted to answ er thi s question and hav e,I think , answ ered i t f or adolescents andY oung adul ts, the answ er being that al umadjuvant does not show any stri k i ng ef f ecton the primary response at least to tetanustoxoid. O n the other hand, the f indings ina recent B ri ti sh Report to the M edical Re-search Counci l by i ts Com m i ttee on D iph-thena T oxoid seem to have dem onstratedthat very large doses of even the present( l ; IV puri f i ed preparations of formol on f l u id diphtheri a tox oid are no t as ef fect iv ef or basic im m uni zati on of chi l dren as toxoidv i th a m ineral adjuv ant.b0

T T NUSTurning now to the tetanus com ponent of

D PT w e learn f rom the m ost recent (1959)volume on the V i tal Stati sti cs of the U ni tedStates, that in that y ear 283 lea t l ls w ere re-

ported due to tetanus of w hich 99 occurredin chi l dren w ho had not yet reached thei rf i f th bi r thday and 32 more in y oung peopleof 5 to 19 y ears of age.11 M ost of these l i vedin the southern and southeastern part of thecountry . T his si tuation ex i sts i n the f ace ofour hav ing, in tetanus toxoid, maybe themost nearl y perf ect of al l imm unizingagents, w hether one considers the low in-cidence of side reactions, or the long duna-ti on of immuni ty . Sev eral groups of in-vestigators have been interested in recentyears i n l earni ng how long af ter basi c im -munization prev iously immunized indiv id-uals w ould display a recal l or anamnesti ctype of response. I f one tests adul ts af ter10 years, as did Staf f ord 2 and also L ooneyand associates13 one f inds an ex cel l ent re-sponse; i f one tests chi ldren af ter 13 years,as did Peterson and his associates,14 onef inds an equal l y excel l ent response; and i fone w ai ts 14 to 18 y ears, as did Goldsm i thand his associates, and also M cCarnol l andassociates 6 the response is sti l l splendid.Indeed, the f indings mentioned above sug-gest that the interval betw een tetanus toxoidbooster injecti ons could w el l be greatl ylengthened.

T his being the case, i t does not seemnecessary , once the basic imm unizationagainst tetanus has been carri ed out, toadm inister a booster dose of tetanus toxoidat the tim e of each injury , prov ided the pa-ti ent has receiv ed a toxoid injecti on w i thinthe past year. I f , how ever, tetanus toxoidis adm inistered for a f resh lacerati on, therapidi ty of the anamnesti c response is suchthat one can use ei ther f l uid tox oid or alumtoxoid w ith equal ef fecti veness.

For som e years i t w as thought that prac-t ical l y no untow ard reaction occurred w i thbooster doses of tetanus tox oid, ev en inadul ts. H ow ever, further experience hasshow n that indi v iduals repeatedly injectedw ith tetanus tox oid do have a higher i n-cidence of unpleasant reactions. I n a studyof thi s phenom enon, L ev ine, Ipsen, andM eComb concluded that these reactionsoccurred in prev iously imm unized persons,that they w ere age dependent, ri sing mark-



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ACT IV E IM MUN IZA T IONedly after the twenty-fif th year but prac-tically insignificant below 20 years of age.8Their data may well lead to further obser-vations, and, at some future time, to alowering of the amount of toxoid containedin the TD , or tetanus diphtheria toxoidadult type.

Intradermal administration of tetanustoxoid has been recommended, especiallyfor booster doses, in order to avoid reac-tions. 7 I t undoubtedly must produce a risein antibody in the majority of individuals,but unfortunately there are few thoroughlysatisfactory data on which to base a formalrecommendation for the use of toxoid in thisfashion. The same comment applies to sev-eral other vaccines such as typhoid and in-fluenza vaccines, where the intradermalroute of administration has from time totime been recommended: it must be effec-tive, but precise data are wanting.)

To give a clear cut outline for the han-dling of tetanus-prone wounds is not p05-sible. Several recent articles give a gooddiscussion of the problems involved.1820The tendency at present is to try to avoidusing tetanus antitoxin whenever possible.Proper cleansing of the wound, togetherwith administration of tetanus toxoid, isrecommended for all individuals w ith eventrivial tetanus-prone wounds; where thewound has been present several days, ismore severe, or obviously infected, suitableantimicrobial drugs should be added to theabove treatment and continued for at leasta week. Only in the previously unimmu-nized, and only where the wound is serious,is tetanus antitoxin recommended in addi-tion to the above regime. Opinions vary asto whether the time-honored dose of 1,500units is optimal despite numerous recordedinstances where tetanus developed subse-quent to such a dose); or whether doses of10,000 to 40,000 units should be preferreddespite the possibility that this may blanket the booster effect of the toxoid ad-ministered simultaneously). Probably every-one would agree that, whenever humanantitetanus globulin is available, it should

be preferred to the animal antisera, andthat far smaller doses should suffice.

PERTUSSISConcerning pertussis vaccine there is at

the moment no startling development. A l-though we may not recently have read muchabout convulsions and encephalopathy fol-low ing pertussis vaccine, an informal pollconducted a year or two ago by one of themanufacturers of pentussis vaccine showedthat this type of reaction is still occurring.21A pparently the public is more or less re-signed to paying a rather high price for im-munity against whooping cough. One canonly hope that current laboratory investiga-tion will lead to a type of immunizing agentagainst pertussis fundamentally differentfrom any now avai labl e.

Q UA DR UP L E A N T IG E N V A C C IN E SNor is there any startling new develop-

ment w ith regard to quadruple antigen vac-cines. A s all of us know by now, the M assa-chusetts Department of H ealth came outin August 1960 with a statement to the ef-feet that the pertussis component of thequadruple vaccine suffered a rapid decreasein potency upon standing.22 This was latershown to be due in part, at least, to the pre-servative used in the quadruple vaccine,where benzethonium chloride had beensubstituted for merthiolate, the latter beingdeleterious to the poliovirus component.T he D ivision of Biologic Standards has nowset a higher standard for the initial anti-pertussis potency of the vaccine, namely14 instead of 12 units, to offset the 6 ormore monthly deterioration in potency; andhas shortened the expiration date to fourmonths from the date of issue from themanufacturer s cold storage.23 U nfortu-nately, these rigorous standards, necessaryfor the protection of the public, render thevaccine economically unsound. T o this prob-lem add the increasing use of tile oral typeof polio vaccine, and it is clear that severalmatters will have to be settled before sucha vaccine could again appear on the market.



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REV IEW A RT I CL E 447S IT E O F D P I IN JE C T IO N

D iphther ia, tetanus, and pertussi s anti -gens, si ngly or i n com binati on, al l have incomm on that they are adm inistered intra-muscularly. T i l e optim al si te f or i ntram us-cular i noculati ons has recently been the sub-j ect of considerable debate. T here seem s tobe l i t t le questi on that the recom m endati ono f 40 years ago is sti l l v al i d: the regiono f the outer si de of the thi gh, w here l i est ile g r e a t v a st u s e x t e r n u s m u sc le is a snearl y as possible tile i deal place f or al lty pes of i ntram uscular i n j e c t i o n 2 1 A t least 5 arti cles hav e appeared in medical j our-nals i n recent years reporti ng serious nervedam age f ol l ow ing intragluteal i nj ecti ons, es-pecial l v in infants. 2 2; T he anter ior aspectof the th igi l and tile del toid areas are alsoto be pref erred to the gluteal region. T hebacteri al contam ination of the sk in i s aptt o be less at these si tes, and they are tra-versed by no m ajor nerve or bl ood vessel .

S M A L L P O XT he more recent developments in the

f ield of sm al lpox vaccination are probablyw idel y k now n. K rav i tz has reported on aningenious plasti c gadget, cal l ed by them anuf acturer M ono-V acc (m anuf acturedby L inco ln L aboratories, I nc., onl y ) to sim- l i f y vaccinati on by ti l e m ul ti pl e puncturemethod.27 I t i s presteri l i zed and disposable,so tl l at i t would seem to deserve w idespreaduse. I f , at some future time, the sm al lpoxvaccine could sati sf actori ly be l yophi l i zed(l i rectl y onto the points of the apparatti s, i tw ould i ndeed be conv enient.

T he optimal age for primary vaccinationis sti l l t i nder di scussion. I t seem s clear thateczema vaccinatum and unduly severe tak es, progressi ve vaccinia, etc., are al li nure com m on under the age of one y ear;and that vaccinial encephal i ti s i s more corn-mon af ter ti l e age of tw o years; thereforethe optimal time f or primary vaccinationw ould seem to l i e betw een the ages of oneand tw o years. 8

W hether cal f l ym ph vaccine should beused, or chick em bryo vaccine, i s hard to

state w i th assurance. B ecause chick em -bry o-denived vaccine is theoreti cal l y lesssubject to contam ination by bacter ia or un-desi rable v i ruses, i t i s perhaps to bepreferred 2O

V accine preserv ed by l yophi l i zationw ould certai nl y seem pref erable to l i qui dv accine, w hich must be so caref ul l y keptat f reezer temperature to preserve i ts po-tency. T his i s parti cularl y true, of course,i n w arm cl im ates.

V accinia immune globul i n, i ts potential i -t i es and the indi cati ons f or i ts use w eredescr ibed in 1959 by K em pe on the occa-sion of in s r ec eiv in g t ile M ead JohnsonA w a r d of the A cadem y of Pediatni cs. A n-oti l er m atter di scussed in ilis address i s ti l eduration of imm uni ty f ol l ow ing v accina-ti on: w hi le an attack of sm al lpox conferslong- lasti ng protecti on, vaccination alsoconfers protecti on, but probably f or a muchshorten time. Current practi ce in the U .S.A rm ed Forces is to revaccinate at least every3 years, w hich probabl y suf f ices to m aintai na reasonably sol i d lev el of herd im muni ty .H ow ev er, f or personnel proceeding to con-ti nental Europe, A sia, A f r i ca, Indonesia,N ew Guinea, annual rev accinati on i s ne-qui red. For ci v i l i ans a sim i lar plan w ouldappear w ise.

I t i s w el l for pediatr i cians to he aw arethat sm al l pox vaccine, w i l en adm ini steredto a pregnant w om an, m ay produce gen-enal i zed vaccinia in the f etus, fol l ow ed byaborti on, as attested by a recent arti cle inth e ritis M ed ica l Jo urn a l B lood dys-crasias, parti cularl y leukem ia and agam-m aglobul i nem ia, and therapy w i th corti -costeroid hormones, consti tute absolute con-traindicati ons to vaccination.

C LIN IC AL E F F E C T IV E N E S S V E R S U SL A B O R A T O R Y T E S T IN G

A l l of the imm unizing agents w hich havebeen discussed up to thi s point have incom mon that they have been tested in thef ield, so to speak , and found to be ef f ecti ve;but even more important, w e i l ave sometest (other than a f ield test) by w hich to



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448 A CT I V E I M M U N I Z A T I ONm easure ef fecti veness, and w e know thatthi s other test (sk i n reacti on af ter di ph-thenia and smal lpox vaccination, serologictests, f l occulati on test i n the case of diph-thenia and tetanus, intracerebral mousechal l enge for pentussi s), trul y m i rrors theef fecti veness of ti l e v accine on toxoid in pre-venting i l l ness f rom infection.

I n the case of the nex t three immunizingagents, no such test ex i sts, and I ref er torabies and ty phoid vaccines, and to B C G.

R A B I E ST he brain ti ssue containing type of rabies

vaccine, the so-cal l ed Semple vaccine, i srapidl y being supplanted by a vaccinem ade f rom duck embryos (E l i L i l l y andCompany only ). From tests of ef f ecti venessin other mammals, w e hav e reason to be-l i eve that thi s i s, i n general , an ef fecti vevaccine, al though a recent report i s di s-turbing in t i la t i t does descr ibe consider-able anti genic vari abi l i ty betw een batches.T he elegant dem onstrati on by Gibbs andI l i s cow ork ensb6 that none of the 22 m di -v iduals immunized w i th duck v accine de-veloped electroencephalographic changes,w hereas 10/69 v accinated w i th brain ti ssuevaccine did, should prov e ex trem ely reassur-i ng to physicians w ho f ind i t necessary toadm inister the 7 or 14 doses of rabies v ac-cine recommended f or persons exposed toa rabid anim al . So f ar there i s on recordonl y one report of transv erse m yel i t i s f ol -l ow ing duck embryo rabies vaccine (anadul t w ho ul timatel y recovered). 7

W e must al l perforce be aw are of the ap-parentl y increasing role played by bats inthe epidem iology of rabies in almost ev erystate of the union. 8 Parti cularl y di sturbingi s the f act that a bat bi te i s not necessaryf or i nfecti on : aerosol transm ission of rabieshas been prov en in bat- i nhabi ted caves.N ow that a relati vel y safe, albei t somew hatpainf ul , rabies vaccine is av ai l able, w eshould consider i ts prophy lacti c use inY oungsters w ho explore caves, trap l i vew i ld anim als, or go to l i v e in parts of thew orl d w here rabies i s endem ic. U nder suchci rcum stances a basic course of three, or

pref erabl y f our i nj ections at i nterval s of 7to 10 days should be f ol l ow ed by a boosterdose 1 to 5 m onths later, as recom-m ended f or veterinar ians, animal handlers,dogcatchers, w i th subsequent boosters everyf ew y ears on on the occasion of possible ex-posune.

W hi le on the subject of rabies, w e w ouldl i ke to mention that the antinabies horseserum f or passive immunization (made byL ederle L aborator ies only ) i s now stand-ardi zed by compari son w i th a ref erenceserum f urni shed by the D iv i sion of B iol ogi cStandands,41 that the dosage is expressedin terms of uni ts rather than m i l l i ters, aspreviously.

BC GT he ef f ecti v eness of B CG in low ering the

incidence of severe f orms of tuberculosi shas been proven in m any studies,42 includ-ing a recent one conducted in G reat B ri tainunder the auspices of the M edical ResearchCounci l . H ow ever most author i ti es areagreed that, i n countr i es l i k e ours w i th arelati vel y low incidence of the disease,B CG (avai l able in the U .S. only f rom theResearch Foundation, C hicago, I l l i noi s)should be reserv ed f or those indiv iduals atgreater than usual r i sk .4 This w ould in-elude al l chi l dren w ho l i ve in householdsw i th adul ts w i lose tubenculous disease hasbeen arrested f or no more than 5 y ears: al soN orth A m er ican chi l dren going to l iv e i nareas of the w orld w here tuberculosi s i sendemic.

V arious author i ti es hav e in t i le past sug-gested t i la t B CG vaccine not be used innew born infants, because of a relati vel yhigher incidence of prolonged vaccinationlesions, because of presumed poor antigenicresponse and because the v accine m ight bediscredi ted i f a true tuberculous infecti onw ere superimposed. Recent reports 5show t ila t u n t o w a r d i ncidents are rare andt i la t the conv ersion rate i s good; there seem sthen ilO f ur ther reason to f ear i ntraderm ali noculati on of new borns w i th B CG, w heret i le r i sk of tuberculous infecti on i s high.

Unfortunately, t ile s t r a in s of bovine



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R E\T IEW A RT ICL E 44 9tul )ercle i )aci l h f ronl w i i i ci i 13CC is made\ ( re al l , unti l recci l tl v , sensi ti ve to iSO i l idZ id .T hus i t w as necessary , 1I 1(l sti l l i s in th iscountry , to choose betw een a(l l l l i ni steningprophy lacti c isoniazid to an exposed chi l d,thus giv ing him instant protecti on of l im i tedduration; or giv ing I l im B CG , w hereprotecti on i s longlasti ng but starts only af teran i nterval of 2 to 4 m onths. W ith the de-v elopment of a strain of bov ine tubenclebaci l l i resi stant to i soniazid, thi s agonizingc ilO ic e is 11 l onger necessary . U nger,Thomas and M uggleton reported in 1961on the laboratory inv estigations On IN Hsi stant B C G, and Gai sf ord and G ni f f i ths int ile sam e issu e o f th e ritish Medica l Jourivil on a successful cl ini cal tr i al i nv olv ingseveral i l undred new borns.#{ 176} W hi le thi s typeo f B CG i s i i ot avai l able in the U ni ted States,t i lOse pediatri cians w ho travel abroad toteach and observ e need to be acquaintedw i th i t: i t presents great prom ise for largeareas of ti l e w orld w here tuberculosi s i s theleading inf ecti ous disease.

TYPHO IDL ast of al l w e come to a considerati on of

ty phoid v accine. H ere, as in the case ofral ) i es and B CG vaccines, there i s no lab-oratory measure of i ts ef f ecti v eness. A rgu-m ents have raged for decades-ev en since i tw as dev eloped by Si r A lm roth W right atthe tim e of the B oen W ar-as to Vi let i ler itw as any good or not. Rev iew of many sepa-rate incidents lef t thi s rev iew er w i th ti l efeel i ng that maybe i t w as 75% ef f ecti ve atbest. T he f i eld studies carri ed out in theB ri ti sh A rmy in I ndia in the earl y y ears ofthi s century w ere considered conv incing atthat time, but Cockburn show ed in 1955that they are no t acceptable by m odernstandards. I t i s thi s general uncertaintyw hich led W .H .O . to co-operate w i th theY ugoslav ian heal th author i ti es in a f ieldtr i al of typhoid v accines, in an area w i lerety phoid fever i s endem ic. T i l e tri al w asdesigned to test tw o types of v accine,namely t i l e alcohol -k i l l ed and preservedvaccine on the one hand; and on the othera heat-k i l led and phenol preserv ed vaccine.

Fronl ti l e start i t w as importai l t r io t onlyto test thC ef f i cacy of the vaccine in an en-( IC i f l iC area, i ) tl t 11s() to f i uid lai )oratory testsfor v accine potency w hich w ould ref l ectcl i ni cal ef f ecti veness. L aborator ies in manycountr i es co-operated in the evaluation, in-eluding ti l e L i sten I nsi tute of M edical Re-search in L ondon and the W al ter ReedA r m y I nsti tute of R esearch in W ashington.T he resul ts of the f i eld study show ed thatthe heat-k i l l ed phenol -preserved vaccinegave protecti on i n about 70% of those accinated, w i lereas ti l e al cohol vaccine w asnot ef fecti ve.5 Parti cularl y di sturbing w asthe fact that none of the presentl y usedlaboratory tests w as f ound consistentl y toref l ect the degree of ef fecti veness of the vac-cine in t i l e N or w as t ile p r esen c eof the so-cal l ed V i antigen in the vaccinedem onstrated to be of any importance w hat-s o e v e r

In t il e a b sen c e o f a d eq u a te laboratorytests f or potency , it becom es im possible totest di f f erent batches of vaccine f or potency ,or to w ork out the optim al schedule f orbasic im munization, on to make any recom-mendation for booster doses. M oreover,some of the typhoid v accines contain para-typhoid A antigen, al though, f or som e ob-scure reason, Salm onel la panaty phi A has dis-appeared com pletel y f rom this country . M yow n f eel i ng i s that in the U ni ted States onlyci l i l dren w i lo l i ve in the household w i th aty phoid carr i er should be immunized, andthen w i th a heat-k i l l ed, phenol -preserv edplain ty phoid vaccine given subcutaneously .T o those vho l i v e or trav el w here Sal -m onel ia inf ecti ons are hyperendem ic, Iw ould recom m end the tri pl e vaccine, l leat-k i l l ed and phenol -preserv ed. In ei ther casethe fam i l y should be told that the vaccinei s not very potent, and that they had bestnot chal l enge i ts ef f ecti v eness.

IN F LUENZA s a sort of postscript, because i t i s

nei ther a v ery old vaccine, nor a very newone, com es inf l uenza v i rus vaccine. N umer-ous f ield tri al s ov er the last tw enty yearshav e demonstrated the ef f i cacy of inf l uenza



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450 A CT I V E I M M U N I Z A TI ONv i rus v accines, and the laboratory tests doseem to correlate w i th cl i ni cal resul ts. 0T he range of ef f ecti ve protecti on seems tol i e betw een 40 and 96% w i th an av er-age around 78 to 80% . U nf ortunatel y thepolyvalent vaccine ordinar i l y employ ed hassev eral serious 37 such as thehigh incidence of untow ard reactions inyoung chi ldren, w hich has been estim ated at8 to 40% , the short durati on of ti l e im muni tyconf erred by thi s v accine w i th the needfor booster doses each autumn, the ongoingm utati on of inf luenza v i ruses w i th the possi -bi l i ty that ex i sti ng vaccines may confer less-than-usual im muni ty against the strains ofv i rus yet to appear on the scene. Final l ythe num ber of studies show ing that the ef -f ecti ve cl i ni cal protecti on conferred uponpreschool chi l dren by anti -i nf l uenza v ac-cination i s v ery l im i ted.

T his being the si tuation i t seems w ise toreserve imm unization w i th polyvalent in-f l uenza v accine f or those chi l dren suf feringf rom chronic debi l i tati ng disease, such asrheum ati c heart di sease, congeni tal or hy-pentensive heart di sease (parti cular l y thosew i th f rank or incipient cardiac insuf f i -ciency); chronic bronchopulmonary , meta-bol i c, renal di sease; or neurological dis-orders.

Ideal l y , a dose of poly valent vaccineshould be adm inistered subcutaneousl y , i nearl y autum n, fol l ow ed by a second injec-t ion about 2 months later.

G E N E R AL C O M M E N T SI t seems w orthw hi le to point out that the

recommendations of the Red B ook are by nomeans alw ays appl i cable to condi ti ons inparts of the w orld other than Canada andthe U ni ted States, and that they m ust al sobe interpreted w i th special care w hen thepatient under consideration has l i vedabroad, or in preparing to travel abroad. Inparti cul ar , booster doses of di phtheri a tox -oid are superf l uous for older chi l dren inm any places and, w hen they do seem mdi -cated, the T D adul t ty pe should be em-ployed f or chi l dren of 8 years and above.T etanus immuni ty should be careful l y m ain-

tamed, and, in countri es w here of le i s l i kel yto be in contact w i th sm al lpox , e.g. Congo,I ndia, Indonesia, N iger ia, Pak istan, smal l -pox rev accination should be practi ced atin terv als of 1 to 3 years. Routi ne ty -phoid imm unization, despi te i ts im perf ec-ti ons, i s indi cated in many parts of thew orld, as i s B CG . \V here rabies i s prevalent,I personal l y w ould seriously consider pro-phy lacti c (i .e. preex posure ) vaccinationagainst rabies, using duck embry o vaccinew i th three-or- four-dose-and-booster ty pe ofschedule. Special i noculati ons against yel -l ow fever, cholera, plague, etc., m ay alsobe indicated, or even requi red by law .

I t i s w el l to remember, I l ow ever, and tow arn patients, that no im munization i s 100%effective 100% of the time. Our v ery bestvaccines are only perhaps 90% ef fecti ve.T he immuni ty w hich they confer f al l s grad-ual l y along a curve w hich v ar ies f rom per-son to person; persons al ready suf fer ingf rom another di sease, or in surgi cal shock ,or pregnant, may be physiological l y m oresusceptible to inf ecti on. M oreover ti l e si zeof the infecti ve dose at t ile t im e of e xposure i s trem endously important. I n short,ev en w hen ful l y im munized against every -thing, one sti l l should not play w i th patho-genie v i ruses and bacter ia the counterpartof the chi l dren s game Rover, Red R over,I dare you com e over.

R E F E R E N C E S1. B atson, R ., and Chri sti e, A . : Immunization

m ethods and m atetri als. J. Pediat., 53:51, 9 5 8

2. D oege, T . C., H eath, C . W . Jr and Sherm an,I. L . : D iphtheri a i n the U ni ted States, 1959-1960. PEDlAnucs, 30 : 1 94 1962.

3. B rainerd, H . D ., et a .: Susceptibi l i ty to di ph-thetria among el der ly per son s. Immunizat ionby the intracutaneous adm ini strati on of tox -oid. N ew Engi . J. M ed., 247:550, 1952.

4. H eath, C . W ., Jr and Z usm an, J. : A n out-break of di phtheri a am ong sk id-row m en.New Engl . J. M ed., 267:809, 1962.

5. Report of the C om m i ttee on the Control ofI nf ecti ous D iseases, A m eri can A cadem y ofPediatri cs, Evanston, I l l i noi s, 1961.

6. V olk , V . K ., et a l.: A nti genic response tobooster dose of di phtheri a and tetanus tox -oi ds-seven to thi rteen years af ter prim ary



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R EV I EW A R TI CL E 45 1i f lOCl l l l t iOn of noni nst i tut ional i zed chi ldren.PIl l) . heal th Rep., 77:185, 1962.

7. Pappenheimer, A . N I ., Jr et c i.: A study ofreactions f ol low i ng adm ini stration of crudeand puri f ied diphtheri a tox oid in an adul tpopulation. A m er. J. Hyg . , 52:353, 1950.

8. L ev ine, L ., I psen, J., Jr and M cCom b, J. A :A dul t im m uni zat ion. Preparation and evalua-t i on of com bi ned f l u id tetanus and di phther iatoxoids f or adul t use. A mer. J. H yg., 73:20,1 9 6 1

9. Report of the M edi cal R esearch Counci l Com -m i ttee on Inocul ation Procedures and N eu-rological L esions. Pol iom yel i ti s and prophy -lati c inoculati on agai nst diphtheria, w hoop-ing-cough, and smal lpox . L ancet, 2:1223,1956.

10. A Report to the M edical Research Counci lby i ts Com m i ttee on D iphtheria T oxoi d.I nef f i ciency of puri f ied diphtheria form oltoxoid in pri mary im munization againstdiphtheria. B ri t. M ed. J. 2:149, 1962.

11. U .S. D epartm ent of H eal th, Educati on, andW el fare. V i tal Stati st i cs of the U ni tedStates, 2:60, 1959.

12. Staf f ord, E. S. : T etanus prophy lax is: thedurati on of protecti on f rom acti ve im m un-i zation. Surg., Gv nec. O bstet., 100:552, 1955.

13. L ooney, J. M ., et a l.: Persi stence of ani tox inl ev els af ter tetanus-toxoid i noculation i nadul ts, and ef f ect of booster dose af ter van-o i l s i ntervals. N ew Engl . J. M ed. 2 5 4 : 61 9 5 6

1 4. P et er so n, J. C Christ ie, A ., and W i l l i am s,\v C. : T etanus im m uni zat ion X I . Studyof durati on of pri mary i mm uni ty and re-sponse to l ate stim ulating doses of tetanustox oid. A mer. J. D is. Chi ld. 89:295, 1955.

15. G oldsm i th, S., Rosenberg, E ., and Pol l aczek ,E. H . : A study of the antibody responseto a booster of tetanus toxoid. N ew Engl .J. M ed. 267:485, 1962.

16. M cC arr ol l, J. R., A brahams, I ., and Skudder,P. A . : A ntibody Response to tetanus toxoid15 years af ter i ni t i al im m uni zati on. A m er.J. Publ . H eal th, 52: 1669, 1962.

17. H ampton, 0 P and H ard, J. : A cti ve im -munizati on against tetanus w i th intraderm altox oid. Sung. C ynec., Obstet., 109:223, 1959.

18. Edsal l , G . : Speci f i c prophy lax is of tetanus.J A M A 171:417, 1959.

19. Staf f ord, E. S. : A cti ve and passi v e anti tetanusi mm unization. J.A .M .A ., 173:539, 1960.

20. Fi l l er , R . M ., and El lerbeck , W . : T etanusprophylaxis. J A M A 17 4: 1 19 60

2 1 Per so nal c om m un ic at io n.22. M assachusetts D epartment of Publ i c H eal th;

Per tussis i mm unizat ion, N ew EngI . J. M ed.,263:410 1980.

23. Pi ttm an, M . : I nstabi l i ty of pertussis-v accinecom ponent in quadruple anti gen v accine.l ) i phthenia and tetanus toxoids and per-tussi s and pol i om y el i t i s vaccines. J.A .M .A .,181:25 1962

24. T urner, G. G . : T he si te f or i ntram usculari nj ecti ons. L ancet 2:819, 1920.

25. G i l les, F. 1-1., and French, J. H . : Po st in jec ti onsciati c nerv e palsi es i n infants an( l chi ldren.J. Pedi at., 58:195, 1961.

26. C urti ss, P. H ., Jr., and T ucker, H . J. : Sci ati cpalsy in prem ature i nfants: a report andf ol l ow -up study of ten cases. J.A .M .A .174:1586, 1960.

27. K rav i tz, H . : A sim pl ied technique for vacci -n a t i o n agai nst sm al lpox . P E D I A T R I C S 27:219,1961.

28. K em pe, C . H . : Studies on sm al lpox and corn-pl i cations of sm al l pox vaccinati on. PEn -AT RICS, 28: 1 76 1960.

29. Cabasso, V . J., et a .: Prim ary response ofchi l dren to gl yceninated or dri ed sm al l poxvacci nes of cal f v accine. A mer . J. Pubi .Health, 44:194, 1954.

30. W eichsel , M ., and H errera, E. G . : V accinati onw i th av i ani zed smal lpox v accine. J. P ed i at .,5 0 : 1 1 9 5 7

31. K em pe, C. H ., et a l .: Com par ison of dr iedsmallpox v accine w i th f resh I ndian buf f al ocal f l ym ph in rev accinations against sm al l -pox. Amer . J. D is. Chi l d., 102:498, 1961.

32. D ow nie, A . W . : I nfection and im m uni ty i nsm al lpox . L ancet 1:419, 1951.

33. T ucker, S. M ., and Sibson, D . E. : Foetal corn-pl icati on of vaccinati on i n pregnancy . B ni t.M ed. J., 2:237, 1962.

34. A nderson, G . H ., e t a .: A v ian em bry o rabiesimmunization : I D uck-em bryo vaccine ad-m ini stered intraderm al l y in m an. A m er. J.Hy g 7 1 : 1 5 8 1960.

35. Greenberg, M ., and Chi l df t ss, J. : Vaccinationagai nst rabies w i th (l uck -em bryo andSem ple v accines. J.A .M .A ., 173:333, 1960.

36. D ean, D . J., and Sherman, I : Potency ofcom m ercial rabies vaccine used in m an. Pub-l i e H eal th Rep., 77:705, 1962.

37. G ibbs, F. A ., et a .: Compari son of rabiesv accines grow n on duck em bry o and onnervous ti ssue; an electroencephalographicstudy . N ew Engl . J. M ed., 265:1002 1961

38. D epartment of H eal th, Education, and W e -f are: M orbidi ty and M or tal i ty W eek ly Re-por t, N ov . 23, 1962.

39. Enni ght, J. B . : Geographical distributi on ofbat rabies in the U .S. 1953-1960. A m er. J.Publ i c H eal th, 52:484, 1962.

40. Constantine, D . G . : Rabies transm issi on bynonbi te route. Publ i c H eal th Rep., 77:287,1 9 6 2

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5 ACT IV E IM MUN IZA T ION41. A tanasiu, P., et (11 .: Rabies neutral izing anti-

body response to different schedules ofserum and vaccine inoculations in non-exposed persons: Part 3. Bull. W .H .O ., 25:1 0 3 1 9 6 1

4 2. R uegsegg er , J. M . : Person al communi cat io n.43. W allgren, A . : BCG past, present, and future.

Amer. Rev. Tuberc. 76:715, 1957.44. Pollock, T . M . : BCG vaccination in man.

Tubercle, 40:399, 1959.45. Tuberculosis Control A dvisory Committee to

the Public H ealth Service: U se of BCGvaccine. Public H ealth Rep. 77:680, 1962.

46. L orber, J. : Freeze-dried BCG vaccination ofnewborn infants by the multiple puncturemethod. Tubercle, 40:21, 1959.

47. M oodie, A . S., and Cheng, G . K . : Con-current BCG and smallpox vaccination innewborn babies. T ubercle, 43: 155, 1962.

48. M ount, F. \V ., and Ferebee, S. H . : T he effectof isoniazid prophylaxis on tuberculosismorbidity among household contacts of pre-viously known cases of tuberculosis. Amer.Rev. Resp. D is., 85:821, 1962.

49. D ormer, B. A ., et al : Prophylactic isoniazid:protection of infants in a tuberculosis hos-

pital. Lancet, 2:902, 1959.50. Ungar, j., Thomas, V ., and \I iiggleton, P.

: Freeze-dried B .C .G. vaccine from anisoniazid-resistant strain : a laboratory in-vestigation. Brit. M ed. J., 1 : 1 4 98 1 9 61 .

51. Gaisford, W ., and Griffiths, M . I . : A freeze-dried vaccine from isoniazid-resistantB .C.G . : a cl inical investigation. Brit. M ed.J 1 : 1 5 0 0 1 9 6 1

52. Cockburn, W . C . : Early history of typhoidvaccination. J. Roy. A rmy M ed. Corps,101:171, 1955.

53. Cvjetanovic, B . B . : Field trial of typhoidvaccines. Amer. J. Public H ealth, 47:578,1957.

54. Y ugoslav Typhoid Commission: Field and labo-ratory studies w ith typhoid vaccines. Bull.WHO., 16:897, 1957.

A c k n o w l e d g m e n tT he author is indebted to D r. Geoffrey Edsall

for his constructive criticism, also to D rs. JohnFox and David K arzon, and to D r. Jorge Esco-bar M elguizo for assistance in the preparation oft he manuscr ip t.



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1963;32;444PediatricsMargaret H. D. Smith

ACTIVE IMMUNIZATION: CURRENT CONSIDERATIONS

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