Combined Immunization Against Diphtheria, Tetanus and Pertussis in Newborn Infants - II

8/12/2019 Combined Immunization Against Diphtheria, Tetanus and Pertussis in Newborn Infants - II

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1949;3;181PediatricsPAUL A. DI SANT'AGNESE

immunization with diphtheria toxoid.

titers after booster dose. Effect of passive immunity to diphtheria on activePERTUSSIS IN NEWBORN INFANTS : II. Duration of antibody levels. Antibody

COMBINED IMMUNIZATION AGAINST DIPHTHERIA, TETANUS AND

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

PrintIllinois, 60007. Copyright 1949 by the American Academy of Pediatrics. All rights reserved.by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarkedPEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication,

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18 2 P A U L A . D I SA N T A G N E S ED U R A T IO N O F A N T IB O D Y L E V E L S

B lo od sam p les w ere ob ta ined fo r d ete rm ina tion o f an tibod y tite rs as fo llow s:A t 13 w e eks o f age (on e m o n th afte r co m ple tion of in jectio ns) .A t abo ut th e age o f six m onths (fo ur m on ths afte r th ird in jec tion ).A t ab out o ne y ea r of ag e (10 m o nths a fte r th ird in jec tio n ).D i p h t h er i a ntitoxin Results of titra tion o f d ip h theria an tito x in are reported in

T ab le I a nd rep resen ted g rap h ica lly in F ig ure 1 .

D IP H TH E R IA P E R T U S S ISP R O T E C T IV E A N T IT O X IN T IT E R S N P R O T E C T IV E A G G L U T IN IN T IT E R S0 .03 U N IT S P E R cc . O R M O R E ) 1 : 3 2 0 O R M O R E )

100 0 0

- H igh T ile rs H igh Ti/e rs iO u n its /c .C . o rm O re ) /:Q O / 3 O Q )

75 75

U U1) 4U C .I 5 IL . 500 0F - I-.

0 C .

2 5 25

T im e a fte r I M O 4 M O S O M O S . T im e a fte r NO . 4 M OS . O M O S .3 in jectio n 3 in jec tionAg e I3 W K S . 6 M O S . I Y R . A ge 1 3 W K S . 6 M O S I YR .

F IG . 1 . D ura tion of a n tibod y ti ters after co m p letion o f ino cu lations .

O f 12 3 in fan ts te sted o ne m o nth a fter th ird in jec tion , 8 4 .6% h ad pro tectiv etiters . T h ree m on ths la te r o n ly 7 0% of th e 10 3 pa tien ts te sted had sim ila r an titox in leve ls .T h is rep re sen ts a sligh t, bu t p rob ab ly s ign if ican t dec rease (X 2 4 .0 7 ; P 0 .043) . N ofurthe r d ro p w as no ted in th e fo llo w ing six m o n ths. T he d iffe ren ce b etw een th e 70 %of pro tec ted ch ild ren at s ix m on ths an d the 7 7% at one year o f age is no t sign ifican tin v iew of th e d isparity in s ize of the g roups (X 2 0 .30 ; P 0 .582) .

T he situ atio n w as q u ite d ifferen t in the case o f in fan ts w ho ach iev ed h igh an titox inlev els . T h e pe rce n ta ge of c h ild re n w ith an t ito x in ti ters of m ore than 1. 0 u n it/cc. d e-c rea sed from 20 % to less than 2 % in th e 1 0 m on ths afte r com p le tion of ino cu la tion ,

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C O M B IN E D IM M U N IZ A T IO N IN N E W B O R N IN F A N T S 1 83

T A B L E IID U R A T IO N O F T E TA N U S A N T IT O X IN T IT E R S

.A nti tox in Titers(u n its c c )*

Nu mb e r o f Ca s e sT im e A fte r C om ple tio n o f In ocu lations

O n e m on th(13 w k. o ld)

F our m on ths(6 m o . o ld)

T e n m on ths(1 yr. o ld )

0 .010 .11 .0

-

-

73

1 18 (92 % )

163

9 1 ( 8 3 % )

-

-

161

4 6 (7 3% )

W itho ut pro tect ive t iter tW ith p ro te ctive t iter

012 8 ( 1 0 0 % )

011 0 ( 1 0 0 % )

063 (10 0% )

T ota l cases 1 2 8 1 1 0 6 3

* U nits refer to A m e ric an units.t Pro tec t ive a n ti tox in ti ter-0 .1 un it/c c . o r m ore.

a d iffe rence w hich canno t b e du e to chance a lone (X 2 = 9 .41 ; P = 0 .002) . T he steadyd ec line in h igh tite rs is seen in F igure 1 .

Te ta nus ntito xin T he resu lts o f titra tion of te tanus an tito x in a re cha rted in T ab le II.I t h as been s ta ted e lsew her& tha t un usu ally h igh leve ls o f te tanu s an titox in w ere

ach iev ed by the in fan ts und er study afte r im m uniza tion w ith trip le com bined an tig en ,(Athydrox) . F urthe r p roo f o f th is s tatem en t is to b e foun d in th e fact tha t du rin g th epe rio d of ob se rva tion the re w ere n o pa tien ts w ho se an tito x in leve ls d ro pped to le ss th anth e p ro tec tive tite r .

I f the pe rcen tage o f case s w ith tite rs o f m ore than 1 .0 un it/c c . is co nsid ered , itis fo un d tha t a s teady dec line in an tib ody leve ls took p lace . T he d ifferen ce in th enum ber o f ch ild ren w ith th ese h igh tite rs a t th e age of 1 3 w eeks (92 % an d a tone yea r o f age (7 3% is h igh ly s ign ifican t (X 2 = 10 .45 ; P 0 .0 01).

P ertussis g glutinins Seru m ag g lu tin in leve ls obse rv ed a t vary ing tim es af te r com ple -t ion of the im m uniz ing in jec tions are desc ribed in T ab le I II and F igure 1 .

A decrease too k p lace in the pe rcen tage of in fan ts w ith p ro tectiv e agg lu tin intite rs from 54 .4% on e m onth afte r, to 33% fou r m on th s a fte r th ird in jec tio n . T h isrep re sen ts a de fin ite redu ctio n in tite rs and is p resu m ab ly no t d ue to sam plin g e rro rx 2 9 .57 ; P = 0 .002) . N o fu rthe r change w as observed in the percen tage ofpro tec ted ch ild ren in the fo llo w ing s ix m onths .

A stead y d ec rease w as obse rved instead , in the 10 m o nths fq llow in g inocu la tion ,in the num b er o f in fan ts w ith titers o f 1 :3 200 (X 2 5 34 ; P 0 .020) . T he sam etren d is ob served in pa tien ts w ith titers o f 1 :1 600 or h igh er (F ig . 1 ), a lthoug h thed ro p is no t m ark ed eno ugh to be sign ifican t sta tis tica lly .

Discuss ion A progre ssive dec lin e in bo th te tanus and d iph th eria an tito x in co n-cen trations a fte r b asic to xo id im m u niza tion is kn ow n to occur. It is a lso know n tha th ig h an titox in tite rs a re lo st m ore rap id ly than low er on es.2 T he re is ev id en ce th aton ce a low lev e l o f c ircu la ting an tibod y , so -called b as ic im mun ity has b een reached



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18 4 P A U L A . D I S A N T A G N E S ET A B L E III

D U R A T IO N O P P E R T U S S IS A G G L U T IN IN T r r a n s

A gglu t in in T i t e r s

N um ber of C asesT i m e af te r C om ple tion of Inocu la tio ns

O ne m onth(13 w k. o ld )

Fou r m onths(6 m o. o ld)

T en m onths(1 yr. o ld )

1: 0 : 51 :100

B reak dow n 1:200o f t ite rs

1 :4001 :800 : 61 :3200

3 8 (3 0% )53

11

1619 22 1 ( 1 7 %)

4 5 (4 1% ) 2

87

87

1 0 (9 % )

22 (47 % )

27

7351

W ithou t pro tec tive titersW ith pro tec tive titer

5 7 ( 4 5 . 6 %)68 (54 .4% )

7 2 (67 % )36 (33% )

31 (66 % )16 (34% )

T otal c ase s 1 25 10 8 47

Pro tec tive agg lu tin in tite r-i :4 00 or h igher.

in fo ur to six m on th s it is m ain ta ined fo r a con side rab le leng th of tim e w ith on ly s lig h tchange .4 A ll o f these fin d ing s w ere p re sen t in our pa tien ts , e sp ec ia lly in the case ofd iph th eria an titox in . T he ch an ges w ere m ore d ifficu lt to eva lua te in the case of te tanusan tito x in , becau se o f the h igh an tibod y lev els ach iev ed a fte r in ocu la tion and thefact th a t 1 .0 un it/cc . w as the m axim um leve l o f an tito x in te sted fo r . In co ntra st to the g ene ra l ag reem en t abo u t the p rog re ssiv e d ec rease in te tanu s an dd ip h the ria an titox in leve ls , w ith p assag e of tim e , it ha s b een sta ted by L ap in ,5 M ishu lo w 6and m o re recen tly b y S a k o 7 and M ille r2 tha t p ertu ssis agg lu tin in s pe rsis t in the b loodof im m unized p atien ts in rela tive ly h igh titer fo r tw o to six yea rs . In a recen t in vestiga -tion , ho w eve r , M ille r8 foun d a co nsid erab le dec rease in the p ercen tag e of pa tien ts w ho ,30 m on ths af te r ino cu latio n , had ag g lu tin in tite rs o f 1 :32 0 o r h igher.

In ou r case s th ere w as a rap id in itia l dec rea se in th e n um b er o f pa tien ts w ithp ro tect ive tite rs , then a leve llin g o ff took p lace and no fu rthe r chan ge w as no tedin the nex t six m o n th s. O n the o the r hand , a s teady dec lin e w as n o ted in the pe rcen tageof in fan ts w ith h igh agg lu tin in leve ls . T o o ur kn ow led ge th is has no t been o bse rvedbe fo re . P e rhaps the yo ung ag e of ou r pa tien ts and the to ta l d ose o f pe rtu s sis vaccin e,le ss than the am o unt recom m end ed by som e au tho rs,9 m ay h av e been resp ons ib le fo rthe se f ind in gs. I t is in te re sting to n o te tha t th e behav io r o f p ertu ss is ag g lu tin ins in ourcase s w as qu ite s im ila r to th a t o f th e d iph th e ria an titox in .

A N T IB O D Y R E S P O N S E T O B O O S T E R D O S ER esu lts obse rved fo llo w in g the ad m in istra tion of a bo oste r dose have b een sum m arized

prev iously ; they w ill be repo rted no w in grea te r de tail.T h e pa tien ts w ere d iv ided in to tw o group s. G ro up Y w as g iven a b oos te r do se a t

six m o n ths o f age , fou r m o n ths a fte r com ple tion of in ocu la tions . G roup Z receiv edth e recall in jectio n a t th e age of one year , 10 m o n ths a fte r th ird in jec tion . A ll bo oste r



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C O M B IN E D IM M U N IZ A T IO N IN N E W B O R N I N F A N T S 18 5in jec tions co nsisted o f 0 .5 cc . o f the sam e trip le com bined vacc ine used in basic im m uni-zat ion .

B loo d specim en s fo r an tib ody titra tion w ere ob ta ined as fo llow s:B e fo re ad m in is tra tion o f the bo oste r d ose .T en to 30 d ay s a fter bo oste r.A b o u t si x m o nths af te r b oos ter do se .D iphtheria ntitoxin D iph the ria an titox in tite rs b efo re and a fte r b oos ter d ose a re

p re sen ted in T ab le IV .T A B L E IV

D n x m x a i A N T I T O X I N T I T E R S A F T E R B O O S T E R D osE

A n titox in tite rs(units/cc.)

N u m b e r o f c as esG ro up Y G roup Z

6 m on th sof ag e

(4 m o. afterthird

injection)

to 30daysaf te r

booster

1 y earo f age(6 m o . af te r

booster )

1 y earo f age

(10 m o. af te rtd. . t ion )rn jec

10 to 3 0dlaafter

b o o s t e r

0 .030 .1 1 .0

1 2 ( 2 3 % )

101

10

3 (8% )

125

24

4

2 5 (40 % )

5 ( 1 2 % )284

1616 (1 4% )

6 ( 2 2 % )184

8

11

612 0 7 0

W ithou t p ro tec tive tite r*

W ith pro tec tive tite r

1 2 ( 23 %)

2 4 ( 6 7 % )

1

6 1 ( 9 8 % )

5 (1 2% )

37 (8 8% )

6 ( 2 2 % )

2 1 ( 7 8 % )

0

29(100%)Total cases 36 62 42 27 29

* P r o t ec t iv e an t it ox in titer-0.03 unit /cc . o r m ore.A n titox in de term in atio ns w ere av ailab le be fo re an d a fter boo ste r in th e sam e in fan ts

in 6 3 cases. A n tibody lev els w ere grea tly inc reased afte r re in jec tion in 61 cases, in tw oin stan ces th ere w as no change .

A m ar k ed in cr ea se w as no ted in G rou ps Y and Z o f pa tien ts w ith p ro tec tive tite rs10 to 30 days afte r th e adm in is tra tion o f a boo ster d ose . T he re sp onse w as equ ally asg o o d w he th er ch ild ren w ere re in jec ted a t th e age o f six m on th s (G roup Y ) or a t theage of one yea r (G roup Z ).

T he situa tion w as qu ite d ifferen t reg a rd in g pa tien ts w ho ach iev ed h ig h an titox intiters a f te r b oos ter . In bo th g roup s a m ark ed in crease w as o bse rv ed in the n um b er o fcase s ach iev in g an tito x in leve ls o f m o re than 1 .0 un it/cc . T he percen tage of ch ild renach iev ing h igh an tib ody leve ls ho w ev er , w as sig n ifican tly g rea te r (X 2 5 .37 ; P0 .0 20) in G ro up Z (re in jec ted a t o ne y ea r o f ag e ) than in G ro up Y (bo oste red a t sixm on ths o f age ) . T he d iffe ren ce in an tibo dy re spo nse a t the tw o age leve ls is show nin Figure 2 .



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186 P A U L A . D I S A N T A G N E S ED iph the ria an tito x in tite rs w ere de te rm ined aga in six m on ths af te r bo oste r in

G rou p Y pa tien ts . In th is in terva l a dec rease in an tibo dy leve ls had taken p lace . T hedec l ine w as m ore m arked in h igh an tito x in tite rs th an in th e lo w er o nes, in keep ingw ith ou r p rev ious obse rva tions .

Te tanu s An titox in : R esu lts o f titra tion of tetanu s an titox in are cha rted in T ab le V .B ecause o f h igh an tibo dy leve ls ob ta ined a fte r basic im m uniza tion and the fact tha t

D IP H TH E R IA P E R TU S S ISHIG H A N TITO XIN TITE R S HIG H AG GLU TIN IN TITE R S

MO R E TH A N 1 .0 U N IT P E R c c .) 1 :1 6 0 0 .1 3 2 0 0 )7 5 7 5

: 50 soU - U4 4C. C.I L I .0 0I -. I -z zw ia0 C .

25 . 25

E l 0 r iB e f o r e 10-30 B e f o r . e 0 - 3 0B o o s te r D o y s A fte r B o o s te r D a y s A fte r

D o s e B o o s te r D o s e D o s e B o o s te r Dose. . U G r o u p V B oo ste r D os e o t 6 M o e . o f A g e

U Q r c w p Z B o o s t . rD o s e o l a Yr o f Ag eF I G . 2. E f f ect of age on an t ib ody p r oduct ion f ol low ing boost er dose.

1 .0 u n it o f an tito x in /cc . w as the m ax im u m leve l tes ted fo r, it w as d if ficu lt to de tec t afu rthe r inc rea se in tite rs af ter re in jectio n .

A n inc rease in the nu m ber o f case s w ith an tito x in tite rs o f m o re than 1 . 0 un it/cc.w as o bse rv ed h ow ev er in bo th g rou ps o f pa tien ts . T he pe rcen tage o f ch ild ren w ith su cht i ter s ro se fro m 8 3% to 95% in G roup Y , fro m 63 % to 97% in G rou p Z . A ntibodypro duc tio n w as app aren tly equ ally goo d w hether cases w ere boo ste red a t six m o nthsor a t on e y ear o f ag e.

T etanu s an titox in tite rs w ere d ete rm ined aga in six m o n ths a fte r ad m in istra tion o fth e reca ll d ose in G roup Y . A dec lin e in an tibody leve ls cou ld no t be de tec ted a tthis t i m e .

P e r t u s s i s Agglu t in ins: P ertussis ag g lu tin in leve ls observed befo re and afte r adm in istra -t ion of a bo oste r do se are desc ribed in T ab le V I.

In 60 cases p er tu ss is agg lu tin in d ete rm ina tions w ere av ailab le befo re and after



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C O M B IN E D IM M U N IZ A T IO N IN N E W B O R N IN F A N T S 187re in jectio n . In 4 3 p atien ts th e an tib ody tite rs inc rea sed afte r rein jec tion , in 1 0 th ey w ereu nchanged and in seven they dec reased .

A sign if ican t and com parab le in crease in th e pe rcen tage of case s w ith p ro tec tiveagg lu tin in tite rs w as fou nd a fter boo ste r do se w he the r ch ild ren w ere re in jec ted a t s ixm on ths o f ag e (G rou p Y ) or a t the age of one y ear (G rou p Z ).

T he num ber o f cases ach iev in g agg lu tin in tite rs o f 1 : 320 0 w as qu ite d ifferen th ow ev er a t the tw o ag e lev els . T h e pe rcen tage of cases w ith such titers ro se o n lyfrom 0 to 5% in G ro up Y , as aga in st an inc rea se fro m 3% to 2 3% in G roup Z .T he d iffe rence is w ith in th e lim its o f sta tis tic al s ign ificance and pre su m ab ly n o t du e tochance a lone (X 2 = 5 .23 ; P = 0 .0220) . T he sam e trend can be d iscerned if p a tien tsw ith tite rs o f 1 : 1 6 00 or h igh er are con side red (F ig . 2 ).

A m arked drop took p lace in agg lu tin in tite rs in the s ix m on th s fo llo w in g bo oste r do se.W h en an tibo dy leve ls w ere de term in ed ag ain at th is tim e in G rou p Y , th e p e rcen tageo f case s w ith p ro tec tiv e tite rs w as no t sig n ifican tly d iffe ren t from w ha t it had b eenbe fo re re in jec tion (X 2 0 .89 ; P 0 345

T A B L E VT E T A N U S A N T IT O X IN T IT E R S A rvaa t B O O S T E R DosE

A ntito x in tite rs(un i ts/cc .)

.

N um be r o f c ase s

G rou p Y G roup Z

6 m on th sof ag e

(4 m o . a fterth ird

in je c t ion)

to 30d a y saf ter

boos te r

1 yearof ag e

(6 m o . afte rboos te r )

1 yearof ag e

(10 m o . afte rth ird

in je c t ion)

10 to 30daysaf ter

boos te r

0 .010 .10 . 1

-

15

-

31 (83% )

-

-

12

61 (95% )

-

-

3-

3 6 (92% )

-

11-

1 9 (6 3% )

-

-

1-

2 9 ( 9 7 % )

W ith ou t p ro tec tive tite rt

W ith pro te ctiv e t iter

0

37 ( 1 0 0 % )

0

6 4 (1 00 %)

0

3 9 (1 00 %)

0

30(100%)

0

30 (100% )

T ota l c ase s 3 7 6 4 3 9 30 3 0

C U nits refer to A merican units. P ro tect ive an t itox in tite r-0 .1 u n it/cc . o r m ore.

Com m ent: It is kno w n tha t the re u sua lly is a g rea t d iffe rence b e tw een re sp onse to thef irs t and subsequen t in jec tions of an an tig en ic m ate ria l. A n tibo dy titers rise to a h igh erleve l and a re m a in ta ined fo r a lon ge r pe rio d of tim e in re spon se to a booster do se thanaf te r p r imary s t imula t ion .b0

T hese fac ts w ere true in th is s tudy regard in g d iph theria an titox in produ ction . T e tanu s



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18 8 P A U L A . D I S A N T A G N E S Ean tito x in resp onse to bo oste r can be assum ed to h av e been sim ila r, thou gh m o re d ifficu ltto eva lua te fo r rea son s p rev ious ly m en tioned .

T he behav io r o f p ertu ss is agg lu tin in .s w as qu ite d iffe ren t. T he percen tage of in fan tsw ho deve lop ed p ro tec tive ag g lu tin in tite rs a fte r a boo ste r dose w as n o t sign ifican tlyd iffe ren t from tha t observed a fte r the b as ic in jectio ns. It app ea red as if the re w erea ce iling (ab ou t 6 0% ) in the num ber o f p atien ts w h o cou ld d ev elo p p ro tec tivetite rs even a fte r re in jectio n . M illers h ad a som ew ha t sim ila r exp erience in a g ro up o f o lde rch ild ren im m unized w ith trip le co m bin ed an tigen (A lh ydrox ) w hen h e w as un success fu lin inc rea sing th e p rop ortio n of case s w ith h ig h agg lu tin in leve ls even a fte r d oub ling theam o un t o f pe rtu ssis vaccin e. T h e p ercen tag e of p a tien ts w ith titers o f 1 : 3 20 or h igh er

T A B L E V IP ER TU SSI S A G G L U T I N I N T rraa ts A rrza B O O S TE R D O S E

A g glu tin in titers

N um ber o f cases

G ro up Y G r o u p Z6 m on th s

ofage(4 m o . af te r

thirdinj ect ion

lO to3Odaysaf ter

booster

lyea ro f age

mo . a f t e rbooster )

1 yearo fage

(10 m o. a fte rthirdin ject ion)

iO to3Odaaf te r

boos te r

1 : 01 : 5 01 :100

B reakdo w n of titers 1 : 20 01 :4001 :8001 :16001 :3200

1 8 ( 5 1 )2424

-

5-

1 0 ( 1 6 )257

101014

3 (5% )

1 3 ( 3 9 )1331.453 (9 % )

1 5 ( 5 0 )-

234531

5 ( 1 7 )-

-

62467 (2 3% )

W itho u t p ro tec tive titer

With pro tectiv e tite r2 6 ( 7 4 % )

9 ( 2 6 % )2 4 ( 3 9 % )

37 (61 %)

20 (61 %)

1 3 (3 9% )

20 (67 %)

1 0 (3 3% )

1 1 ( 3 7 % )

1 9 ( 6 3 % )

T o t a l cases 35 61 33 30 3 0C P ro te ctiv e ag g lu tin in tite r-i :400 o r higher .

w as grea te r in M ille rs than in the p resen t se r ies . I t is rea son ab le to assu m e tha t th isw as due to the d iffe rence in ag e be tw een the tw o g rou ps at th e tim e of basic im m un iza -t ion .

T h e age fac to r p layed an unexpec ted ro le in cond ition in g an tibod y re spo nse to b oos terdo se. T h e str ik ing d iffe ren ce observed in p e rtu s sis agg lu tin in leve ls a fte r re in jec tion a tsi x m on ths and a t o ne yea r o f age m ust be a ttr ibu ted to im m atu rity o f the im m uneme c ha n i s ms in th e yo ung er ag e g rou p , w h ich p reven ted fu ll an tibo dy pro duc tio n . Inth e case of d ip h the ria an tito x in an add ed fac to r m ay have been the pe rsis ten ce in som epa tien ts o f an titox in passiv ely acqu ired th roug h th e p lacen ta .

T he re w as con v inc ing ev idence th at a pe riod of 1 0 days after b oos te r w as eno ugh fo ra m ark ed inc rease in c ircu la ting an tibac te ria l and an titox ic an tibod y to take p lace.



10/16

C O M B IN E D IM M U N IZ A T IO N IN N E W B O R N I N F A N T S 18 9E F F E C T S O F P .s sw E IM M U N IT Y T O D IP H T H E R IA O N Ac-r ivE I M M U N I Z A T I O N

W IT H D IP H T H E R IA T o x o mResults T he resu lts o f de te rm ina tion of d iph th eria an tito x in a fte r im m un izatio n in

2 96 p atien ts are rep orted in T ab le V IL T he cases are d iv ided in to th ree g ro ups acco rd in gto th e leve l o f d iph th eria an tito x in p re sen t a t b ir th . T h e m in im um tite r te sted fo r w as0 .0 3 un its /cc . W hile the m ajo rity o f n ew b orn s w ith le ss th an th is leve l can beassum ed to have had n o c ircu la ting an titox in , in som e cases low an t ib od y t it e r s m u sth av e been presen t .

T A B L E V IIDIP umxniA A n o x I N TrrEas A C H I E V E D A n xn Acrw.E I I a (UNIZATION B Y I N FA NT S

W rra m W I T H O U T PASSWE I cu rx T O D IP HT HE R IA A T BirrH

A n t i t O x i ntiters

units/cc.

O ne m on th a fte rt h i rd i n j ec t i o n(13 w k . o f a ge)

F ou r m on ths afte rt h i rd i n j e ct i o n(6 m o. o f a ge)

10-30 day s a fterb oo st er d os e

(6 -12 m o. o f a ge)

G r o u p t

G rou pt G rou pti U In n m i n m

0.0 3< 1.0G r ou p I n -H igh lev e ls -1 .0 or m or e

O ne m o nth afte r th ird in jectio n the g reat m a jo rity o f ch ild ren in G rou p I (< 0 .03un i ts of an tito x in /cc . a t b irth ) and to a so m ew ha t le sser ex ten t tho se in G roup II(m o de ra te am ou n ts o f an titox in a t b ir th ) had an titox in tite rs w ith in the p ro tec tiverang e. T he h igh p ercen tag e of pa tien ts in G rou p III (h ig h an titox in lev e ls at b ir th ) w h oach iev ed a lev el o f 0 .03 un its /cc . o r m ore afte r ino cu la tion shou ld be la rgely d iscoun ted .In m an y ins tan ces th ese titers m ust have b een d ue to a co m bin a tion o f p as sive ly transm ittedd ip h the ria an titox in s tiL t p re sen t in the circu la tion and ac tive ly p rod uced an tibo dy . F ou rm o n ths a fte r th e la st ino cu latio n the p ercen tag e o f p ro tec ted in fan ts h ad decreased in a llth ree g ro ups.

S e ro log ic re spo nse to rein jec tion is the c ritic a l te st o f an tibod y-fo rm in g tissu e sen si-tiza tio n . A fter adm in istra tion of a b oos ter do se a ll p atien ts tes ted , w ith on e ex cep tio n ,had d iph the ria an tito x in tite rs o f 0 .03 un its /cc . o r m o re . T h e resu lts ob se rv ed p o i n tto th e fac t tha t activ e im m u nizatio n aga inst the d ip h th eria an tigen w as ach iev ed ina lmos t a ll in s tan ces d esp ite th e passiv ely transm itted an titox in p resen t a t b ir th in o ve rha lf the cases . In ev alua ting these find ing s it m u st b e k ep t in m ind tha t by th e ageof 6 to 1 2 m on ths, w h en b oos ters w ere adm in istered , c ircu la ting p ass ive an titox in m usthave been co m ple te ly o r la rge ly e lim ina ted an d the refo re co u ld no t h av e a ffec ted theresu lts . T w elve of the in fan ts w ith tite rs o f 0 .0 3 un its/cc . o r m o re afte r boo ste r w erea m o n g th e 1 7 w h o h ad fa iled to ach ieve a p ro tec tive an titox in tite r on e m o n th a fterth ird in jection .



11/16

I

m l

19 0 P A U L A . D I S A N T A G N E S EW hile passiv e d iph the ria an titox in p resen t in the circu la tion d id no t p rev en t sensitiz a -

tion o f th e an tibod y-fo rm in g tis su es to the d iph theria an tigen , it d id d ecrease sign ifi-can tly the am oun ts o f an titox in ac tive ly produced in respo nse to prim ary inocu lat ion .T his is show n in F igu re 3 , in w hich is charted the percen tage of ch ild ren ach iev ing1 .0 un it o f an titox in /cc . o r m ore . H ere ag ain the pa tien ts a re d iv ided in to th ree g ro upsacco rd ing to the lev el o f p as sive an titox in p re sen t a t b irth .

O n e m o nth a fte r th ird in jectio n 48 % of in fan ts in G roup I ( little o r no an tito x in a tb ir th ) h ad d iph the ria an tito x in leve ls o f 1 .0 u n it/cc . o r m ore , w h ile on ly 2 0% o fch ild ren in G ro up II (m o de ra te am oun ts o f an titox in a t b irth ) ach ieved s im ila r lev els .

D iP H T H E R IA A N T IT O XIN T ITE R S60 A T B IR T H u nits / c . c .G ro up I -N o n e < 0.0 3)

G ro u p M o d e ra te le ve ls > 0.0 3 0 .1 )G ro u p s -H ig h le v e ls 1 .0 o r m ore

5 0 UU iU.

C.) 40 -U -0I-3 0 -C.)

Ui0. 20

10-

O N E M O N TH 4 M O N TH S 0 - 30A FTE R TH IR D A FTE R TH IR D D A Y S A FTE RI N J E C T I O N IN JE C TIO N B O O S TE R D O S E

A G E I3W K S . 6 M O S . 6-12 M O S .F IG . 3 . P rop or tion of ca ses w ith an d w itho u t pas siv e immuni ty at b irth w ho ach iev ed a d ip h th eria

an titox in tite r o f 1 .0 un it pe r cc. o r m o re afte r co m p letion of in ocu lat ion s.

T he d ifference be tw een th e tw o grou ps is h igh ly s ign if ican t (X 2 9 35 ; P 0 .002)an d ref lec ts the pronou nced d efec t in ac tive an tibo dy prod uc tio n caused by the presenceo f passiv e an tito x in .

O f the pa tien ts in G rou p III (h igh an tito x in lev e ls a t b irth ) 38% w ere fo und to h aved ip h the ria an titox in tite rs o f 1 .0 un it/cc . o r m ore one m onth afte r th ird in jec tio n . T heh igh an titox in lev els obse rved a t th is tim e in G roup III m u st have been due in m anyinstances to a com bina tion of s till p resen t d iph theria an tito x in pass ive ly transm ittedand ac tive ly p rod uced an tib ody . F our m on ths a fte r a th ird in jec tion the pe rcen tage ofcases w ith an titox in tite rs o f 1 .0 un it/cc . o r m ore drop ped to a s im ila r leve l (17% )in a ll th ree g rou ps. P a rt o f the d ec rease in the g roup w ith h igh p re -im m un ity titers(I II) m us t h av e been due to the grad ua l e lim in a tion o f pass ive ly transm itted d iph theria

an t i tox in .T he resp onse to a bo oste r dose , as show n in F ig ure 3 , fu rth e r em phas izes tha t sa tis -

facto ry tis sue sens itiza tio n took p lace even in p a tien ts in w ho m antito x in prod uc tionhad been quan tita tiv ely decreased by the presence of passive an tib ody . T he resp onse to



12/16


13/16

192 P A U L A . D I S A N T A G N E S E

can b e exp ec ted t o d isa p p ea r f r om th e c ir cu la t io n in tw o t o t h r ee w eeks .18 It ha s alsob een sho w n th a t hom olog ou s an titox in is ex cre ted m ore slow ly than its he te ro logo usco un te rpa rt.9 F rom the inv estig a tio ns o f C oo ke and Jones15 it appea rs th a t a lthou ghind iv idua l d iffe ren ces a re g reat the rate o f d isappea rance o f in jec ted h ete ro log ous an ti-bod ie s is rou gh ly p rop ortiona l to the ir o rig in a l leve l.

It can be sa fe ly s tated tha t in the m a jo rity o f in fan ts , w h ose passiv e d iph th eriaan titox in leve ls a t b ir th w ere n o t u nusua lly h ig h , by th ree o r fo u r m on th s o f age thepass ive an tito x in w ill have d is ap peared o r dec reased su ff ic ien tly so as no t to p reven t sensitiz a tion o f the im m un e m ech an ism s fo llow ing d iph th eria to xo id in jec tion .

S UMMARYA dditio na l se ro log ic stud ie s a re p re sen ted o f a g rou p of n ew bo rn in fan ts w h ose

an t ibody produ c tion fo llow ing com b ined p ro phy lac tic in ocu la tion aga inst tetanu s, d iph -th er ia and p ertuss is w as reported in a p rev ious p ap er .

D uration of Antibody Titers: In the 10 m o nths fo llow ing th e last in jec tion of trip lecom bined an tigen a steady ded in e in d ip h the ria an titox in tite rs w as o bse rv ed w hichw as m ore m ark ed in p atien ts w ho had ach iev ed h ig h an tibod y lev els . A sim ila r dec reasew as fou nd in th e p ercen tag e of in fan ts w ith h ig h tite rs o f te tanus an tito x in , b u t the rew ere no cases w hose tetanu s an tito x in lev el d ropp ed to le ss than th e p ro tectiv etite r (0 .1 un it/cc .) . P rog re ssive dec rease in d iph the ria and te tanu s an titox in titers w ithp as sag e of tim e is in ag reem en t w ith find ings o f o the rs .

A fte r the th ird and last im m u n iz ing in jec tio n , a rap id in itia l dec rea se w as n o ted inthe n um ber o f p atien ts w ith p ro tec tive p e rtu s sis agg lu tin in tite rs (1 :4 00 o r h ig he r) ;then a leve lling o ff took p lace an d no fu rth er chang e w as n o ted in th e nex t s ix m o n t h s .O n t h e o t h er h a n d , a st ea d y d ec lin e w as fo und in th e pe rcen tage o f in fan ts w ith h ig hagg lu tin in lev els (1 :320 0). T o o ur kno w led ge th is ha s no t b een observed b efo re . T h eyoung age of our p atien ts a t th e tim e o f th e basic in jectio ns m ay have been re spo nsib lefo r the fin d ing s.

Antibody Titers After B ooster D ose: O ne grou p of in fan ts w as rein jec ted a t th e ageof si x m onth s (fou r m on ths a f ter the th ird an d last im m un iz ing in jec tion ), ano th erg ro up a t one y ea r o f age ( 1 0 m onth s af te r the las t in jection ) . A ll b oos ter d oses co nsis tedof 0 5 cc . o f the sam e tr ip le co m bin ed an tigen used in b as ic im m un iza tion .

A fte r boo ste r a m ark ed inc rease w as no ted in d iph th eria an tito x in titers to a leve lh igh e r th an th at observed fo llow ing the b asic im m un izin g in jec tions . T e tanus an tito x inre spo nse w as con side red to h av e been e qua l ly g ood , a lthou gh m ore difficult to ev alu atebecau se o f the h igh an tito x in leve ls p re sen t b e fo re re in jec tion .

I n t h e case o f p er t u ssis a gg lu t in in s, it ap pea red as if th ere w ere a ceilin g o fabou t 60 % of in fan ts w ho cou ld , even a fte r rein jec tion , d ev elo p a p ro tec tive agg lu tin intite r (1 :40 0 or h ighe r).

A st r ik in g d if f e r en ce w as o b ser v ed in b o th p er tu ss is agg lu tin in leve ls and d ip h theriaan tito x in tite rs ach iev ed by in fan ts rein jec ted a t si x m onth s and o ne y ea r o f age . T h isw as tho ug h t to be d ue to im m atu rity o f th e im m u ne m echan ism s in the yo ung er ag eg ro up . A n added fac to r in the case o f d ip h the ria an titox in in so m e pa tien ts m ay h av eb een the pe rs is ten ce o f passive an tibod ies acqu ired transp lacen ta lly .

A nt ibody tite rs a lso w ere de te rm in ed six m o n ths a fte r b oo ster do se in the in fan ts w hoh ad been re in jected at the age of six m on th s. A m arked decrease w as ob se rved in thepe rcen tage o f pa tien ts w ith p ro tec tive pe rtu ssis ag g lu tin in tite rs an d h igh (1 .0un it/cc .) d iph th e ria an titox in leve ls . N o reduc tion w as n o ted in te tanus an titox in tite rs .



14/16

C O M B IN E D IM M U N IZ A T IO N IN N E W B O R N IN F A N T S 19 3E ffec ts o f Pa ssive imm un ity to D iph the ria on A c tive im m un iza tion w ith D ip h the ria

T oxo id : W ith o n ly o ne excep tio n , a ll in fan ts tes ted afte r a b oos ter dose had beenadm in iste red be tw een 6 and 12 m on th s of age had pro tec tiv e d iph theria an titox intite rs (0 .0 3 un its/cc . o r m ore) A ctive im m uniza tion ag ain st d iph th eria w as the refo recons ide red to h av e been ach ieved in all ca se s (w ith on e excep tio n ) d esp ite thepassive ly tran sm itted an titox in p resen t a t b ir th in ove r ha lf the cases.

W hile passive d iph theria an titox in presen t a t b irth d id n o t p reven t sensitiz a tiono f the an tib od y-fo rm in g tissu es to th e d ip h the ria an tigen , it d id dec rease s ign if ican tlyth e am o un ts o f an titox in ac tive ly p ro duced in re spo nse to basic in ocu la tion .

R easo ns fo r the su ccess o f ac tive d iph the ria im m un iza tion in th is se rie s a re d iscussed .A rgum ents aga ins t ac tive im m u niza tion of m oth ers in p regn an cy fo r p ro tec tion of the iroffsp ring are cons ide red .

ACKNOWLEDGEMENTSW e w ish to ackn ow led ge ou r ind eb ted ness to D r. W alte r E . W ard , M ed ical D irec to r

o f C u tte r L abo ra to r ie s , w hose coo pe ra tion and assis tance m ad e th is investig atio n p ossib le.O ur s incere app rec iatio n is a lso ex tended to M r. R . B . C la rk , fo rm er D irecto r, an dD r. E . H . N ew kom , p re sen t D irec to r o f C lin ical R esea rch , fo r the ir he lp fu lness an dco n tinu ed su ppo rt.

R E F E R E N C E S1. d i S an tA gne se, P . A ., C o m b ine d im m un iza tio n aga ins t d iph the ria , te tanus and pertussis in n ew -

born in fan ts; I. P rodu ction o f a n tibod ies in ear ly in fan cy , P E D I A T R I C S 3:20 , 1 94 9 .2 . M iller , J . J ., Jr. , S ilve rbe rg , R . J ., S a ito , T . M and H um ber, J. B ., A gg lu tina tive reac tion fo r

H . pertussis; I. P e rsis ten ce of ag g lu tin ins a fte r vacc in e, J . P ed ia t. 2 2 :63 7 , 1 9 4 3 .3 . B ig ler , J. A ., and W erner, M ., A c tiv e im m uniza tion aga inst te tan us an d d ip h the ria in in fan ts

a nd ch ild ren , J.A .M .A . 11 6:2 35 5 , 194 1 .4 . R a ther, B ., A lle rgy , A naphy lax is an d Im m un otherapy , W illiam s and W ilk ins C o ., B a ltim ore ,

194 3 , p . 323 .5 Lapin , J. H ., S tim ulation dose in w h oop ing cough , J . P ed iat. 2 0 : 1 8 , 1942 .6 . M ish u low , L ., and o thers, S tim ula tio n of pertussis -p ro tec tiv e an tib od ies by vacc in a tion ; co rn-

pa rative s tud y of pro tec tive , ag g lu tin a ting , and co m plem en t- fix ing an tibod ies , A m . J . D is .C hild . 62 :12 05 , 1941.7 . S ako , W ., S tu d ie s o n pe rtus sis im m un iza tion , J. Ped ia t. 30 :29 , 1 9 4 7 .

8. M iller , J. J., J r., and R yan , M ary L ou ise , Im m uniza tion w ith com bined d ip h theria and tetanusto xo ids (a lum inum hyd ro x ide adso rbed ) con tain ing H . pe rtu ssis vacc ine ; H . D u ra tion of sero lo g ici m m u n i t y , P E D I A T R I C S 1 : 8, 1 948 .

9 . E dsa ll, G ., M ed ica l p rog ress ; active im m un iza tion , N ew E ngland J . M ed . 23 5:2 56 , 19 46 .1 0 . T op ley , W . W . C ., an d W ilson , G . S ., P r inc ip le s o f B acte r io log y a nd Im m un ity , V ol. II , W il-

ham s and W ilk ins C o., B altim ore, 1946 , p . 1 1 1 4 .1 1 . P ark , W . H ., an d S chrod er, M . C ., D iph the ria tox in -a ntito xin an d toxo id : co m parison , A m .

J. P ub . H ea lth 2 2 :7 , 1932.12 . B lum , J. , A ge fac to r in ac tive im m uniza tion of in fan ts aga inst d iph th eria , J .A .M .A . 9 8: 1 62 7,

1932.13 . G reen gard , J., and B ern ste in , H ., Passive i m m U n i t y in in fan ts an d the ir re sp onse to diph ther ia

to xo id , J .A .M .A . 105 :34 1 , 1 9 3 514 . C o ok e, J. V ., e t a l., A n tib ody fo rm ation in ear ly in fan cy ag ain st d iph ther ia and teta nu s tox o id s,

J. Ped ia t . 3 3: 14 1, 1 94 8.15 C oo ke , J . V ., and Jo nes, F . G ., Durat ion of passiv e te tanu s im m unity and its e ffec t on ac tiveim m un iza tion w ith te ta nus tox o id , J.A .M .A . 12 1:1 20 1 , 19 43 .

16 . C o h e n , P ., and S cad ron , S . J. , E ffec ts of act ive im m u nization of m other upon o ffsp ring , J.P ed ia t. 29 :60 9 , 194 6 .

17 . G und el, M ., and K o en ig , F ., c ited by D ow nie , A . W ., et a l., C o m bin ed ac tive an d passiveim m uniza tio n aga in st d iph theria ; I. S tud ies o f an titox in response in norm al studen ts , B rit. M . J.2 :71 7 , 1941 .



15/16

19 4 P A U L A . D I S A N T A G N E S E1 8 . Z insser, H ., and B ayne-Jones , S ., T ex tbo ok of B ac te rio logy , D . A pp le ton-C en tu ry , N ew Y ork

a nd L ondo n, 1 9 3 9 p 1 6 319 M o l o n ey , P. J ., and F rase r, C . J ., c ited b y G re en ga rd .

S P A N IS H A B S T R A C TInmunizac ion C o m bin ad a C o n tra D if te ria , T e tanos y P e rtus is en In fan te s R ecien

N acid os. I I . D u r ac ion d e C an t id ad es d e A n ticu erpo s, T itu los d e AnticuerposD esp u es d e la D os is td I m p u lsad o r a , E f ect o S e I n in u n ica d P as iv a a la

D ifter ia S o bre Inmunizac ion Activa con T ox in a D if t e r icaD u rac i {2 43} ne tI tu los d e an ticu erpo : E n los 10 m eses que sigu en a la {252}l t iman y e c c i { 2 4 3 } nd e a n t Ig e n o

co m binado trip lo se observ { 243}u na dec linac i { 243} n en los tItu los an titox ino s d e d ifte ria, Ia q ue f u { 23 3} { 22 5} sm arcada en pacien tes que hab lan alcanzado can tidades de an ticuerpo a ltas . U n descen so sim ila r seencon tr { 243}en c i po rcen ta je d e in fan tes con tI tu lo s de an titox ina de t { 233} tano sltos, pe ro no hub ie ro ncasos cu ya can tida d d e a n ti tox ina de t { 23 3} tan os ba jara a m en os d el tItu lo pro tec tivo (0 . 1 u n id ad /cc).U na dism in uc i { 243 }n p rogres iva en los tItu los d e an tito x ina de d ifte ria y d e t {23 3} tan os c on el transcursode l t iempo est {2 25 }e a cue rdo c on lo s d esc ubr im ien tos de o tros .

D esp u {2 33 }sd e Ia te rce ra y { 25 2} ltim a in ye cci { 243 }n in m uniz an te , se no t { 24 3}una d ism in uci { 243 }n in icia l r {2 25 }p idaen e l n {2 25}m erode pac ien tes con tItu los ag lu tin os de pertusis p ro tec tivos ( 1 : 40 0 o m {2 25 }slto s);d e sp u { 2 3 3} s e v e ri fi c { 2 4 3} n e m p a re j am i e nt o y no hu bo m {2 25} sam bio e n lo s pr { 24 3} xim os seis m eses. P or o trolado , s e en con tr {2 43 } un a d ism in u c i {243 }n co n t in u a en e l po rcen ta je de in fan tes c on alia s ca n tid ad es deag lu t inas ( 1 : 3 20 0 ) . S e g {2 52} n sa bem os e sto no se ha b la o bse rva do an tes . P u ed a ser q ue Ia t iern a e dadd e nue stros pa cie n te s al tiem po de pon ersele s las iny ecc ion es b {2 25} sicas h aya sid o resp onsab le po r losdescubr imien tos .

T Itu los de an ticu erp o de spu { 233 } s de la do sis im pu lsa dora : U n g rup o d e in fan tes fu ero n re-in ye ctad osa Ia e dad d e se is m eses (cua tro m ese s d esp u { 23 3} s d e Ia te rce ra y {2 52 }lt im a iny ecc i { 24 3} n inm un iza n te) ; o trog rup o a la eda d de un a { 241 }o 1 0 m e ses d esp u { 2 33} s de Ia { 25 2} ltim a in ye cci { 243 }n ) . T oda s las d osis im p ulsado rasc onsis t ie ron de 0 5 cc . d el m ism o an tIg en o co m binado trip lo .

D espu { 233} sde Ia in yecc i { 243} n m pulsadora se no t {24 3}n aum ento en los tItu los de a n t i t o x i n a d e d ifte riaa un a c an t ida d m { 22 6} slta qu e Ia q ue se ob serv {24 3} d espu {233 }s de la s inye ccione s inm unizan tes b aja s. S ecrey { 243}ue Ia resp uesta de an titox in a de t {23 3}tanos ab la s ido igu a lm en te b uena , au nque m { 225 }sificilde ava luar a cau sa de las a las can tidades de an titox ina presen tes an tes de Ia rein yecc i { 243} n .

E n e l caso de ag lu tina s d e pe rtu sis , p areci {24 4}om o si hub iera un lim ite d e poco m { 225 }sm en os60% de n iflos quiene s po dla n , a { 2 25} nesp u {2 33} s de Ia re -in yec ci {2 43} n , d esa rro llar un tI tu lo de ag lu tin in apro tect ivo ( 1 :4 00 o m u alto ).

S e o bs e rv { 2 43 }n a gran d ife renc ia en am bas can tidad es de ag lu tin ina de pertusis y los tI tu lo s dean t i tox ina de d ifte ria Ilevados a cab o en in fan tes re -iny ectados a lo s seis m eses y un a { 24 1} oe eda d .Se p en s { 243}ue esto se deb la a Ia fa lta d e desa rro llo de los m ecan ism o s inm unes en c i g rupo de edadm e n o r . U n fac to r ad ic ion al en e l ca m d e an titox in a d e d ifte r ia en algun os pac ien tes pu ede ha bers ido Ia pe rs is ten c ia de los an ticue rpos p asiv os a dq uirid os tra ns pla ce ntar ia me nte .

L os tItu lo s de a ntic ue rp o tam bi { 23 3}nueron de te rm inad os seis m eses despu { 233} se Ia d osis im pu lsado raen los n ifio s que hab lan s id o re -iny ectados a Ia edad d e se is m eses . S e observ { 243}una d ism inuc i {2 43}nm arcad a en c i po rcen ta je de pac ien tes con tItu los de ag lu tin ina de tos ferina pro te ctiv os y a lto s (1 .0un idad /cc . ) can tidades d e an titox ina d e d ifte r ia . N o se no t {2 43}ingu na reducc i { 243} n en las can tid ad esde an t i tox ina d e t { 23 3} ta no s.

E fec tos de in m u nid ad pa siv a a la d ifteria en in m u niza ci { 2 43 }n activa con to x in a d ift { 23 3} ric a: C onso lamente un a e xce pci { 243 } n , todo s los n ifios e xam in ado s d esp u { 2 33} s d e hab erseles adm in istrado una do sisim pu lsadora en tre los 6 y 12 m e ses de ed ad tuv ieron tItu lo s de a n ti tox ina d ift { 233 }r ica (0 .03 un ida des /cc . m { 2 2 5 } s )La in m u niza ci {2 43 }n a ctiv a c on tra la d if ter ia se co nsider { 233 }, po r consigu ien te , haber sid o a lca nza daen tod os los casos (con u na excepc i { 243 }n)a p e s a r de Ia an titox ina pas ivam en te transm itida , p resen tea l nac im ien to en m { 2 2 5 } se la m itad de los caso s.

A u n q u e Ia an titox ina d if t {233 }rica pasiva presen te a l nac im ien to no ev it {2 43}sens ib i lida d de lo ste j idos qu e fo rm an el a n t i c u e r p o al a n t i g e n o dift {233}rico,o d i sm i n u y { 2 4 3} s i gn i li c at i va m e n te l as c an ti da de sde an t i tox ina a c t i v a me n t e prod uc ida en respues ta a l a i n o cu lac i { 2 43 } n { 2 2 5 } s ica .

S e tra tan la s razon es para e l { 23 3} xi toe la in mu niz ac i { 24 3} nd e Ia d ifte ria a ctiva e n esta s se ries . S eco nside ran argum entos con tra la inmunizac i {243}n ac tiva d e m a dre s en c i e m b ara zo pro te cci { 243 }n de su sniflos.97 Broadway



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1949;3;181PediatricsPAUL A. DI SANT'AGNESE

immunization with diphtheria toxoid.titers after booster dose. Effect of passive immunity to diphtheria on active

PERTUSSIS IN NEWBORN INFANTS : II. Duration of antibody levels. AntibodyCOMBINED IMMUNIZATION AGAINST DIPHTHERIA, TETANUS AND

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Combined Immunization Against Diphtheria, Tetanus and Pertussis in Newborn Infants - II

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