COMBINED IMMUNIZATION AGAINST DIPHTHERIA, TETANUS AND PERTUSSIS IN NEWBORN INFANTS : III.

Relationship of Age to Antibody Production PAUL A. DI SANT'AGNESE Pediatrics 1949;3;333

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/3/3/333

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1949 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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COMBINED TETANUS III.

IMMUNIZATION AND Relationship

By PAUL

AGAINST IN NEWBORN

DIPHTHERIA, INFANTS Production

PERTUSSIS of Age
A. New
DI

to Antibody
M.D. N.Y.

SANTAGNESE, York,

EPORTS
briefly work with response nor has those of to an

in
shown

the
that

literature
on individuals stimulus that of a immunologic

on
previous of in the

the

influence
occasion. of

of
It the species. animals animal. been

age
was The does

on

antibody
animal production not correspond of

production
that are of experimental not

were
identical in

reviewed older antigenic to

concluded

processes the same newborn mature has

newborn

antibodies qualitatively applying these

quantitatively to the

fully infant

The

validity in recent

conclusions

human

newborn

questioned results of

years.

In
to

this

report,
stimuli

we

aim
through

to evaluate in a group

the of

effect
of

of increasing
the

age

on antibody

response
inoculation

antigenic In all

a comparison

prophylactic was at which used, the

in newborn
lowing the

infants
instances same the

and
routine.

older

children.
antigen was in (Aihydrox) the age and folinoculations

same The

triple only

combined difference

were in the intervals

second evaluated findings The lactic months from

administered. newborn of
at the

One period. weeks.

age been of

group. Three The

five

(designated injections first dose

and detail to of three two in

Series of the was

third previous as months, injections at

X in the triple
nine

present at the

report) antigen age

age.

was were one

injected given week,

were

combined
weeks of

at the The

four

administered of antibacterial
reports. Series in were most given

of
The

weeks,

results

by determination
have older inoculation and
the

of serum
in (referred the The age other

levels

and
B) cases at

antitoxic
received between intervals

antibodies.
the the of six first ages four

reported after

children

hereafter

prophyof six

one

year.

weeks

first. The
have

results been

of antibody reported
and

determinations Antibody
of older administration term

one

month titrations

and done
dose be

months one year

presented

after after
for in view

third

injection
of

previously.
after the

completion

inoculations is realized

a booster may

are

the first time. It

that

children

misleading

of of

the young simplicity The material

age of the majority of the term older children used

and

the

patients
will be levels

in Series
used.

B. However, inoculation,
protective response
Hospital,

for the

the

sake

for
the

immunization,
serum effect antibody

the

schedule

of

laboratory
have been

methods

employed

considered age on
the Calif.

discussed

elsewhere.
to evaluating
of from and publication the Pediatrics, Cutter

In addition
From and the Supported Submitted College (Received the Sloane in for

of increasing
Columbia University, Berkeley, for University.

antibody
Babies

to antigenic
Vanderbilt Clinic

Department Hospital. by a grant partial

Laboratories, of the Columbia 6, 1948.)

fulfillment Surgeons, July

requirements

the

degree

of

Doctor

of Medical

Science,

of Physicians

333

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334 stimuli, this and

PAUL
paper
will include a

A.

DI

SANTAGNESE
between

comparison

the

two

age

groups

in

regard

to

local

systemic

reactions
REACTIONS

to prophylactic
TO PROPHYLACTIC

inoculation.
INOCULATION

Some administration

observations

can

be

made

on

the

incidence
infants

of
(Series

systemic
X)

reactions
as

resulting

from

of the vaccine 60
U)

to newborn

compared

with

older

Series

6 X

Older

Children /nfon/s

w
U)

4
C.) Li. 0

U
20-

Series

- Newborn

I.-

Lii

C.)
Lii

a-

Injection I
FIG.

El
fever

ri

r
Injection
injections of

lnjectionfl

ffi
triple combined antigen.

1.

Proportion

of patients

with

37.8#{176}-40#{176}C. following

children sequent

(Series injections
1 no this

B).
in is shown

The
newborns,

incidence
while

and the

severity reverse

of

these was

reactions true of
the

increased older

with

sub-

children.

In

Figure

injection

elevations

in the case of fever (37.8#{176}-40#{176}C.). In response to the first of temperature were observed among the newborn infants (Series
TABLE I
ACHIEVED BY

COMPARISON

OF

TETANUS (SERIES

ANTITOXIN

TITERS OLDER

NEWBORN

INFANTS

X)

AND

CHILDREN

(SERIES

B)
of inoculations 10 to 30 days

Time

after

completion

Tetanus
.

antitoxin titers

One

Mo.

4 to 6 Mo.

10 to

14 Mo.

after

booster dose

X Without With
Total

B 0

X 0

B 0

X 0

B 0 100% 27 67%

X 0

B 0

protective protective
cases titer

titer*

100%
128

100%
82 95% unit/cc,

100%
110 83% or more.

100%
80 91%

100%
63 73%

100%
30 97%

100%
19 95%

With
*

high

titert
antitoxin antitoxin titers-0.1

92%

Protective High

f X)
second Series existed

titers->1.0

unit/cc.

in contrast
injection
X

with
the

an incidence
number with
two

of 33%
of patients B.

in the
with the After

older
fever third was

children still
injection

(Series

B).

After

the

considerably
almost

smaller no
difference

in

as
behavior

compared
the may

Series

between

groups.

This

be

explained

by

the

lack

of

general

reactivity

characteristics

of

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COMBINED

IMMUNIZATION

IN

NEWBORN

INFANTS

335

newborn common.
Local

infants.
reactions

With did

increasing
not follow

age, the and

febrile pattern severity

responses of the

to infectious systemic reactions. and

stimuli Only

become slight in the

more varitwo

ance

was

evident

in the

incidence

of erythema

infiltration

PERTUSSIS
(1.3200

AGGLUTININS
OR MORE)

u, 100
75

e5o

25WJ1
DIPHTHERIA
,j,

ANTITOXIN
PER CC.)

4,

100

(>1.0

UNITS

75 5O 25

Jill
TETANUS ANTITOXIN
PER CC.) (>1.0 UNITS

100

1EI11F
TIME AFTER COMPLETION.MONTH
OF INOCULA-

4-6 MONTHS

10-14 MONTHS

BOOSTER

DOSE

TIONS GROUP - INFANTS)

FIG.

(NEWBORN

fl
-i

GROUP B (OLDER CHILDREN) titers achieved (Series by newborn B) infants (Series X)

2. Comparison

of high antibody
and older

children

groups. older combined

However children, antigen

five may

sterile have been

abscesses which responsible

OF

were

observed to explain. for these

in the findings.

newborns, lots

none of the

in the triple

a difference

is difficult

Different

TITRATION

TETANUS

ANTITOXIN

Results

of titration

of tetanus

antitoxin

in Series

X and

Series

B appear

in Table

I.

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336
In the year following

PAUL
completion infants) antitoxin

A.
of and titers X

DI
the B

SANTAGNESE
immunizing (older (>1.0 injections children) unit/cc.), of Series had one B had all patients tested tetanus the third levels. in

both antitoxin
As

Series
for

X titers
high

(newborn
(0.1

protective month such after antitoxin

unit/cc,
tetanus 92%
in the

or more). of Series number Four and 95% with after than

prophylactic A steady with toxin only the 83% levels

injection
decrease

of patients to six months

high the in the

antibody inoculations older titers of more

titers the children. than

was decline
1.0

observed in antitime unit/cc.

passage was of

of time. more patients

marked tested

in the newborns in Series X had

TABLE

At this

antitoxin
II

COMPARISON

OF

DIPHTHERIA

ANTITOXIN

TITERS

ACHIEVED (SERIES

BY NEWBORN

INFANTS

(SERIES

X)

AND

OLDER

CHILDREN

B)
of inoculations 10 to 30 days

Time after completion

Diphtheria antitoxin titers

One Mo.

4 to 6 Mo.

10 to 14 Mo.

after

booster

dose
X B 1% 99% 82 X 28% 70% 103 B 0 X 23% B 15% 85% 27 X 0 0 B

Without With
Total

protective protective cases titer

titer*

15% 85% 123

100%
80

77%
57

100%
29

100%
19

With high titert

*

20% titer-0.03 unit/cc,

84%

12% or more.

41%

0.5%

26%

70%

95%

Protective
}iigh antitoxin 91%

antitoxin
titers-> in

1.0 unit/cc.

as against with high

Series

B. Ten 67%
after

to
titers

14

months
was not

after

injection

the percentage
different in the

of children
two groups, B and X

tetanus

antitoxin equally the

significantly dose, injection.

73%
Both cases

for
10

Series
groups to
14

X and
responded months

for

Series
well third

B.
to booster administered to both prophylactic

The period

similarity (X) and

in tetanus several

antitoxin months after

production birth
OF

between (B) is seen

infants in Figure

injected
2.

in the newborn

TITRATION

DIPHTHERIA

ANTITOXIN

Titration
III summarizes

of the
the

serum
results

levels
of and third

of diphtheria
statistical high inoculation diphtheria

antitoxin
of antitoxin

are
the

reported
numbers titers.

in Table
of children

II. Table
in the

comparison

two older

series One

with month children

protective after (B) the had

85%
antitoxin

of newborn
titers of 0.03 the groups injection, the

infants
units/cc. difference of

(X)
or

and
more

99%
(proWhen the (X)

of

diphtheria

tective tested series

titer).
again, of patients

The
four

difference
to six had months increased.

between
after At the that

the

two third time,

is significant

statistically. between newborns

two with

percentage

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COMBINED
protective antitoxin titers to 14

IMMUNIZATION
had months declined after to the

IN
70%,

NEWBORN
while all there the had

INFANTS
older been children a decline

337
were from unit/cc.

protected. 100
ence

By in Series
the

10

injections

to 85%
between

in the

number B, while
two age

of children no
groups

with decrease
this time

diphtheria was
was not

antitoxin observed
significant

titers in Series

of 0.03 X. The

or more sumably
administered

further
at

differand pre-

statistically

due series high

to
one

chance
year

distribution
after completion

(Table
of the

III) antitoxin

Ten

to

30

days

after
100% after

booster
of

dose,
patients

immunizing

injections, achieved

in both The
are

had
in

protective
Figure 2.

diphtheria antitoxin was

older

levels.
unit/cc.) inoculation

diphtheria

titers observed
children

(>

1 .0

represented

A very injections
toxin titers

significant between
(20%)

difference the the

number and of

one (X)
(B) months

month who
with

after achieved
such

completion high
antibody

of diphtheria
levels

the

three anti-

of newborns diphtheria
four to

(84%).

In
seen

both
in

groups
Figure

high difference

antitoxin
six

titers
and

declined
10 to

steadily
14 months

thereafter
after

as
inocu-

2. Upon

retesting

lation, (B) the

a significant consistently

persisted

between

the of high with

two

series. diphtheria

The

older

children

showed

a greater

percentage of newborns 95%

and

antitoxin titers of more

2)
.

titers
than

than
1.0

newborn infants After booster dose

rose is not to 70% significant

(X). the percentage

as against statistically

antitoxin children
due been

unit/cc., ference

for
could

the

older
have

(Fig.

This

dif(Table

to sampling

error

III).
TITRATION OF PERTUSSIS AGGLUTININS

In Table
Table agglutinin V are

IV are summarized
recorded titers the results after third achieved after the

the
of the

results
three

of titration
by immunizing a very significant

of serum
statistical injections

pertussis
methods in the was

agglutinins.
of the two present pertussis series in

In
of the

a comparison

cases.
One month injection difference

two
after The there

groups X;

in the 86%
of

percentage in Series
the protected no change

of cases B. Upon
children in the

with

protective three
the two time Series

pertussis months
series dropped B of to (82%).

agglutinin later
cases 33% In

titers
even

: 54%
greater.

in Series

retesting
at this figure for

(four
was

to six months
X, while six the

inoculations) percentage was virtually

difference

between

in Series the

following

months the situation was reversed, there being titers to 50% in Series B, no change in Series injections, 1:400 After marked in Series between significance The the or higher booster increase the two (Table difference was dose, in the groups V). of cases in Figure difference the percentage with 2. existed high one pertussis month with not in the statistically one small year of percentage of cases about of the numbers after of significant the protective

a marked X (34%). patients (Table third titers V).

decline in pertussis Ten to 14 months

two

antibody
after

in the prophylactic

groups injection, in Series time limits the

with there

titers was

of a

to 63% tested within titers

X and the

92%

B. Because

number cannot

of patients be considered

at this

difference

of statistical X and Series

percentage

agglutinin after completion titers

in Series of the three

B are compared A significant

inoculations in

immunizing between

of cases

agglutinin

of 1:3200

or higher

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338

PAUL

A.

DI
TABLE

SANTAGNESE

m
DIPHTHERIA
AND OLDER

RESULTS
BY

OF

STATISTICAL

COMPARISON
INFANTS (SERIES

OF

AHTrroxix
CHILDREN

TITERS (SERIES

ACHIEVED

NEWBORN

X)
Cases

B) Cases
high

with
titers

with
titers

Time

after

completion
,2*

protective

of inoculations

P
00019

x
78.2

P <<0.0001 <0.0001
0.0018

1 month

9.67

4-6 months
10-14 10-30
*

23.1
0.31 after booster dose
-

<<0.0001
0.5755
-

18.1
9.78

months days

3.19 3.84 and 6.64, the

0.0740

In this
two age

table
groups

and in Table
will

V, when

the value
of borderline Values for

for

is between
significance.

difference

between

the

be considered significant.

considered

statistically

P (probability)

Values for x of 6.64 or greater will be are also given for each comparison.

TABLE
CoMP1SoN OF PERTUSSIS (SERIEs

IV
TITERS ACHIEVED BY NEWBORN INFANTS

AGGLUTININ

X)

OLDER

CHILDREN

(SERIES

B) of inoculations 10 to 30 days after booster dose X 37% B 8% 92% 12 92%

Time Pertussis agglutinin titers

after

completion

One Mo.

4 to 6 Mo.

10 to 14 Mo.

X Without
With

B 14%

B 50%

protective
titer

titer*

46%
54%

67% 33%
108 9%

18% 82%
80 46%

66% 34%
47 0.5%

protective

86%
82 38%

50%
26 31%

63%
30 23%

Total With
*

cases high titert

agglutinin agglutinin titers-i titer-i

125 17%
:400

Protective High

or higer.

:3200

or higher.

TABLE
RESULTS OF STATISTICAL COMPARISON

V
AGGLUTININ CHILDREN TITERS (SERIES ACHIEVED BY

OF PERTUSSIS

NEWBORN

INFANTS

(SER.IES

X) *.m
Case

OLDER

B)
Cases
high

with
titers

Time

after

completion

protective

with titers P 0.0012 <<0.0001 0.0014 0.0002

of inoculations

-______________ x2
P <<0.0001 <<0.0001
0.2757

x2
10.5 31.5 10.2 13.7

1 month

20.0

4-6 months 10-14 months 10-30 days after booster dose

42.8 1.18 2.12

0.1450

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COMBINED
Series to six X (17%

IMMUNIZATION B (38% group.

IN
This 9%

NEWBORN
was even had

INFANTS
more high pronounced titers at this

339
four time

) and Series
after the

).
Only

difference of newborns

months

injections.

against
to
14

46%
months series.

in
after The
infants

the after

older
inoculation.

Similar

findings

were

obtained antibody
older

upon levels
group

retesting

10

Ten
in in

to 30 days

booster
was

a marked
much

increase
more marked

in pertussis
in the

was noted
(92

both
newborn

increase
(23%

% ) than
the small

) . The
highly

difference
significant

between
statistically

the

two

groups,
V)

despite

number

of

patients,

was

(Table

DISCUSSION

1 . Effect pertussis

of

Age

on

Antibody achieved

Production: after prophylactic

A great of older tested

infants with the

difference
by

existed
a group

in the
of

levels
newborn

of V

agglutinins

injections

infants
Figure

(X)
2)
.

as compared The patients pertussis

was age

with in the agglutinin

a group older age titers No

at birth

children

(B) (even against

(Tables after intervals whooping

IV booster after
The after

and dose)

group when passive

in the

consistently immunity
under
older

showed pletion

higher of
in the agglutinins)

at various

comcough
poorer

prophylactic
younger

inoculations.
present group

( serum
results

investigation.1

as compared

children,

injection

of
must

equal

amounts
be

of

the

same

immunizing
solely to

material
immaturity of

and
the

following
immune

the younger
period

same infants.

schedule,
which

therefore

attributed

mechanisms

prevented

full

sensitization

of antibody-forming

tissues following
in the several

in the active
newborn

On the other hand, tetanus antitoxin production I, Figure 2) was equally good in infants injected
in those
.

immunization
(Series after birth

(Table
X) and (Series

who

received

their

prophylactic

inoculations

months

B)

How

can

this

be explained pertussis immunizing contains

on antigenic

in view

of the
was

foregoing

claim

that

poor

antibody

re

sponse

following ? The stated,

great

immunization agent used tetanus toxoid

the basis stimulus of the

due

to immaturity

of antibody-producing (Alhydrox), capacity. It may

inoculation to immune-mechanism that, if

mechanisms as we have
be reasonably a sufficiently
immaturity

in the present investigation of unusually high antigenic

results the following handicap tetanus due

assumed

is given,

may

be overcome

and

satisfactory III,

immunization by the results Figure 2)

inoculated the difference be therefore in

achieved. of inoculation against diphproduced higher diphtheria

the in assumed newborn antitoxin that period. levels the degree After between of

These conclusions are theria. Older children

antitoxin administration
the

further emphasized (Tables II and

than dose, significant. the It however, must

titers groups

after of was against

injection a booster not

infants

two

immunization

diphtheria

achieved of the newborn acquired by combined

by

both infants

age

groups

was

comparable. at least Here again

The partly the

relatively to the
powerful

poor presence
antigenic

initial of

showing
stimulus

may

be attributed antitoxin.3

trans-placentally
afforded

diphtheria

potent
passive

enough immunity conclusion age

to overcome to diphtheria. that cannot

the

a total of handicaps to an

75 Lf of diphtheria of tissue immaturity stimulus obtained conclusion be as good makes not increases

toxoid was and existing with ad-

The vancing response results

antibody-response in humans fully agree very inoculation. in the the with young

antigenic evidence age may

confirms We

experimental Sako2 that more infant Another

by other is that

authors while the older

in animals. of

no difference

in immune

to prophylactic immunization

cautious

as in the

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340 child a significant degree of

PAUL

A.

DI

SANTAGNESE
against dinical infections may be obtained by

protection

starting that
stances

prophylactic the immunologic

by the increasing

injections handicap
the and antigenic

in the due

newborn

period. immaturity

In can place
critical

this

respect

our

conclusion in many in-

to tissue
stimulus

be overcome ? Evidence
period of

is especially

important.

When
from

does

maturation the the

several levels

of immune
from our own

mechanisms
results that

take
the

can

be gathered
tissue

literature

immune

immaturity to booster period

place for

is in doses points
at least

first fact,

few

weeks and

after a year that

birth. of age full

The

difference

in antibody in the does Diphtheria

IV)

response newborn not take and older investiga.

antibody over have We

at six months to
months.

in infants immunologic should

titers

immunized maturation

however,

One
tetanus

more
antitoxin

effect

of age on antibody
and pertussis

production
agglutinin

be pointed
(Tables I, II

out.
and

decreased

more
children
2.

readily
(Series Limitations should age of be

in infants
B). of the

injected
Present First, was mainly

in the

newborn

period Some

(Series

X)

than

in the of this
whose

Invectigation: the group with between

of the
older newborn and

limitations
children infants, one year

tion the

mentioned. months,

of so-called that six of months

response

to inoculation three

compared

were of

children age.

presented
the of immune this Evaluation

evidences
mechanisms series two of age the control the

in a discussion
at six of groups results of cases might the months had

of antibody
of been have three basic age been greater

production
are more inoculations still the

following
relatively difference in newborn in

re-injection,
If antibody infants was the

that
age levels based

immature.

between

marked.

on
ing

antibody
injection.

titrations
The

carried
antibody

out
levels

one

month

after

administration
the

of the third
composite result

immunizof three

achieved

represented

injections instances
to the in nine these weeks Another first

of vaccine the
cases after limitation injection may

given

at intervals tissues
at the only

of four of
age the

weeks. newborns
one

It is quite were
Success injection, week.

possible
too

that

in some to react

antibody-producing
administered have birth followed respectively. of this study,

the
of second

immature
given at

in tissue-sensitization five and

or

third

especially

in

the

case

of

tetanus

antitoxin, antibody

is the level.

fact that titrations of this This made interpretation toxin would

tions Other

antibody were not carried of results more difficult, the

It

beyond a certain top as in most instances for had were

in

tetanus after
antitoxin

antibasic
levels

levels have
been facts

higher inoculation. been

carried to

than found
to be the taken

maximum
possible

level
that

tested groups
are the

obtained
tetanus

prophylactic

is quite

a difference

between
highest into

the
level.

two

age

tetanus

antitoxin
Different

determinalots of the

consideration

following:

triple combined antigen were used in carrying out capacity of different lots of the vaccine presumably
to both affect Series the X results and significantly. Series error B decreased which may The number of

the basic differed

patients

inoculations. somewhat,
tested for variation

The antigenic but not enough

antibody in the levels in

as time
have

went
been

on.
introduced

However
by

statistical

analysis
size

took
of

due the

account groups

of tested.

any

The suggest

foregoing possibilities

limitations do not invalidate for further investigation.

previously

drawn

conclusions,

but

rather

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COMBINED
3. Pertussis Evaluation in Newborn

IMMUNIZATION
of highly Prophylactic The results satisfactory.

IN
inoculation of It

NEWBORN
Against been stressed

INFANTS
Tetanus, by Diphtheria against Miller5 tetanus that

341

of

Results
infants:

and in in

prophylactic has

inoculation

newborn

infants

were

pediatrics
ence
lactic

tetanus
antitoxin

immunization
in
These

should
as
were

imply
high
met

complete
as
in

protection-the
be attained
series

continued
transiently by Throughout cases.

presprophythe

of

concentration
conditions

can
this

antitoxin.

of

period of observation all patients had more than 0.1 units/cc. of tetanus antibody titers achieved after inoculation were unusually high and were by other
clear that
Diphtheria

antitoxin. equalled used.4 were in the The

of had

The only It is
potency.

series
the

of
tetanus
antitoxin

patients
toxoid
titers

in which
contained
attained

the
in

same
this

immunizing
preparation

material
has great

was

antigenic

by newborns children by the

the

after use antibody

been

basic of the levels

inoculations same observed satisfactory.

by the number cases

not agent younger results

Schick-

as

high
and

as those
following

achieved
the same

in dose

older are
after

immunizing

routine.

However,

age
of
negative

group
immunization

after
patients

booster
against observed
units/cc.

to be considered
have inoculation. usually All

as eminently
gauged our of newborn

diphtheria

antitoxin

levels greater majority

The

of

0.03

or generally

more

after conceded

re-injection. as sufficient
of

This

antitoxin

level

is

7#{189} times
in the
were not

than of
results

the
of

titer

to induce
infants

Schick-negativity
against pertussis

individuals.7
prophylactic inoculation newborn

as good
number

as those of
than infants

achieved infants
even

by the with
after

older

children agglutinin
of

with
a booster

the use of the same of

dose. far and less at any 1 :400 The than age.5 or more proportion the

vaccine.
was of 90%

The
never newwhich

young
63%, with is the

pertussis
administration titers

titers

greater born apparently

protective maximum obtainable

was with

therefore any dose

The
agglutinin did
known

relatively
titers

low of
substantial

percentage
1 :400

of children more
immunity

injected lead
to pertussis

in the newborn assumption

inoculation. after

period that

who many
However,

showed of titers them

it is

or
number

would of patients

to the with low the

not

develop
that a

satisfactory

pertussis Final degree

agglutinin

are inti-

found of

not

to be susceptible inoculation

when must

exposed be deferred

to infection. until

judgment

as to the upon

results

prophylactic

of protection if the the

Against against

mate familial exposure to whooping cough can be ascertained. The question as to whether better results might be realized, tussis thus
4.

amount

of perstimulus
Diphand

vaccine rendered
Advisability and and

in the more
of
Pertussis:

triple potent,
Routine

combined cannot
conclusion,
inoculations

antigen be answered
of

were
Newborn

increased without
infants

and further

antigenic
Tetanus, diphtheria

investigation.

theria
tetanus

In

satisfactory

immunization

a significant

degree

of

protection

against

pertussis

may

be

realized

by

starting is done the

If
immunity

prophylactic and until the

can combined

inoculations in the newborn degree of clinical protection be

evaluated, a conservative are inoculations

period. However, until more work (after exposure to infection) afforded

approach to at the the age problem of three is urged. months,

individual against age of

prophylactic

undertaken

diphtheria, five
the

tetanus several are of three started

and months months

pertussis, earlier at six the to nine critical

in than

most months period

cases,

will the immune

be
The

achieved
literature

by

the

months, injections
age

by following of age.8 of

conventional mechanism

schedule
suggests

in which
that by

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342 immaturity will presumably

PAUL have

A.

DI

SANTAGNESE
Also, by the age of three months the

been

passed.

levels not to toxoid The

hydrox lit
2nd

of passively prevent injection. following

is used: 0.5 injection:
injection:

transmitted the sensitization schedule

cc. at the cc. at the

diphtheria of

antitoxin the immune

will

have

decreased

sufficiently

so as

mechanisms is

following recommended

diphtheria when Al-

for
age

prophylactic
of three age of four months

inoculation

1 .0 I .0 0.5

months

3rd
Booster

injection.
dose:

cc. at the age of five months

cc. at the of pertussis age of 18 months vaccine alone should be administered whenever an im-

booster

dose

munized
less than

child
20

is exposed
billion H.

to whooping
pertussis organisms

cough.
in

Under
saline

these
should

circumstances,
be injected.

a dose

of not

SUMMARY

A comparison children In
same

was

made

of triple
First

antibody inoculation combined

injection

production against antigen

of the vaccine

by newborn diphtheria, (Alhydrox)

was

infants tetanus was

and and used,

to all

by older pertussis. and

newborn

following instances
routine of age and
increased

prophylactic the same of

followed.

all

the
12

was

administered

infants
months Incidence
antigen

at seven

days
at first severity
with

age.
of No

Most
systemic such Five

of

older
to in was

children
administration

were
of infants the

between
the two in triple reverse age the

six

and

injection. reactions injections difference sterile after than significantly combined was groups newborns; (even period. titers after true in newborn found were ; the

subsequent

of the
local none after in

older
the

children. to

between observed were injected diphtheria

reactions

inoculation.

abscesses immunization in infants higher

older
dose)

children. titers in older produced achieved children consistently in the antitoxin higher newborn

Pertussis booster Older prophylactic

agglutinin

children

injection than

the

newborn production

infants. in the

After
two

administration age groups levels was

of a booster comparable. after achieved

dose, inocu-

however, No
lation

diphtheria difference was by the newborn

antibody

found at any infants and

time in tetanus antitoxin the older children. first year increases

It was concluded that during the in response to an antigenic stimulus that

come of

of life the capacity to produce antibodies with advancing age. It was felt, however, due to tissue immaturity prophylactic
against

in some

instances

the

immunologic

handicap

can

be overinjection

if a sufficiently great antigenic stimulus is given. Evaluation of antibody titers achieved by newborn infants
triple combined antigen reveals that the results of

after

immunization

tetanus

and

diphtheria to be
tective

were unsatisfactory,

satisfactory. mainly titers

approach that the

The fell far to the

until age of

results short
problem

of inoculation the of proportion the

of work months. 90%

against of which infants

pertussis who is the

were maximum
in early

considered prothat
infancy inoculations

because

produced

agglutinin

can
is

be expected.
A urged. not be conservative It is suggested before active is done, immunization routine further three prophylactic

started

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COMBINED

IMMUNIZATION
ACKNOWLEDGEMENTS

IN

NEWBORN

INFANTS

343

We of
and
and

wish Our
to Dr.
continued

to acknowledge Laboratories, sincere

E. H. Newkom,

our whose

indebtedness cooperation is also extended

to Dr. and
of

Walter

E. Ward, made this

for

Medical investigation former

their

Director posDirector,
helpfulness

Cutter

assistance to Mr.
Clinical

sible.

appreciation

R. B. Clark,
Research,

present

Director

support.
REFERENCES

1.

di

SantAgnese, born infants;

P.

A.,

Combined of Combined of on of 1947. antibody active age; B.,

immunization antibodies immunization, immunization levels; immunization imrunization inLiuding and Dowrie, an in early

against infancy,

diphtheria,
PEDIATRICS

tetanus 3:20, tetanus booster toxoid, tetanus effectiveness with H.

and
1949.

pertussis

in

new-

production

2. 3.

Sako, di born

W.,

Studies
P.

on pertussis
A., duration

J.

Pediat. against

30:29, titers diphtheria

1947. and dose;

PEDIATRICS

SantAgnese, infants; immunity

diphtheria, after

pertussis effects pertussis of

in

new1949.

antibody with against

passive in chil-

to diphtheria P. three A., months 31:251, Humber, (aluminum and over

3: 181, two

4.

di

SantAgnese, dren agents,

Combined

diphtheria, of

and of combined

evaluation
Immunization

immunizing

5. Miller, tetanus

J. Pediat. J. J., Jr.,

toxoids
1944.

J.

J. 0.,

diphtheria vaccine,

hydroxide-adsorbed) Mary Louise, Immunization

containing with H. pertussis

pertussis

J.
and of

and Pediat.
tetanus serologic 1943, Diseasc$

24:281,
6. Miller, toxoids

J. J.,

Jr.,

Ryan,

combined vaccine; and for Evanston,

diphtheria duration

(aluminum
PEDIATRICS

hydroxide-adsorbed 1 :8, 1948.

)
and

containing

immunity, 7. Ratner, B.,

p. 168. 8. Toomey, and on

Allergy,
Report

Anaphylaxis
of of the Committee

Immunotherapy, on Therapeutic of

Williams Procedures Pediatrics,

Wilkins, Acute Ill.,

Baltimore, Infectious
1947,

J. A.,

Biologicals

American

Academy

p.

2.

SPANISH

ABSTRACT

Inmunizacion Nacidos.
Se mayores el mismo parte La triplo niflos mayores. Los tItulos de hizo una antIgeno vacuna niflos los

Combinada II!.

Contra Reiacion
de triplo, tenlan de

Difteria, de Edad
de

Tetanos

y Pertusis de

en

Infantes

Recien

a Ia Produccion
anticuerpo difteria, reci#{233}nnacidos 12 meses Ia de edad fu#{233} usado, en infantes

Anticuerpo
y en todos La La la los niflos casos mayor primera En

comparaci#{243}n combinado mayores y No Cinco severidad inyecciones se abscesos

producci#{243}n Alhydrox a los de

reci#{233}nnacidos rutina. de edad. les puso

despu#{233}s de

Ia inoculaci#{243}n fu#{233} administrada

profil#{225}ctica contra infantes seis a

t#{233}tanos y pertusis. y se sigui#{243}la misma a los siete dias se del lo edad cuando

primera

inyecci#{243}n de inyecci#{243}n. incidencia mayores.

reacciones subsecuentes diferencia

org#{225}nicas a en infantes entre los observados a cabo

administraci#{243}n reci#{233}nnacidos; dos en grupos los de

antIgeno contrario en reacciones

combinado sucedi#{243} con locales

aument#{243} con

encontr#{243} tal

a Ia inoculaci#{243}n.

est#{233}riles fueron lievados

reci#{233}n nacidos;

ninguna
fueron

en niflos
consistenteinyectados m#{225}s altos Ia

de aglutinina

de pertusis

despu#{233}s de la inmunizaci#{243}n

mente m#{225}s altos reci#{233}nnacidos. despu#{233}s de dosis edades No alcanzada Se cuerpos en Ia impulsardora,

(a#{252}n despu#{233}s de Ia dosis impulsadora) en niflos mayores Los niflos mayores produjeron titulos de antitoxina de inyecci#{243}n profil#{225}ctica sin embargo, diferencia en de estimulo que que los infantes de reci#{233}nnacidos. Ia producci#{243}n en los durante ning6n infantes el primer

que en infantes difteria mucho de

Despises

administrarles

anticuerpo
en ao con de las nacidos

de difteria
cantidades y en la de

en los grupos
de niflos edad. antitoxina mayores. para Se creyO,

de las dos
de t#{233}tanos

fu#{233} comparable. se encontr#{243} ninguna despu#{233}s de lleg#{243} a Ia respuesta conclusion a un tiempo reciCn Ia inoculaci#{243}n

vida

capacidad

producir sin

anti.
embargo,

antig#{233}nico aumenta

el avance

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on March 29, 2013

344 que puede La inyecciOn sideraron tItulos Se de Se incita sugiere principiar en algunos subsanar casos
51

PAUL el los de impedimiento un tItulos antigeno satisfactorios. principalmente protectiva hasta que se haga conservativo de tres meses. estImulo de

A.

DI

SANTAGNESE debido a cabo revela de que que de Ia de 90% las en que a Ia grande. infantes el resultado contra de activa profil#{225}cticas reciCn de nacidos Ia pertusis infantes se puede en de rutina que despuCs no esperar. infancia. no deben de se de contra conIa inmunizaci#{243}n falta de desarrollo del tejido se

inmunolOgico anticuerpo combinada Los a fu#{233} menos m#{225}s trabajo, causa del llevada triplo resultados

Se da

antig#{233}no suficientemente

avaluaci#{243}n de profil#{225}ctica satisfactorios, aglutinina un que antes

t#{233}tanos y difteria

fueron

inoculaciOn proporciOn

produjeron

es el m#{225}ximo que inmunizaciOn

acercamiento de Ia edad

al problema

la temprana

inoculaciones

3975

Broadway

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COMBINED IMMUNIZATION AGAINST DIPHTHERIA, TETANUS AND PERTUSSIS IN NEWBORN INFANTS : III. Relationship of Age to Antibody Production PAUL A. DI SANT'AGNESE Pediatrics 1949;3;333
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1949 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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