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MULTIPLE ANTIGEN IMMUNIZATION OF INFANTS AGAINST POLIOMYELITIS, DIPHTHERIA, PERTUSSIS, AND TETANUS

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MULTIPLE

ANTIGEN

IMMUNIZATION

OF

INFANTS

AGAINST

POLIOMYELITIS,

DIPHTHERIA,

PERTUSSIS,

AND

TETANUS

An

Evaluation

of

Antibody

Responses

of

Infants

One

Day

Old

to

Seven

Months

of

Age

at

Start

of

Inoculations

Clarence D. Barrett, Jr., M.D., I.

William

McLean, Jr., M.D., Joseph G.

Molner, M.D., Eugene A. 11mm, Ph.D., and Charles F. Weiss, M.D.

Department of Health, City of Detroit, and Department of Clinical Ineestigation and Virus Research,

Parke, Davis & Company

(Accepted for publication, May 15, 1962.)

Aided by a research grant from the Department of Clinical Investigation, Parke, Davis & Company.

ADDRESS: (C.F.W.) Research Laboratories, Parke, Davis & Company, Ann Arbor, Michigan.

Pwnucs, November 1962

720

T

HE ACE at vhich inoculation should

take place for active immunization

against diphtheria, pertussis, tetanus, and

poliomyelitis is a question of major

con-sideration in determining optimal

sched-ules for the routine protection of infants

during their first year of life. With the

ad-vent of multiple antigen preparations,

corn-bining poliomyelitis vaccine with the DPT

mixture, this question has reached new im-portance in terms of the general desirability

of protection of infants as soon after birth

as is practicable.

Conflicting reports have appeared in the

literature concerning the ability of the

young infant to respond to antigenic

stim-uli.112 This question has mainly centered in recent years on the question of maternal

antibody interference in respect to

polio-myelitis immunization,5#{176} although the same

controversy has at one time or another

in-volved diphtheria and pertussis

irnmunza-tion as well.1, 2, 3, S, UI Some investigators

sug-gest that a satisfactory antibody response

can be achieved when inoculations are

started at 6 weeks of age or earlier. Others

are admonishing that immunizations with any agent containing poliomyelits vaccine

should be delayed until the infant is 6 to

9 months old. Interference of active

anti-body production by the infant due to the

relatively high concentration of circulating

maternal antibody prior to this age is the

basis for this recommendation.

The capacity of the neonate to respond

to different antigenic stimuli is a complex

function influenced by the pre-existing

anti-body pattern of the mother, the

permea-bility of the placenta to different types of

antibodies, the developmental maturity of

the fetus at birth and the type of antigenic

stimulus received.12 Without adequate

con-trols and sufficiently large sample size, it is

difficult to arrive at valid conclusions in

determining to what extent the presence of

maternal antibody and the infant’s age at

time of initial inoculation influence the

pro-duction of active antibody. The earliest age

at which infants might be immunized with

a multiple vaccine containing poliomyelitis,

diphtheria, pertussis, and tetanus antigens,

with satisfactory antibody response to all

antigen components, was the objective of

this investigation.

There are several reasons why the

clini-cian is desirous of starting immunizations

as early in life as possible. Pertussis may

pose a serious threat to in infants under

3 months of age. Paralytic cases of

polio-myelitis have been reported in the

6-to-12-month age group with disturbing

fre-quency.14-16 There is also a greater

likeli-hood of completing the recommended series of injections if immunizations can be started

early in infancy and co-ordinated with other

reasons for the baby’s being brought to the

physician’s office or clinic. For most practi-tioners the age of 4 to 6 weeks would be

a convenient time to start the series of

(2)

721

pertussis, and poliornyelitis. At this age the

baby is starting his series of health

super-vision visits and the mother is due for her

traditional postpartum examination at about

this time.

The presence of maternal antibody to

any given disease in the newborn infant

affords temporary protection to the

in-fant 6, 12, 13, 17, 18, 19 and should thus mitigate

against any haste to begin immunizations.

However, the opportunity for any given

infant to be born with such passively

ac-quired protection against any specific

dis-ease is a function of either the mother’s

previous experience with natural infection

or her previous artfficial immunization and

the amount of antibody capable of passing

the placental barrier into the fetal

circula-tion. “The duration of immunity so

con-ferred on the infant depends upon the rate

of elimination of antibody from the infant

and on the amount present at birth.”1 Thus,

the amount of circulating maternal

anti-body to any particular disease in an

in-fant at any given point in time can be a

highly variable and unpredictable factor in

assessing the degree of protection afforded

the infant during the early months of life.

Other factors of major importance which

influence the age at which immunization

should be started are (a) the physiologic

maturity of the antibody-producing

mecha-nism; (b) the potency of tile immunizing

agent; (c) the number and spacing of doses;

(d) the problem of side reactions and

com-plications attributable to the vaccine.

The ability of the host to maintain an

adequate antibody level for a long period

of time and to respond satisfactorily to a

booster dose is of critical importance in

determining the long-range effectiveness of

a particular antigen.1’6’9’19 Failure of the

child to show a significant increase in

anti-body titer following the booster would

indi-cate that a true conditioning of the

im-munologic mechanism by the primary series

of inoculations had not occurred. Apparent

lack of “sensitization” by the primary series

of antigen injections and the failure of the

infant to respond to a “booster” injection has

been reported.6”#{176}

METHOD

Selection of subjects for this study was

based on age alone; however, immature or

sick infants were excluded. All children had

negative histories with respect to diphtheria,

tetanus, pertussis, and poliomyelitis

im-munizations. Within each major

stratum-the age group-were three subgroups based

on the multiple antigen to be given.

Sub-jects were selected from babies born in the

obstetrical service of Herman Kiefer

Hos-pital, the local municipal lying-in facility

for the care of indigent families. Mothers

were informed of the availability and

pur-pose of the program by letter or personal

contact and were invited to participate on a

voluntary basis. From this group, 633

in-fants were selected ranging in age from

1 day through 6 months of age at the time

of receiving their initial vaccine injection.

Subjects in the 1 to 6 month age range were

assigned to the various subgroups in the

order in which they arrived at the clinic

for admission; assignment of the newborns

was likewise random. Approximately 20 to

25 infants of each monthly age category

plus 75 to 80 newborns (1-2 days old) were

assigned to each antigen subgroup.

Three vaccines were used for the primary series of inoculations (Table I) : a DPT

vac-cine (Triogen,#{176} Lot 031995B) and two lots

of a DPT-polio vaccine (Quadrigen,#{176} Lots

X-7323 and X-7324). The two lots of

Q

uadrigen were identical in every respect

except for the addition of protamine sulfate

to the latter. The DPT component in the

Q

uadrigen preparation was from a different

lot than that used for the Triogen vaccine

in this particular study.

Each 0.5-mi dose of all vaccines used in

this study contained a full immunizing dose

for each of the component antigens in

ac-cordance with the minimum standards

es-tablished by the Division of Biologic

Stand-ards of the National Institute of Health for

o Triogen and Quadrigen are, respectively,

Parke-Davis trade-mark names for diphtheria and

tetanus toxoids combined with pertussis vaccine,

aluminum phosphate adsorbed; and the same

(3)

monovalent vaccines

(

as cited previously).19

Immunization Schedule

The primary series consisted of a 0.5-mi

injection of the respective vaccine for each

group, given at four intervals approximately

4 weeks apart. The newborn infants

re-ceived their first dose of vaccine within their

first 24 to 48 hours of life. The superiority

of a four-dose primary series over three

doses in subjects less than 6 months of age

had been shown to our satisfaction in a

previous investigation of Quadrigen.bo The

vaccine injections were given

intramuscu-larly into the right and left buttock

alter-nately.

All children remaining in the study were

given, 9 months after the start of the

pri-mary series, a uniform “booster” dose of

0.5 ml of a new lot of Quadrigen (X-7513).

For the group of infants who had received

Triogen as their initial series, this “booster”

actually constituted their first dose of

polio-myelitis vaccine. These children

subse-quently received three more doses of

polio-myelitis vaccine0 at monthly intervals, to

complete their primary series against this

disease.

Collection of Sera

In the newborn infants, blood was

col-lected from the cord at birth, and maternal

bloods were obtained within 24 hours

fol-lowing delivery. Tile cord blood constituted

their preprimary specimen. Subsequent

blood specimens were obtained by femoral

puncture at 1, 2, and 3 months of age

and 2 weeks postprimary. For the children

in the 1 to 6 month age range, venous blood

specimens were collected immediately prior

to the first vaccine injection, one month

fol-lowing the third and 2 weeks

postpri-mary. Approximately 4 months later all of

the infants from the DPT-immunized group,

0 The poliovaccine used for this series was a 2X concentration of poliovirus types 1, 2. and 3 adsorbed onto aluminum phosphate (Lot X-7644); the dosage was 0.5 ml and was equivalent in

terms of antigenic potency to a 1-mi dose of

regu-lar poliovaccine.

as well as the newborns from both

DPT-polio groups, were re-called for a special

bleeding. This interim bleeding was made

to determine more accurately the rate of

loss of maternal antibody. Also, it allowed

us to monitor tile impact of an epidemic of

paralytic poliomyeiitis on the study

popula-tion which was occurring in the community

at the time.1#{176}

In January of 1959, about 460 children

of the original 633 who were started on the

primary series of inoculations in March and

April of 1958 returned for their prebooster

bleeding, and most of these were bled again

2 weeks following their “booster.” Another

postbooster blood specimen was collected

3 months later, or approximately 13 months

from the beginning of the trial. For the

children involved in the original

DPT-im-munized group, this latter bleeding

corre-sponded to a 2-week postprimary specimen

insofar as their poliomyelitis immunization

was concerned.

Determination of Antibody Levels

Poliomyelitis neutralizing antibody levels

were determined in monkey-kidney tissue

cultures in plastic panels.0 Strains used for

challenge virus (approximately 100 TCID50)

were those used in making the vaccine

(type 1-Mahoney; type II-MEF-1; type

III-Saukett). The more sensitive procedure

of 3 to 4 IlOurs’ incubation at 37#{176}Cof the

serum-virus mixture before adding the cells

was used.hl Titers given are expressed as the

greatest dilution of serum (before addition

of virus and cells) protecting the cells from

the cytopathogenic effect of the virus as

determined by microscopic observation

after 7 days’ incubation at 36#{176}C.

Pertussis agglutinin titers were

deter-mined by adding 0.6 ml of agglutinating

antigen to varying ratios of saline and

serum sample so that serum dilutions

rang-ing from 1:10 to 1:1,000 were obtained. The

live Bordetella pertussis suspension is

di-luted to contain 20 billion organisms per

milliliter. The resultant mixture is incubated

at 37#{176}Cfor 18 hours. Each tube is examined

(4)

Components

Quadrigen

Triogen

Lot 0319951?

Polio 2X AIPO4

Adsorbed

Lot X7641..

Lot X7323 Lot X732. Lot X7513

Poliovirus*

type I

type 2

type S

Diphtheriat

Tetanus

Pertussis

1.7

4.0

2.6

4+

6+

13.0

1.9 6.0

3.3

4+

6

19.1

2.4

4.2

4.5

4

2

11.1

2

2

20.3

1.7

5.4

5.1

Guinea pig antitoxin units per ml.

§

Mouse antigenic units per 1.5 ml.

TABLE I

ANIMAL POTENCY TEST RESULTS BY STANDARD GOVERNMENT METHODS FOR THE ANTIGENS USED IN THS STUDY

* Monkey potency factors.

tGuinea pig antitoxin units per ml.

graded from 0 to 4-plus. In a normal

titra-tion, the endpoint is taken as the last tube

showing a 1-plus agglutination.

Procedures for the determination of

re-sponses to diphtheria and tetanus antigens

were the same as previously reported.19

Statistical Treatment of Data

Serum dilutions used to determine

polio-myelitis antibody titers ranged from 1 : 4 to

1 : 2,048 in twofold increments. Three

lab-oratory determinations were made at each

dilution.

Titration endpoints are presented in terms

of the lowest actual titer obtained in any

series of confirmatory determinations. For

example, if a series of three titrations on

the same serum specimen read 1:256, 1:512,

and 1:512, this has been treated as a 1:256

titer rather than shown as a geometric

mean of 1 :400. Multiple titration values for

diphtheria, tetanus, and pertussis were

in-terpreted similarly. Thus, all antibody

titra-tion values shown in the tables and

illustra-tions used in this paper are base values and

represent a conservative approach in the

interpretation of the data.

Positional statistics are used throughout

to describe the group characteristics of the

data. The median, rather than the geometric

mean, is used as the measure of central

tendency and tile 10th, 25th, 75th, and 90th

percentiles are used as rough measures of

dispersion.

The results of the two lots of Quadrigen

used in the primary series are combined,

since the two DPT-polio vaccines did not

produce significantly different antibody

re-sponses to any of the antigen components

under study.

Influence of 1 958 Detroit Poliomyelitis

Epidemic

The primary series of vaccine

inocula-tions for infants participating in this study

was completed in July of 1958. Boosters

were scheduled 6 months later and were

given in January of 1959. Midway between

the end of the primary series and the booster

inoculation, there occurred, during

Septem-ber and October, the highest incidence of

reported cases in Detroit’s explosive

polio-myelitis epidemic of 1958. Although cases

occurred throughout the city and county,

they were most prevalent in the central

sector of the city. Virus isolation studies

from the stools of 124 paralytic poliomyelitis

patients residing in the central area of the

city revealed a preponderance of type I

poliovirus infections (75% of the total

speci-mens found positive for poliovirus) with

type III being involved to a lesser extent

(25% of the positive stools). Type II

polio-virus was not isolated from any of these

pa-tients. Nearly all of the infants participating

in the current DPT-polio vaccine trial came

from families residing in the epidemic area,

(5)

cmi-cally recognizable poliomyelitis.

Neverthe-less, 121 of these children experienced an

unexplained twofold or greater rise in

anti-body titer as revealed by prebooster

deter-minations. So far as is known, none of these

children had received any poliomyelitis

vaccine inoculations during this interim

period. An increase in type I antibody

oc-curred in 79% of these determinations, and

type III in 21%. This ratio closely parallels

that seen in the poliovirus isolations from

reported cases of the disease22 and

sup-ports our impression that the increase in

antibody titer in these children can be

at-tributed to inapparent infections of type I

or III poliovirus. The serologic data from

these individuals were excluded from

con-sideration in evaluating the booster response

to the poliovirus component of the vaccines

under study.

RESULTS

Poliomyelitis Maternal Antibody

Ninety-five per cent of the mothers were

found to have polio antibody titers of 1:512

or higher to type I, 90% to type II, and

88% to type III, in maternal blood

speci-mens collected immediately postpartum.

Sixty-five per cent of the mothers had

re-ceived poliomyelitis vaccine inoculations

during the course of their pregnancy

ac-cording to their prenatal clinic records.

However, it appears that the probability

of environmental exposure was apparently

very great in this population as indicated

by the high levels of poliovirus neutralizing

antibody found in mothers whose

immuni-zation history for poliomyelitis vaccination

was negative.

Correlation between maternal and cord

blood poliovirus antibody levels was quite

high (r = 0.85 for type I, 0.81 for type II,

and 0.74 for type III). Seventy-five per cent

of the newborn infants carried passively

acquired antibody at titers of 1:512 or more

for type III, and 83% for types I and II.

It is a well-known observation that

ma-ternally transmitted poliomyelitis antibody

degradates at a uniform rate with a

calcu-lated half-life of about 26 to 28 days, as

was borne out in this study. Ninety per cent

of the nonimmunized subjects had titers of

less than 1 :32 by the time they reached

9 months of age, and the majority were

be-low 1 : 4. The median antibody titer in

non-vaccinated subjects at the age of 6 months

was found to be 1:16 for type I, 1:32 for

type II, and 1:16 for type III.

Poliomyelitis Antibody Response to

Immunization

Response to inoculations by any one age

group was compared with the preceding

and succeeding age groups to elicit

“break-points” in response to antigens. These

com-parison tests revealed several discrete

groups alike within age groupings but

dis-tinctly and significantly different in

re-sponse to antigens between groups. Values

for the newborn infants approximated those

for 1-month and 2-month-old infants, but

showed sufficient deviation to justify

sepa-rate classification. Like-responding age

groups were consolidated and will be

de-scribed as a group entity rather than in

individual monthly increments. These

groups will be (1) infants 24 to 48 hours old

at time of first inoculation, (2) infants 1 to 2

months old at time of first inoculation, (3)

infants 3 to 4 months old at time of first

inoculation, and (4) infants 5 to 6 months

old at time of first inoculation.

The capacity of infants to respond to

poliomyelitis immunization at various ages

at time of initial inoculation is illustrated

in Figure 1. Although it is evident that this

response improves progressively with age

through the first 6 months of life, the

over-all antibody levels achieved by the 3 to 4

month age group closely approaches the

levels reached by the 5 to 6 month age

group. This evidence is presented in more

detail in Table II.

A more critical criterion of adequacy of

serologic response can be made by

examin-ing the 10th percentile titer values. This

figure represents the antibody level of the

tenth individual in any series of 100

(6)

high-2 WEEKS 2 WEEKS

POSTPRIMARy POSIBOOSTER

2048

1024

512 256

128

64

z a

S

z

a

52048

1024

512

256

128

64

z 32

a

16

8

4

Type III

4 5 6 7 8 9 10 11 12 13

TIME IN MONTHS

5th

0 2 3

I

I

I

I

1st 2nd 3rd 4th INJECT ION

AGE OF SUBJECTS AT TIME OF INITIAL INJECTION OF ANTIGEN:

1DAY ..1-2MONTHS 3-4MONT1IS 5-6MONTHS

Fic. 1. Poliomyelitis antibody median titers for types I,II, and III, in relation to age of

sub-jects at time of initial injection of antigen. Allsubjects were given a four-dose primary series

of a DPT-polio antigen (Quadrigen) one month apart followed by a fifth dose (booster) 6

(7)

TABLE II

P0LI0MYELITIs ANTIBODY TITER PERCENTILE DISTRIBUTIONS AT VARIOUS STAGES OF Two IMMUNIZATION SCHEDULES IN SUBJECTS (A) 1-2 DAYS OLD, (B) 1-2 MONTHS OLD, (C) 3-4 MONThS OLD, AND

(D) 5-6 Morrriis OLD AT TIME OF INITIAL INOCULATION

1mm unzzaiio n Schedule: DPT-poli & 9 montha

o’ at 0, 1, ,5,

Stage of Immunization

Immunization Schedule: DPTt at 0, 1, 5, & S month8 and DPT.polio at 9 months Total Percentile Values

Sub-jects 10th 25th Median 75th 90th Percentile Values Total

Sub-90th jeets 10th 25th .ifedian 7.5th

.4.1-Sd ays old at time of initial inoculation

3 3 16 <1 4 4 I8 3 3 < 4 <4 6b 16 Ni <4 4 <4 I,Ote 18 64 <4 4 8 1,O4 1S 1S <4 8 4 5H Ft8 Ft8 <4 16 4 >2,048 >t,048 256 1 ,O4 256 SF1 4 16 8 61 16 U8 >2,048 >,O8 256 1,O4 512 1 ,O4

4 I 32 56 16 nt >2,048 >,OI8 512 >,O48 512 1,O4 4 16

64 1 ,O4

16 56 >,O48 >,O48 I ,O4 1 ,O4 >,O8 >,O48 >,O48 >,O48 >,O48 61 >,O48 I ,1N4 >,O18 >,O48 >,O8 18 >,O48 >,O48 I6 105 94 60 53 49 16 106 95 63 54 49 161 103 89 63 33 49 Type I Pre-immunization Post 3rd inoculation (1 mo)

Post 4th inoculation ( wk) Post 4th inoculation (6 mo) Post sth inoculation ( wk) Post 5th inoculation (4 mo)

Type II

Pre-immunization Post 3rd inoculation (I mo) Post 4th inoculation ( wk) Post 4th inoculation (6 mo)

Post 5th inoculation ( wk) Post sth inoculation (4 mo)

Type III

Pre-immunization

Post 3rd inoculation (1 mo)

Po8t 4th inoculation ( wk)

Post 4th inoculation (6 ma) Post 5th inoculation ( wk) Post 5th inoculation (4 mo)

79 61 .51 9 7 80 61 .50 30 S 78 59 51 30 8

64 1,O4 >2,048 >t,048 >,048

8 S 256 5l I ,O4

8 3 64 56 I,O4 <4 <4 4 8 5I

<4 <4 4 8 >,O48

64 511 >2,048 >,O48 >,O48 8 S1 128 51 >,O48

4 S 64 56 I ,O4

<4 <4 4 8 16

4 8 8 ‘3 lS

16 18 1,024 >,O8 >,O8

<4 16 128 51 I ,O4

<4 8 64 56 I,O4

<4 <4 <4 4 16 <4 <4 <4 8 S

B. 1-2 ma nths of age at time offirat inoculation

<4 8 16 <4 <4 4 s 8 16 <4 8 4 s 64 64 <4 4 4 .56 3 3 <4 4 8 256 3 64 <4 16 16 556 18 18 <4 64 8 512 1,O4 128 56 64 56 <4 8 32 51 32 556 1,024 >,O48

256 1 ,O4

128 51

4 16

128 1 ,04

32 556

1,024 >,O48

512 1,054

512 1 ,054

8 35 512 >5,048 32 1,054 >,O48 51 SFt 16 >,O48 5l >,O48 1,054 I 054 64 >,048

1,054

>,O48 >Q,048 >,048 515 >5,048 >5,048 79 70 7 5 5 45 81 70 7 5 5 45 81 7 73 55 55 45 Type I Pre-immunization

Post 3rd inoculation (I mo) Post 4th inoculation ( wk)

Post 4th inoculation (6 mo) Post 5th inoculation (5 wk)

Post 5th inoculation (4 mo) Type II

Pre-immunization

Post Srd inoculation (1 mo) Post 4th inoculation ( wk)

Poet 4th inoculation (6 mo)

Post sth inoculation ( wk) Post sth inoculation (4 mo)

Type III

Pre-immunization

Post 3rd inoculation (1 mo)

Post 4th inoculation S wk)

Post 4th inoculation 6 ma)

Post 5th inoculation S wk) Post .5th inoculation 4 mo)

43 40 37 19 41 4 38 19 42 41 38 SQ 19

8 18 512 1,ttI4 >,O48

<4 8 32 18 51

<4 8 32 64 51

<4 <4 <4 4 5 <4 <4 <4 4 64

18 51 1,024 >,O48 >,O48

4 16 128 .51 I ,O4 <4 16 64 Ft8 I ,O4

<4 <4 4 4 8

<4 <4 8 16 64

64 56 512 >5,048 >,O48

4 16 64 51 1,O4

<4 8 16 556 1054

<4 <4 <4 <4 8

<4 <4 4 8 1,054

* Quadrigen-inoculated group.

tTriogen-inoculated controls.

est order of magnitude; i.e., 10 subjects

of similar age, preprimary antibody status

and given identical antigenic stimulation

would be expected to have titer values at

or below this figure, and 90 might be

ex-pected to have the same value or higher.

A 10th percentile reading of “4” means that

90% of the infants in the sample under study

had a poliomyelitis antibody titer of 1 :4 or

higher. A reading of “<

4”

would indicate

that at least 10% of the subjects were

with-out demonstrable antibody.

On this basis, the immunologic response

of the 3 to 4 month old infants as

deter-mined by their postbooster (post 5th) titers

may be considered to be adequate in

re-spect to all three poliovirus types. Fifty

per cent of the postbooster titers for this

age group reached a level of 1 : 1,024 or

greater which may be considered an

excel-lent response.

Although the poliomyelitis antibody

re-sponse of the 1 to 2 month age group at

time of initial inoculation was distinctly

better than that of the newborns, their

im-munologic behavior was more like that of

the newborns than of the 3-month and

older children.

Not only is the over-all pattern of

re-sponse of the newborns to poliomyelitis

im-munization appreciably weaker than that

(8)

TABLE II (Continued)

Immunization Schedule: DPT-polio’ at 0, 1, 2, 3. Immunization Schedule: DPTt at 0. 1. 5, & S & 9 months months and DPT-polio aJ 9 months

Percentile Values Total Stage of Immunization j Pencotit Values

Sub- Sub-

-10th 55th Median 75th 90th jects jects 10th S5th %fedian 711th 90th

C. 3-4month., ef age at time offirst inoculation

<4 S 128 515 1,054

4 16 32 158 556

8 16 64 515 1 054

<4 <4 8 158 >5,048 4 64 1,024 >5,048 >5,048 8 64 1,024 >5,048 >5,048

8 35 128 1,054 >5,048

8 35 128 1 ,054 >5,048

8 35 128 1,054 >5,048

<4 4 16 158 >5,048

4 64 1 .024 >5,018 >5,048 8 35 256 >5,048 >5,048

<4 64 256 1,054 1,054

16 64 256 1 054 >5,048 64 556 1,024 >5,048 >5,018

<4 8 64 515 1 054

35 1,054 >2,048 >5,048 >5,018 16 556 1 ,024 >5,048 >5,048

101 93 9 70 69 54 10 94 95 70 68 54 101 96 94 70 69 54 Type I Pre-immunization Post 3rd inoculation (1 mo) Post 4th inoculation (5 wk) Post 4th inoculation (6mo) Post 5th inoculation (5 wk) Post 5th inoculation (4 mo)

Type II Pre-immunization Post 3rd inoculation (I mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post 5th inoculation (5 wk) Post 5th inoculation (4 mo)

Type III

Pm-immunization

Post 3rd inoculation (1mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post 5th inoculation (5 wk) Post .5th inoculation (4 mo)

44 35 39 54 53 44 37 38 53 53 44 35 38 54 53

<4 <4 32 536 1,04

<4 <4 8 35 64

<4 <4 8 16 64

<4 <4 <4 <4 4

<4 <4 <4 <4 4

<4 S 128 5l l,04

<4 4 16 35 64

<4 4 8 3 64

<4 <4 <4 <4 4

<4 <4 4 4 4

<4 itt 128 556 1,054

<4 <4 8 16 556

<4 <4 4 16 158

<4 <4 <4 <4 <4

<4 <4 <4 <4 4

D. 5-6months of age at time offirst inoculation

<4 <4 16 64 556

<4 8 32 158 515

8 16 128 315 >5,048

<4 4 64 1,054 >5,048

55 1,051 >2,048 >5,048 >5,048 4 158 1 ,024 >5,048 >5,048

<4 <4 64 556 1,054 4 16 64 515 >5,048

16 85 512 >5,048 >5,048

<4 8 64 515 1,054

16 556 >2,048 >5,048 >5,048

35 158 1,024 >5,048 >5,048

<4 4 32 556 1,054

S 64 512 >5,048 >5,048 35 556 1,024 >5,048 >5,048

4 35 256 1,054 >5,048

556 >5,048 >2,048 >5,048 >5,048 64 .515 >2,048 >5,048 >5,048

83 78 84 56 35 46 84 75 83 55 55 46 81 79 84 56 54 46 Type I Pre-immunization Post 3rd inoculation (1mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post 5th inoculation (5 wk) Post 5th inoculation (4 mo)

Type II

Pre-immunization Post 3rd inoculation (1mo) Post 4th inoculation (5 wk) Post 4th inoculation (6mo) Post 5th inoculation (5 wk)

Post 5th inoculation (4 mo)

Type III Pre-immunization Post 3rd inoculation (1 mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo)

Post sth inoculation (5wk) Post 5th inoculation (4 mo)

35 55 58 19 18 36 57 58 19 18 35 57 57 19 18

<4 4 16 64 556

<4 <4 <4 4 16 <4 <4 <4 4 8 <4 <4 <4 <4 <4 <4 <4 <4 <4 8

<4 <4 16 158 515

<4 <4 <4 4 16

<4 <4 <4 4 16 <4 <4 <4 <4 <4 <4 <4 <4 4 3

<4 8 32 556 515

<4 <4 <4 8 64

<4 <4 <4 4 <4 <4 <4 <4 <4 <4 <4 <4 <4

poor response to a booster dose indicates

that the antibody producing mechanism for

the group as a whole was inadequately

stimulated by their primary course of

im-munization (Fig. 1). However, a

measura-ble pomomyemtis antibody response in the

newborn infant dose occur in many

in-stances, but because of the masking effect

of declining passive maternal antibody

throughout and immediately following the

primary series of antigen inoculations, this

response is not readily discernible. When

the percentile values for the DPT-polio

im-munized subject are compared to their DPT

injected controls throughout each stage of

treatment, these differences become

appar-ent (Table II). Had it not been for the DPT

injected “controls” and the fact that a

“booster” dose was given to both groups

some 6 months postprimary, the production

of active antibody during the primary phase

and resultant sensitization of the

immuno-logical system might well have been

over-looked entirely. This is illustrated in Figure

2, where it is seen that the rate of antibody

decline for the DPT-polio immunized in..

fants is somewhat slower than that of the

DPT injected controls. When both groups

were given a single injection of DPT-polio

antigen at approximately 9 months of

age-the fifth for the DPT-polio primed group

and the first for the controls-the

immuniz-ing effect of the poliomyelitis antigen

com-ponent in the preparation is evident from

the higher median levels achieved by the

DPT-polio primed group.

In general, it can be concluded from this

trial that for infants under 3 months

of age, poliomyelitis antibody levels, for all

(9)

pri-U A

NEWBORNS

COMPOSITE

#{149}= TYPE I

A TYPE II

a = TYPE III

2048

1024

512

256

128

64

32

16

8

4

U

4= TYPE II

= TYPEIII

A

a a

0 1 2 3 4 5 6 7 8 9 1.0

‘U

I-z

0

‘U

itt

t

1sf- 2nd- 3rd.

Injection

4th-= DPT

-

POLIO PRIMARY

= DPT PRIMARY

(CONTROL GROUP)

TIME IN MONTHS

+

5th

Injection

DPT

-

POLIO TO

BOTH GROUPS

Fic. 2. Comparison of poliomyelitis antibody response in subjects one day old at time of first injection,

one group receiving four doses of DPT-polio antigen (Quadrigen) at monthly intervals and the control

group receiving four doses of a DPT antigen (Triogen). Both groups were given an injection of

DPT-polio antigen 6 months later, which constituted the first dose of poliomyelitis antigen for the controls.

mary series of inoculations than the levels

occurring in uninoculated control infants.

On the other hand, the antibody titers are

appreciably lower for this age range than

for infants 3 months of age and older at the

time of first inoculation, and their response

to a booster is far inferior to that seen in

the older infants.

Response to Pertussis Immunization

Although nearly 47% of the sample of

newborn infants tested had prevaccination

agglutinin titers of 1 :25 or greater, none

of the 28 preimmumzation specimens from

1-month-old infants contained significant

pertussis agglutinin titers, and less than 6%

(10)

2WEEKS

POSTPRIMARY PERTUSSIS

2WEEKS P011 BOOSTER 1000

500

250

100

50

25

10

uJ

I-z

a uJ

TIME IN MONTHS

0 1 2 3 4 5 6 7 8 9 10 11 12 13

t

ft

t

4th- 5th

Inj.ct ion

1.,. 2nd. 3rd. Inject ion

- =1 DAY OLD AT TINE OF INITIAL INJECTION;

=1.2 MONTHS OLD AT TIME OF INITIAL INJECTION; - I- U - U

-f

=3-4 MONTHS OLD AT TIME OF INITIAL INJECTION; =5-6MONTHS OLD AT TIME OF INITIAL INJECTION.

IUIIIUS11U,

Fic. 3. Pertussis agglutinin levels in relation to age of subjects at time of initial injection of antigen.

All subjects were given a four-dose primary series of a DPT-polio antigen (Quadrigen) one month apart

followed by a fifth dose (booster) 6 months later.

729

month age group had titers of 1:25 or

greater. Thus, it is quite apparent that what

little passive pertussis antibody the

new-born infants did acquire from their mothers

was quickly lost, so that for all practical

purposes the problem of maternal antibody

interference in respect to pertussis

ag-glutinin titers did not exist in this study

population.

From Figure 3, it is seen that the

re-sponse to the pertussis antigen component

by infants in the various age groups closely

paralleled their respective responses to

poliomyelitis antigen, with one notable

ex-ception: The postbooster response by the

1 to 2 month age group is essentially as

good as that of the older infants. The

post-primary agglutinin titers for the newborn

and 1 to 2 month old infants were decidedly

inferior to the levels achieved by the older

infants.

Response to the pertussis antigen was not

significantly different in infants receiving

DPT-polio vaccine from those receiving a

primary series of DPT inoculations (Table

III). From these data, there was no

evi-dence of either an enhancement or

sup-pression phenomenon in respect to pertussis

agglutinin response whether the pertussis

antigen was administered as DPT or in

combination with poliomyelitis vaccine as

DPT-polio.

Response to Diphtheria and Tetanus

Immunization

Of the 177 newborn infants in the

com-bined DPT and DPT-polio groups, 12.4%

(22) had preprimary diphtheria antitoxin

unit values of 1.0 ml. Only five infants had

any demonstrable preprimary tetanus

anti-toxin, and these were all at 0.1 unit/ml.

Diphtheria and tetanus antibody

re-sponses to four monthly doses of the

DPT-polio preparation were found to be

essen-tially the same regardless of age of initial

inoculation (Table III). Even the newborns

responded quite satisfactorily to the

im-munization schedule utilized. The presence

of poliomyelitis antigen in the preparation

did not appear to enhance nor inhibit the

response to diphtheria or tetanus

(11)

TABLE III

PERTUSSIS, DIPHTHERIA, AND TETANUS ANTIBODY TITER PERCENTILE DISTRIBUTIONS AT VARIOUS STAGES OF Two IMMUNIZATION SCHEDULES IN SUBJECTS (A) 1- DAYS OLD, (B) 1- MONTHS OLD, (C) 34

MONTHS OLD, AND (D) 5-6 MONTHS OLD AT TIME OF INITIAL INOCULATION

Immunization Schedule: DPT-polio#{176} at 0. 1, 2, 3. ti?9 months

Stage of Immunization

Immunization Schedule: DPTt at 0. 1, 5, & S months and DP T-polio at 9 months

Total Percentile Values

Sub-

-jects 10th 55th Median 75th 90th

Percentile Values Total

.

Sub-10th 55th Median 75th 90th jocts

A. 1-5 days old at time of initial inoculation

<10 <10 <10 30 100

<10 <10 25 100 250

<10 10 50 550 .500

<10 <10 <10 <10 53 <10 <10 50 100 530 <10 <10 10 50 100

<0.1 <0.1 0.1 0.1 1.0

<0 .I 0.1 0. 1 0.I 0.I

0_I 0.1 0.1 0.1 0.1

<0.1 <0.1 0.1 0.1 0.1

0.1 1.0 1 .0 1.0 1.0

<0.1 <0.1 <0.1 <0.1 0.1

1.0 1.0 1.0 1.0 1.0

1.0 1.0 1.0 1.0 10.0

0.1 0.1 1.0 1.0 1.0

1.0 1.0 10.0 10.0 10.0

115 81 78 83 76 67 114 80 74 81 75 115 79 75 81 75 Pertussis (Agglutinin titers) Pre-immunization

Post 3rd inoculation (1 mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post sth inoculation (5 wk) Post 5th inoculation (4 mo)

Diphtheria

(Antitoxin units/mI)

Pre-immunizstion

Post 3rd inoculation (1 mo) Post4th inoculation (5 wk) Post 4th inoculation (6 mo) Post 5th inoculation (5 wk)

Tetanus (Antitoxin units/mi)

Pre-immunization

Post 3rd inoculation (1 mo)

Post4thinoculation(dwk)

Post 4th inoculation (6 mo)

Post5thinoculation(fwk) 64 49 44 44 39 63 47 41 45 40 63 47 41 44 39

<10 <10 <10 .50 100

<10 10 50 100 530

<10 55 50 550 300

<10 <10 <10 55 50

10 50 100 550 300

<01 <0.1 0.1 01 0.1

<0 .I <0 .1 0.1 0.I 0.1

0.1 0.1 0.1 0.1 1.0

<0.1 0.1 0.1 01 0.1 1.0 1.0 1 .0 1.0 10.0

<0.1 <01 <0.1 <0.1 <0.1

1.0 1.0 1.0 1.0 1.0

1.0 1.0 1.0 1.0 10.0

0.1 0.1 1.0 1.0 1.0

1.0 100 10.0 >53.0 >53.0

B. 1-5 months of age at time offirat inoculation

<10 <10 <10 <10 <10

<10 55 100 530 500

53 100 100 530 300

<10 <10 <10 50 100

53 50 100 530 300

10 50 100 550 500

<0.1 <0.1 <0.1 <0.1 0.1

<0.1 0.1 0.1 0.1 1.0

0.1 0.1 1.0 1.0 1.0

0. 1 0.1 0. 1 0-1 1.0

1.0 1.0 1.0 1.0 10.0

<0_I <0.1 <0.1 <0.1 <0.1

0_i 1.0 1.0 1.0 1.0

1.0 1.0 1.0 10.0 10.0

0. 1 1 .0 1 .0 1 .0 1 .0

10.0 10.0 10.0 >55.0 >55.0

33 43 36 75 66 55 55 46 35 69 66 55 46 36 69 66 Pertuesie (Agglutinin titers) Pre-immunication Post 3rd inoculation (I mo) Post 4th inoculation (5 wk)

Post4thinoculation(6mo)

Post 5th inoculation (5 wk) Post 5th inoculation (4 mo)

Diphtheria

(Antitoxin units/mi)

Pre-immunization

PostSrd inoculation (1 mo)

Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post3thinoculation(Swk)

Tetanus (Antitoxin units/mi)

Pre-immunization Post 3rd inoculation (I mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo)

Post5thinocuiation(Swk) 18 35 54 38 31 19 35 35 36 31 19 33 35 36 Si

<10 <11) <10 <10 55 <10 <10 100 530 550

10 100 250 500 300

10 <10 <10 100 550

10 100 250 300 >1,000

<0.1 <0.1 <0.1 <0.1 01

0.1 0.1 0.1 1.0 1.0

0.1 0.1 1.0 1.0 1.0

0-I 0.I 0.1 0.5 1 .0

10 5.0 1.0 10 10.0

<0.1 <0.1 <0.1 <0.1 0.1 1.0 1.0 1.0 10.0 10.0

1 .0 1.0 1.0 10.0 10.0

1 .0 1 .0 1 .0 1 .0 1.0

10.0 10.0 10.0 >530 >55.0

S quadrigen-inoculated group. t I riogen-inoculated group.

in diphtheria and tetanus antitoxin levels injections with the DPT-polio vaccine used.

in the group receiving DPT-polio primary Infants receiving DPT-polio maintained a

immunization as compared with the DPT higher median poliovirus antibody than did

controls (Table III). controls receiving DPT vaccine; DPT-polio

inoculated infants also had a lower unit

COMMENT loss than did the controls. If the half-life of

The majority of infants under 3 months passive maternal antibody for DPT-polio

of age had high pre-immunization titers of inoculated infants remained the same as for

poliomyelitis antibody. This tended to mask those receiving DPT, this reduced unit loss

the serologic manifestation of active im- can only be explained as a response by the

munity development during and immedi- infants to the antigen. It would appear that

ately following the primary series of inocu- the higher median poliomyelitis antibody

lations. Despite this complication, there was levels represent a composite of residual

ma-definite evidence of active polio-antibody ternal antibody plus antibody produced by

(12)

731

TABLE III (Continued)

Immunization Schedule: DPT.polio#{176}at 0. 1, 2, 5, &9 months

Stage of Immunization

Immunization Schedule: DPTt at 0. 1, 5, & S

months and DPT-polio at 9 months Percentile Values Total

-

Sub-10th P5th Median 7.5th 90th jects

TOIa1 Percentile Values

Sub-jects 10th 55th Median 75th 90th

C. .3-4 months of age at time offirst inoculation

<10 <10 <10 <10 <10

10 50 250 300 >1,000

30 100 500 300 > I,000

<10 <10 25 100 530 53 100 250 500 > 1,000

10 100 100 5.50 300

<0.1 <0.1 <0.1 <0.1 0.1

0.I 0.I 0. 1 1.0 1.0

0.1 0.1 1 .0 1.0 1.0

0. 1 0. 1 0.1 0. 1 0. 1

1.0 1.0 1.0 10.0 10.0

<0.1 <0.1 <0.1 <0.1 <0.1

1.0 1.0 1.0 1.0 10.0

1.0 1.0 10.0 10.0 10.0

1.0 1.0 1.0 1.0 1.0

10.0 10.0 >25.0 >55.0 >53.0 77 70 77 90 85 66 76 68 77 81 78 76 68 76 88 78 Pertussis (Agglutinin titers) Pre-immunization Post 3rd inoculation (1 mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post 5th inoculation (5 wk) Post 5th inoculation (4 mo)

Diphtheria (Antitoxin units/mi)

Pre-immunization Post 3rd inoculation (1 mo) Post 4th inoculation (5 wk)

Post 4th inoculation (6 mo)

Post3thinocuiation(Swk)

Tetanus (Antitoxin units/mi)

Pre-immunization

Post 3rd inoculation (1 mo)

Post4thinoculation(Swk) Post 4th inoculation (6 mo) Post .5th inoculation (5 wk)

33 33 40 45 59 33 35 40 41 39 33 33 40 41 39

<10 <10 <10 <10 30

53 50 100 500 .500

55 250 500 500 > I,000 <10 50 100 530 550 50 100 500 > 1 000 > I 000

<0.1 <0.1 <0.1 <0.1 <0.1 0.I 0.1 1 .0 1.0 1 .0 0.1 1.0 1 .0 1.0 1.0

0. 1 0. 1 0.1 0.1 1.0

1.0 1.0 10.0 10.0 10.0

<0.1 <0.1 <0.1 <0.1 <0.1

1.0 1.0 10.0 10.0 >53.0

1.0 10.0 10.0 >55.0 >53.0 1.0 1.0 1.0 5.0 10.0

10.0 10.0 >25.0 >55.0 >55.0

D. 5-6 months of age at time offirst inoculation

<10 <10 <10 <10 <10

53 100 250 500 > I 000 100 530 500 >1 000 >1 000

<10 <10 50 530 530

50 530 250 500 >1,000 50 100 250 500 >1 ,000

<0.1 <0.1 <0.1 <0.1 <0.1

0.1 0.1 1.0 1.0 1.0

1.0 1.0 1.0 1.0 1.0

0.1 0.1 0.1 0.1 1.0

1.0 1.0 1.0 10.0 10.0

<0.1 <0.1 <0.1 <0.1 <0.1

1.0 1.0 1.0 10.0 10.0

1.0 1.0 10.0 10.0 >53.0

1.0 1.0 1.0 10.0 10.0

10.0 10.0 >25.0 >53.0 >25.0

65 60 63 75 71 60 59 58 63 74 68 39 58 63 74 68 Pertuuis (Agiutinin titers) Pm-immunization

Post 3rd inoculation (1 mo) Post 4th inoculation (5 wk) Post 4th inoculation (6 mo) Post 5th inoculation (5 wk) Post 5th inoculation (4 mo)

Diphtheria

Antitoxin units/mi) Pre-immunization PostSrdinoculation(lmo) Post4thinoculation(Swk) Post 4th inoculation (8 mo) Post 5th inoculation (5 wk)

Tetanus (Antitoxin units/mi) Pre-immunization Post3rdinocuiation(Imo) Post4thinocuistion(Swk) Post4thinocuiation(Bmo) Post3thinocuiation(fwk) 31 23 30 35 31 58 53 59 33 SI 58 53 59 35 SI

<10 <10 <10 <10 <10

55 100 250 300 >1,000 50 250 500 >1 000 >1000

<10 30 100 530 500

100 550 500 >1,000 >1,000

<0.1 <0.1 <0.1 <0.1 0.1

0.1 1.0 1.0 1.0 1.0

1.0 1.0 1.0 1.0 1.0

0.1 0.1 1.0 1.0 1.0

1.0 1.0 10.0 10.0 10.0

<0.1 <0.1 <0.1 <0.1 <0.1

1.0 1.0 10.0 10.0 >23.0

1.0 10.0 10.0 >23.0 >53.0

1.0 1.0 1.0 1.0 10.0

10.0 10.0 >25.0 >25.0 >23.0

The host’s ability to respond to a booster

dose of antigen when administered some

6 months or more after the primary is

an-other means of determining the

effective-ness of an immunizing agent. A sharp and

significant rise in antibody titer following

the booster should indicate that the immune

mechanism had been conditioned or

sensi-tized by the primary course of antigen

inoculations.

Very few of the children in the control

group who had received DPT vaccine as

their primary showed any poliomyelitis

anti-body response to a single dose of DPT-polio

vaccine given some 6 months later. In

con-trast, there was a dramatic response to a

booster dose of DPT-polio in those children

who had been primed with DPT-polio

vac-cine. The older infants responded best, with

84% achieving titers of 1 :32 or greater

against types I and II, and 94% to type III;

for the 0 to 2 month old infants, comparable

figures were 44%, 62%, and 72% respectively.

Several 12 have reported

on the inferior response of infants under

6 months of age to poliomyelitis vaccine.

Both maternally transmitted passive

anti-body and physiologic immaturity of the host

have been charged with causing the poor

response. To determine the effect of

ma-ternal antibody, preprimary titers were

grouped into three classes : under 1:32,

1:32-1:256, and 1:512 and over, and

corn-pared with postpriniary and postbooster

values for each group. These data are shown

in Table IV.

High maternal antibody levels definitely

(13)

TABLE IV

CORRELATION BETWEEN PREPRIMARY AND POSTBOOSTER POLIOMYELITIS ANTIBODY VALUES ARRANGED ACCORDING TO Low, MEDIUM, AND HIGH VALUES IN INFANTS RECEIVING DPT-P0LI0 ANTIGEN (BY

AGE GROUP AT TIME OF FIRST INOCULATION AND PoLlovntus TYPE)

Prepriuzary Titer LeveLs

0-2 MO7lthS 3+ Months

.

Postbooster Titer Levels

Total

infants

. Postbooster Tzter LeveLe

Total Infanh,

<-16 32-256 512+ <-16 32-256 519+

Type I

High 512+

Idium 3-56

Low <4-16

49

6

3

15

3

0

8

8

10

7

17

13

8

9

2

3

4

6

s

38

35

19

51

43

Total 58 18 6 1O 19 13 81 113

Type II

High512+

Medium 3-56

Low<4-16

37

I

2

28

3

2

17

13

2

8

17

6

9

7

3

11

4

3

l1

30

l5

41

41

31

Total 40 33 3 105 19 18 76 113

Type III

High 51+

Medium 32-56

Low <4-16

7

0

24

0

1

32

9

7

83

11

8

6

1

0

7

3

6

3

31

39

36

34

Total 29 25 48 1O 7 12 90 109

booster; yet similar preprimary titer levels

result in different booster responses-higher

for each succeeding age group. Thus, both

maternal antibody and physiologic

im-maturity play a role in the lowered response

of the younger infant to a subsequent

booster dose.

The crucial question then arises as to

how early in infancy can poliomyelitis

im-munization be started with the

expecta-tion that the majority of children, if not all,

will develop an effective immunity. The

answer to this question is largely governed

by the objective of the immunization

pro-cedure. As has been previously noted, the

booster response in the newborn and 1 to 2

month age groups was appreciably less

than that seen in the older children.

Gen-erally speaking, one-quarter of the children

who were under 3 months of age at the

time their primary immunization was started

failed to establish a good conditioning of

their immunity mechanism as evidenced by

On these grounds, it would seem advisable

to withhold the initiation of

polio-immuni-zation until the infant is at least 3 months

old. The desirability, however, of

establish-ing some degree of active immunity against

poliomyelitis before the infant is 6 months

of age because of the increasing risk of

paralytic disease after that age is well

recognized. For this reason, it is suggested

that the initial series of inoculations be

started not later than the third month of

life because over 75% respond with high

titers (1 :32 or greater) and at least 90%

will show some degree of circulating

anti-body (1 :4 titer or greater) after a booster.

If, on the other hand, the object is to

achieve the highest attainable circulating

antibody levels and to reduce the

proba-bility of serologic failures (titers of < 1:4

postimmunization) to the lowest possible

level or even to zero, then poliornyelitis

immunization should be withheld until the

(14)

733

lem of maternal antibody interference

en-tirely, then initial poliomyelitis

immuniza-tion should be delayed until the child is

12 to 15 months old. Even then 10 to 25%

will have circulating antibody levels of

1:512 or more (Table II). How much of

this may be due to natural exposure to

poliovirus is problematical.

The actual relationship between the

height of antibody titer and the degree of

protection against paralytic poliomyelitis

is not known. According to Salk,23 “the high

antibody levels developed after the booster

dose are not required for induction of the

immune state; effective immunity to

paraly-sis can be induced by a primary antigenic

stimulus.” He goes on to say that “whether

a persistently demonstrable level of

anti-body is essential for persistently effective

immunity to paralysis is not certain, since

there is reason to believe that immunity to

paralysis continues in those rendered

im-munologically hyperreactive by contact with

the antigen, and in whom antibody may no

longer be detectable by usual methods.”

The level of pertussis agglutinins was

very low in the maternal population and

few significant titers were demonstrable in

the preimmunization serum of the infants.

The very young infant, therefore, is at

rela-tively great risk to pertussis infection and

should be inoculated with pertussis antigen

as early in life as possible. However,

ag-glutinin response to initial inoculation is

significantly better when the infant is at

least 3 months of age or older. The poorer

response in this instance appears to be solely

a function of physiological immaturity of

the immune system and not maternal

anti-body interference because there was

vir-tually none present in the subjects under

study. Thus, 3 months as the age for

starting immunization is also efficacious

for pertussis. Occasions of disease

preva-lence or the lack of available quadrivalent

antigen (DPT-polio) may require

modifica-tion of this routine and selective use of

monovalent pertussis vaccines might be

advisable.

It

is to be emphasized that the results

obtained in this trial and the conclusions

derived therefrom are based upon a

four-dose primary series given at monthly

in-tervals followed by a fifth (booster) dose

given 6 months later. This means that the

3-month-old infants at time of first

inocula-lion were 6 months of age when they

re-ceived their fourth injection and one year

old at the time of their fifth. The data in

Table II suggest that the poliomyelitis

levels in the 3 to 6 month age range are

improved slightly following the fourth

in-jection of DPT-polio vaccine as compared

to those seen after the third injection.

From this evidence, it would appear that

the administration of a three-dose or

four-dose primary series of inoculations to young

infants, rather than the usual two-dose

pri-mary recommended for routine

polio-myelitis immunization of older children and

adults, tends to overcome the inhibiting

ef-fect of passively acquired poliomyelitis

ma-ternal antibody. As Salk points out,

how-ever, “the diminishing return of successive

doses emphasizes the desirability of

achiev-ing the highest level of immunization with

the fewest injections.”23 He feels that the

uncertainty of effect in young infants

at-tributable to a variable amount of maternal

antibody is greatest with vaccines of

border-line potency and can be overcome by more

potent antigens.

Although in this study the fourth dose

was empirically scheduled one month

fol-lowing the third, there is no reason to

be-lieve that a similar or even better antibody

response would not occur if this time

inter-val were extended by several months.24

This assumption is in keeping with the

recommendations of other investigators who

have reported that a reinforcing dose of

antigen (including poliomyelitis vaccine)

given some 6 to 12 months after the primary

series greatly enhances the circulating

anti-body titers over the levels seen immediately

tprimary226

If the objective is to obtain maximum

protection in the shortest period of time

as evidenced by a solid antibody response

to all three poliovirus types in the majority

of subjects iimnunized, then the schedule

References

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