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 shouldtake 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
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 respectexcept for the addition of protamine sulfate
to the latter. The DPT component in the
Q
uadrigen preparation was from a differentlot 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
monovalent vaccines
(
as cited previously).19Immunization 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
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,
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
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
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 indicatethat 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
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
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 TOBOTH 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%
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
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
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
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
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 resultsobtained 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