Half-Dose
Immunization
for Diphtheria,
Tetanus,
Pertussis:
Response
of
Preterm
Infants
July Bembaum,
MD, Andrea
Daft,
RN, Joel Samuelson,
MD, and
Richard
A. Polin,
MD
From the Divisions of Neonatology and General Pediatrics, Children ‘s Hospital of Philadelphia, Department of Pediatrics, UnWersity of Pennsylvania School of Medicine, Philadelphia, and Connaught Laboratories, Swiftwater, PennsyWania
ABSTRACT. The American Academy of Pediatrics
cur-rently recommends administering full-dose diphtheria,
tetanus, pertussis, (DTP) vaccine to preterm infants,
beginning at 2 months’ chronologic age. Many physicians,
however, continue to administer DTP vaccine at a
re-duced dosage in an attempt to lessen side effects. This
study was designed to quantitate the immune response
of 20 preterm infants immunized with half-dose DTP
vaccine and to determine the nature and extent of side
effects. Control subjects were 25 preterm infants
immu-nized with full-dose vaccine. Although 96% of infants
who received a full dose were able to mount a serologic
response to pertussis after a second dose of DTP, 45% of
infants who received a half dose were unable to mount a similar immune response to pertussis even after a third
dose of DTP and required a full-dose (fourth dose of
DTP) vaccine to better ensure protection. Serologic
re-sponses to diphtheria and tetanus were similar in the two
groups. The incidence of side effects in preterm infants
receiving both full-dose and half-dose DTP was less than that seen in a full-term population. Thus, the physician caring for the preterm infant should adhere to the
Amer-ican Academy of Pediatrics’ recommendation for the
immunization ofpreterm infants and offer full-dose DTP vaccine at the routine time intervals of 2, 4, 6, and 15 or 18 months’ chronologic age to ensure adequate protec-tion. Pediatrics 1989;83:471-476; diphtheria, pertussis,
tetanus vaccine, immunization, preterm infant, pertussis.
the world for the past 40 years.’ The effectiveness
of this policy is reflected in the marked decrease in
morbidity and mortality from these illnesses.2’3
De-spite recent evidence to support the
recommenda-tions made by the Committee on Infectious
Dis-eases of the American Academy of Pediatrics,’2
physicians continue to administer routine
immu-nizations at a reduced dosage to preterm infants.5
The rationale given for this practice is to introduce
a smaller antigenic load that may help decrease the
chance of side effects intuitively thought to be
greater in this higher risk population.
Barkin et al6 have shown that full-term infants
immunized with half-dose DTP vaccine at routine
intervals were able to mount a serologic response
that indicated immunogenicity. No data exist,
how-ever, to support this practice in preterm infants.
To evaluate the efficacy of half-dose diphtheria,
tetanus, pertussis (DTP) vaccine and the nature
and extent of side effects, a comparative study using
half-dose and full-dose DTP vaccine in preterm
infants was undertaken.
MATERIALS
AND
METHODS
Routine immunization against diphtheria,
teta-nus, and pertussis in infancy and childhood has
been widely advocated and generally practiced in
the United States and most developed countries of
Received for publication Jan 6, 1988; accepted May 9, 1988. Reprint requests to (J.B.) Children’s Hospital of Philadelphia, Division of General Pediatrics, 34th and Civic Center Blvd,
Philadelphia, PA 19104.
PEDIATRICS (ISSN 0031 4005). Copyright C 1989 by the
American Academy of Pediatrics.
After informed parental consent was obtained,
45 infants (29 boys, 16 girls) were enrolled in the
study. Of these infants, 25 received a full dose of
DTP between March 1983 and October 1985 and
have been described previously.5 The 20 remaining
infants (seven girls) received half-dose DTP
be-tween March 1984 and May 1986. They had a mean
± SD birth weight of 1.46 ± 0.45 kg (range 890 to
2,550 kg) and mean gestational age of 31 ± 2 weeks
(range 28 to 34 weeks). These values were not
statistically different from the birth weights and
DTP. Ventilatory support for respiratory distress
syndrome was required by 76% of infants; however,
they were all medically stable at the time of their
first immunization.
All infants in the half-dose group were
immu-nized with 0.25 mL (or half the routine dosage) of
DTP vaccine (diphtheria, tetanus toxoids, and
per-tussis vaccine adsorbed for pediatric use). The
vac-cine was produced in accordance with licensed
man-ufacturing procedures by Connaught Laboratories,
Swiftwater, Pennsylvania, and was shown by assay
to contain 8.8 mouse protective units and 25 opacity
units per milliliter of pertussis antigen, 10 limit
flocculation units of tetanus toxoid, and 13.33 limit
flocculation units ofdiphtheria toxoid per milliliter.
A single lot (No. 3298PB) of the vaccine was used
and administered IM into the vastus lateralis
mus-cle at 8, 16, and 24 weeks as well as 18 months after
birth, regardless of the infant’s gestational age.
Control infants were immunized with the routine
0.5 mL of DTP vaccine from the same lot of vaccine
(No. 3298PB) at the same time intervals.
For both groups of infants, serum DTP-specific
antibody responses were obtained by venipuncture
prior to each of the three primary and 18-month
immunizations and 2 to 3 months after completion
of both the initial series and the 18-month vaccine.
Maternal serum samples were obtained at the
mi-tial time of enrollment from 15 women whose
in-fants received half-dose and 18 women whose
in-fants received full-dose vaccines.
Immunologic responses in both groups of infants
were assayed using standard methods by
Con-naught Laboratories, whose laboratory personnel
were unaware of group assignment. Bordetella
per-tussis antibody was measured by a
microagglutina-tion technique with an antigen prepared from B
pertussis strain BB460 supplied by the Office of
Biologics and Research and Review. Evidence of a
serologic response was considered at an agglutina-tion titer of >1:16 (geometric mean agglutination titer log2 > 4)#{149}7Agglutination titers have been used previously as an indication of immunogenicity.’#{176}
Tetanus toxin neutralization was assayed by IM
injection of serum-toxin mixtures into mice and
diphtheria toxin neutralization was measured by
intradermal inoculation of serum-toxin mixtures
into rabbits. Tetanus- and diphtheria-specific toxin
neutralization of >0.01 U/mL was considered
pro-tective and represented an adequate immune
re-sponse.”’4
If an infant showed inadequate serologic
conver-sion after completion of the initial three vaccines,
a fourth full-dose immunization was given 6 weeks
after the third, and DTP-specific antibody titers
were observed until protection was attained.
To evaluate the nature and extent of side effects,
parents, who were unaware of the group assignment
of their infant, were asked to complete a reaction
reporting form during the 24 hours following each
immunization. This questionnaire elicited
infor-mation regarding maximum body temperature,
acute behavioral changes, and local reactions based
on the Barkin and Pichichero scale.’5 Parental
re-port of the need for physician contact or use of
antipyretics within a 72-hour period was recorded.
Parents were advised to use antipyretics only if
axillary temperature was >38.9#{176}C(102#{176}F).
The percentage of infants with diphtheria and
tetanus protective antibodies and agglutination
ti-ter for pertussis at each time interval was compared
in study (half-dose) and control (full-dose) infants
by Fisher exact test.’6 Geometric mean titers to
pertussis antigen in full-term and preterm infants
at each time interval were compared by one-tailed
dependent t test analysis.
The percentage ofpreterm infants receiving
half-dose DTP vaccine who demonstrated side effects
after each immunization in the series was compared
with those receiving full-dose vaccine. Differences
in reactions with each sequential immunization in
the series were compared for both groups.
x2
analy-sis was used for both sets of evaluations.
RESULTS
All mothers tested in both groups had adequate
antibody levels to diphtheria, tetanus, and
pertus-sis. At 8 weeks of age when infants received their
first DTP immunization, the mean ± SD weights
for study and control infants were 2.8 ± 0.8 and 2.5
± 0.7 kg, respectively, and mean postconceptional
ages were 39 ± 1.8 and 39 ± 2 weeks (P value
nonsignificant).
Serologic Response
The percentage of infants in each group who
showed an adequate serologic immune response to
diphtheria and tetanus and immune response to
pertussis is shown in Figs 1 to 3. The six time
periods correlate with the times when serologic
studies were performed.
Protective levels of diphtheria antibody were
found prior to their initial vaccination (P value
nonsignificant) in 65% of infants receiving
half-dose u 85% of infants receiving full-dose vaccine
(Fig 1). After the first dose of DTP, 60% of infants
who received half dose v 85% of infants who
re-ceived full dose mounted an adequate immune
re-sponse (P value nonsignificant). It was not until
an-PREel PRE*2 PRE3 POST3 PREl8mos. POS’flmos. a. Toil. Niv?rallz.tIon 0 OP U/NI
D.0022
PREI PRE2 PRE3 POST3 PRE Imos,POSTSmos.
U. N,sNis5 0.OI U/NI
Fig 2. Tetanus.
. /2 0032
z
0 U)
LU >
z
0 U
.
z
0 U)
LU
z
0 U) LU
>
z
0 U
a
/2 DOSE
Fig 1. Diphtheria.
/2 0022
PREI PRE*2 PRE3 POST PRE Cmos. POST I8mos
a. Tils, ?I’ IC (lS4)
Fig 3. Pertussis.
tibody levels developed in all but one preterm
in-fant. This child, who had received half-dose
vac-cine, seroconverted after a third dose of DTP.
These levels remained protective for at least 3
months after completion of the initial vaccine series
and did not show a decrease in protection prior to
the 18-month vaccine. The 100% seroconversion
rate was maintained for both groups after the
18-month vaccination.
As with diphtheria, no significant differences
were noted between infants who received half dose
and infants who received full dose demonstrating
seroconversion for tetanus either before
immuni-zations were begun (90% v 80%, half dose v full
dose) or in response to any of the doses received
during the study period (Fig 2). It was not until
after a second dose of DTP that all infants studied
in both groups showed protection against tetanus.
This protective serologic response was maintained
for at least 3 months after the initial vaccine series
and remained unchanged following the 18-month
vaccination.
A geometric mean agglutination titer (log2 > 4)
or titer greater than 1:16 was considered a positive response to pertussis. Before receiving the first dose
of DTP, 40% of infants who received a half dose
compared with 15% of infants who received a full
dose had a geometric mean titer of >4 (P value
nonsignificant) (Fig 3). There was a response to the
first dose of DTP by 25% of infants who received a
full dose and a comparable number (15%) of infants
who received a half dose (P value nonsignificant).
When comparing the mean antibody levels of
moth-ers whose infants responded v antibody levels of
mothers whose infants did not respond to each
component of the vaccine, we found no relationship
between the level of maternal antibody and the
infants’ own response to all DTP vaccines. In ad-dition, preexisting titers against any of the three
components of the vaccine had no effect on the
response of the infants to any of the vaccines in the series. As for diphtheria and tetanus, it was not
until after a second dose of DTP that all (96%)
infants receiving full-dose vaccine showed a
posi-tive serologic response that persisted for at least 2
to 3 months after completion of the initial vaccine series. However, most infants receiving half-dose
vaccine were unable to mount comparable response
to pertussis after their second immunization (P <
.01) and only 55% responded to a third dose of DTP
(P < .05). The nine infants (45%) who received a
half dose, and one infant (4%) who received a full
dose, who were less responsive to a third dose of
DTP received a fourth vaccination with full-dose
DTP 6 to 8 weeks after a third dose of DTP.
Following this immunization, all but one infant who
received a half dose showed a positive serologic
response against pertussis. Both half-dose and
full-dose groups showed a decrease in the number of
infants with geometric mean titers >4 (titer 1:16)
against pertussis prior to the 18-month vaccination
(55% V 57%, half dose v full dose, P value
nonsig-nificant). Both groups of infants, however, showed
a substantial “booster” effect following the
Pre-DTP Post-DTP Post-DTP Pre-18 mo Post-18 mo No. 3 No. 3 No. 4t
Vaccine-Related
Side Effects
As can be seen in Table 2, neither group of
preterm infants showed significant differences in
the incidence of fever after the first or second dose
of DTP or the 18 month vaccine. Additionally, no
differences in behavioral or local reactions during
the entire series were noted between the two groups
of preterm infants. It was only after the third dose
of DTP that a fever developed in a significantly
greater percentage of infants receiving full-dose
vaccine as compared with those infants receiving
half-dose vaccine (P < .05). There was no report of
any child in either group experiencing high fever
(>38.9#{176}C [102#{176}F]). One child receiving full-dose
vaccine experienced screaming episodes. Crying
was no more common in infants receiving full-dose
than in those receiving half-dose vaccine. No apnea,
encephalitis, seizures, or other neurologic
compli-cations were observed. Antipyretics were
adminis-tered for fever >37.8#{176}C (100#{176}F)or irritability to
20% of infants who received a half dose and 24%
of infants who received a full dose of vaccine.
DISCUSSION
This study demonstrated that preterm infants
receiving half-dose DTP vaccine at routine
inter-vals beginning at 2 months of age are able to mount
an adequate serologic response to diphtheria and
tetanus after their second dose of vaccine but may
not show a serologic response against pertussis
comparable with that of infants receiving full-dose
vaccine even after a third dose of DTP. Poorly
responsive infants in this study were given a fourth
full-dose vaccine following the completion of the
initial vaccine series to ensure protection. In
con-trast, preterm infants receiving full-dose vaccine at
the same routine intervals were able to mount a
serologic response that was considered protective
against diphtheria, tetanus, and pertussis after a
second dose of DTP vaccine. Preterm infants in
this study experienced far fewer local and systemic
side effects compared with that reported previously in full-term infants.5
Prior to the first immunization, all of the preterm infants had antibody concentrations against
diph-theria, tetanus, and pertussis that were
signifi-cantly less than those reported for full-term
in-fants.5 In contrast, 100% of the mothers tested had
adequate immunity against diphtheria and tetanus
and a titer of greater than 1:16 against pertussis.
Persistence of maternal antibodies to diphtheria
and tetanus was expected. It was interesting to note,
however, that all of the mothers tested showed a
TABLE 1. Geometric MeanAgglutination Titer for Pertussis*
Mother’s Pre-DTP Pre-DTP
Titers No. 1 No.2
Infants who received a 6.49 ± 1.54 3.60 ± 1.35 2.70 ± 1.26 3.20 ± 2.04 4.25 ± 2.33 4.75 ± 2.25 4.50 ± 2.30 7.55 ± 2.06 half dose (n = 20)
Infants who received a 5.92 ± 1.58 2.86 ± 1.15 2.76 ± 1.83 5.52 ± 1.62#{176} 6.4 ± 2.10L 4.00 4.00 ± 2.00 7.66 ± 1.34
fulldose(n=25)
* Values are given as mean titers (log2) ± SD. DTP, diphtheria, tetanus, pertussis vaccine. Statistical values: #{176}P < .01; IL < .05; all other P values were nonsignificant.
t These infants required a full dose of DTP (fourth dose) because they were unprotected after completion of three primary doses of
DTPs. :1:n = 8.
§n=1.
TABLE 2. Percentage of Infants With Vaccine-Related Side Effects*
Post-DTP No. 1 Post-DTP No. 2 Post-DTP No. 3 Post-18-mo
Half Dose Full Dose Half Dose Full Dose Half Dose Full Dose Half Dose Full Dose
Systemic febrile response (#{176}C)
Noneor<37.8 90 92 90 92 100 76t 100 100
37.8-38.9 10 8 10 8 0 24t 0 0
>38.9 0 0 0 0 0 0 0 0
Acute behavioral change
None 40 48 30 24 40 48 60 56
Irritable 60 52 70 68 50 36 30 44
Crying 0 0 0 8 10 12 0 0
Screaming 0 0 0 0 0 4 0 0
Local reactions
None 70 76 80 76 80 84 90 88
Redness, swelling, tenderness 30 24 20 24 20 16 10 12
* DTP, diphtheria, tetanus, pertussi s vaccine.
titer of 1:16 or greater to pertussis. This was not
solely due to the young age of mothers in the study
population. The mean maternal age was 26 years
with only six mothers being between 16 and 19
years of age. It is possible that the presence of
antibodies against pertussis may be a result of the
pertussis bacterium in the community resulting in
a resurgence of immunity. The lack of protective
antibodies against diphtheria and tetanus among
our study infants may be related to their
prematu-rity and shorter time in utero. In addition,
diphthe-na and tetanus antibodies may belong to an IgG
subclass that is less efficiently transferred from the
maternal to the fetal circulation.’7”8 The large
num-ber of preterm infants (60% to 85%) with small
levels of pertussis antibody prior to their first
im-munization was also expected because of the
short-ened time of the preterm infants in utero as well as
catabolism of maternal antibodies that would have occurred in the 2-month interval prior to the first immunization of the infants. This may account for the difference between our findings and those of
Burstyn et al’9 who found an inverse relationship
between cord blood titers and the response of the
infants to their first vaccination. However, infants
in their study received their first immunization
within the first week oflife when maternal antibody
was still present. Low levels of pertussis antibody
have been noted in full-term infants prior to their
first immurnzation.5”7”8
In contrast to the antibody titers obtained before
the first immunization, titers obtained after each
subsequent immunization were presumed to
mdi-cate the immune responses of the infants to theDTP vaccine.20 No significant change was noted in
the percentage of conversion of either preterm
group to diphtheria, tetanus, or pertussis after the
first dose of DTP vaccine, whether or not the infant
was presented with a full dose or half dose of antigenic stimulus.
All preterm infants (half dose and full dose of vaccine) except for one infant who had received a half dose showed an adequate serologic response to
diphtheria and tetanus after the second
immuni--zation. In contrast to full-term infants who showed
complete protection against diphtheria and tetanus
after the first vaccination, preterm infants given
either full- or half-dose vaccine required two
im-munizations to produce the same protection. This
diminished response, which is more evident in
pre-term as compared with that reported in full-term
infants,5 may be related to B lymphocyte
immatu-rity, an increased number of suppressor T
lympho-cytes, or a functional immaturity of the
macro-phages to process these antigens.2125
Most disturbing was the inadequate response of
preterm infants receiving half-dose pertussis
vac-cine. Although most preterm infants receiving
full-dose vaccine showed a positive serologic response
against pertussis after the second dose, 45% of
preterm infants receiving half-dose vaccine were
unable to mount a comparable serologic response
even after the third dose of vaccine. All of these
infants required a fourth full-dose vaccine to which
all but one had a satisfactory immune response.
This response might not have occurred, however,
without the prior stimulus of the half-dose vaccine.
At the end of this extended series, infants who had
received a half dose had a conversion rate not
significantly different from the infants we studied
who had received a full dose and the full-term
vaccine recipients who received half-dose vaccine
described by Barkin et al.6 US licensed pertussis
vaccines are required to have a minimum of eight
mouse protective units per three single human
doses. One single dose may contain as little as 2.67
mouse protective units (one third of eight);
how-ever, there can be much variability in the
quantifi-cation of mouse protective units per unit of vaccine.
The vaccine used in this study was measured to
contain 8.8 mouse protective units per milliliter or
4.4 mouse protective units per 0.5 mL, the amount given in a full dose of vaccine. A half dose of this
vaccine could contain 2.2 mouse protective units,
an amount that is less than the lower limit of
pertussis potency found in a full dose ofthe vaccine.
This may account for the poor response rate to
half-dose vaccine.
There is much controversy in the scientific and
lay literature about the pertussis component of the
DTP vaccine.2 However, it is of concern that
preterm infants, especially those with underlying
residual lung disease, remain unprotected against
pertussis. Work is now in progress evaluating the
efficacy of an acellular pertussis vaccine. These
vaccines have shown promising results with
ade-quate serologic responses shown to occur without
the high incidence of local and systemic side effects
described among full-term infants using whole-cell
preparations.3#{176}32 It is expected that these vaccines will soon be used in the United States for the
routine immunization of all children.
We have shown that preterm infants may be
unable to mount a satisfactory serologic response
to half-dose DTP vaccine given at routine intervals
of 2, 4, and 6 months of life. If immunized with
full-dose vaccine, preterm infants are adequately
pro-tected against diphtheria, pertussis, and tetanus
after the second immunization. Because the
mci-dence of side effects in the preterm population is
less than that seen in the full-term population and
unaltered by the use of reduced dosage of vaccine,
there is no basis for administering reduced dosage
dosage of DTP may not provide adequate
protec-tion, especially from pertussis. It is appropriate,
therefore, that the physician caring for the low birth
weight preterm infant adhere to the American
Academy of Pediatrics recommendations for the
immunization of preterm infants and offer full-dose
DTP vaccine at the routine time intervals of 2, 4,
6, and 18 months of age (without correction for
prematurity) to ensure adequate protection against
diphtheria, tetanus, and, most importantly,
pertus-sis, provided there are no contraindications to its
use.
ACKNOWLEDGMENT
This work was supported, in part, by
Connaught-Squibb Laboratories, Swiftwater, PA.
REFERENCES
1. Immunization Practices Advisory Committee: Diphtheria, tetanus and pertussis: Guidelines for vaccine prophylaxis and other preventive measures. MMWR 1981;30:392-396,
401-407
2. Immunization Practices Advisory Committee: Diphtheria, tetanus and pertussis: Guidelines for vaccine prophylaxis and other preventive measures. Ann Intern Med
1985;103:896-905
3. Cherry JD: The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: Acomparative study. Curr Probl Pediatr 1984;14:7 4. Report of the Committee on Infectious Diseases: The 1986
Red Book, ed 20. Elk Grove Village, IL, 1986, American Academy of Pediatrics, 1986
5. Bernbaum JC, Daft AL, Anolik R, et al: Response of preterm infants to routine diphtheria-tetanus-pertussis immuniza-tions. J Pediatr 1985;107:184-188
6. Barkin RM, Samuelson JS, Gotlin L: DTP reactions and serologic response with a reduced dose schedule. J Pediatr 1984;105:189
7. Manclark CR, Meade BD: Serologic response to Bordeteila pertussis, in Rose NR, Friedman H (eds); Manual of Clinical
Immunology, ed 2. Washington, DC, American Society for Microbiology, 1986, pp 496-499
8. Miller JJ, Silverberg RJ, Saito TM, et al: An agglutinative reaction for Haemophiliuspertussis. II. Its relation to clinical immunity. J Pediatr 1943;22:644
9. Manclark CR: Microagglutination Procedure for Bordetella
pertussis Antibody. Washington, DC, Division of Bacterial Products, Bureau of Biologics, Food and Drug Administra-tion, 1980
10. DeGara PF, Mayer SA: The agglutinative reaction for He-mophilus pertussis following whooping cough and following immunization. J Pediatr 1947;30:171
11. Fraser DJ: Diphtheria antitoxin determination. Trans R Soc
Can 1931;25:175
12. Craig JP: Immune response to Corynebacterium diphtheriae and Clostridium tetani, in Rose NR, Friedman H (eds):
Manual of Clinical Immunology. American Society for Mi-crobiology, 1986, pp 408-414
13. Taylor EM, Maloney PJ: Assay of diphtheria and tetanus antitoxin in small volumes of blood. Can J Public Health 1960;51:135
14. Barile MF, Koib RW, Pittman M: United States standard diphtheria toxin for the Schick test and the erythema po-tency assay for the Schick test dose. Infect Immun 1971;4:295
15. Barkin RM, Pichichero ME: Diphtheria-pertussis-tetanus vaccine: Reactogenicity of commercial products. Pediatrics
1979;63:256
16. Zar JH: Biostatistical Analysis. Englewood Cliffs, NJ, Pren-tice-Hall, 1974
17. Valquist B: The transfer of antibodies from mother to off-spring. Adv Pediatr 1958;10:305
18. Finland M: Pertussis, in Charles D, Finland M (eds): Ob-stetric and Perinatallnfectioris. Philadelphia, Lea &Febiger, 1973, pp 322-324
19. Burstyn DG, Baraff U, Peppler MS, et al: Serologic
re-sponse to filamentous hemagglutinin and lymphocytosis promoting toxin of Bordeteila pertussis. Infect Immun 1983;41:1150-1156
20. Van Furth R, Schuit RE, Hijman W: The immunological development of the human fetus. J Exp Med 1965;122:1173 21. Lawton AR, Self KS, Royal SA, et al: Ontogeny of B
lymphocytes in the human fetus. Clin Immunol
Immuno-pathol 1972;1:84
22. Hayward AR, Lawton AR: Induction of plasma cell
differ-entiation of human lymphocytes: Evidence for functional immaturity of T and B cells. J Immunol 1977;119:1213 23. Krestchmer RR, Stewardson PB, Papiernak CK:
Chemotac-tic and bactericidal capacities of human newborn monocytes.
J Immunol 1976;117:1303
24. Schuit RE, Powell DA: Phagocytic dysfunction in monocytes of normal newborn infants. Pediatrics 1980;65:501-504 25. Miller ME: The inflammatory and natural defense system,
in Stiehm, Fulginiti (eds): Immunological Disorders in
In-fants and Children. WB Saunders Co, Philadelphia, 1980,
pp 166-167
26. Cody CL, Baraff U, Cherry JD, et al: Nature and rates of adverse reactions associated with DTP and DT immuniza-tions in infants and children. Pediatrics 1981;68:650-660 27. Baraff LI, Cody CL, Cherry JD: DTP-associated reactions:
An analysis by injection site, manufacturer, prior reactions, and dose. Pediatrics 1984;73:31-36
28. Madsen T: Vaccination against whooping cough. JAMA
1933;101:187
29. Stewart GT: Vaccination against whooping cough. Lancet
1977;1:234
30. Aoyama T, Murase Y, Kato T, et al: Efficacy of an acellular pertussis vaccine in Japan. J Pediatr 1983;107:180-183
31. Edwards KM, Lawrence E, Wright PF: DPT vaccine: A comparison of the immune response and adverse reactions to conventional and acellular pertussis components. Am J
Dis Child 1986;140:867-871
