Pediatrics and Neonatology (2011) 52, 38e41

available at www.sciencedirect.com

journal homepage: http://www.pediatr-neonatol.com

BRIEF COMMUNICATION

Adverse Effects of Tetanus Toxoid, Reduced

Diphtheria Toxoid, and Acellular Pertussis Vaccine
in 6- to 7-Year-Old Children
Sung-Hsi Wei a, Yen-Nan Chao a, Song-En Huang a, Tsuey-Feng Lee a,
Luan-Yin Chang b,*

a
Taiwan Centers for Disease Control, Department of Health, Taiwan
b
Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taiwan

Received Mar 3, 2010; received in revised form Apr 9, 2010; accepted May 21, 2010

Key Words Although the safety profile of tetanus toxoid, reduced diphtheria toxoid, and acellular
acellular pertussis; pertussis (Tdap) vaccines in adolescents and adults has been documented, few data have
adacel; reported about their adverse events in children. Healthy 6- to 7-year-old children who were
adverse events; immunized with Tdap vaccine were evaluated for adverse events on Days 1, 2, 4, and 7 post-
children; immunization. Information of sex, body mass index (BMI), and previous diphtheria-pertussis-
reduced diphtheria tetanus (DPT) immunization history was obtained and evaluated for the association with the
toxoid adverse events. A total of 243 6- to 7-year-old children were immunized with Tdap. Among
the 243 children immunized, remarkable adverse events included redness more than or equal
to 10 mm in 47 (19%) children, induration more than or equal to 10 mm in 57 (23%), tenderness
in 130 (53%), and fever in 12 (5%). Redness and induration resolved in 7 days and fever resolved
on Day 4. The adverse events were not associated with gender, BMI above the mean value, or
the type of fourth DPT immunization. Adverse events after Tdap vaccination were mild and dis-
solved within 7 days in 6- to 7-year-old children.
Copyright 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.

* Corresponding author. Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University,
No.7, Chung Shan South Road, Taipei 100, Taiwan.
E-mail addresses: [email protected], [email protected] (L.-Y. Chang).

1875-9572/$36 Copyright 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.pedneo.2010.12.010
Adverse effects of Tdap vaccine 39

1. Introduction participation in the study. All the children were examined

for enrollment by a physician before immunization.
A tetanus toxoid, reduced diphtheria toxoid, and acellular The demographic data, including gender and age, and body
pertussis (Tdap) vaccine product, Adacel (Sanofi-Pasteur, mass index (BMI) measured within 3 months of vaccination,
Swiftwater, PA, USA), was licensed as a booster vaccine were provided by the school health center. The immunization
against diphtheria, tetanus, and pertussis for adolescents records of the previous 4 doses of either DTwP or DTaP were
and adults in the United States in 2005. Although the safety obtained from the National Immunization Information System
and efficacy of the Tdap vaccine in adolescents and adults (NIIS), a digital immunization registry system, which physi-
have been documented, few reports describing the adverse cians have to record all vaccines administered in children. For
events in children have been published.1e3 the previous immunization, DTwP vaccine had been provided
According to the data of the Notifiable Disease Surveil- by the government and was a product of Sanofi Pasteur, Tor-
lance System of Taiwan, the number of patients with labo- onto, Ontario, Canada. However, DTaP was provided by
ratory-confirmed pertussis increased from 6 in 2001 to 41 in multiple manufacturers in the private market, and the specific
2008.4 During the same period, the number of suspected brand of DTaP was not available in NIIS.
pertussis cases was between 154 and 190 annually. A total of All the enrolled subjects received a booster dose of Tdap
239 suspected pertussis cases and 89 microbiologically vaccine (Adacel, Sanofi Pasteur, Toronto, Ontario,
confirmed infections were recorded in Taiwan in 2009 Canada) on Day 0. Each dose of the Tdap vaccine contained
(unpublished data). In view of the increased pertussis burden 2 limit of flocculation (Lf) diphtheria toxoid, 5 Lf tetanus
in Taiwan, the Taiwan Advisory Committee on Immunization toxoid, 2.5 mg detoxified pertussis toxin, 5 mg filamentous
Practices recommended Tdap vaccine, rather than teta- haemagglutinin, 3 mg pertactin, 5 mg each of fimbriae types
nusediphtheria (Td) vaccine, to be administered in grade 1 2 and 3, 0.33 mg aluminum hydroxide, and 3.3 mg 2-phe-
children in primary school starting in 2009. With the imple- noxyethanol. The vaccine was of the same lot and admin-
mentation of Tdap immunization in early 2009, reports of istered intramuscularly into the deltoid muscle of the non-
adverse reactions such as large redness or induration after dominant arm, using a 1-inch-long 25-gauge needle by
vaccination drew the attention of the public health author- a single nurse who had been trained for Tdap immunization.
ities (Figure 1). We thus conducted a prospective observa- Enrolled children were assessed by the same study
tional study to assess the adverse events following Tdap physician on Day 1 (24 hours later), Day 2 (48 hours later),
vaccination in 6- to 7-year-old children. Day 4 (96 hours later), and Day 7 (168 hours later). Solicited
adverse events included injection site redness, induration,
tenderness, itching, fever, headache, and gastrointestinal
2. Method symptoms. Unsolicited symptoms were recorded according
to the childrens description.
The study was conducted at a primary school. All healthy 6- c2 analysis and multivariable logistic regression models
to 7-year-old children of the first grade who had no were used to identify risk factors for local and systemic
contraindication to receive immunization were eligible for adverse events including redness, induration, fever, and
immunization. Children were excluded if they received tenderness. Potential risk factors included sex, BMI above
medications (including antihistamines) regularly, had the mean value of the enrolled children, and the type of
received any blood product within 3 months, or had infec- the fourth DTwP/DTaP vaccination. Statistical analyses
tious ailments including upper respiratory tract infection or were performed using Stata software, version 10 (Stata
infectious gastroenteritis. Minor health conditions such as Corp LP, College Station, Texas, USA). A p < 0.05 was
eczema, asthma, and minor abrasions did not exclude considered to be statistically significant.

3. Results

A total of 263 children were evaluated. Among these chil-

dren, 20 were excluded. The mean age of the 243 children
enrolled was 7.2 years (range, 6.7e7.8 years). Forty-four
percent were male. The mean height was 121.2 cm (range,
105.0e139.2 cm). The average BMI was 16.8 (range,
12.6e30.8).
Of the 243 enrolled subjects, 242 (99.6%) received 4
doses of DTwP/DTaP vaccine as the priming immunization,
and 1 received the first 3 doses and missed the fourth dose
of DTwP/DTaP. All the 243 children received government-
provided DPwT vaccine for the first 3 doses. For the fourth
dose, 222 (91.7%) received DPwT and 20 (8.3%) received
DTaP vaccine.
After vaccination with Tdap, 170 (70%) reported at least
Figure 1 An induration and redness with a diameter of 1 adverse event (Table 1). Five (2%) had Tdap immuniza-
6.7 cm was found at the left arm of a 7-year-old child who had tion-related adverse events (i.e., fever and local tender-
received Tdap immunization 2 days before. ness) severe enough to result in missed school for at least
40 S.-H. Wei et al

Table 1 Signs and symptoms among 243 grade one students who received Tdap immunization, observed on Days 1e7
postimmunization
Observed Day 1 (%) Day 2 (%) Day 4 (%) Day 7 Total (%)
Redness (mm)
10 5 (2) 44 (18) 5 (2) 0 47 (19)
25 4 (2) 41 (17) 5 (2) 0 44 (18)
50 2 (1) 7 (3) 2 (1) 0 10 (4)
Induration (mm)
10 22 (9) 47 (19) 5 (2) 0 57 (23)
25 20 (8) 40 (16) 2 (1) 0 49 (20)
50 2 (1) 7 (3) 1 0 10 (4)
Tenderness 72 (30) 77 (32) 46 (19) 13 (5) 130 (53)
Itching 7 (3) 6 (2) 4 (2) 9 (4) 21 (9)
Fever
37.5 C 11 (5) 1 0 0 12 (5)
39 C 1 0 0 0 1
Headache 12 (5) 11 (5) 8 (3) 9 (4) 31 (13)
Vomiting 5 (2) 1 1 1 8 (3)
One child had a swollen arm and numbness of all the digits on Day 2 and his symptom had subsided by Day 4.
One child had general skin rash on Day 1 through Day 4.

1 day. Proportion of children with redness and induration needles and reminding the vaccine-delivery personnel to
peaked on Day 2. The most severe redness occurred in a girl deliver the vaccines appropriately.
4 days after vaccination, measuring 85 mm in diameter. The Given that gender preponderance in response to Tdap
most prominent induration occurred in a boy 2 days after antigens remained unclear, we did not find significant
vaccination, measuring 66 mm in diameter. One overweight association between gender and local or systemic reac-
boy with a BMI of 23.1 reported numbness of the digits of tions. In a study on adverse events of Tdap in adult health
the vaccinated arm on Day 2, and his numbness resolved by care workers, women were three times more likely to
Day 4. General macular rash was found in a boy from Day 1 experience local adverse events after Tdap administration
through Day 4. Twenty-one (9%) children reported itching than men.9 In another study, Scheifele et al reported that
around the injection site, with or without local redness and a significantly greater proportion of children with large
induration. No children were found febrile after Day 4. All reactions to DTaP-IPV were male.
the redness and induration resolved on Day 7. None of the Safety and immunogenicity of mixed scheduled immu-
children in our study experienced seizure, major neurologic nization of DTwP, DTaP, and Tdap have been an issue of
reaction or other uncommon events. concern. It has been reported that adverse events following
Sex, BMI above the mean value of the same age group, the fifth dose of DTaP vaccine were similar whether given as
and the type of the fourth DTwP/DTaP vaccination were not a fifth sequential dose of the same vaccine, a mix of
associated with redness (10 mm, 25 mm, 50 mm), different brands of DTaP vaccines in the 5-dose sequence,
induration (10 mm, 25 mm, 50 mm), tenderness or or after 3 DTwP and 1 DTaP vaccinations.10 In this study, we
fever (37.5 C) in both univariate and multivariate analysis. found that the local and systemic adverse events following
the fifth dose of Tdap vaccination were generally similar in
children who had previously received 4 DTwP immuniza-
4. Discussion tions or 3 DTwP and fourth DTaP immunization. Our data,
together with previous studies, suggested the encouraging
Reactogenicity of DTaP has been shown to be increased safety profile in mixed scheduled vaccination.
with successive doses in older children.5 There are prece- Currently, there are two Tdap vaccines licensed for
dent studies reporting the immunogenicity and reac- vaccination in adolescents and adults in the United States:
togenicity of vaccines with reduced antigens as a fifth dose Boostrix (GlaxoSmithKlines, Rixensart, Belgium) and Ada-
for children.1,6,7 Scheifele et al1 had reported that Tdap cel. Although both comprise reduced antigens of diph-
vaccination in 4- to 6-year-old children primed with 4 doses theria, tetanus, and pertussis, they are different from each
of DTaP caused significantly fewer local reactions than other in quantity and type of antigens. Blatter et al have
DTaP did. Our study featured the reactogenic profile of shown that overall safety profile of Boostrix was generally
Tdap vaccine in children primed with mainly doses of DTwP. comparable to that of Adacel in adults aged 19e64 years.3
It has been reported that children with a BMI above the Comparing with Blatters report, we found local reactions
median value were more likely to have local redness and fever elicited by Adacel in children were comparable to
because Tdap vaccine is less reliably injected into muscle those in adults. However, the rate of headache in children
tissue of these children.8 In the present study, no similar seemed less than that in adults (13% vs. 31%).3 Huang et al7
trend was observed. We sought to minimize the probability had assessed the immunogenicity and reactogenicity of
of inadequate depth vaccine delivery by using 1-inch-long Boostrix in 6- to 8-year-old children primed with 4 doses of
Adverse effects of Tdap vaccine 41

DTwP/DTaP. We found higher rates of severe local reactions injection site reactions to the preschool booster dose of
and fever in children who received Adacel than those who diphtheriaetetanuseacellular pertussis vaccine: results of
received Boostrix (redness 50 mm, 4% vs. 0%; induration a randomized, controlled trial. Pediatr Infect Dis J 2005;24:
50 mm, 4% vs. 0%; fever 37.5 C, 5% vs. 0%). Whether it 1059e66.
2. Ward JI, Cherry JD, Chang SJ, et al. Efficacy of an acellular
suggested that Boostrix causes milder symptoms than
pertussis vaccine among adolescents and adults. N Engl J Med
Adacel in children deserves further investigation. However, 2005;353:1555e63.
the comparison is not exempted from potential observa- 3. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immuno-
tional bias with different observers and settings. genicity and safety of a tetanus toxoid, reduced diphtheria
Our study has several limitations. We only monitor the toxoid and three-component acellular pertussis vaccine in
adverse events for 7 days and may have missed late- adults 19e64 years of age. Vaccine 2009;27:765e72.
occurring events. Although we observed the adverse events 4. Centers for Disease Control Taiwan. Statistics of Communi-
by a single study physician to minimize the observer-asso- cable Diseases and Surveillance Report. Taipei: Centers for
ciated difference, some parameters, e.g., diameter of Disease Control, Department of Health, R.O.C. (Taiwan); 2009.
induration, might be difficult to be measured consistently. p. 90.
5. Blennow M, Granstrom M. Adverse reactions and serologic
In the absence of a control group, it is possible that the
response to a booster dose of acellular pertussis vaccine in
adverse events observed did not represent an adverse children immunized with acellular or whole-cell vaccine as
reaction. However, we found no evidence to support this infants. Pediatrics 1989;84:62e7.
possibility. 6. Lin TY, Wang YH, Huang YC, et al. Booster vaccination at 6e8
Although some children/subjects experienced adverse years of age with a reduced antigen content dTpaeIPV vaccine
events after Tdap immunization, the adverse events were is immunogenic and safe after priming with whole-cell
mild and resolved within 7 days. Sex, BMI above the mean pertussis vaccine. Hum Vaccin 2008;4:50e3.
value, and the fourth dose of DTwP/DTaP were not asso- 7. Huang LM, Chang LY, Tang H, et al. Immunogenicity and
ciated with the occurrence of adverse events. reactogenicity of a reduced-antigen-content diphtheriae
tetanuseacellular pertussis vaccine in healthy Taiwanese
children and adolescents. J Adolesc Health 2005;37:517.
Acknowledgments 8. Scheifele DW, Halperin SA, Ferguson AC. Assessment of injec-
tion site reactions to an acellular pertussis-based combination
The authors are grateful to their colleagues in the 2nd vaccine, including novel use of skin tests with vaccine anti-
Division of the Centers for Disease Control for their tech- gens. Vaccine 2001;19:4720e6.
9. Sandora TJ, Pfoh E, Lee GM. Adverse events after administra-
nical consultation. The authors declare that no financial
tion of tetanusediphtheriaeacellular pertussis vaccine to
support or interest conflicts in this study.
healthcare workers. Infect Control Hosp Epidemiol 2009;30:
389e91.
References 10. Pichichero ME, Edwards KM, Anderson EL, et al. Safety and
immunogenicity of six acellular pertussis vaccines and one
1. Scheifele DW, Halperin SA, Ochnio JJ, Ferguson AC, whole-cell pertussis vaccine given as a fifth dose in four- to six-
Skowronski DM. A modified vaccine reduces the rate of large year-old children. Pediatrics 2000;105:e11 [abstract].