Safety Surveillance of Diphtheria

and Tetanus Toxoids and Acellular

Pertussis (DTaP) Vaccines
Pedro L. Moro, MD, MPH,​a Silvia Perez-Vilar, PharmD, PhD,​b Paige Lewis, MSPH,​a
Marthe Bryant-Genevier, MD, MPH, MHS,​b Hajime Kamiya, MD, MPH,​c,​d Maria Cano, MD, MPHa

OBJECTIVE: To assess the safety of currently licensed diphtheria-tetanus-acellular pertussis abstract

(DTaP) vaccines in the United States by using data from the Vaccine Adverse Event
Reporting System (VAERS), a spontaneous reporting surveillance system.
METHODS: We searched VAERS for US reports of DTaP vaccinations occurring from January 1,
1991, through December 31, 2016, and received by March 17, 2017. We reviewed available
medical records for all death reports and a random sample of reports classified as nondeath
serious. We used Empirical Bayesian data mining to identify adverse events that were
disproportionally reported after DTaP vaccination.
RESULTS: VAERS received 50 157 reports after DTaP vaccination; 43 984 (87.7%) of them
reported concomitant administration of other vaccines, and 5627 (11.2%) were serious.
Median age at vaccination was 19 months (interquartile range 35 months). The most
frequently reported events were injection site erythema (12 695; 25.3%), pyrexia (9913;
19.8%), injection site swelling (7542; 15.0%), erythema (5599; 11.2%), and injection
site warmth (4793; 9.6%). For 3 of the DTaP vaccines, we identified elevated values for
vaccination errors using Empirical Bayesian data mining.
CONCLUSIONS: No new or unexpected adverse events were detected. The observed
disproportionate reporting for some nonserious vaccination errors calls for better
education of vaccine providers on the specific indications for each of the DTaP vaccines.

aImmunization Safety Office, Division of Healthcare Quality Promotion and cEpidemiology Intelligence Service, WHAT’S KNOWN ON THIS SUBJECT: Prelicensure
Meningitis and Vaccine Preventable Diseases Branch, National Center for Immunization and Respiratory studies revealed that the most common adverse
Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; bCenter for Biologics Evaluation and reactions to 6 US licensed diphtheria-tetanus-
Research, Food and Drug Administration, Silver Spring, Maryland; and dInfectious Disease Surveillance Center,
acellular pertussis vaccines (Infanrix, Daptacel,
National Institute of Infectious Diseases, Tokyo, Japan
Pediarix, Pentacel, Kinrix, and Quadracel) were
Dr Moro conceptualized and designed the study, reviewed medical records and reports, injection site and systemic reactions.
conducted part of the analysis, and drafted the initial manuscript; Drs Perez-Vilar and Bryant-
Genevier conducted the data mining analyses and reviewed and revised the manuscript; WHAT THIS STUDY ADDS: Postlicensure surveillance
Drs Kamiya and Cano reviewed medical records and reports and reviewed and revised the of adverse events after the 5 licensed diphtheria-
manuscript; Ms Lewis conducted the analysis and reviewed and revised the manuscript; and all tetanus-acellular pertussis vaccines over a 19-year-
authors approved the final manuscript as submitted. period did not find any new or unexpected safety
The findings and conclusions in this report are those of the authors and do not necessarily concerns in the Vaccine Adverse Event Reporting
represent the official position of the Centers for Disease Control and Prevention or the US Food System.
and Drug Administration.
DOI: https://​doi.​org/​10.​1542/​peds.​2017-​4171
Accepted for publication Feb 16, 2018
Address correspondence to Pedro L. Moro, MD, MPH, Immunization Safety Office, Division of
Healthcare Quality Promotion, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS
To cite: Moro PL, Perez-Vilar S, Lewis P, et al. Safety
D26, Atlanta, GA 30333. E-mail: [email protected]
Surveillance of Diphtheria and Tetanus Toxoids and Acellular
Pertussis (DTaP) Vaccines. Pediatrics. 2018;142(1):e20174171

Downloaded from www.aappublications.org/news by guest on July 18, 2018

PEDIATRICS Volume 142, number 1, July 2018:e20174171 ARTICLE
Whole cell pertussis–containing influenzae type b (Hib) detecting potential vaccine
(DTwP) vaccine was developed conjugate vaccine, licensed in safety signals.‍25 VAERS
in the 1930s and used widely in June 2008‍8 as a 4-dose series; accepts reports from vaccine
clinical practice by the mid-1940s.‍1 (3) Kinrix (GlaxoSmithKline manufacturers, health care
DTwP vaccine was 70% to 90% Biologicals); and (4) Quadracel providers, vaccine recipients,
effective in preventing serious (Sanofi Pasteur, Ltd), each a and others. The VAERS report
pertussis disease.‍1 Concerns about combination of DTaP and IPV, form collects information on
safety (particularly severe local licensed in June 20089 and in age, sex, vaccines administered,
reactions, febrile seizures, and March 2015,​‍10 respectively, as dose and lot number, the AE
reports of acute encephalopathy a fifth dose in the 5-dose series. experienced, and health history.
after vaccination) led to the Prelicensure studies of these Signs and symptoms of AEs are
development and licensure of vaccines revealed that the most coded by trained personnel by
diphtheria-tetanus-acellular common AEs after vaccination using the Medical Dictionary for
pertussis (DTaP) vaccines.‍2–4‍ The were injection site and systemic Regulatory Activities (MedDRA), a
first DTaP vaccine was approved reactions.‍5–‍‍‍ 10
‍ clinically validated, internationally
by the Food and Drug standardized terminology.‍26 A
Administration (FDA) for use in Postmarketing observational studies VAERS report may be assigned 1
the United States in 1991 and have shown that the DTaP-containing or more MedDRA preferred terms
recommended in place of DTwP vaccines have a good safety (PTs). A PT is a distinct descriptor
for the fourth and fifth doses of record.‍11–‍‍‍‍‍‍‍‍ 22
‍ In 2 studies of DTwP for a symptom, sign, disease,
the recommended series among and DTaP vaccines conducted in the diagnosis, therapeutic indication,
children ≥15 months of age.‍4 In Vaccine Adverse Event Reporting investigation, surgical, or medical
1997, the Advisory Committee System (VAERS) in the early 1990s, procedure, or medical, social,
on Immunization Practices no major safety concerns were or family history characteristic,​‍26
recommended DTaP for all 5 identified. AEs and hospitalizations but PTs are not necessarily
doses in the childhood vaccination were less common with DTaP than medically confirmed diagnoses.
schedule. DTaP is reported to have with DTwP.‍23,​24 ‍ However, these System Organ Class is the highest
mild local and systemic adverse initial VAERS studies covered short level of the MedDRA hierarchy that
reactions and less frequent serious periods of time and did not include provides the broadest classification
adverse events (AEs) compared the DTaP vaccines currently available for AEs (eg, nervous system
with DTwP.‍4 DTwP is no longer in the United States; therefore, the disorders).27 Reports are classified
licensed nor is it available for use in safety information provided in as serious or nonserious. A report
the United States.‍4 these analyses are limited.23,​24 ‍ In is considered serious on the basis
the current study, we used VAERS of the Code of Federal Regulations
Currently, there are 2 DTaP to assess the safety of currently (21) definition if 1 or more of the
vaccines licensed in the United available DTaP vaccines in the following are reported: death, life-
States for the entire 5-dose United States. threatening illness, hospitalization
series: Infanrix (GlaxoSmithKline or prolongation of existing
Biologicals, Rixensart, Belgium) hospitalization, or permanent
and Daptacel (Sanofi Pasteur, METHODS disability.‍28 For serious reports,
Ltd, Swiftwater, PA), which were medical records are routinely
approved in 1997 and 2002, VAERS requested and made available to
respectively.‍5,​6‍ In addition, VAERS is a US national VAERS personnel.
the following 4 combination vaccine safety surveillance
DTaP-containing vaccines have system created in 1990 and We searched the VAERS database
been licensed: (1) Pediarix coadministered by the Centers for reports after DTaP vaccination
(GlaxoSmithKline Biologicals), a for Disease Control and Prevention received by March 17, 2017, for
combination of DTaP, hepatitis (CDC) and the FDA. It receives persons given any of the currently
B vaccine, and inactivated spontaneous reports of AEs after licensed DTaP vaccines from January
polio vaccine (IPV) approved in vaccination. Vaccination errors 1, 1991, through December 31, 2016.
December 2002‍7 and approved not describing an AE may also be Non-US reports and duplicate reports
for use as a 3-dose series; (2) reported.‍25 With VAERS, whether were excluded. We summarized the
Pentacel (Sanofi Pasteur, Ltd), an AE is causally associated with most common MedDRA terms for
a combination of a DTaP-IPV vaccination generally cannot be serious and nonserious DTaP vaccine
component and Haemophilus assessed, but it may be useful for reports. Quadracel was not included

Downloaded from www.aappublications.org/news by guest on July 18, 2018

2 MORO et al
in our search because few reports is being reported at least twice (Infanrix, Daptacel, Pediarix,
had been received by VAERS at the as often as expected) to define Kinrix, Pentacel) in the United States
time of data extraction. vaccine-event pairs requiring from January 1, 1991, through
further evaluation.‍31 Elevated data December 31, 2016 (‍Table 1).
Clinical Review of Serious Reports mining statistics should not be DTaP vaccines were reported as
interpreted as evidence of a causal administered concurrently with 1
All death reports after DTaP
relationship between a vaccine or more other vaccines in 43 984
vaccines were manually reviewed
and an AE; vaccine-event (87.7%) reports. Among all DTaP
by a physician. The cause of death
combinations identified as potential vaccine reports, 5627 (11.2%) were
was obtained from the autopsy
signals by data mining methods coded as serious, including 844
report, death certificate, or medical
may be useful to generate a (1.7%) death reports. The most
records. In this review, we made
hypothesis that can be tested with frequently reported PTs for all
no attempt to assess causality of
controlled studies.31,​32
‍ reports were injection site erythema
the reported AEs. We conducted a
(12 695; 25.3%), pyrexia (9913;
clinical review of a simple random
We clinically reviewed the 19.8%), injection site swelling
sample of 5% of nondeath serious
DTaP vaccine reports with PTs (7542; 15.0%), erythema (5599;
reports after DTaP vaccines. The
that exceeded the data mining 11.2%), and injection site warmth
primary diagnostic category was
threshold. We excluded reports (4793; 9.6%) (not shown in tables).
assigned into a System Organ
of AEs described in the vaccine ‍Table 2 shows the 10 most common
Class.‍27 We also searched for all
package insert and those that, PTs reported for serious and
reports of anaphylaxis after DTaP
in the judgment of the clinicians nonserious reports.
vaccines by using the following
(P.L.M. and M.C.), represented
specific MedDRA PTs: anaphylactic
potential confounders or were
reaction, anaphylactic shock, Death Reports
noninformative or unspecific.
anaphylactoid reaction, and
Unspecific conditions are those In total, 844 deaths were reported
anaphylactoid shock. Reports of
referring to symptoms, signs, or to VAERS after receipt of DTaP
anaphylaxis were classified by
laboratory tests and/or results vaccines. Death certificates, autopsy
using the Brighton Collaboration
that may not be assignable to a reports, or medical records were
case definition or physician’s
particular cause, condition, or obtained for 725 (85.9%) reports
diagnosis.‍29
category. Unspecific events may (‍Table 3). Among these 725 reports,
have myriad causes and are often the most frequent cause of death
noninformative on their own. (350 of 725; 48.3%) was sudden
Data Mining
For the remaining reports, we infant death syndrome (SIDS). Most
We used Empirical Bayesian data reviewed all reports for vaccine- SIDS cases (217 of 350; 62.0%)
mining adjusted for sex and year of events pairs with disproportionate occurred among male infants; the
receipt of the report‍30 to identify reporting if the total number of predominant age group was infants
DTaP vaccine–event combinations reports was ≤50. For vaccine-event <6 months of age (318 of 350;
reported more frequently than pairs containing >50 reports, we 90.9%).
expected among children up to 7 reviewed a simple random sample
years of age. In the first analysis, we of 20% of the total.
restricted the analysis to serious
Because VAERS is a routine Nondeath Reports
US reports entered in VAERS as of
surveillance program designed to
December 31, 2016. In the second Characteristics of a random
improve an immunization program,
analysis, we included all serious sample of 240 nondeath serious
it does not meet the definition of
and nonserious US reports as of reports (5% of the total 4783
research; therefore, this work was
December 31, 2016. We conducted nondeath serious reports) occurring
not subject to institutional review
the analyses using the Multi-Item after the 5 currently licensed DTaP
board evaluation and informed
γ Poisson Shrinker algorithm‍30,​31
‍ vaccines included in our analyses
consent requirements.
in Oracle’s Empirica Signal are shown in ‍Table 4. They were
System. The main statistical scores similar when single DTaP and
computed are the Empirical Bayes combination DTaP-containing
Geometric Mean, EB05, and EB95, vaccines were assessed separately
RESULTS
the latter of which represent the (data not shown). The most common
90% confidence interval. We used VAERS received 50 157 reports diagnostic categories among
EB05 ≥2.0 as a cutoff (the pair involving receipt of DTaP vaccines nondeath serious reports were

Downloaded from www.aappublications.org/news by guest on July 18, 2018

PEDIATRICS Volume 142, number 1, July 2018 3
TABLE 1 Characteristics of All Reports After Currently Licensed DTaP Vaccines in VAERS Among 1, 33 met BL category 2, and 1
Persons Vaccinated From January 1, 1991, Through December 31, 2016 (Receipt March 17, met BL category 3. Thirty-seven
2017) did not meet BL criteria but were
Characteristics No. (%) considered as anaphylaxis by
Total reports 50 157a the attending physician. Thirty
Serious 5627 (11.2) reports did not contain sufficient
Median age (interquartile range), mo 19 (35) information for evaluation of BL.
Age <6 y 46 836 (93.4)
Male sex 25 781 (51.4) Data Mining
Median onset interval (range), d 1 (0–5115)
DTaP vaccines (n = 50 282)a The first disproportionality analysis
  DTaP (Infanrix) 17 484 (34.8) included a total of 18 240 serious US
  DTaP (Daptacel) 13 153 (26.2)
reports. Of them, 5467 included any
  DTaP-HepB-IPV (Pediarix) 8906 (17.7)
  DTaP-IPV-Hib (Pentacel) 5464 (10.9) DTaP vaccine temporarily associated
  DTaP-IPV (Kinrix) 5275 (10.4) with the reported events. The
  DTaP vaccines given in combination with other vaccines 43 984 (87.7) analysis revealed an elevated EB05
Most common vaccine combinations given concomitantlyb (≥2.0) for 9 vaccine-event pairs,
  MMR II 15 021 (34.6)
all of them related to injection site
  Polio 14 229 (32.4)
  Pneumococcal vaccine (Prevnar7)c 11 794 (26.8) reactions, urticaria, and
  Varicella (Varivax) 8772 (19.9) anaphylaxis.
  Rotavirus vaccine 8266 (16.4)
  Hib (ActHib) 7530 (17.1) The second analysis included a total
Type of reporter (n = 49 272)d of 159 818 serious and nonserious
  Vaccine provider 31 478 (62.8) US reports; 46 798 corresponded
  Othere 11 842 (23.6) to DTaP vaccines. The data mining
  Manufacturer 3359 (6.7)
  Parent 2593 (5.2)
analyses revealed an elevated
  Subject recovered by the time VAERS form was submitted 31 677 (63.2) EB05 for 55 vaccine-event pairs
HepB, hepatitis B; MMR II, measles, mumps, and rubella II.
for DTaP vaccines that fulfilled
a Some individuals received >1 DTaP vaccine. criteria to be reviewed. No new or
b Concomitant vaccines are not mutually exclusive.
c Prevnar 13 given with DTaP in 6427 (14.6%) reports not shown.
unexpected AEs were detected, but
d Eight hundred and eighty-five reports with missing reporter information. we identified 3 types of vaccination
e Secretary or office assistant. errors disproportionally reported:
incorrect product formulation
(n = 26; no AEs reported), product
neurologic conditions (60; 25.0%), vaccines resulted in 182 reports quality issue (n = 23), and drug
followed by gastrointestinal with 1 or more of the specific administered at inappropriate
conditions (56; 23.3%), and MedDRA PTs. Clinical review site (n = 19). Most AEs reported
general disorders and vaccine revealed 12 reports of allergic (53%; 36 of 68) after these
administration site conditions nonanaphylactic reactions, 7 vaccination errors included
(47; 19.6%). Seizure was the with other nonhypersensitivity mild injection site reactions.
most common diagnosis among conditions, and 163 reports Most (74%; 17 of 23) reports
neurologic conditions (48 of 60; of anaphylaxis or possible of incorrect product formulation
80%); 13 were reported as anaphylaxis. Among the 163 reports administered involved inadvertent
febrile seizures. The most of anaphylaxis, the median age administration of only 1 of the
common gastrointestinal was 4 years (range 0–14 years). components of the vaccine (ie,
diagnosis was intussusception Among 103 reports for which vaccine administrator neglected
(44 of 56; 78.6%); rotavirus the symptom onset time could be to combine all the components
vaccine was reported as determined, 75 (73%) occurred per the manufacturer’s package
coadministered with DTaP within 30 minutes postvaccination. insert).
vaccine in all except 2 reports of Most of the DTaP vaccines
intussusception. administered (94.4%) were given
DISCUSSION
concomitantly with other routinely
recommended vaccines.‍33 Among We performed a review of AE reports
Anaphylaxis Reports
the 163 reports of anaphylaxis or received over the course of 19 years
The automated search of possible anaphylaxis, 62 reports after administration of currently
anaphylaxis reports after DTaP met Brighton Level (BL) category licensed DTaP vaccines in VAERS.

Downloaded from www.aappublications.org/news by guest on July 18, 2018

4 MORO et al
TABLE 2 Serious and Nonserious AEs (N = 50 157) in DTaP Recipients Reported to VAERS, 1991–2016 of these AEs.‍11–‍‍‍‍‍‍‍‍ 22
‍ A retrospective
MedDRA Code, Severitya N (%) cohort study in the Vaccine Safety
Serious 5476 (100)
Datalink (VSD) found that the
  Pyrexia 1959 (34.8) rate of local reactions after DTaP
  Vomiting 1565 (27.8) vaccines was higher than for
  Irritability 1238 (22.0) inactivated influenza or hepatitis A
  Convulsion 939 (16.7) vaccines. The study also revealed
  Intussusception 817 (14.5)
  Crying 761 (13.5)
that for children aged 12 to 35
  Diarrhea 747 (13.3) months, vaccination in the arm
  Lethargy 648 (11.5) was associated with a significantly
  Hypotonia 567 (10.1) greater risk of local reactions
  Cough 560 (10.0) compared with vaccination in the
Nonserious 44 530 (100)
  Injection site erythema 12 444 (27.9)
thigh.‍14
  Pyrexia 7954 (17.9)
  Injection site swelling 7349 (16.5) Seizures or convulsions ranked
  Erythema 5345 (12.0)
as the fourth most common PT
  Injection site warmth 4670 (10.5)
  Injection site edema 3186 (7.2) among serious reports. Febrile
  Injection site pain 3124 (7.0) convulsions are a type of seizures
  Injection site induration 3084 (6.9) relatively common in childhood,
  Rash 2932 (6.6) occurring in 2% to 4% of
  Urticaria 2800 (6.3)
individuals.‍34 Febrile seizures may
a The MedDRA codes reflect the 10 most frequent codes appearing in serious and nonserious reports made after receipt
be related to febrile infections and
of DTaP vaccines. Reports for all licensed DTaP products included in this study have been combined, and other vaccines
may have been administered concomitantly with the DTaP vaccine. A report may contain ≥1 PT. have also been associated with
DTwP, pneumococcal 13-valent
conjugate, and trivalent inactivated
TABLE 3 Confirmed Cause of Death Among Death Reports After the Administration of DTaP Vaccines
in VAERS influenza vaccines.‍34 Seizures
had been observed sporadically
Cause of Deatha No. (%)
during prelicensure clinical trials
Total 725 for Pentacel, Daptacel, Pediarix,
SIDS 350 (48.3)
Undetermined 98 (13.5)
and Infanrix.‍5–‍ 8‍ The authors of
Injury, poisoning, and certain other consequences of external causes 70 (9.7) a retrospective observational
Asphyxia or suffocation 49 (6.8) study in the VSD did not find an
Diseases of the respiratory system 49 (6.8) increased risk of seizures among
Pneumonia 24 (3.3) children aged 6 weeks to 23 months
Diseases of the circulatory system 28 (3.9)
Certain infections and parasitic diseases 29 (4.0)
who received DTaP.‍12 A recent
Sepsis or septicemia 20 (2.8) safety study on simultaneous
Congenital malformations, deformations, and chromosomal abnormalities 26 (3.6) administration of DTaP with other
Diseases of the nervous system 26 (3.6) vaccines revealed a small increased
Diseases of the digestive system 18 (2.5) risk for febrile seizures during the
Intussusception 6 (0.8)
External causes of morbidity 10 (1.4)
24 hours after a child receives the
Otherb 21 (2.9) inactivated influenza vaccine at the
a Confirmed by review of death certificate, autopsy report, or medical record.
same time as the pneumococcal
b Other causes include the following: symptoms, signs, and abnormal clinical and laboratory findings not elsewhere 13-valent conjugate vaccine or
classified (8); complications of prematurity (5); certain conditions originating in the perinatal period (3); endocrine, DTaP.‍20
nutritional, and metabolic diseases (3); and neoplasms (2).

This included automated analysis of The most common PTs observed Among death reports for which
all reports, clinical review of death among nonserious and serious sufficient records were available for
reports and a sample of serious reports were injection site reactions review, SIDS was the leading cause
reports, and data mining analyses to (eg, injection site erythema) and of death (48%), which is consistent
assess disproportionate reporting. certain systemic reactions (eg, fever, with infant mortality data that
Our findings were consistent with vomiting), findings consistent with places SIDS as the fourth leading
those from prelicensure trials and those from prelicensure clinical cause of death in the United States
postlicensure studies for these trials.‍5–‍‍‍ 10
‍ Several postmarketing among infants.‍35 Similarly, SIDS was
vaccines.‍5–‍‍‍ 10
‍ studies also noted the occurrence the second leading cause of death

Downloaded from www.aappublications.org/news by guest on July 18, 2018

PEDIATRICS Volume 142, number 1, July 2018 5
TABLE 4 Diagnostic Categories for the Random Sample of 240 Reports of AEs After DTaP Vaccines of serious DTaP reports, we also
in VAERS Among Persons Vaccinated January 1, 1991, Through December 31, 2016 (Receipt noted that intussusception was the
March 17, 2017) most common diagnosis among
Diagnostic Category N (%) gastrointestinal events, and in all
Nervous system disorders 60 (25.0) these selected reports, rotavirus
Seizuresa 48 vaccines were coadministered
Gastrointestinal disorders 56 (23.3) with a DTaP vaccine. Data mining
Intussusceptionb 44
findings involving the PT “apparent
General disorders and administration site conditions 47 (19.6)
Local reactionsc 20 life-threatening event” (ALTE) did
Immune system disorders 23 (9.6) not report a specific condition,
Anaphylaxisd 11 but rather a variety of serious
Infections and infestations 19 (7.9) conditions (eg, seizures, high fever,
Respiratory, thoracic, and mediastinal disorders 16 (6.7)
or apneic events) reported as
Blood and lymphatic system disorders 6 (2.5)
Psychiatric disorders 5 (2.1) ALTE by the attending physician.
Musculoskeletal and connective tissue disorders 3 (1.3) ALTE has been replaced by the
Othere 4 (1.7) term “brief resolved unexplained
a Febrile seizures comprised 13 reports. event.”‍50
b Rotavirus vaccine given concurrently in 42 reports.
c Local reactions comprised 45.2% of AEs in this group. A number of vaccination errors
d One report met BL criteria 1, 1 met BL 2, 1 met BL 3, and 1 was not verified as a Guillain-Barré syndrome case.
e Other includes 1 report each of cardiac disorder, endocrine disorder, eye disorder, and metabolism and nutrition
were disproportionally reported
disorder. for DTaP vaccines. Some of
these errors involved the
administration of the incorrect
among children aged 0 to 18 months children receive a vaccine or vaccine formulation
in the VSD.‍36 The authors of a recent relatively large number of or administration of vaccine at
study in Taiwan assessed the risk recommended vaccinations.‍43 the wrong site. Education and
of sudden unexplained infant death Other common causes of death training of providers on Advisory
after DTaP vaccine administration, observed (eg, asphyxia or Committee on Immunization
which was introduced in that suffocation, pneumonia, or Practices recommendations and
country in 2010,​‍37 and found sepsis or septicemia) are package insert indications may help
DTaP vaccine administration did consistent with the top 10 leading alleviate and prevent these errors.
not increase the risk of sudden causes of death in the vaccinated Although our study cannot
unexplained infant death. SIDS in the age groups.‍35 be compared with controlled,
United States have been declining denominator-based studies, the
since the early 1990s for a variety of Through data mining, we found authors of 2 observational studies
factors that include recommended disproportional reporting for in the VSD assessed the safety of
changes in sleeping position and injection site reactions. Increased DTaP-IPV-Hib (Pentacel) and DTaP-
environment, clarification of the local reactogenicity after a booster IPV (Kinrix).‍17,​18
‍ The authors of the
case definition, and diagnostic of DTaP-containing vaccines has first study compared children aged
coding shifts.‍38–40
‍ There is a been well documented, and it 6 weeks to 2 years who received
large body of evidence in which has been potentially attributed DTaP-IPV-Hib (Pentacel) with
it is shown that vaccination is not to cellular and humoral immune children who received other DTaP-
causally associated with SIDS,​‍41–44
‍‍ responses to the vaccine.‍45,​46
‍ We containing vaccines. Children who
including an Institute of Medicine also found higher disproportional received DTaP-IPV-Hib vaccine had
review in 2003 that rejected a reporting mainly for other a statistically significant higher risk
causal association between the labeled events, “intussusception,​” of fever, but no increased risk was
DTwP vaccine (which is no longer in “hematochezia,​” and other related observed for seizure; meningitis,
use in the United States) and SIDS, gastrointestinal conditions that encephalitis, and myelitis; or
as well as between exposure to may have been related to the nonanaphylactic allergic reaction.
multiple simultaneous vaccines and concomitant administration of The second study of Kinrix in
SIDS.‍40 It would not be uncommon rotavirus vaccines for which the children aged 4 to 6 years did
to observe a coincidental close associations with intussusception not find a statistically significant
temporal relationship between and/or hematochezia have been increased risk of meningitis
vaccination and SIDS because this well documented.‍46–‍ 49
‍ Through and/or encephalitis, seizures,
condition peaks at a time when our clinical review of a sample stroke, Guillain-Barré Syndrome,

Downloaded from www.aappublications.org/news by guest on July 18, 2018

6 MORO et al
Steven-Johnson syndrome, had been received in VAERS
anaphylaxis, serious allergic at the time of data extraction.‍10
ABBREVIATIONS
reactions other than anaphylaxis, The safety of this vaccine will AE: adverse event
and serious local reactions. be assessed once a larger number ALTE: apparent life-threatening
of reports has been event
received. BL: Brighton Level
Strengths of VAERS include its broad
CDC: Centers for Disease Control
national scope and timeliness.‍25
and Prevention
VAERS may be particularly useful
CONCLUSIONS DTaP: diphtheria-tetanus-acellu-
for detecting potential safety signals,
lar pertussis
which can be further evaluated in
In this assessment of the safety of DTwP: whole cell
larger data sets by using controlled
DTaP vaccines (Infanrix, Daptacel, pertussis–containing
epidemiologic methodologies. As a
Kinrix, Pediarix, and Pentacel), EB05: fifth percentile of the con-
passive surveillance system, VAERS
we did not identify any new or fidence interval for the
has several inherent limitations that
unexpected safety issues. However, Empirical Bayes geometric
call for careful interpretation of its
the presence of vaccination errors mean
findings. Some of these limitations
calls for measures to prevent their FDA: Food and Drug
include over- or underreporting,
occurrence. CDC and FDA will Administration
biased reporting, and inconsistency
continue to monitor AEs after DTaP Hib: Haemophilus influenzae type
in quality and completeness of
vaccination in VAERS. b
reports.‍25 VAERS generally cannot
IPV: inactivated polio vaccine
assess if a vaccine caused an AE.
MedDRA: Medical Dictionary for
VAERS does not collect data on
ACKNOWLEDGMENTS Regulatory Activities
number of vaccines; therefore, it does
PT: preferred term
not provide denominator data to We thank the CDC’s Immunization
SIDS: sudden infant death
calculate incidence rates of AEs. Safety Office staff whose work
syndrome
allowed this activity to be conducted
VAERS: Vaccine Adverse Event
Our review did not include the and Irene Walborsky and Bethany
Reporting System
recently licensed Quadracel vaccine Baer for their assistance on the data
VSD: Vaccine Safety Datalink
because few reports for this vaccine mining analyses.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by the Centers for Disease Control and Prevention and the Food and Drug Administration.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.​pediatrics.​org/​cgi/​doi/​10.​1542/​peds.​2018-​1036.

REFERENCES
1. Diphtheria, tetanus, and pertussis: adverse reactions following diphtheria- cines/​Vaccines/​ApprovedProducts/​
recommendations for vaccine use tetanus-pertussis vaccine in infancy. ucm101572.​htm. Accessed March 27,
and other preventive measures. Pediatrics. 1990;85(3):294–302 2018
Recommendations of the Immunization 4. Pertussis vaccination: use of acellular 6. US Food and Drug Administration.
Practices Advisory committee pertussis vaccines among infants and Infanrix vaccine insert. Available
(ACIP). MMWR Recomm Rep. young children. Recommendations at: www.​fda.​gov/​BiologicsBloodVac​
1991;40(RR-10):1–28 of the Advisory Committee on cines/​Vaccines/​ApprovedProducts/​
2. Cody CL, Baraff LJ, Cherry JD, Marcy Immunization Practices (ACIP) ucm101568.​htm. Accessed March 27,
SM, Manclark CR. Nature and rates [published correction appears 2018
of adverse reactions associated in MMWR Morb Mortal Wkly Rep. 7. US Food and Drug Administration.
with DTP and DT immunizations in 1997;46(30):706]. MMWR Recomm Rep. Pediarix vaccine insert. Available
infants and children. Pediatrics. 1997;46(RR-7):1–25 at: www.​fda.​gov/​BiologicsBloodVac​
1981;68(5):650–660 5. US Food and Drug Administration. cines/​Vaccines/​ApprovedProducts/​
3. Long SS, Deforest A, Smith DG, Lazaro Daptacel vaccine insert. Available ucm146759.​htm. Accessed March 27,
C, Wassilak GF. Longitudinal study of at: www.​fda.​gov/​BiologicsBloodVac​ 2018

Downloaded from www.aappublications.org/news by guest on July 18, 2018

PEDIATRICS Volume 142, number 1, July 2018 7
 8. US Food and Drug Administration. poliovirus, and Haemophilus influenzae Available at: www.​pediatrics.​org/​cgi/​
Pentacel vaccine insert. Available type B. JAMA. 2012;307(8):823–831 content/​full/​106/​4/​e51
at: www.​fda.​gov/​BiologicsBloodVac​ 25. Shimabukuro TT, Nguyen M, Martin
17. Nelson JC, Yu O, Dominguez-Islas CP,
cines/​Vaccines/​ApprovedProducts/​ D, DeStefano F. Safety monitoring
et al. Adapting group sequential
ucm172502.​htm. Accessed March 27, in the Vaccine Adverse Event
methods to observational postlicensure
2018 Reporting System (VAERS). Vaccine.
vaccine safety surveillance: results of a
9. US Food and Drug Administration. pentavalent combination DTaP-IPV-Hib 2015;33(36):4398–4405
Kinrix vaccine insert. Available at: vaccine safety study. Am J Epidemiol. 26. Medical dictionary for regulatory
www.​fda.​gov/​BiologicsBloodVac​ 2013;177(2):131–141 activities. Available at: www.​meddra.​
cines/​Vaccines/​ApprovedProducts/​
18. Daley MF, Yih WK, Glanz JM, et al. org. Accessed March 27, 2018
ucm172495.​htm. Accessed March 27,
2018 Safety of diphtheria, tetanus, 27. International Conference on
acellular pertussis and inactivated Harmonisation of Technical
10. US Food and Drug Administration. poliovirus (DTaP-IPV) vaccine. Vaccine. Requirements for Pharmaceuticals
Quadracel vaccine insert. Available 2014;32(25):3019–3024 for Human Use. MedDRA. Available at:
at: https://​www.​fda.​gov/​downloads/​
19. Hansen J, Timbol J, Lewis N, www.​ich.​org/​products/​meddra.​html.
BiologicsBloodVac​cines/​Vaccines/​
et al. Safety of DTaP-IPV/Hib Accessed March 27, 2018
ApprovedProducts/​UCM439903.​pdf.
Accessed March 27, 2018 vaccine administered routinely 28. Food and Drug Administration. 21 CFR
to infants and toddlers. Vaccine. Part 600.80. Postmarketing reporting
11. Jackson LA, Carste BA, Malais D, 2016;34(35):4172–4179 of adverse experiences. Fed Regist.
Froeschle J. Retrospective population-
1997;62:52252–52253
based assessment of medically 20. Duffy J, Hambidge SJ, Jackson LA, et al;
attended injection site reactions, Vaccine Safety Datalink. Febrile seizure 29. Rüggeberg JU, Gold MS, Bayas JM, et al;
seizures, allergic responses and risk after vaccination in children one Brighton Collaboration Anaphylaxis
febrile episodes after acellular to five months of age. Pediatr Neurol. Working Group. Anaphylaxis: case
pertussis vaccine combined with 2017;76:72–78 definition and guidelines for data
diphtheria and tetanus toxoids. Pediatr collection, analysis, and presentation
21. Moore DL, Le Saux N, Scheifele
Infect Dis J. 2002;21(8):781–786 of immunization safety data. Vaccine.
D, Halperin SA; Members of the
2007;25(31):5675–5684
12. Huang WT, Gargiullo PM, Broder Canadian Paediatric Society/Health
KR, et al; Vaccine Safety Datalink Canada Immunization Monitoring 30. DuMouchel W. Bayesian data mining
Team. Lack of association between Program Active. Lack of evidence of in large frequency tables, with an
acellular pertussis vaccine and encephalopathy related to pertussis application to the FDA spontaneous
seizures in early childhood. Pediatrics. vaccine: active surveillance by IMPACT, reporting system. Am Stat.
2010;126(2):263–269 Canada, 1993-2002. Pediatr Infect 1999;53(3):177–190
13. Jackson LA, Yu O, Nelson JC, et al; Dis J. 2004;23(6):568–571 31. Szarfman A, Machado SG, O’Neill RT.
Vaccine Safety Datalink Team. Injection 22. Zangwill KM, Eriksen E, Lee M, et al. Use of screening algorithms and
site and risk of medically attended A population-based, postlicensure computer systems to efficiently signal
local reactions to acellular pertussis evaluation of the safety of a higher-than-expected combinations
vaccine. Pediatrics. 2011;127(3). combination diphtheria, tetanus, of drugs and events in the US FDA’s
Available at: www.​pediatrics.​org/​cgi/​ acellular pertussis, hepatitis B, and spontaneous reports database. Drug
content/​full/​127/​3/​e581 inactivated poliovirus vaccine in a Saf. 2002;25(6):381–392
14. Jackson LA, Peterson D, Nelson JC, et al. large managed care organization. 32. Ball R. Methods of ensuring vaccine
Vaccination site and risk of local Pediatrics. 2008;122(6). Available at: safety. Expert Rev Vaccines.
reactions in children 1 through 6 years www.​pediatrics.​org/​cgi/​content/​full/​ 2002;1(2):161–168
of age. Pediatrics. 2013;131(2):283–289 122/​6/​e1179
33. Centers for Disease Control
15. Andrews N, Stowe J, Wise L, Miller 23. Rosenthal S, Chen R, Hadler S. The and Prevention. Recommended
E. Post-licensure comparison of the safety of acellular pertussis vaccine immunization schedule for children
safety profile of diphtheria/tetanus/ vs whole-cell pertussis vaccine. and adolescents aged 18 years or
whole cell pertussis/haemophilus A postmarketing assessment. younger; United States, 2018. Available
influenza type b vaccine and a Arch Pediatr Adolesc Med. at: https://​www.​cdc.​gov/​vaccines/​
5-in-1 diphtheria/tetanus/acellular 1996;150(5):457–460 schedules/​hcp/​imz/​child-​adolescent.​
pertussis/haemophilus influenza type html. Accessed March 27, 2018
24. Braun MM, Mootrey GT, Salive ME, Chen
b/polio vaccine in the United Kingdom. RT, Ellenberg SS. Infant immunization 34. Leroy Z, Broder K, Menschik D,
Vaccine. 2010;28(44):7215–7220 with acellular pertussis vaccines in Shimabukuro T, Martin D. Febrile
16. Sun Y, Christensen J, Hviid A, et al. Risk the United States: assessment of the seizures after 2010-2011 influenza
of febrile seizures and epilepsy after first two years’ data from the Vaccine vaccine in young children, United
vaccination with diphtheria, tetanus, Adverse Event Reporting System States: a vaccine safety signal
acellular pertussis, inactivated (VAERS). Pediatrics. 2000;106(4). from the Vaccine Adverse Event

Downloaded from www.aappublications.org/news by guest on July 18, 2018

8 MORO et al
 Reporting System. Vaccine. Sudden Unexpected Death in Infancy. monovalent rotavirus vaccination.
2012;30(11):2020–2023 Washington, DC: The National N Engl J Med. 2014;370(6):513–519
35. Kochanek KD, Murphy SL, Xu J, Tejada- Academies Press; 2003 46. Scheifele DW, Ochnio JJ, Halperin
Vera B. Deaths: final data for 2014. Natl 41. Vennemann MM, Höffgen M, SA. Cellular immunity as a potential
Vital Stat Rep. 2016;65(4):1–122 Bajanowski T, Hense HW, Mitchell EA. cause of local reactions to booster
36. McCarthy NL, Weintraub E, Vellozzi C, Do immunisations reduce the risk vaccination with diphtheria and
et al. Mortality rates and cause-of-death for SIDS? A meta-analysis. Vaccine. tetanus toxoids and acellular
patterns in a vaccinated population. Am 2007;25(26):4875–4879 pertussis antigens. Pediatr Infect
J Prev Med. 2013;45(1):91–97 42. Vennemann MM, Butterfass-Bahloul Dis J. 2009;28(11):985–989
37. Huang WT, Chen RT, Hsu YC, Glasser T, Jorch G, et al; GeSID Group. Sudden 47. Merck & Company. Rotateq vaccine
JW, Rhodes PH. Vaccination and infant death syndrome: no increased insert. Available at: https://​www.​
unexplained sudden death risk in risk after immunisation. Vaccine. merck.​com/​product/​usa/​pi_​circulars/​
Taiwanese infants. Pharmacoepidemiol 2007;25(2):336–340 r/​rotateq/​rotateq_​pi.​pdf. Accessed
Drug Saf. 2017;26(1):17–25 43. Brotherton JM, Hull BP, Hayen A, March 27, 2018
38. Centers for Disease Control and Gidding HF, Burgess MA. Probability 48. GlaxoSmithKline. Rotarix vaccine
Prevention. Sudden unexpected of coincident vaccination in the 24 insert. Available at: https://​www.​
infant death and sudden infant death or 48 hours preceding sudden infant gsksource.​com/​pharma/​content/​dam/​
syndrome. Available at: www.​cdc.​gov/​ death syndrome death in Australia. GlaxoSmithKline/​US/​en/​Prescribing_​
sids/​. Accessed June 9, 2017 Pediatrics. 2005;115(6). Available at: Information/​Rotarix/​pdf/​ROTARIX-​PI-​PIL.​
www.​pediatrics.​org/​cgi/​content/​full/​ PDF. Accessed March 27, 2018
39. Jorch G, Tapiainen T, Bonhoeffer J, et al;
115/​6/​e643 49. Yih WK, Lieu TA, Kulldorff M, et al.
Brighton Collaboration Unexplained
Sudden Death Working Group. 44. van der Lee S, Kemmeren JM, de Intussusception risk after rotavirus
Unexplained sudden death, including Rond LGH, et al. Elevated immune vaccination in U.S. infants. N Engl
sudden infant death syndrome (SIDS), response among children 4 years of J Med. 2014;370(6):503–512
in the first and second years of life: age with pronounced local adverse 50. Tieder JS, Bonkowsky JL, Etzel RA,
case definition and guidelines for events after the fifth diphtheria, et al; Subcommittee on Apparent Life
collection, analysis, and presentation tetanus, acellular pertussis Threatening Events. Brief resolved
of immunization safety data. Vaccine. vaccination. Pediatr Infect Dis unexplained events (formerly apparent
2007;25(31):5707–5716 J. 2017;36(9):e223–e229 life-threatening events) and evaluation
40. Institute of Medicine. Immunization 45. Weintraub ES, Baggs J, Duffy J, et al. of lower-risk infants. Pediatrics.
Safety Review: Vaccinations and Risk of intussusception after 2016;137(5):e20160590

Downloaded from www.aappublications.org/news by guest on July 18, 2018

PEDIATRICS Volume 142, number 1, July 2018 9
Safety Surveillance of Diphtheria and Tetanus Toxoids and Acellular Pertussis
(DTaP) Vaccines
Pedro L. Moro, Silvia Perez-Vilar, Paige Lewis, Marthe Bryant-Genevier, Hajime
Kamiya and Maria Cano
Pediatrics 2018;142;
DOI: 10.1542/peds.2017-4171 originally published online June 4, 2018;

Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/142/1/e20174171
References This article cites 37 articles, 8 of which you can access for free at:
http://pediatrics.aappublications.org/content/142/1/e20174171#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Infectious Disease
http://www.aappublications.org/cgi/collection/infectious_diseases_su
b
Vaccine/Immunization
http://www.aappublications.org/cgi/collection/vaccine:immunization
_sub
Public Health
http://www.aappublications.org/cgi/collection/public_health_sub
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on July 18, 2018

Safety Surveillance of Diphtheria and Tetanus Toxoids and Acellular Pertussis
(DTaP) Vaccines
Pedro L. Moro, Silvia Perez-Vilar, Paige Lewis, Marthe Bryant-Genevier, Hajime
Kamiya and Maria Cano
Pediatrics 2018;142;
DOI: 10.1542/peds.2017-4171 originally published online June 4, 2018;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/142/1/e20174171

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
1073-0397.

Downloaded from www.aappublications.org/news by guest on July 18, 2018