Robert P. Wise, John Iskander, R. Douglas Pratt, Scott Campbell, Robert Ball, Robert P. Pless, M. Miles Braun. Postlicensure Safety Surveillance for 7-Valent Pneumococcal Conjugate Vaccine. JAMA. 2004;292(14):1702–1710. doi:10.1001/jama.292.14.1702
Author Affiliations: Division of Epidemiology,
Office of Biostatistics and Epidemiology (Drs Wise, Ball, and Braun), and
Division of Vaccines and Related Products Applications, Office of Vaccines
Research and Review (Dr Pratt), Center for Biologics Evaluation and Research,
Food and Drug Administration, Rockville, Md; Immunization Safety Branch, Epidemiology
and Surveillance Division, National Immunization Program, Centers for Disease
Control and Prevention, Atlanta, Ga (Drs Iskander and Pless and Mr Campbell);
and Immunization Safety Unit, Immunization and Respiratory Infections Division,
Centre for Infectious Disease Prevention and Control Health Canada, Ottawa,
Ontario (Dr Pless).
Context Clinical trials evaluate a vaccine’s safety before approval, but
some risks may escape detection or adequate characterization until larger
population exposures occur after licensure.
Objective To summarize reports of events occurring after vaccination with 7-valent
pneumococcal conjugate vaccine (PCV), including those that may warrant further
investigation to assess possible causation by PCV.
Design Descriptive epidemiology of reports submitted to the Vaccine Adverse
Event Reporting System (VAERS), a national passive surveillance database.
Setting and Patients United States during first 2 years after licensure of PCV (February
2000 through February 2002). Reports studied were for children younger than
18 years and vaccinated with PCV.
Main Outcome Measures Numbers and proportional distributions of reports.
Results A total of 4154 reports of events following PCV were submitted to VAERS,
for a rate of 13.2 reports per 100 000 doses distributed. Multiple vaccines
were given in 74.3% of reports.The most frequently reported symptoms and signs
included fever, injection site reactions, fussiness, rashes, and urticaria.
Serious events were described in 14.6% of reports. There were 117 deaths,
23 reports of positive rechallenges, and 34 cases of invasive pneumococcal
infections possibly representing vaccine failure. Immune-mediated events occurred
in 31.3% of reports. All 14 patients with anaphylactic or anaphylactoid reactions
survived. Thrombocytopenia developed in 14 patients and serum sickness in
6 others. Neurologic symptoms occurred in 38% of reports. Seizures described
in 393 reports included 94 febrile seizures.
Conclusions The majority of reports to VAERS in the first 2 years after licensure
of PCV described generally minor adverse events previously identified in clinical
trials. The proportion of reports portraying serious events was similar to
that for other vaccines. Although there are important limitations in passive
surveillance data, and caution in their interpretation is necessary, symptoms
experienced by a few children more than once after successive PCV doses, including
allergic reactions, prolonged or abnormal crying, fussiness, dyspnea, and
gastrointestinal distress, warrant continued surveillance, as do reports of
rare but potentially serious events, such as seizures, anaphylactic or anaphylactoid
reactions, serum sickness, and thrombocytopenia.
The Food and Drug Administration (FDA) licensed the 7-valent pneumococcal
conjugate vaccine (PCV, trade name Prevnar, Wyeth Pharmaceuticals, Philadelphia,
Pa) on February 17, 2000. The recommended vaccination series includes doses
at ages 2, 4, 6, and 12 to 15 months, with catch-up doses through 9 years
of age.1 Pneumococcal conjugate vaccine has
been rapidly adopted into routine pediatric practice, reflecting concern for
the gravity of serious pneumococcal infections and confidence in the efficacy
and safety of PCV.
Prior to licensure, almost 19 000 infants and children received
PCV in randomized clinical trials that demonstrated good efficacy against
invasive infections and a favorable safety profile. Common adverse events
in the first days after vaccination included injection site reactions, fever,
irritability, drowsiness, restless sleep, decreased appetite, vomiting, and
diarrhea.1 However, rare vaccine complications
may not emerge before licensure for a variety of reasons, particularly the
relatively limited sample sizes of trials.2 In
addition, the control group in the main study received another experimental
vaccine, rather than a placebo.3 If both vaccines
provoked similar adverse effects, little or no difference between the 2 groups
might have been evident. Therefore, postmarketing safety surveillance remains
essential. This report summarizes data from the Vaccine Adverse Event Reporting
System (VAERS) in the first 2 years after PCV licensure.
We studied case reports to VAERS of events occurring after PCV vaccinations
through February 2002, allowing at least 3 months for potential follow-up
of each case. We excluded 86 foreign reports and 19 reports detailing patients
older than 17 years but applied no other criteria, such as minimum or maximum
intervals after vaccination.
Jointly operated by the FDA and the Centers for Disease Control and
Prevention (CDC) since 1990, VAERS accepts voluntarily submitted reports of
events from manufacturers, health care workers, and patients.4- 6 (Manufacturer
reporting to VAERS is required but mainly comprises transmission of information
that had been voluntarily supplied by physicians, patients, or other primary
reporters.) Although experiences reported to VAERS are generally voluntary,
unsolicited, and reflect concern or suspicion of a possible relationship to
1 or more vaccine products, VAERS received a few reports for events detected
through a systematic safety surveillance study in a health maintenance organization.
Because of important limitations in passive surveillance, data from VAERS
require cautious interpretation.3 Reported
events may be a small fraction of all that occur, and they frequently defy
facile assessment of whether vaccinations played a causal role. Nonetheless,
the potential to detect important clues from patterns among collected reports
warrants careful surveillance.
We used information from the VAERS report form on the vaccinee (name,
date of birth, age, sex, address); the event(s) (date of onset, therapy, and
clinical course); and vaccine(s) administered (date, lot identifier, and dose
sequence). The VAERS database indexes reported events with standardized coding
terms7 that trained nurses assign after reviewing
each submitted report. The date of onset refers to the earliest symptom in
each report. Although most reports received multiple codes, we obtained intervals
from vaccination to onset of pertinent events for selected subsets during
individual case reviews. We also queried free text fields from the report
form and follow-up notes. For example, we sought potential anaphylaxis cases
by looking for the anaphylaxis code as well as “anaphyl,” “epineph,”
To select subsets of reported cases for analysis, we weighed their frequencies
and medical severity as indicators of potential population impact, as well
as practical preventability and plausibility for relationship with vaccination.8 Regulatory criteria were used to classify VAERS reports
as serious and mainly involved death, life-threatening illness, hospitalization,
or persistent disability.5,9 Positive
rechallenge reports, events that followed PCV and recurred after a subsequent
dose, were analyzed in detail, as such reports suggest (but cannot confirm)
causal association with vaccination. Neurologic and immune-mediated events
were also highlighted. Because of the suggestion of more seizures in the PCV
group than in the comparator group in the primary clinical trial,2 we planned to study the first 100 seizure reports
with supplementary follow-up to clarify previous medical history and subsequent
clinical course. The final data set excluded 2 duplicates, leaving 98 cases
for analysis. For injection site reactions, we reviewed reports in the first
year after PCV licensure to identify the pertinent vaccine in cases with multiple
immunizations. Many physicians understand that no vaccine is 100% effective
and, therefore, do not consider vaccine failure to be an adverse event. However,
we included reports of pneumococcal infections subsequent to administration
of PCV as potential vaccine failures.
Unless otherwise specified, we excluded missing data when calculating
proportions. Reporting rates are calculated by dividing numbers of reports
by estimated PCV doses distributed, extrapolated from CDC biologics surveillance
Among 4154 reports of events after immunization with PCV, 608 (14.6%)
described serious events, including 117 deaths (Table 1). The number of reports received increased over the first
year after licensure and then declined. Infants younger than 6 months accounted
for 27.3% of reports. Females accounted for slightly less than half of all
cases (47.5%). Based on an estimated distribution of 31.5 million doses within
the United States during the first 2 years after licensure of PCV, the overall
reporting rate was 13.2 per 100 000 vaccinations and 1.9 per 100 000
for serious reports. Three fourths (74.3%) of reports described multiple vaccines
administered together (Table 2). Reported
symptoms began within 1 week after vaccination in 86.6% of cases. The most
frequently reported symptoms and signs included fever, injection site reactions,
fussiness, rashes, urticaria, and vasodilation.
Table 2 provides a detailed account
of reported events. Data are summarized below for reports of death, positive
rechallenges, neurologic events, potentially immune-mediated events, and reports
of pneumococcal infection.
Reports to VAERS described 117 deaths after vaccination with PCV (Table 3). A cause was identified in 37.6%. Median
intervals from vaccination to death were 51 days in the 12 cases reported
from the health maintenance organization active surveillance and 3 days for
the other 105.
Three patients who died had seizures without evident etiologies. A 9-month-old
female developed status epilepticus 2 days after her second dose of PCV, given
with hepatitis B vaccine and a tuberculin skin test. She had a recent diagnosis
of “gross motor delay”; no autopsy was performed. A pair of fraternal
twins had seizure disorders that began after immunizations. One died at 12
months of age with no cause identified at autopsy. Her sister died 4 months
later; postmortem histology indicated she had bronchopneumonia, and the pathologist
attributed death to a seizure disorder.
Three deaths involved incidental liver pathology. One patient had liver
enzyme elevations with septic shock and meningitis due to Streptococcus pneumoniae (serotype 14). The conclusion after postmortem
examination of the second patient was probable sudden infant death syndrome
(SIDS) with mild nonspecific hepatic and pulmonary congestion. The autopsy
for the third also disclosed hepatic congestion, but the cause of death remained
Autopsies on 2 patients identified acute encephalopathy after multiple
immunizations. A previously healthy 10-week-old female died 11 days after
vaccinations. Her postmortem examination disclosed anoxic encephalopathy,
“resuscitated SIDS,” and multisystem ischemia. A 12-month-old
male with a history of premature birth had vomiting, diarrhea, and fever 1
day before multiple vaccinations and then died with acute cerebral edema less
than 1 day afterward.
A patient with frequent diarrheal episodes over the previous few months
was waiting for surgery when he died 3 days after multiple vaccinations. A
barium enema had disclosed intussusception.
In 23 reports, patients experienced the same event after PCV (often
with additional vaccines) more than once. These positive rechallenges involved
fever, irritability, or other nonspecific symptoms (7 cases); respiratory
symptoms (4 cases); prolonged or abnormal crying (4 cases); gastrointestinal
(GI) disturbance (3 cases); possible allergic reactions (2 cases); seizures
(2 cases); and hair loss (1 case).
Of all PCV reports, 37.9% included at least 1 potential neurologic symptom
or diagnosis. Among the first 98 patients with reported seizures, supplementary
follow-up disclosed that 79 (80.6%) had a prior history of seizure or a fever
at the time of the seizure; the other 19 (19.4%) had no fever reported with
the seizure and did not appear to have a medical history that might account
for the seizure. By 2 months after the initial postvaccinal seizure, 12 of
the 19 patients had no further seizures and were not receiving anticonvulsant
therapy. Two others experienced at least 1 additional seizure associated with
high fever or epilepsy diagnosed after vaccination but were not treated with
anticonvulsants. The remaining 5 patients did receive anticonvulsant medications.
Three of these 5 continued receiving therapy, 2 for epilepsy and 1 for atypical
Aicardi syndrome (a congenital neurologic seizure disorder); the other 2 children
discontinued anticonvulsants 1 month and 5 months after their initial seizures
and remained free of seizure activity.
The 54 patients with ataxia (11 cases), abnormal gait (39 cases), or
both (4 cases) developed symptoms from hours to weeks after vaccination, except
for 1 patient who developed ataxia more than 2 months after receiving PCV
and varicella vaccine. In 19 cases, patients had received live virus vaccines
for varicella (12 cases) and/or measles, mumps, and rubella vaccine (15 cases).
One patient who received only PCV and hepatitis B vaccine began to vomit repeatedly
and manifested truncal ataxia (inability to stand despite having begun to
walk 2 weeks earlier) and nystagmus about 13 hours after vaccination, interpreted
as acute cerebellar ataxia. Three reports described ataxia, and 12 described
gait disturbance after PCV alone. One patient’s ataxia began before
his vaccination. The second developed ataxia and slurred speech 3 weeks after
vaccination and was later diagnosed as having Sydenham chorea. The third had
persistent otitis media, already treated with 2 antibiotics before vaccination,
when his physician added cefpodoxime (possible adverse effects include dizziness,
vertigo, shakiness), followed 6 to 12 hours later by onset of ataxia.
Almost one third of reports (31.3%) describe allergic or other syndromes
that might reflect abnormal immune responses. In particular, anaphylactic
or anaphylactoid reactions were described in 14 reports; 12 of the 14 patients
had received only initial doses of PCV, and the other 2 reports described
no problem after previous doses. All 14 patients survived; at least 8 received
epinephrine. Symptoms emerged 5 to 30 minutes after vaccination in 8 patients
and after 1 to 4 hours in the other 6. Three patients received PCV alone;
2 of them had symptoms within 5 to 10 minutes. One patient developed symptoms
150 minutes after receipt of PCV and diphtheria and tetanus toxoids and acellular
pertussis vaccine. An allergist later learned that a second feeding with a
particular infant formula preceded symptoms by 30 minutes. The baby had previously
developed erythema and swelling of his lips after the first trial of that
formula. With this history and consistent skin test results, the allergist
concluded that casein in the formula had most likely been at fault.
Although 78 reports described possible thrombocytopenia (with descriptions
of thrombocytopenia, petechiae, purpura, or ecchymosis), only 14 provided
documentation of depressed platelet counts, with 2 mildly affected patients
(50 000-150 000 platelets/mm3) and 12 with severely depressed
counts (<20 000/mm3). None died. One of the 14 patients
developed immune thrombocytopenic purpura and aplastic anemia 1 week after
her first dose of PCV, given alone. The other 13 patients developed symptoms
1 to 35 days after multiple immunizations. At least 8 patients had vaccines,
medications, or viral or bacterial infections as potential causes, including
4 who had received measles, mumps, and rubella vaccine (28.6% vs 17.5% of
other PCV reports). Among the other 64 reports with possible thrombocytopenia
but platelet counts unspecified or higher than 150 000/mm3,
27 involved injection site bruising or other local reactions, and 25 involved
Antibiotics provided an alternative etiology for 1 patient with serum
sickness, but a large fraction of these case reports (5/6) described no additional
vaccine given with PCV.
Among 7 patients who died with pneumococcal infections, 6 had received
only 1 or 2 PCV doses, and 2 had vaccine serotypes identified. A 9-month-old
male died with serotype 14 pneumococcal meningitis 19 days after his first
dose of PCV. A 13-month-old male died with serotype 19F pneumococcal meningitis
4 months after his third PCV dose. His history included premature birth, congenital
bronchomalacia, a tracheostomy, duodenal atresia, and a tracheoesophageal
Invasive S pneumoniae infections developed
in 34 patients with meningitis, pneumonia, or sepsis after 1 PCV dose (11
cases), 2 doses (11 cases), 3 doses (10 cases), or 4 doses (2 cases). Ten
of 23 patients with pneumococcal meningitis had received only initial doses
of PCV (Table 4). Of 21 reports with
serotype data from any invasive pneumococcal infection, 19 identified vaccine
serotypes (4, 6B, 9V, 14, 18C, 19F, 23F). Every vaccine serotype except type
4 appeared in at least 1 report; the most frequently occurring serotype was
19F (7 cases).
The great majority of reports in the first 2 years after PCV licensure
described minor signs and symptoms previously recorded during clinical trials.
The proportion of reports portraying serious events (14.6%) was similar to
that for other vaccines (14.3%).10 Still, rare
reports of serious events, including seizures, anaphylactic or anaphylactoid
reactions, serum sickness, and thrombocytopenia, might represent uncommon
risks and warrant further assessment. Symptoms that recurred in children after
repeated doses of PCV, including allergic reactions, prolonged or abnormal
crying, fussiness, dyspnea, and GI distress, also warrant further study.
The interpretation of VAERS reports requires caution because many reported
events may not be due to the vaccine. In addition to the fact that other vaccines
were administered in two thirds of PCV reports, all of the events described
in these 4154 reports (except for true vaccine failures) can occur independently
of immunizations. Children frequently develop fever, vomiting, diarrhea, and
rashes in the absence of any vaccination. Febrile seizures are not rare. Even
anaphylaxis can have nonvaccine causes. With time after vaccination, intercurrent
exposures to nonvaccine antigens (food or others) may occur, as illustrated
by the patient with anaphylaxis whose positive rechallenge and skin test evidence
implicated casein in formula as the offending antigen. Local reactions at
vaccine injection sites are common and nearly always benign and transient.
With both temporal and anatomic associations between injection site reactions
and recent vaccination, we usually infer causation, as reflected in terminology
(“reaction” rather than “report”), but even these
events may stem from immunization technique, host experience (prior exposure
to antigens, as in Arthus reactions), or other factors apart from a vaccine’s
intrinsic composition. Positive rechallenges seem less likely to arise by
chance alone, but they do not absolutely confirm that a vaccine caused an
adverse event, especially when the vaccination and event are both common.
Passive surveillance systems have important limitations, including underreporting.11 Despite incomplete case ascertainment, however, the
value of VAERS-based safety surveillance was demonstrated when a small number
of initial intussusception reports for rotavirus vaccine led to epidemiologic
studies that verified the hazard. Even after publicity stimulated additional
reporting, VAERS received information on only an estimated 47% of cases that
had actually occurred.12 Underreporting of
adverse events undoubtedly affects PCV as well. The increasing report numbers
in the first year probably reflect growing utilization, along with the “Weber
effect” of greater reporting enthusiasm or diligence for new products.13 The subsequent decrease may relate in part to PCV
shortages, which occurred between August 2001 and late 2002,14 as
well as waning of reporting enthusiasm and reporting delays.
Although limitations of VAERS preclude ascribing reported seizures to
PCV, vaccination may have played a role in at least some cases. In the primary
clinical trial before licensure, a few more patients had seizures within 3
days after PCV than after the meningococcal comparator vaccine (8 vs 4), raising
concern about a possible association. However, all of these seizure patients
had received at least diphtheria, tetanus, and whole cell or acellular pertussis
vaccine concomitantly. We found that most of nearly 400 seizures reported
to VAERS followed multiple vaccinations. One patient had a positive rechallenge,
but his febrile seizures were associated with infections as well as vaccinations.
Like other vaccines, PCV can provoke fever, which could trigger a febrile
seizure. From prelicensure studies, up to 23.9% of PCV recipients developed
fever of 38°C or higher in the first 2 days, and 0.9% to 2.5% had fever
higher than 39°C.2 However, about 1 in
5 patients with a seizure reported to VAERS did not have a history of fever
or a previous seizure disorder. Most of these patients did not require subsequent
Similarly, some allergic reactions may be attributable to PCV. Reported
allergic events included anaphylactic or anaphylactoid reactions within minutes
to hours after PCV. Many other patients with urticaria, facial edema, angioedema,
pruritus, or unspecified allergic reactions may have had immediate hypersensitivity
reactions of lesser intensity. Some patients had symptoms only days after
Pneumococcal conjugate vaccine may have contributed to some of the other
reported immune-mediated adverse events. The 12 reports of thrombocytopenia
with profoundly depressed platelet counts illustrate uncertainties in the
interpretation of passive surveillance data. Thrombocytopenia is a recognized
complication of measles-containing vaccines15- 17 and
has been reported after varicella vaccine.18 Although
both products have live viruses, an immunologic mechanism might not require
a live virus agent.19 On the other hand, most
patients had received multiple vaccines, their intervals from vaccination
to onset varied, and several had infectious or drug exposures that might account
for their thrombocytopenia.
Postvaccinal vasculitis has been described after other immunizations,
including varicella vaccine,18 and Henoch-Schönlein
purpura is rare in young children.20 However,
we suggest caution in assessment of this diagnosis as a potential risk of
PCV. Several rash illnesses are common in young children; many vasculitis
reports to VAERS lack clinical details and laboratory evidence, and none had
a biopsy. Most reports of Henoch-Schönlein purpura did not describe arthralgias
or intestinal symptoms.
After extensive review of medical literature and clinical vaccine trials,
Jefferson and Demicheli21 found “no evidence
of a link between IDDM [insulin dependent diabetes mellitus] and vaccination
in humans.” The Institute of Medicine recently concurred with this assessment,22 and 2 recent studies described no association between
vaccines and diabetes mellitus.23,24 The
6 reports of diabetes mellitus after PCV amount to very few cases when contrasted
with the millions of vaccine doses administered. Their appearance after PCV
seems more likely to be purely coincidental, with reporting stimulated by
publicity about potential relationships to vaccination.25
We previously described alopecia reports to VAERS with 3 clear positive
rechallenges for hepatitis B and 1 with influenza virus vaccine.26 One
of the 2 reports for PCV now provides a second positive rechallenge case for
a vaccine other than hepatitis B. On both occasions, alopecia began 1 week
after administration of PCV with 2 other bacterial vaccines. The sequence
suggests that alopecia may be a nonspecific response to vaccinations or other
immunologic stimulation, rather than necessarily having a specific relationship
with hepatitis B.
The reported deaths cannot be attributed to PCV. Even among fatalities
from pneumococcal infection in PCV recipients, only 1 patient had an infection
with a pneumococcal serotype included in the vaccine after receiving more
than 2 doses. We analyzed all reported deaths, but the 12 from active surveillance
might differ from most VAERS cases in various ways. Most importantly, clinical
concern about a possible relationship with vaccination probably motivates
most voluntary reporters after they see an unexpected event in a recently
immunized patient. We believe that the short median interval from vaccination
until death for the spontaneously reported cases reflects this psychology,
in clear contrast to the substantially longer median for the 12 actively ascertained
cases. Silvers et al27 reviewed fatality reporting
to VAERS during a period prior to PCV licensure. Unexplained deaths predominated
then as they do for PCV reports now. A report to VAERS is less likely for
a death after evident illness or when an autopsy identifies pathology. In
contrast, deaths that remain unexplained after investigation are more likely
to engender concern over a possible relationship to recent vaccinations. Several
systematic studies failed to find an association between SIDS and vaccinations.28- 32 The
Institute of Medicine recently reviewed sudden unexpected infant deaths, finding
that the weight of evidence does not support causal linkage between SIDS and
multiple vaccinations routinely scheduled together.33
Most or all of the GI symptoms reported with PCV might not relate to
vaccination, despite positive rechallenges, since diarrhea and vomiting are
so prevalent during infancy. The tendency for reported symptoms to follow
soon after vaccination (eg, nearly half of GI cases in the first day) may
reflect selective reporting. Physicians and patients’ families would
be progressively less likely to wonder about a possible vaccine role as the
postvaccination interval increases. The Weber effect and publicity about rotavirus
vaccine and intussusception may have stimulated reporting to VAERS for the
5 intussusception cases with PCV, even though it is neither a live virus nor
an orally administered vaccine. However, it is routinely given to infants,
the age group in which intussusception typically occurs.
A report of neonatal hyperbilirubinemia after accidental gestational
exposure to PCV is the only pregnancy exposure to come to light thus far.
Neonatal hyperbilirubinemia is common, usually promptly recognized and treated,
and has no known relationship to immunizations. Although PCV is not a live
virus product and is not indicated for adults, additional case reports would
contribute to clarifying any potential risk from gestational exposure. The
Institute for Safe Medication Practices described 3 other adults who received
PCV by mistake.34 We found misclassification
of the 2 pneumococcal vaccines, PCV and the polyvalent polysaccharide vaccine,
in several cases. Inadvertent product substitutions could deprive an adult
of protection from several serotypes included in polyvalent polysaccharide
vaccine but not in PCV. Conversely, if a young child receives the adult product,
rather than PCV, immunogenicity would be inadequate.
Although VAERS receives reports of suspected vaccine failures, no vaccine
protects every recipient. The main clinical trial of PCV demonstrated efficacy
of 100% after 3 or 4 doses for protection against pneumococcal infections
with serotypes in PCV (with a lower 95% confidence estimate of 75.4%).1 Efficacy calculated for prevention of any invasive
pneumococcal infection (not just vaccine serotypes) among children who received
1 or more doses was 88.9% (with a lower 95% confidence limit of 63.8%).1 If PCV has 90% protective efficacy against any invasive
pneumococcal infection, roughly 150 children per million vaccinees younger
than 3 years could be expected to contract these infections each year. Although
few reports to VAERS for invasive pneumococcal infections had serotype information
(21 cases over the 2 years after licensure of PCV), such reports are shared
with a new CDC surveillance program (available at: http://www.cdc.gov/nip/diseases/pneumo/PCV-survrpts/default.htm) that seeks to systematically identify serotypes of isolates from normally
sterile sites. By monitoring for infection shifts toward strains not in PCV,
this program could guide serotype selections for future polyvalent pneumococcal
In the first 2 years after PCV licensure, the great majority of VAERS
reports portray minor adverse events already observed during clinical trials.
Our focused follow-up of the first 98 seizure reports addressed a concern
arising from the prelicensure trial. We found that the large majority of reported
seizures were febrile or in patients with a previous history of seizures.
Although allergic reactions, prolonged or abnormal crying, fussiness in infants,
dyspnea, and GI distress are common childhood symptoms apart from immunizations,
their occurrence with positive rechallenges after PCV increases the possibility
of occasional causal relationship with vaccination and, therefore, warrants
continued surveillance for these events. The FDA and CDC will also continue
to monitor VAERS for reports of rare but potentially serious events, such
as seizures, anaphylactic or anaphylactoid reactions, serum sickness, and
Corresponding Author: Robert P. Wise, MD,
MPH, Center for Biologics Evaluation and Research, Food and Drug Administration,
HFM-225, 1401 Rockville Pike, Rockville, MD 20852-1448 (R.P.Wise@cber.fda.gov).
Author Contributions: Dr Wise had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Wise, Iskander, Ball,
Acquisition of data: Wise, Pless, Campbell.
Analysis and interpretation of data: Wise,
Iskander, Pratt, Ball, Campbell, Braun.
Drafting of the manuscript: Wise, Iskander,
Critical revision of the manuscript for important
intellectual content: Wise, Iskander, Pratt, Pless, Ball, Campbell,
Administrative, technical, or material support:
Wise, Iskander, Pless, Ball, Campbell, Braun.
Study supervision: Wise, Ball, Braun.
Technical expertise: Wise, Iskander, Pratt,
Campbell, Ball, Pless, Braun.
Disclaimer: This report reflects work by the
coauthors in their capacity as federal employees of the US Food and Drug Administration
(FDA) and the Centers for Disease Control and Prevention (CDC). They received
no additional funding or support. Data collection and management of the Vaccine
Adverse Event Reporting System (VAERS) database is a joint responsibility
of the FDA and CDC.
Role of the Sponsors: The coauthors are solely
responsible for the design and conduct of the study, the analysis and interpretation
of the data from the VAERS program, and the preparation of the report. Supervisors
at the FDA and CDC reviewed drafts, recommended improvements, and approved
the final version.
Acknowledgment: Susan Ellenberg, Frank DeStefano,
Karen Goldenthal, Karen Midthun, Mary McCauley, Beth Begier, and Ann McMahon
offered very helpful comments on advanced drafts. Staff of Constella Group,
Inc (formerly Analytical Sciences, Inc) supplied critical database support.
Wyeth-Ayerst-Lederle Vaccines submitted many VAERS reports and assisted in
identification of occasional duplications. We also appreciate the support
of the other VAERS Working Group members (at CDC: Robert Chen, Roseanne English-Bullard,
Penina Haber, Sharon Holmes, Anne Huang, Elaine Miller, Susanne Pickering,
Vitali Pool, Ali Rashidee, Weigong Zhou; at FDA: David Davis, Evan Macosko,
Tatiana Oussova, Phil Perucci, Sarah Richman, Sean Shadomy, Lise Stevens,
Frederick Varricchio, Xu Wang, Jane Woo). We feel special gratitude to all
patients and their parents, nurses, pharmacists, physicians, and others who
reported adverse events to the VAERS program.
Other Resources: The following Internet sites
provide additional information for people wishing to file a report to VAERS
or to learn more about the VAERS program: http://www.vaers.org; http://www.fda.gov/cber/vaers/vaers.htm; http://www.cdc.gov/nip.