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Wise RP, Salive ME, Braun MM, et al. Postlicensure Safety Surveillance for Varicella Vaccine. JAMA. 2000;284(10):1271–1279. doi:10.1001/jama.284.10.1271
Author Affiliations: Division of Epidemiology, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research (Drs Wise, Salive, and Braun) and Laboratories of Molecular and Developmental Immunology, Division of Monoclonal Antibodies, Office of Therapeutics Research and Review (Dr Rider) and DNA Viruses, Division of Viral Products, Office of Vaccines Research and Review (Dr Krause), Food and Drug Administration, Rockville, Md; and Branches of Vaccine Safety and Development (Dr Mootrey) and Child Vaccine Preventable Diseases (Dr Seward), Division of Epidemiology and Surveillance, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Ga.
Context Since its licensure in 1995, the extensive use of varicella vaccine
and close surveillance of the associated anecdotal reports of suspected adverse
effects provide the opportunity to detect potential risks not observed before
licensure because of the relatively small sample size and other limitations
of clinical trials.
Objectives To detect potential hazards, including rare events, associated with
varicella vaccine, and to assess case reports for clinical and epidemiological
Design and Setting Postlicensure case-series study of suspected vaccine adverse events
reported to the US Vaccine Adverse Event Reporting System (VAERS) from March
17, 1995, through July 25, 1998.
Main Outcome Measures Numbers of reported adverse events, proportions, and reporting rates
(reports per 100,000 doses distributed).
Results VAERS received 6574 case reports of adverse events in recipients of
varicella vaccine, a rate of 67.5 reports per 100,000 doses sold. Approximately
4% of reports described serious adverse events, including 14 deaths. The most
frequently reported adverse events were rashes, possible vaccine failures,
and injection site reactions. Misinterpretation of varicella serology after
vaccination appeared to account for 17% of reports of possible vaccine failures.
Among 251 patients with herpes zoster, 14 had the vaccine strain of varicella
zoster virus (VZV), while 12 had the wild-type virus. None of 30 anaphylaxis
cases was fatal. An immunodeficient patient with pneumonia had the vaccine
strain of VZV in a lung biopsy. Pregnant women occasionally received varicella
vaccine through confusion with varicella zoster immunoglobulin. Although the
role of varicella vaccine remained unproven in most serious adverse event
reports, there were a few positive rechallenge reports and consistency of
many cases with syndromes recognized as complications of natural varicella.
Conclusion Most of the reported adverse events associated with varicella vaccine
are minor, and serious risks appear to be rare. We could not confirm a vaccine
etiology for most of the reported serious events; several will require further
study to clarify whether varicella vaccine plays a role. Education is needed
to ensure appropriate use of varicella serologic assays and to eliminate confusion
between varicella vaccine and varicella zoster immunoglobulin.
In March 1995, the Food and Drug Administration (FDA) licensed a live
virus varicella vaccine (Varivax; Merck & Co, Inc) to prevent chickenpox.
for nearly universal use of the new vaccine reflected the magnitude of morbidity
and mortality due to varicella: 4000 to 9000 hospitalizations and 100 deaths
per year from serious secondary infections or central nervous system and other
complications.4,5 The FDA based
licensure on studies of safety and efficacy for varicella prevention in almost
9500 healthy children and more than 1500 adolescents and adults.6
Usually well tolerated,7-12
varicella vaccine protects most recipients against primary chickenpox, and
most breakthrough cases are mild.13-15
Adverse events identified before licensure included injection site pain and
erythema and a generalized varicella-like rash in 4% to 6% of vaccinees, usually
appearing 5 to 26 days after the first dose.16
After licensure, with increasing use of a vaccine in larger and more
diverse populations, rare risks that previously escaped detection can emerge.17-20 The
fraction of children aged 19 to 35 months vaccinated against varicella rose
from 14% in the third quarter of 199621 to
43% in all of 1998.22 Some 9.7 million doses
had been sold through July 1998.23 (This projection
also used from unpublished Centers for Disease Prevention and Control [CDC]
data for 1996-1997 [Robert Synder, MA, CDC National Immunization Program,
oral and written communications, Fall 1998] and earlier information). Therefore,
in this article, we review and summarize spontaneously reported adverse events
from the first 3 years of postlicensure safety surveillance. By itself, such
passive surveillance has important limitations, but we interpret the data
within the context of previous studies and other information, including Merck's
postmarketing study of acute safety24,25
and the pregnancy registry for varicella vaccine (telephone: 800-986-8999),
which seeks information about pregnancies with conception during the 3 months
following receipt of varicella vaccine or with varicella vaccine administration
during any trimester.26
These analyses encompass reports received by the Vaccine Adverse Event
Reporting System (VAERS) from March 17, 1995, through July 25, 1998. Jointly
operated by the FDA and the CDC, VAERS consolidates voluntarily submitted
reports of suspected vaccine adverse effects from manufacturers, health care
workers, and patients for postlicensure vaccine safety surveillance.20,27-29 Although
the National Childhood Vaccine Injury Act of 1986 (Pub L No 99-660) obliges
physicians to submit certain reports, VAERS data are typical of passive drug
safety surveillance programs, with case counts that represent unknown but
probably highly variable fractions of actual event numbers. Nonetheless, with
its national scope and open-ended format, VAERS can reveal potential vaccine
safety problems with new vaccines,30 increased
numbers for previously reported events,31 and
potential associations between vaccines and entirely unanticipated events32 that might not have occurred in the relatively small
prelicensure clinical trials. (The National Technical Information Service
distributes VAERS data [http://www.ntis.gov], and the FDA provides
additional information [http://www.fda.gov/cber/vaers/vaers.htm].)
The VAERS report form solicits information regarding the vaccinee (name,
date of birth, current age, sex, and address), the adverse event or events
(date of onset, therapy, and clinical course), and vaccine or vaccines administered
(date, lot identifier, and dose sequence). VAERS adapted standardized coding
terms to index each patient's reported events.33
In selecting syndromes and other subsets for description here, we weighed
medical severity, frequency, and potential preventability. Serious cases mainly
encompass fatal or life-threatening events, hospitalizations, and permanent
Reporting rates are numbers of reports divided by estimated varicella
vaccine doses sold.23 They cannot be interpreted
as incidence rates because of potentially substantial underreporting and overreporting.
In positive rechallenge cases, an adverse event recurred after a second dose
of varicella vaccine. Occasional reports include information from a research
laboratory's polymerase chain reaction (PCR) studies of viral DNA, which can
confirm the presence of varicella zoster virus (VZV) in an isolate. Restriction
fragment length polymorphisms can then often distinguish the Japanese-origin
Oka vaccine strain from wild-type VZV circulating in the United States.34 Vaccine failure refers to primary (breakthrough)
wild-type VZV infection long enough after vaccination for most subjects to
develop protective immunity. Because few patients had confirmatory PCR studies,
we classified reports of generalized varicella at least 6 weeks after vaccination
as possible vaccine failures.
VAERS received 6574 varicella vaccine reports between March 1995 and
July 1998 (Figure 1), an overall
rate of 67.5 reports per 100,000 doses distributed, with largest numbers of
reports soon after licensure. There were 0.1 deaths, 2.8 other serious adverse
events, and 64.5 nonserious adverse events per 100,000 doses. Number of reports
by age, sex, and severity are presented in Table 1. Table 2 presents
selected adverse events. Approximately 4% of cases (2.9/100,000) were serious,
including 14 deaths
(Box 1). Among all reports, 82% of patients received only
varicella vaccine, 12% also received measles, mumps, and rubella vaccine (MMR),
and other vaccine combinations (without MMR) accounted for the balance. For
children, the sex ratio was close to 1, but females predominated among reports
for teenagers and adults. Patient reports came from every state, and 9 reports
Patient A. Shortly before her eighth birthday,
a girl with history of chronic severe asthma received a tuberculosis tine
test and multiple vaccines (DT, MMR, OPV, and VV), which were followed by
hives. Her brother had chicken pox 3 years earlier. The patient's medications
included inhaled corticosteroids. She was hospitalized for asthma during the
month after the vaccinations and again 19 months later, when she required
intubation. She died with coagulopathy and Staphylococcus
aureus sepsis. No rash had been recognized antemortem, but at autopsy
2 of several scattered papules showed "intraepidermal vesicles with viral
inclusions and multinucleated cells." The autopsy disclosed fulminant hepatitis,
esophagitis, and epiglottitis, with disseminated intravascular coagulation
and positive varicella virus cultures from pharynx, lung, blood, and urine.
Her liver was diffusely necrotic, and the few surviving hepatocytes showed
viral cytopathic changes. The pathologist interpreted thymic depletion (weight
13.9 g vs 31.0 g expected at her age) and marked depletion of splenic white
pulp as effects of corticosteroid therapy. Polymerase chain reaction studies
identified wild-type VZV.
Patient B. A 16-month-old girl with history
of upper respiratory tract infections was receiving an antibiotic for otitis
media when she was immunized with HiBV and VV. Three days later, she began
to vomit, developed progressive lethargy, and died the next day. At autopsy,
she had meningitis, hepatitis, and otitis media. Chronic inflammatory cell
infiltrates and multiple foci of isolated necrosis were found in the liver,
but no viral inclusions were found. Viral culture of liver tissue was negative.
Polymerase chain reaction identified wild-type VZV in brain tissue.
Patient C. A healthy 18-month-old boy had no
history of allergy or any prior postvaccinal adverse event when he received
multiple vaccinations (DTaP, OPV, VV) 2 to 3 weeks after a viral syndrome.
He was admitted to the intensive care unit 4 days later with a low platelet
count. He began to bleed from the mouth, had an abnormal computed axial tomography
scan of the head, and died 2 days later from cerebral hemorrhage after an
emergency left frontal lobectomy. His autopsy showed profound thrombocytopenia
with changes compatible with idiopathic thrombocytopenic purpura, including
hypercellular bone marrow with abundant megakaryocytes. Polymerase chain reaction
studies detected neither wild-type nor Oka-strain VZV. Because of the short
interval from vaccinations until recognition of thrombocytopenia, the prevaccination
viral syndrome is thought to be a more plausible trigger for idiopathic thrombocytopenic
purpura than the varicella or poliomyelitis vaccine strains.
Patient D. A 15-year-old boy's history included
microcephaly, cerebral palsy, quadriplegia, mental retardation, multiple episodes
of aspiration pneumonia, permanent tracheostomy, and thrombocytopenia thought
to be secondary to an anticonvulsant drug. One month after vaccination against
varicella, he developed adult respiratory distress syndrome with severe varicella
pneumonia, disseminated varicella sepsis, and renal failure. He died 10 days
later; no autopsy or PCR studies were performed.
Patient E. A 12-month-old boy received VV at
a well-baby visit. He had no significant history beyond colds and ear infections,
but his father and grandfather had apparently viral enteritis. The patient
vomited once and became irritable 3 days after vaccination. He received acetaminophen
the next day for irritability and fever (102° F [38.9 °C]). A rash
developed 1 week after vaccination, which a physician diagnosed as roseola,
describing it as erythematous, maculopapular, and extending from torso to
groin. An apparently minor recent head trauma from a fall was also noted.
Five days later the patient seemed well, but he became irritable and received
acetaminophen. Some 6 hours later, his mother heard a "shrill" cry and found
the patient supine and convulsing. Emergency personnel found the patient apneic
and pulseless. At autopsy, he had no histologic signs of VZV. "Morphologic
findings to suggest varicella as an etiology are not seen. The findings are
interpreted to be most suggestive of early changes of viral meningoencephalitis.
. . ."
DT indicates diphtheria and tetanus toxoids, pediatric strength; MMR,
measles, mumps, and rubella vaccine; OPV, oral polio vaccine; VV, varicella
vaccine; HiBV, Haemophilus influenzae type b conjugate
vaccine; VZV, varicella zoster virus; DTaP, diphtheria and tetanus toxoids
with acellular pertussis vaccine; and PCR, polymerase chain reaction; Box
describes only individual case reports cited in text. Details of the 9 other
reported fatalities are available on
Rash and Possible Vaccine Failure. Rashes, usually vesicular, accounted for more than half of all reports
(3640 cases, 37.4/100,000 doses) (Table
2). Polymerase chain reaction studies found VZV in 70 adequate rash
specimens. Wild-type virus appeared in 43 patients (61%), who had symptoms
at a median of 1 week postimmunization, while the Oka strain was identified
in 22 patients (31%) whose symptoms began a median of 4 weeks after vaccination.
The VZV type could not be distinguished in 5 cases. Of the 1260 reports of
possible vaccine failure (12.9/100,000), 51% described rash; 9 patients had
complications, particularly secondary bacterial infections of vesicles. Negative
serologic tests, rather than varicella infections, seemed to prompt 17% of
the reported possible vaccine failures.
Injection Site Reactions. Among 575 patients with reported injection site reactions (5.9/100,000),
the majority of reactions followed varicella vaccine administration by less
than a week, and 77% of patients received no other vaccine. Eight reports
described positive rechallenge. Four patients developed a shingles-like rash
in the immediate vicinity of the injection site from 2 to 16 weeks after vaccination.
Most of 10 serious cases involved the injection site only incidentally or
as a possible portal of initial infection.
Herpes Zoster. The characteristic rash of herpes zoster (HZ) (asymmetric, dermatomal,
and vesicular) facilitates specific diagnosis, but the reactivated virus may
be of wild-type or Oka strain. Polymerase chain reaction studies verified
VZV in specimens from 26 of 251 patients with HZ; 12 patients had the wild
type at a median of 3 weeks after varicella vaccine vaccination, while 14
had the Oka strain a median of 19 weeks after vaccination.
Pharyngitis. Pharyngitis (172 reports) frequently accompanied a rash (62% of reports),
sore throat, malaise, fever, or other upper respiratory symptoms. Two of 3
rash specimens from patients with pharyngitis were positive for Oka-strain
VZV and 1 for wild type. Nine reports of stomatitis with no specific pharyngeal
involvement included 1 positive rechallenge.
Cellulitis. Among 38 patients with cellulitis, 1 had a positive rechallenge, and
8 cases were serious. Almost half (17) of the reports involved the varicella
vaccine injection site 4 to 20 days after injection. Several patients with
infected remote vesicles of breakthrough varicella or HZ developed cellulitis
but usually without clear evidence for a role of varicella vaccine. An exception
was a 5-year-old girl with a zosteriform eruption 3 weeks after vaccination;
unilateral facial lesions involved her eye. She required hospitalization for
group A β-hemolytic streptococcal infection complicating HZ with culture-proven
VZV and PCR confirmation of Oka strain.
Hepatic Pathology. Twenty-five reports described hepatitis, elevated enzyme levels, or
other signs of hepatic pathology. Three reports specified encephalopathy,
raising the question of possible vaccine-related Reye syndrome. However, 1
of the 3 patients had a wild-type VZV infection with extensive hepatic necrosis
20 months subsequent to vaccination
(Box 1, Patient A). Encephalopathy developed
in the other 2 patients about a week after vaccination, without evident cause,
but neither patient had Reye syndrome, based on cerebrospinal fluid (CSF)
in one and magnetic resonance imaging in the other. A patient with vomiting
(another potential sign of Reye syndrome) and lethargy died with meningitis
and chronic hepatic inflammation; brain tissue yielded wild-type VZV
(Box 1, Patient B). Two patients had vomiting without encephalopathy. One had hepatitis
A, and the other probably had Gilbert syndrome.
Pneumonia. Nineteen patients with pneumonia included 5 with predisposing immunodeficiencies
from acquired immunodeficiency syndrome (AIDS), corticosteroids, or other
conditions. In addition, 2 mothers developed severe varicella pneumonia during
pregnancy. One received "shots" that may have included varicella vaccine at
5 months' gestation after her children developed chickenpox. The vaccinated
child of the other mother developed a mild rash 2 weeks after vaccination,
with the mother's varicella and pneumonia ensuing after another 2 weeks. Neither
mother had PCR confirmation of VZV strain. A severely immunodeficient 13-month-old
human immunodeficiency virus (HIV)–positive boy with pneumonia did have
direct evidence of vaccine involvement. Approximately 10 weeks after vaccination,
while he was hospitalized for gram-negative pneumonia, serology and a bronchoalveolar
lavage specimen had positive results for VZV, and PCR studies from the lavage
and a lung biopsy both identified the Oka strain.
Erythema Multiforme and Stevens-Johnson Syndrome. Erythema multiforme (EM) or its more severe form, Stevens-Johnson syndrome
(SJS), or both developed in 46 patients. Among 42 cases reported as EM, 16
patients described symptom onset within 1 week after vaccination, and disease
developed in 23 patients 1 to 5 weeks postvaccination; 3 reports lacked dates.
One individual progressed to SJS; and 4 other patients (not reported as having
EM) developed SJS. Three of the 5 SJS cases began within 1 week after vaccination.
Except for 3 adults with EM, all patients with EM or SJS were younger than
Arthropathy. Adults accounted for about half of the 45 reports of arthropathy. Thirteen
patients developed arthritis, and 32 reported only arthralgias. Specified
joints in arthritis reports included knee, ankle, metacarpal, metatarsal,
or hip, but 3 patients described neck stiffness or pain. Although arthritis
usually affected multiple joints, 3 patients had monoarticular presentations,
and 2 had negative bacterial cultures. Arthritis developed in 8 patients within
2 days after vaccination, including 4 patients with EM-associated symptoms.
Five patients had first symptoms of probable reactive arthritis 1 to 4 weeks
Thrombocytopenia. Fifteen children in the second year of life accounted for almost half
of 31 thrombocytopenia reports. Two patients died. One received varicella
vaccine shortly after a viral illness and then developed fulminant idiopathic
(Box 1, Patient C). The other patient had a history
of drug-related thrombocytopenia
(Box 1, Patient D). Symptoms in most cases
(24/31) began 4 to 28 days after vaccination. Five patients had borderline
platelet count depressions (120-147×109/L), but 22 had counts
of 52×109/L or less, including 10 below 10 ×109/L. A 14-year-old boy with probable positive rechallenge noted petechiae
on his extremities about 1 week after receiving varicella vaccine and tetanus-diphtheria
toxoid. Ten days after his second dose of varicella vaccine, his platelet
count fell to 11,000.
Anaphylaxis. All 30 patients with anaphylaxis survived (9 reports specified anaphylaxis,
and we classified another 21 as probable cases, based on compatible clinical
features, including respiratory and skin symptoms within 4 hours after vaccination).
In half of 22 detailed reports, symptoms developed within 15 minutes after
vaccination. Five of the 30 patients had significant past medical histories
of surgery for congenital cardiac anomalies or spina bifida, and several others
had asthma. Four patients had food sensitivities, including 1 with a history
of egg allergy and a similar reaction to MMR. Three patients had medication
allergies to antibiotics (2 patients) or to atropine and an unspecified ophthalmic
solution (1 patient).
Vasculitis. Among 15 vasculitis reports, 3 children aged 1 to 3 years appeared to
have Kawasaki syndrome, and 10 patients developed Henoch-Schönlein purpura
within 7 weeks of vaccination. Eight of these 10 patients were younger than
8 years; one also had EM, and 4 had associated joint pain, swelling, or both.
Aplastic Anemia. Two boys, 1 and 6 years old, developed aplastic anemia 2 months after
administration of varicella vaccine alone or with MMR. Both children required
bone marrow transplantation. Four patients had milder degrees of cytopenia
in conjunction with arthritis (3 cases) or SJS (1 case).
Neuropathies. Reports for 193 patients include a wide variety of central and/or peripheral
neuropathic signs or symptoms at a median of 4 days after vaccination, with
90% of symptoms reported as beginning within 5 weeks. In 50 of 193 cases,
the primary pathology may have been associated encephalopathy, ataxia, meningitis,
Fifteen patients developed Bell palsy, including 6 teenagers or adults,
at intervals from less than 24 hours to almost 1 month after vaccination.
Another 15 patients, aged 1 to 38 years, developed demyelinating syndromes
6 to 128 days after vaccination: transverse myelitis (5 patients), optic neuritis
(4 patients), acute demyelinating or disseminated encephalomyelitis (3 patients),
Guillain-Barré syndrome (3 patients), and multiple sclerosis (1 patient).
One patient had optic neuritis and transverse myelitis together. An unusual
16th report described a mother who developed transverse myelitis 1 month after
her infant daughter's immunization (no live vaccine product); transverse myelitis
recurred 1 year later, 3 days after the daughter's vaccination against varicella.
Among the remaining neuropathy reports, main adverse events included
hypokinesia (33 cases), paresthesia (22 cases), and hypotonia (19 cases).
A patient with positive rechallenge had paresthesias after his first dose
of varicella vaccine, followed by resolution prior to exacerbation 2 weeks
after his second dose.
Convulsions. Most of 163 reported seizures involved children aged 12 to 23 months.
Febrile seizures accounted for about one half of reports and usually occurred
after multiple immunizations. A larger proportion of reported seizures after
administration of MMR with varicella vaccine occurred in the second week postvaccination
than did reported seizures without preceding MMR (31/79 [39%] vs 9/82 [11%]).
In 25 reports, patients with no prior seizure history received only
varicella vaccine and had no evident pathology to account for convulsions.
Children younger than 5 years accounted for 12 of 13 febrile seizures in this
subset, and 10 of these 13 had convulsions within 4 days after vaccination.
Ataxia. Forty-three reports of ataxia included 22 patients younger than 2 years.
In 39 patients with interval information, symptoms began 7 to 42 days after
vaccination in 21 patients; symptoms developed during the first week in 12
cases and more than 6 weeks after vaccination in 6 patients. Many cases appeared
consistent with transient cerebellar ataxia, although 7 included encephalopathic
features. Unrelated etiologies emerged in 2 patients: a possible brain tumor
in one, and a congenital metabolic defect in the other.
Encephalopathy. Among 32 reports of encephalopathy (including encephalitis), 8 patients
had evidence for etiologies independent of varicella vaccine, such as brain
tumors in 3 patients. The primary pathology in 6 reports seemed to be aseptic
meningitis. Three patients were diagnosed as having acute demyelinating or
disseminated encephalomyelitis. The remaining 15 had a variety of symptoms,
usually 1 to 4 weeks after vaccination. In one of the better documented cases,
a 15-month-old girl developed hemiparesis 18 days after receiving diphtheria
and tetanus toxoids with acellular pertussis vaccine, Haemophilus
influenzae type b conjugate vaccine, and varicella vaccine. Her CSF
was normal, with no VZV found in PCR studies. Magnetic resonance imaging showed
edema of the left basal ganglia.
Meningitis. None of 11 meningitis reports, including 2 deaths
(Box 1, Patients B
and E), had PCR evidence of Oka-strain VZV in CSF or other specimens. Two
patients had bacterial infections (Neisseria meningitidis and Borrelia burgdorferi). Brain tissue yielded
wild-type VZV in a 16-month-old girl with vomiting, lethargy, and hepatitis
(Box 1, Patient B). Another patient developed a high fever almost 24 hours
after vaccination and progressed to aseptic meningitis. In a third case, a
33-month-old girl developed right facial HZ and viral meningitis. She had
received varicella vaccine at age 1 year when her sibling had fresh chickenpox
vesicles. Polymerase chain reaction studies identified wild-type VZV from
HZ lesions in the trigeminal distribution and no VZV in the CSF. The remaining
2 adults and 3 children all developed meningitis approximately 2 to 3 weeks
after vaccination. One woman developed a broadly distributed vesicular rash
with 75 to 100 lesions 13 days after receiving varicella vaccine, followed
after another 9 days by aseptic meningitis. Neither her CSF (by viral culture)
nor rash (by PCR) had evidence of VZV, but her 2 children developed varicella
2 and 4 weeks after the appearance of their mother's postvaccinal rash.
Reports of unintentional exposures to varicella vaccine include 145
possible secondary transmissions from vaccinees, usually without PCR confirmation
of vaccine strain VZV; 43 administrations to infants younger than 12 months
(Table 1); 19 vaccinations of
pregnant women given varicella vaccine by mistake (instead of varicella zoster
immune globulin) after chickenpox exposures; 6 ocular contacts (from splashing
during administration), usually followed by irritation and redness, with no
case of HZ ophthalmicus; 5 unintended double doses (at the same visit or months
apart), associated with injection site reactions, irritability, and anxiety;
and 2 cutaneous exposures leading to localized vesicles.
VAERS received reports of 87 women who received varicella vaccine prior
to or during pregnancy. None depicts characteristic features of congenital
varicella infection in the exposed offspring. Several reports describe gestational
varicella vaccine exposure followed by malformations (eg, Down syndrome and
tetralogy of Fallot).
Growing use of varicella vaccine in the United States promises substantial
control of chickenpox and its serious complications. Consistent with experiences
in clinical trials, our review of 6574 spontaneous reports of suspected adverse
effects from varicella vaccine during the first 3 years after licensure found
that the vast majority of reported cases were not serious. Symptoms like fever,
rash, and injection site reactions can be expected from this live virus vaccine,
while the vaccine's role in most of the infrequent reports of serious adverse
events remains unconfirmed.
VAERS data, subject to the inherent limitations of passive safety surveillance,
merit cautious interpretation. Most reports cannot prove whether vaccination
caused the subsequent symptoms. Not all adverse events that occur after vaccination
are reported, and many reports describe events that may have been caused by
confounding factors, including medications and diseases. Chickenpox remains
prevalent, and the wild-type virus accounts for many reported events, including
some serious cases. Follow-up disclosed tumors or other causes unrelated to
vaccines in other cases of serious adverse events. Larger numbers of reports
soon after licensure probably reflect the "Weber effect" of greater adverse
event reporting for new drugs.35,36
The quality of reported information varies widely, and simultaneous administration
with other vaccines (especially MMR) confounds attribution. In addition, crude
sales data preclude calculation of age-specific reporting rates. However,
surveillance data can stimulate hypotheses for systematic evaluation through
This study extends safety data from clinical trials and postlicensure
studies. Serious adverse events had not been seen before licensure, and a
systematic search afterward in hospitalization and other records of almost
90,000 vaccinated members in a health maintenance organization found no case
of an acute, serious adverse event.24,25
In clear contrast, VAERS received multiple reports of anaphylaxis. All of
these patients survived without complications. The offending allergen may
be a gelatin stabilizer in varicella vaccines, MMR, and other products.38-40
The majority of patients for whom serious adverse events were reported,
including pneumonia, encephalitis, ataxia, thrombocytopenia, SJS, arthritis,
vasculitis, and hepatitis, lacked varicella strain testing. Wild-type VZV
and other mechanisms could also cause these syndromes, and alternative etiologies
were confirmed for some patients through follow-up. Nonetheless, these and
other diseases described in multiple serious reports are plausible as potential
effects of varicella vaccine. Some are commonly recognized complications of
natural chickenpox, particularly ataxia, cellulitis, and encephalitis.41 Others have also been described with wild-type VZV
infections, including arthropathy, EM and SJS, aplastic anemia, pneumonia
(usually in adults),7 thrombocytopenia,42-47
Henoch-Schönlein purpura or vasculitis of the central nervous system,48-50 and central and peripheral
Positive rechallenge reports (eg, for idiopathic thrombocytopenic purpura
and paresthesias) bolster suspicion of relationships with varicella vaccine.
Continued safety surveillance and epidemiologic evaluations may clarify whether
these and other rarely reported adverse events can be attributed to varicella
vaccine. Since many adverse events may be caused by wild-type VZV, physicians
should obtain appropriate specimens for laboratory evaluation, including strain
identification. While commercial laboratories do not yet have this capability,
physicians can consult with CDC's National Varicella Reference Laboratory
(Scott Schmid, PhD, telephone: 404-639-0066, e-mail: firstname.lastname@example.org).
Reported seizures after administration of varicella vaccine and MMR
clustered in the second week after vaccination to a much greater extent than
did reported seizures after receipt of varicella vaccine alone. These patterns
support a role of MMR in postvaccination febrile seizures, but further research
Where autopsy and other follow-up data were available, investigations
of reported deaths often disclosed clear causes unrelated to vaccination,
including malignancies, wild-type VZV, respiratory syncytial virus, and echovirus.
An immunocompromised patient died with clinical diagnoses of varicella sepsis
and pneumonia but without laboratory studies to confirm VZV or distinguish
the strain. Another patient, severely asthmatic, died with wild-type VZV documented
21 months after vaccination. She may have had a primary varicella infection
prior to vaccination, with subsequent disseminated HZ under the influence
of corticosteroid therapy. Alternatively, corticosteroids, other asthma medications,
or both might have attenuated her response to vaccination or later depressed
her immune defenses.
The most commonly reported adverse events included rash,
possible vaccine failures, and injection site reactions.
Many cases likely represent unrelated infectious diseases. Wild-type
VZV accounts for much of the postvaccinal varicella-like rash. If caused by
VZV, rash within 7 days after vaccination is almost certain to be wild-type
virus, while cases occurring 1 to 6 weeks after vaccination may be either
Oka-strain or wild-type virus; almost all disseminated varicella rash beyond
6 weeks after vaccination is caused by wild-type virus and represents partial
or complete vaccine failure. Most suspected secondary transmissions occurred
between 7 and 42 days after vaccination and would require laboratory studies
to distinguish between Oka-strain and wild-type VZV.
Vaccine-strain HZ may occur among vaccinated immunocompromised patients
at a lower rate than in similar patients after natural varicella.57 Our data verify that Oka-strain HZ can also occur
in immunocompetent vaccinees. However, half of the reported HZ cases with
adequate laboratory specimens had wild-type virus, which is evidence of natural
VZV infection before immunization. The short intervals after vaccination until
HZ occurrence in several patients seem consistent with the intriguing hypothesis
that varicella vaccine might, in rare cases, provoke reactivation of latent
Involvement of the Oka strain in an immunocompromised patient with pneumonia
was confirmed with PCR studies. Immune deficits (eg, congenital or resulting
from AIDS or drug-induced immunosuppression) may contraindicate live virus
vaccination. In addition, a postlicensure field study found lower vaccine
effectiveness among children with asthma.15
Further studies should examine immune responses to vaccination in asthmatics
receiving various treatment regimens. For patients who require varicella vaccine
prior to planned immunosuppression, risks may be minimized by first allowing
some weeks for the acute vaccine-induced VZV infection to resolve. (However,
this precaution may not be necessary with relatively low-dose therapy.1) Vaccinees with potentially impaired defenses should
be closely monitored for the possible need to treat complications with acyclovir.
VAERS reports confirm that secondary transmission of the vaccine virus
can occur, probably rarely. The risk of person-to-person passage of Oka-strain
VZV is quite small6,59,60
and probably limited to patients with a rash.7
Only 3 cases of secondary transmission have been confirmed in immunocompetent
persons.3 Public health authorities recommend
that family members and other close contacts of immunocompromised persons
should receive varicella vaccine, in view of the threat otherwise faced by
these patients from natural chickenpox and its complications.1,2
If a vaccinee develops a rash, isolation from the immunocompromised person
can reduce the transmission risk, but even with contact, vaccine-strain disease
is unlikely and usually mild.
No vaccine has perfect efficacy, but varicella vaccine nearly always
protects against severe varicella.15 Three
postlicensure studies have demonstrated vaccine effectiveness in the range
of 85% to 90% for prevention of all disease and 100% for prevention of severe
Currently, approximately 1 in 10 vaccinated children may develop mild breakthrough
disease following exposure to chickenpox. As exposures to natural varicella
decline with increasing vaccine coverage, numbers of breakthrough cases should
More than 200 reports of possible vaccine failure apparently stemmed
from misinterpretation of negative postvaccination serologic results as failures
to seroconvert. Commercial assays are not sufficiently sensitive to detect
all protective antibody responses following vaccination.16
Physicians and pertinent laboratory personnel should recognize this limitation
in available tests.
Merck and the CDC jointly monitor potential fetal risks from gestational
exposures through a pregnancy registry,26 which,
like VAERS, has received no report of congenital varicella syndrome.63 However, reported pregnancy exposures highlight the
need for physicians to ask women of childbearing age, before administering
varicella vaccine, about the possibilities of current pregnancy or planned
or potential conception in the next month. Gestational exposures to varicella
vaccine through confusion with varicella zoster immune globulin delay protection
against VZV64 and expose the developing embryo
to a potentially teratogenic virus.65 Continued
reporting of this error despite initial publicity66
indicates a need for additional educational interventions.
Chickenpox can be serious and even deadly, but varicella vaccine can
now prevent serious varicella infections with a high degree of reliability.1-3 Safety surveillance
through VAERS confirms that most of the vaccine's adverse effects are minor.
Although reports to VAERS provide either tentative or clear evidence for a
variety of serious vaccine risks, all appear to be rare, and the majority,
while plausible, lack confirmation of causation by Oka-strain VZV. The manufacturer,
in consultation with the FDA, has revised safety labeling for varicella vaccine
(Table 3) based on continuous
assessment of postmarketing spontaneous reports. Additional studies6 and ongoing investigations within the CDC's Vaccine
Safety Datalink (VSD) Project37 will evaluate
several of the hypothesized vaccine risks, including ataxia, aplastic anemia,
encephalopathy, seizures, and thrombocytopenia. Our analysis also suggests
that further educational measures might help assure appropriate use and interpretation
of varicella serologic assays and eliminate inadvertent substitutions of varicella
vaccine for varicella zoster immune globulin, particularly in pregnancy. With
continuing improvements in varicella vaccine coverage, evidence for control
of varicella will emerge as declines in disease incidence, varicella-related
hospitalizations, and mortality.67
A summary of safety reports received since preparation of this article
is presented in Box 2.
Vaccine safety surveillance is an ongoing process. VAERS received over
3000 additional varicella vaccine case reports in the 18 months after July
1998, with most patterns remaining stable as reports continue to accrue. However,
3 reports from this period subsequent to our primary analysis have positive
rechallenge or other special information value.
Patient A. A 13-month-old boy with severe combined
immunodeficiency developed hepatitis and respiratory distress 2 weeks after
receiving varicella vaccine. Liver biopsy showed VZV infection, and PCR testing
of the biopsy supernatant and of a rash specimen 6 weeks after vaccination
both identified Oka-strain VZV. This case verifies vaccine virus involvement
in hepatic pathology. In addition, as in the HIV-positive patient who developed
pneumonia, it demonstrates persistence of vaccine virus activity for at least
6 weeks in an immunocompromised host.
Patient B. A 16-year-old boy without previous
convulsions had an absence seizure 3 days after varicella vaccine. One month
later, 2 generalized tonic-clonic seizures followed his second vaccine dose
at the same interval. This patient's positive rechallenge for seizure activity
increases suspicion that varicella vaccine may be more than a coincidental
factor in observations of postvaccinal convulsions.
Patient C. Two weeks after receiving varicella
vaccine, a 4-year-old girl developed hemiparesis with evidence from magnetic
resonance imaging for cerebral infarctions in the putamen and internal capsule.
Her apparent cerebrovascular accident assumes particular importance after
recent description of a significant statistical association between natural
chickenpox and subsequent ischemic strokes in children.68