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5
Varicella Virus Vaccine
INTRODUCTION
Varicella, more commonly known as chickenpox, is caused by the hu-
man alpha herpesvirus varicella zoster virus (VZV). Transmitted through
direct contact with or inhalation of infectious fluid, VZV is highly con-
tagious and infects approximately 90 percent of susceptible household
contacts and 10 to 35 percent of individuals with limited exposure (Arvin,
1996; Ross et al., 1962).
The incubation period of VZV from exposure to illness is 10–21 days
(Arvin, 1996). During most of this time, the individual is asymptomatic.
About 50 percent of cases will experience fever, headache, abdominal pain,
or general malaise within 24–48 hours prior to the onset of typical chick-
enpox rash (Arvin, 1996). The varicella rash is characterized by pruritic,
erythematous papules which develop into small, fluid-filled vesicles usually
beginning on the scalp, face, or torso before spreading to proximal limbs
and mucosal areas such as the conjunctivae (eye), oropharynx (back of the
throat), and vagina (Arvin, 1996). In uncomplicated VZV infection, new
lesions may form for up to 7 days (Arvin, 1996). The infected individual
is considered contagious from 1–2 days prior to the appearance of the first
lesion until all lesions have crusted, approximately 24–48 hours after the
appearance of the last lesion, and generally within 4–7 days of symptom
onset (AAP, 2009; Arvin, 1996).
Possible complications from varicella infection include pneumonia and
secondary bacterial infections typically due to Staphylococcus aureus and
streptococcus; transient hepatitis; thrombocytopenia; and various neu-
239
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240 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
rologic complications including cerebellar ataxia, encephalitis, Guillain-
Barré syndrome (GBS), meningitis, and transverse myelitis (Ey et al., 1981;
Fleisher et al., 1981; Guess et al., 1986; Jackson et al., 1992; Liu and Urion,
1992; Preblud, 1986). Immunocompromised individuals such as those
treated for cancer or with congenital defects in cellular immunity often
experience more severe varicella infection and are at greater risk of fatal
infection (Whitley, 2010).
Following the acute phase of the infection, the primary VZV infection
is resolved, and the virus begins a dormant phase in the sensory nerve gan-
glia of the individual. The individual usually has lifetime immunity against
reinfection, and will not again have an illness that resembles primary
chickenpox; however, the latent VZV may be reactivated and cause shingles
(also called herpes zoster [HZ]). Shingles (or HZ) is a painful, unilateral,
pruritic rash appearing on dermatomal areas of one or more sensory-nerve
roots (Arvin, 1996). Risk factors for shingles include aging, immunosup-
pression, and VZV infection prior to 12 months of age (Arvin, 1996). An
estimated 15 to 30 percent of the population develops shingles, a percentage
that is expected to increase with increasing life expectancies (CDC, 2007).
Postherpetic neuralgia (PHN) is the most common complication of herpes
zoster, especially in older individuals (CDC, 2007). The pain of PHN can
last from 4 weeks to 10 years, and in one study, it lasted more than 1 year
in 22 percent of study participants (Arvin, 1996; Ragozzino et al., 1982).
Additional complications of herpes zoster include herpes ophthalmicus,
dissemination, and central nervous system, pulmonary, and hepatic disease
(CDC, 2007).
Prior to the development and dissemination of the varicella vaccine in
1995, varicella was a common childhood disease in the United States. The
Centers for Disease Control and Prevention (CDC) estimates that from
1980 through 1990, 4 million cases of varicella occurred annually with
approximately 77 percent of cases in children 9 years old and younger, and
more than 90 percent in children less than 15 years of age (CDC, 2007).
Furthermore, national seroprevalence data from 1988–1994 showed that
95.5 percent of adults aged 20–29 years, 98.9 percent of adults aged 30–39
years, and 99.6 percent of adults aged 40 years and older were immune to
varicella (Kilgore et al., 2003).
From 1988 through 1995, hospitalizations due to varicella ranged
from 2.3 to 7.0 per 100,000 cases (CDC, 2007). Among those most often
hospitalized were adults 20 years of age and older, and children 4 years
and younger, respectively representing 31.9 and 44.4 percent of varicella-
related hospitalizations (Galil et al., 2002). Despite adults being less likely
to require hospitalization due to varicella infection, from 1990 to 1994
adults were 25 times more likely to experience fatal varicella infections than
children between the ages of 1 and 4 years (Meyer et al., 2000). Secondary
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241
VARICELLA VIRUS VACCINE
infections, central nervous system complications including encephalitis, and
pneumonia were among the most common causes of hospitalization and
death, and these instances occurred most often in healthy individuals who
were not severely immunocompromised or undergoing immunocompromis-
ing treatments (Meyer et al., 2000).
Since the 1980s, VZV infections in immunocompromised individuals
have been treated with acyclovir, a synthetic nucleoside analog that inhibits
the replication of human herpes viruses including VZV. In 1992, acyclovir
was approved for the treatment of VZV infection in healthy children (CDC,
2007). Used within 24 hours of initial presentation, intravenous acyclovir
effectively lessens illness severity and fatality in immunocompromised indi-
viduals (Nyerges et al., 1988; Prober et al., 1982). In 1992, oral acyclovir
was approved for treatment of varicella in healthy children based on study
data indicating favorable clinical outcomes, for example shortening of dis-
ease and contagious state, and severity of symptoms, if administered within
24 hours of rash onset (CDC, 2007). However, in 1993, the American
Academy of Pediatrics Committee on Infectious Disease issued a statement
that the benefit of acyclovir was not sufficient to justify routine administra-
tion in healthy children (CDC, 2007). Instead, they recommended that the
oral treatment be reserved for otherwise healthy individuals at increased
risk for moderate to severe varicella such as individuals 13 years or older
and persons with chronic skin or pulmonary disorders (Hall et al., 1993).
The first live attenuated varicella vaccine was developed and tested
in Japan by Takahashi and colleagues in the 1970s. The virus, designated
Oka strain, was isolated from vesicular fluid of a healthy 3-year-old boy
infected with VZV (Takahashi et al., 1975). The virus was attenuated
through serial passaging through human embryonic lung cells, guinea-pig
cells, and human diploid cells (WI-38 and MRC-5) (Arvin and Gershon,
1996). Takahashi et al. inoculated 51 healthy children who subsequently
experienced a 92 percent VZV antibody formation rate (Takahashi et al.,
1975). Following this study, Takahashi and his associates studied the im-
pact of the vaccine on the VZV seroconversion in children with underlying
diseases such as nephritis, asthma, and hepatitis. This study showed that
the VZV vaccine was safe for children receiving low to moderate doses of
steroids (Takahashi et al., 1974, 1975).
Reports of varicella vaccination in immunocompromised children
showed that with suspended chemotherapy, children with leukemia could
be vaccinated successfully against VZV (Arvin and Gershon, 1996). These
studies spurred similar studies in the United States and Canada. In 1979,
the National Institute of Allergy and Infectious Diseases sponsored the
Varicella Vaccine Collaborative Study that looked at the effectiveness of
the vaccine on children whose leukemia was in remission. The Collabora-
tive Study showed seroconversion in 88 percent of leukemic children after
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242 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
the first dose and a 98 percent conversion after the second dose (Gershon
and Steinberg, 1989).
In 1995, the live, attenuated virus vaccine, Varivax (Merck & Co.,
Inc.) was licensed in the United States for use in healthy individuals greater
than 12 months of age (CDC, 2007). The vaccine contains 1,350 plaque-
forming units (PFUs) of Oka/Merck VZV; 25 mg of sucrose; 12.5 mg of
hydrolyzed gelatin; and trace amounts of neomycin, fetal bovine serum,
and residual components of MRC-5 (CDC, 2007). In 2005, Merck received
licensure from the Food and Drug Administration to release the combina-
tion measles, mumps, rubella, and varicella (MMRV) vaccine ProQuad
(Merck) for use among healthy children aged 12 months through 12 years
(CDC, 2007). Each dose of ProQuad contains at least 3.0 log10 TCID50 of
measles virus, 4.3 log10 TCID50 of mumps virus, and 3.0 log10 TCID50 of
rubella virus in addition to 3.99 log10 PFUs of the attenuated varicella virus
(Merck & Co., Inc., 2009).
Currently, two 0.5-mL doses of varicella vaccine are recommended
for children older than 12 months, adolescents, and adults who show no
evidence of prior immunity (CDC, 2007). For children aged 12 months to
12 years, the recommended minimum interval between the two doses is 3
months (CDC, 2007). For persons greater than 13 years of age, the recom-
mended minimum interval is 4 weeks (CDC, 2007). Because of greater as-
sociation with fevers and febrile seizures after MMRV vaccine as compared
to the MMR and monovalent varicella vaccines as separate injections, the
Advisory Committee on Immunization Practices recommends that indi-
viduals between 12 and 47 months of age receive the MMR and monova-
lent varicella vaccines as separate injections or MMRV for the first dose of
the vaccines at the discretion of the administering physician and the parents
(CDC, 2010b). The combination MMRV vaccine is preferred as a second
dose for individuals aged between 12 months and 12 years, and as a first
dose for individuals greater than 4 years of age when all four vaccines are
needed and none are contraindicated (CDC, 2006, 2010b). Since 2005,
about 90 percent of U.S. children aged 19–35 months have received at least
one dose of varicella vaccine (CDC, 2010a).
DISSEMINATED OKA VZV WITHOUT
OTHER ORGAN INVOLVEMENT
This review of adverse events related to disseminated Oka VZV or
vaccine-strain viral reactivation is divided into four sections. Two sections
deal with initial adverse events (1) limited to the skin or (2) involving dis-
semination to other organs. The other two sections report cases of VZV
reactivation as zoster either (1) involving dissemination limited to the skin
or (2) involving dissemination to other organs. In the cases limited to the
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VARICELLA VIRUS VACCINE
skin, the committee reports cases in which the rash appeared in more than
one dermatome and, hence, had disseminated beyond the site of the initial
vaccination. Not all cases could easily be assigned to one or another sec-
tion. The committee arbitrarily placed all cases reporting herpes zoster in
the viral reactivation sections even when these rashes appeared early after
administration of the vaccine.
“Disseminated” in this section refers to the spreading of the rash be-
yond the dermatome involved in the vaccination. Reports in which there
were a few vesicles at the site of the injection were not included. The cases
that were used to definitively show the association were those in which
(i) the patient received the varicella vaccine currently in use in the United
States or one similar, (ii) the rash extended to dermatomes beyond that of
the initial injection, and (iii) vaccine virus was demonstrated in skin lesions.
Epidemiologic Evidence
The committee reviewed three studies to evaluate the risk of dissemi-
nated Oka VZV without other organ involvement after the administration
of varicella vaccine. These three studies (Chaves et al., 2008; Sharrar et al.,
2001; Wise et al., 2000) were not considered in the weight of epidemiologic
evidence because they provided data from passive surveillance systems and
lacked unvaccinated comparison populations.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between varicella vaccine and disseminated Oka VZV
without other organ involvement.
Mechanistic Evidence
The committee identified 54 publications reporting disseminated Oka
VZV without other organ involvement after vaccination against varicella.
Thirty-three publications either did not provide evidence beyond temporal-
ity or demonstrated wild-type varicella virus in the vesicles (Alpay et al.,
2002; Austgulen, 1985; Barton et al., 2009; Barzaga et al., 2002; Brunell
et al., 1982; Chaves et al., 2005; Diaz et al., 1991; Donati et al., 2000; Haas
et al., 1985a,b; Hadinegoro et al., 2009; Heath and Malpas, 1985; Heller
et al., 1985; Kamiya et al., 1984; Katsushima et al., 1982; Konno et al.,
1984; Kreth and Hoeger, 2006; Lassker et al., 2002; Leung et al., 2004;
Lydick et al., 1989; Minamitani et al., 1982; Nunoue, 1984; Oka et al.,
1984; Quinlivan et al., 2009; Shah et al., 2007; Shiow et al., 2009; Slordahl
et al., 1984, 1985; Sorensen et al., 2009; Sugino et al., 1984; Takahashi
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244 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
et al., 1985; Ueda et al., 1977; Zamora et al., 1994). These publications
did not contribute to the weight of mechanistic evidence.
Described below are 21 publications reporting clinical, diagnostic, or
experimental evidence that contributed to the weight of mechanistic evi-
dence. The studies are grouped to indicate the certainty that the vaccine was
sufficiently similar to that used currently in the United States and that there
was primary dermal dissemination of vaccine virus. The vaccine which has
been in use in the United States since 1995 contains a minimum of 1,350
PFUs of Oka VZV virus. Studies from prior to general use of the vaccine
report many rashes and other adverse events associated with wild-type
varicella virus because of the high prevalence of wild-type disease.
Cases of Primary Dermal Dissemination of Vaccine Virus
Jean-Philippe et al. (2007) describe an 18-month-old girl, subsequently
diagnosed with a T cell dysfunction, presenting with fever and papulo-
vesicular/pustular skin lesions beginning on the trunk and spreading to
cover the patient’s entire body including the soles, palms, and scalp five
weeks after receiving a varicella vaccine. New lesions continued to appear
for more than 14 days after the appearance of the initial lesions. Vaccine-
strain varicella was demonstrated, by polymerase chain reaction (PCR), in
a biopsy of the skin lesions.
Angelini et al. (2009) describe a 17-month-old girl presenting with
fever and vesicular-hemorrhagic lesions on the entire body 23 days after
receiving a varicella vaccine. Laboratory tests showed pancytopenia re-
flecting macrocytic-normochromic-hyporegenerative anemia. Vaccine-strain
varicella virus was demonstrated, by PCR, in skin lesions.
Kraft and Shaw (2006) described a 36-year-old man presenting with
pruritic lesions on the face, limbs, and trunk 24 days after receiving a
varicella vaccine and 2 years after undergoing a heart transplant. The pa-
tient was taking mycophenylate mofetil and cyclosporine twice daily. New
lesions developed 3 days later. Vaccine-strain varicella virus was demon-
strated, by PCR, in the lesions.
Other Cases
There were five publications describing reports submitted to passive
surveillance systems regarding rash associated with vaccine virus without
other organ involvement in the first 42 days after vaccination. The limita-
tion of these publications is that the distribution of the rash is not reported,
so the committee cannot conclude that the rash disseminated beyond the
site of the initial injection. Chaves et al. (2008), Galea et al. (2008), Sharrar
et al. (2001), and Wise et al. (2000) described the development of rashes
after administration of a varicella vaccine reported to either the Vaccine
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VARICELLA VIRUS VACCINE
Adverse Event Reporting System (VAERS) or Merck’s Worldwide Adverse
Experience System (WAES). Sharrar et al. (2001) report that all of the
reports submitted to WAES are submitted to VAERS. Due to the use of
the same databases, it is likely that many of the cases overlap in the four
publications.
Chaves et al. (2008) identified 8,262 reports of rash submitted to
VAERS from May 1995 through December 2005. The authors reported
that of 209 specimens, submitted to the National VZV Laboratory at the
CDC, 55 were wild-type varicella virus and 37 were vaccine-strain varicella
virus. The remaining specimens either tested negative for varicella virus or
were inadequate for testing.
Galea et al. (2008) identified 3,192 reports of rash developing within
42 days of vaccination submitted to WAES in the first 10 years of the
licensure of the varicella vaccine in the United States. The authors report
that of 130 specimens submitted to the Varicella Zoster Virus Identification
Program (VZVIP), 42 were wild-type varicella virus and 37 were vaccine-
strain varicella virus. The remaining specimens were negative for varicella
virus, positive for varicella virus but untypable, or inadequate samples.
Sharrar et al. (2001) identified 1,349 reports of rash developing within
42 days of vaccination submitted to VAERS and WAES during the first
4 years of marketing the varicella vaccine licensed in the United States.
Ninety-seven specimens were available for analysis by PCR. Of these, 38
were wild-type varicella virus, 24 were vaccine-strain varicella virus, 19
were inadequate, 8 were negative for varicella virus, and 8 were positive
for varicella virus but the strain was not identified.
Wise et al. (2000) identified 3,640 reports of rash submitted to VAERS
from March 1995 through July 1998. Varicella virus was demonstrated, by
PCR, in 70 rash specimens. Of these, the strain was not identified in 5, 43
were wild-type varicella virus, and 22 were vaccine-strain varicella virus.
Goulleret and colleagues (2010) used data from the European VZVIP
to study adverse events reported after vaccination against varicella after
introduction of the varicella vaccine, licensed for use in the United States,
in Europe. The authors identified 259 reports of rash developing within 42
days after vaccination. Specimens were collected from 44 of these cases and
analyzed by PCR. Of these, 3 were inadequate samples, 4 were negative for
varicella virus, 32 were wild-type varicella virus, and 5 were vaccine-strain
varicella virus.
Described below are 13 publications in which vaccine-strain varicella
was demonstrated in the skin in individuals after vaccination. However, the
vaccine was either not that used in the United States, it is unclear which
vaccine was used, or it is unclear that the rash was disseminated beyond
the dermatome in which the vaccine was administered.
Bancillon et al. (1991) administered a varicella vaccine to 33 acute
lymphoblastic leukemia (ALL) and 4 acute myeloblastic leukemia children.
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246 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Maintenance therapy consisting of 6-mercaptopurine, methotrexate,
vincristine, and prednisolone for ALL patients and 6-mercaptopurine and
cytosine arabinoside for acute myeloid leukemia patients was suspended
8 days before and 8 days after vaccination. Eight of the children experi-
enced varicella developing 21 to 87 days postvaccination. Vaccine-strain
varicella virus was demonstrated in one patient. This report is included
in the “primary infection” section despite the length of days (up to 87) in
which the rashes appeared because these children were immunosuppressed.
It is likely that primary infection could manifest itself with a different time
course than that of normal healthy children.
Brunell et al. (1987) administered a varicella vaccine (from three
sources) to 52 children with acute lymphocytic leukemia. In children receiv-
ing chemotherapy the treatment was suspended 1 week prior to vaccination
and 1 week after vaccination. The authors reported fever, lymphadenopa-
thy, malaise, back and joint pain, and vesicular rashes after vaccination.
Vesicular lesions developed between 18 and 36 days after vaccination in
5 of the 52 children immunized. Vaccine-strain varicella virus was dem-
onstrated, by restriction endonuclease analysis, in vesicular fluid isolated
from two of the five children presenting with vesicular rashes. In the three
remaining children either no virus was demonstrated in vesicular fluid or
specimens were not obtained.
Christensen et al. (1999) describe a girl 3 years, 6 months old with
acute lymphocytic leukemia presenting with typical varicella 32 days after
vaccination and 29 days after receiving a bolus of vincristine. Maintenance
chemotherapy consisting of 6-mercaptopurine and methotrexate was sus-
pended before and after vaccination. Vaccine-strain varicella virus was
demonstrated in vesicular fluid by restriction endonucelase analysis.
Gelb et al. (1987) administered a varicella vaccine (“research” and
“consistency” lots) to 350 children with acute lymphocytic leukemia in
remission for at least 1 year and 117 normal adults. The authors report
that rashes were more common in children receiving chemotherapy than in
those who completed chemotherapy. The rashes developed between 1 and 6
weeks after vaccination. Varicella virus demonstrated in eight children was
determined to be vaccine-strain varicella virus in three children and wild-
type varicella virus in three children by restriction endonuclease analysis.
In two children the type of varicella virus was not determined.
Gershon et al. (1984a) administered a varicella vaccine to 191 children
with acute leukemia in remission for 1 year or more. Of the children, 53
were no longer receiving chemotherapy while chemotherapy was suspended
in 138. Two of the 53 children no longer receiving chemotherapy and 49
of the 138 children whose chemotherapy was suspended developed rashes
after vaccination. Vaccine-strain varicella virus was demonstrated in two
of these children by restriction endonuclease analysis. A follow-up publi-
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VARICELLA VIRUS VACCINE
cation on the same group of children had similar results (Gershon et al.,
1984b). Gershon et al. (1985) presented data from this collaborative study
after the total enrollment had increased to 240 children. They reported that
vaccine-strain varicella virus was demonstrated by restriction endonuclease
analysis in rashes in four children undergoing maintenance chemotherapy.
After the enrollment had increased to 307 children with acute lymphocytic
leukemia, Gershon et al. (1986) published updated follow-up results. At
this time point, the children had been in remission from 9 to 52 months.
The authors reported maculopapular or papulovesicular rashes developing
about 1 month after vaccination in three children not receiving maintenance
chemotherapy and 100 children receiving maintenance chemotherapy.
Vaccine-strain varicella virus was demonstrated, by restriction endonuclease
analysis, in eight children. When enrollment had reached 437 children with
leukemia in remission for 1 year or more, Gershon et al. (1989) published
another follow-up report. As reported in the previous publications, for
those patients receiving maintenance chemotherapy, therapy was suspended
1 week before and after vaccination. Seven of the 65 patients no longer
receiving chemotherapy and 149 of the 372 patients whose chemotherapy
was stopped for the vaccination developed rashes. Vaccine-strain varicella
virus was demonstrated in 17 of these children by restriction endonuclease
analysis. In this report, Gershon et al. (1989) reported that the source of
vaccine for the entire study to that time included multiple lots from two
different companies.
Ninane et al. (1985) administered a varicella vaccine to 45 children
with either acute leukemia or solid malignant tumors. In leukemia patients
maintenance therapy was suspended 1 week before and 1 week after vac-
cination. In patients with solid tumors the vaccine was administered in the
middle of a 4-week interval in their therapy. Clinical varicella developed
in 8 of the 45 children. Vaccine-strain varicella virus was demonstrated
in a vesicle in one of the eight children. In the remaining seven children,
wild-type varicella virus was demonstrated in four and no virus was dem-
onstrated in three.
White et al. (1991) reviewed data from a multicenter trial of five pro-
duction lots of vaccine in 3,303 children and adolescents. Three of the five
lots had fewer than the current minimum 1,350 PFUs per dose. The authors
reported cases of injection site complaints and rashes developing after vac-
cination. Specimens were collected from 32 patients for analysis. Of these,
11 were varicella virus. Nine of these samples were further analyzed by
restriction endonuclease analysis. Of these nine specimens, eight were wild-
type varicella virus and one was vaccine-strain varicella virus.
Hughes et al. (1994) describe a 5-year-old boy, diagnosed with ALL,
presenting with maculopapular lesions on the right cheek and right leg 8
days after receiving a varicella vaccine and 2 years after remission was
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248 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
achieved. He was given the varicella vaccine as part of the vaccine study de-
scribed by Gershon et al. (1984a,b, 1985, 1989). The source of the vaccine
was not listed in the report. Maintenance chemotherapy was suspended for
the week before and week after vaccination. New skin lesions continued to
appear over the next 10 days. The patient had more than 200 skin lesions
32 days after vaccination. The 3-year-old sister of the vaccinee developed
vesicles on her face and trunk 14 days after the vaccinee was hospitalized.
Furthermore, 16 days after the vaccinee’s hospitalization the 22-month-old
brother of the vaccinee developed vesicles on his scalp and trunk. Vaccine-
strain varicella was demonstrated, by PCR, in the lesions developing on
the vaccinee’s siblings. Although vaccine virus was not demonstrated in the
vaccine recipient, this report is included because the siblings developed a
rash associated with vaccine virus.
One case describes primary dissemination of vaccine virus, but it is not
proven that vaccine virus was involved. Levitsky et al. (2002) described
a 60-year-old woman who received a varicella vaccine 11 months after
undergoing an orthotopic liver transplant. At the time of vaccination she
was taking tacrolimus, sirolimus, and prednisone daily. Three weeks after
vaccination she presented with small blisters on her abdomen, back, and
shoulders. The blisters resolved after undergoing treatment with acyclovir.
Two days after completing the acyclovir treatment a pruritic erythema-
tous rash developed on her legs and abdomen followed by the eruption of
clear vesicles in a multidermatomal distribution. The vesicles resolved after
undergoing treatment with acyclovir. Varicella virus was detected, by a
direct fluorescent antibody test and rapid shell vial test, in scrapings of the
vesicles. The virus was unable to be cultured and was not typed. Given the
age of this subject, even though she did not remember having had varicella,
it is possible that the rash was wild type, not vaccine related.
Weight of Mechanistic Evidence
Infection with varicella zoster virus manifests as a rash, malaise, and
low-grade fever (Whitley, 2010). The rash, which is a hallmark of infection,
consists of vesicles, maculopapules, and scabs in varying stages (Whitley,
2010). The committee considers the effects of natural infection one type of
mechanistic evidence.
In addition, the 21 publications described above presented clinical
evidence sufficient for the committee to conclude the vaccine was a contrib-
uting cause of disseminated Oka VZV without other organ involvement.
There were three cases that unequivocally showed that vaccination with the
current vaccine caused a rash that spread beyond the injection dermatome
without involvement of other organs. These rashes occurred in immunode-
ficient patients. In five publications describing reports submitted to passive
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249
VARICELLA VIRUS VACCINE
surveillance systems it was unclear if the rash extended beyond the derma-
tome in which the vaccine was administered, but vaccine virus was demon-
strated in the rash from some of the subjects. In nine case reports and five
publications from a large study of children with leukemia it was not clear
that the vaccine administered was equivalent to that currently used in the
United States. In one case of dermal dissemination in an immunosuppressed
adult, it was not proven that vaccine virus was involved in the rash. In all
publications described above the vaccine administered contained the Oka
varicella strain described in the introduction to the chapter. Rashes were
reported in individuals with and without demonstrated immunodeficien-
cies (e.g., genetic or acquired). Vaccine-strain varicella was demonstrated
in skin biopsy and vesicular fluid in 20 of the publications described above
although it should be noted that five publications represent reports over
time of the same multicenter study.
The latency between vaccination and development of rash in the pub-
lications described above ranged from 8 to 87 days suggesting direct viral
infection as the mechanism responsible for disseminated Oka VZV without
other organ involvement, It should be noted that the publications did not
provide evidence linking autoantibodies, T cells, or complement activation
to disseminated rash after varicella vaccination.
The committee assesses the mechanistic evidence regarding an as-
sociation between varicella vaccine and disseminated Oka VZV
without other organ involvement in individuals with or without
demonstrated immunodeficieincies as strong based on cases1 pre-
senting definitive clinical evidence.
Causality Conclusion
Conclusion 5.1: The evidence convincingly supports a causal re-
lationship between varicella vaccine and disseminated Oka VZV
without other organ involvement.
DISSEMINATED OKA VZV WITH OTHER ORGAN INVOLVEMENT
“Disseminated” in this section refers to disease present in organs in ad-
dition to the skin in a time frame associated with acute infection. The cases
that were used to definitively show the association were those in which
(1) the patient received the vaccine currently in use in the United States,
1 Due to the use of the same surveillance systems in some publications it is likely that some
of the cases were presented more than once, thus it is difficult to determine the number of
unique cases.
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282 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
tests during hospitalization revealed a platelet count of 29,000 on day 1
and 62,000 on day 3. The patient’s platelet count was 198,000 on day 6.
Weight of Mechanistic Evidence
While rare, infection with wild-type varicella virus has been associated
with bleeding diathesis (Whitley, 2010). The committee considers the effects
of natural infection one type of mechanistic evidence.
The publication described above did not present evidence sufficient
for the committee to conclude the vaccine may be a contributing cause of
thrombocytopenia. The symptoms described in the publications referenced
above are consistent with those leading to a diagnosis of thrombocytopenia,
but the only evidence that could be attributed to the vaccine was recurrence
of symptoms upon vaccine rechallenge. Autoantibodies and complement
activation may contribute to the symptoms of thrombocytopenia; however,
the publications did not provide evidence linking these mechanisms to
varicella vaccine.
The committee assesses the mechanistic evidence regarding an asso-
ciation between varicella vaccine and thrombocytopenia as weak
based on knowledge about the natural infection and one case.
Causality Conclusion
Conclusion 5.15: The evidence is inadequate to accept or
r eject a causal relationship between varicella vaccine and
thrombocytopenia.
CONCLUDING SECTION
Table 5-1 provides a summary of the epidemiologic assessments, mech-
anistic assessments, and causality conclusions for varicella vaccine.
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TABLE 5-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for
Varicella Vaccine
Studies Cases
Contributing to Contributing to
Epidemiologic the Epidemiologic Mechanistic the Mechanistic Causality
Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion
a
Varicella Disseminated Oka VZV Insufficient None Strong – Convincingly
without Other Organ Supports
Involvement
Varicella Disseminated Oka VZV Limited 1 Strong 9 Convincingly
with Subsequent Infection (subsequent infection (in individuals Supports
Resulting in Pneumonia, resulting in pneumonia) with demonstrated (in individuals
Meningitis, or Hepatitis immunodeficiencies) with demonstrated
Insufficient None
immunodeficiencies)
(subsequent infection
resulting in meningitis
or hepatitis)
a
Varicella Vaccine-Strain Viral Insufficient None Strong – Convincingly
Reactivation without Supports
Other Organ Involvement
Varicella Vaccine-Strain Viral Limited 1 Strong 6 Convincingly
Reactivation with (subsequent infection Supports
Subsequent Infection resulting in encephalitis)
Resulting in Meningitis
Insufficient None
or Encephalitis
(subsequent infection
resulting in meningitis)
Varicella Encephalopathy Insufficient None Lacking None Inadequate
Varicella Seizures Limited 1 Weak None Inadequate
283
continued
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TABLE 5-1 Continued
284
Studies Cases
Contributing to Contributing to
Epidemiologic the Epidemiologic Mechanistic the Mechanistic Causality
Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion
Varicella Cerebellar Ataxia Insufficient None Weak None Inadequate
Varicella Acute Disseminated Insufficient None Weak None Inadequate
Encephalomyelitis
Varicella Transverse Myelitis Insufficient None Weak 1 Inadequate
Varicella Guillain-Barré Syndrome Insufficient None Weak None Inadequate
Varicella Small Fiber Neuropathyb Insufficient None Lacking None Inadequate
Varicella Anaphylaxis Limited 1 Strong 76c Convincingly
Supports
Varicella Onset or Exacerbation of Insufficient None Lacking None Inadequate
Arthropathy
Varicella Strokeb Limited 1 Weak None Inadequate
Varicella Thrombocytopenia Insufficient None Weak 1 Inadequate
aDue to the use of the same surveillance systems in some publications it is likely that some of the cases were presented more than once; thus, it is
difficult to determine the number of unique cases.
bAlthough not originally charged to the committee by the sponsor, the committee considered this adverse event in its review of the literature.
cIn addition, at least 30 cases were reported to passive surveillance systems; however, it was not possible to know how many represented unique
cases or were reported elsewhere.
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285
VARICELLA VIRUS VACCINE
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