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Adverse Effects of Vaccines: Evidence and Causality (2012)

Chapter: 5 Varicella Virus Vaccine

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Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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5

Varicella Virus Vaccine

INTRODUCTION

Varicella, more commonly known as chickenpox, is caused by the human alpha herpesvirus varicella zoster virus (VZV). Transmitted through direct contact with or inhalation of infectious fluid, VZV is highly contagious 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 chickenpox 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-

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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 ganglia 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, immunosuppression, 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

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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 individuals (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 disease 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 administration 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 impact 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 Collaborative Study showed seroconversion in 88 percent of leukemic children after

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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 combination 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 recommended minimum interval is 4 weeks (CDC, 2007). Because of greater association 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 individuals between 12 and 47 months of age receive the MMR and monovalent 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 dissemination 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

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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 section. 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 beyond 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 disseminated 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 temporality 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

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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 evidence. 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 papulovesicular/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. Vaccinestrain 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 reflecting 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 patient was taking mycophenylate mofetil and cyclosporine twice daily. New lesions developed 3 days later. Vaccine-strain varicella virus was demonstrated, 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 limitation 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

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

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 experienced 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 receiving chemotherapy the treatment was suspended 1 week prior to vaccination and 1 week after vaccination. The authors reported fever, lymphadenopathy, 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. Vaccinestrain varicella virus was demonstrated, 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 suspended 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-

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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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 vaccination. 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 demonstrated in three.

White et al. (1991) reviewed data from a multicenter trial of five production 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 vaccination. Specimens were collected from 32 patients for analysis. Of these, II 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

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

achieved. He was given the varicella vaccine as part of the vaccine study described 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 erythematous 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 contributing 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 immunodeficient patients. In five publications describing reports submitted to passive

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

surveillance systems it was unclear if the rash extended beyond the dermatome in which the vaccine was administered, but vaccine virus was demonstrated 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 immunodeficiencies (e.g., genetic or acquired). Vaccinestrain 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 publications 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 association between varicella vaccine and disseminated Oka VZV without other organ involvement in individuals with or without demonstrated immunodeficieincies as strong based on cases1presenting definitive clinical evidence.

Causality Conclusion

Conclusion 5.1: The evidence convincingly supports a causal relationship 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 addition 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.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

(2) the disease, not mildly abnormal laboratory values, was found in organs with or without skin involvment, and (3) vaccine virus was demonstrated in the organ.

Epidemiologic Evidence

Pneumonia

The committee reviewed five studies to evaluate the risk of pneumonia after the administration of varicella vaccine. Four studies (Chaves et al., 2008; Goulleret et al., 2010; 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.

The one remaining controlled study (Black et al., 1999) contributed to the weight of epidemiologic evidence and is described below.

Black et al. (1999) conducted a retrospective cohort study in 89,753 patients (12 to 18 months of age, older children, and adults) enrolled at the Northern California Kaiser Permanente Medical Care Program (KPMCP) from April 1995 through December 1996. Eligible patients were identified in the clinical database, and received at least one dose of varicella vaccine during the study period. Potential adverse events were obtained from the database; diagnoses from hospitalizations, emergency room (ER) visits, and outpatient clinic visits were included in the analysis. The risk periods for diagnoses recorded at outpatient clinic visits, ER visits, and hospitalizations were defined as 1–30 days, 0–30 days, and 0–60 days after vaccination, respectively. Three control periods were used in the analysis. A historical cohort was available for the ER visit and hospitalization analysis; children who were 1–2 years of age 1 year before the study began were matched to the exposed group on birth date, sex, and date of MMR vaccination. Events following routine pediatric vaccinations within the equivalent 30- or 60-day risk period were recorded for the historical cohort. Prevaccination and postvaccination control periods were included in the analysis. The prevaccination periods were defined as 31–60 days before outpatient clinic visits or ER visits, and 31–90 days before hospitalizations. The postvaccination periods were defined as 91–120 days after outpatient clinic visits or ER visits, and 91–150 days after hospitalizations. The relative risk of pneumonia in the 1-year age group recorded during clinic visits within 30 days of varicella vaccination (81 cases), compared to the 31–60 prevaccination control period (59 cases), was 1.42 (95% CI, 1.02–1.99). Only statistically significant increased risks were reported in the study; analyses were not

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

available for other age groups or comparison groups. The large number of comparisons conducted in the study increased the potential for type I error.

Meningitis

The committee reviewed three studies to evaluate the risk of meningitis after the administration of varicella vaccine. These three studies (Chaves et al., 2008; Goulleret et al., 2010; 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.

Hepatitis

The committee reviewed two studies to evaluate the risk of hepatitis after the administration of varicella vaccine. These two studies (Chaves et al., 2008; 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 committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between varicella vaccine and disseminated Oka VZV with subsequent infection resulting in pneumonia.

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and disseminated Oka VZV with subsequent infection resulting in meningitis or hepatitis.

Mechanistic Evidence

Pneumonia

The committee identified 11 publications reporting disseminated VZV with pneumonia after administration of a varicella vaccine. Four publications did not provide evidence beyond temporality (Chaves et al., 2008; Goulleret et al., 2010; LaRussa et al., 1996; Lohiya et al., 2004). One case reported in publications by Ghaffar et al. (2000), Galea et al. (2008), Sharrar et al. (2001), and Wise et al. (2000) did not contribute to the weight of mechanistic evidence owing to the failure to isolate vaccine-strain varicella from the bronchial lavage fluid. In this case, rhinovirus, enterovirus,

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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and parainfluenza type III were isolated from the bronchoalveolar fluid suggesting the presence of concomitant infections (Ghaffar et al., 2000).

Described below are five cases reported in six publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

One case, a 5-year-old boy with a history of cerebral palsy, quadriplegia, seizure disorder, and reactive airway disease treated with clonazepam, carbamazepine, albuterol, budesonide, and intermittent steroid therapy, was described in two publications (Galea et al., 2008; Sharrar et al., 2001). The patient presented with a rash and pneumonia 10 and 17 days, respectively, after receiving a varicella vaccine. The vaccine was administered 7 days after the patient finished a steroid taper. Vaccine-strain varicella virus was demonstrated, by PCR, in endotracheal secretions.

One case, a 16-month-old boy who presented with fever, respiratory distress, and lower extremity weakness was described in four publications (Galea et al., 2008; Kramer et al., 2001; Sharrar et al., 2001; Wise et al., 2000). The patient had developed a rash 1 month earlier. The patient had oral thrush; the patient’s history revealed recurrent thrush from 11 months of age. The patient received MMR and varicella vaccines at 13 months of age. The patient was found to have a total CD4 count of 8 cell/mm3 and was diagnosed with human immunodeficiency virus (HIV)-1 infection. An open-lung biopsy revealed multinucleated giant cells. Vaccine-strain varicella virus was demonstrated via PCR in the lung biopsy and bronchoalveolar lavage fluid. The patient recovered after treatment with acyclovir and antiretrovirals.

One case, a 13-month-old boy who had previously been diagnosed with DiGeorge syndrome and found to have low T cell numbers (396 CD3 T cells; normal range 2,400–6,900/mm3) at 8 months of age was described in two publications (Galea et al., 2008; Waters et al., 2007). The patient underwent heart surgery for congenital heart disease at 10 months of age. At 12 months of age the patient received the measles, mumps, and rubella (MMR) vaccine together with the varicella vaccine. The patient presented 1 month later with lethargy, vomiting, decreased oral intake, and an episode of hematemesis. Respiratory examination revealed tachypnea and bilateral inspiratory crackles. Evaluation of bronchoscopy specimens demonstrated multinucleated giant cells with nuclear inclusions. Vaccine-strain varicella virus was demonstrated via PCR in tracheal aspirates and vesicular lesions obtained 7 weeks postvaccination. Measles virus was not detected by PCR. The patient remained intubated, and died 6 months later of pulmonary hemorrhage.

One case, an 11-year-old girl who developed an erythematous rash over the trunk and scalp, cough, labored breathing, increased respiratory

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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secretions, lethargy, hypothermia, and hypoxemia 5 weeks after varicella vaccination was described in two publications (Galea et al., 2008; Levy et al., 2003). The patient had congenital cytomegalovirus and a history of recurrent, presumably viral infections. Varicella virus was demonstrated via PCR in endotracheal fluid. Subsequent restriction fragment length polymorphisms analysis revealed the virus to be vaccine-strain varicella. The patient was treated with acyclovir, and recovered. A comprehensive immunologic evaluation of the patient revealed a deficiency of natural killer (NK) cells. Galea et al. (2008) described a 48-year-old man with Down syndrome who developed pneumonitis 13 days after varicella vaccination. The patient developed a generalized rash 2 weeks later. Vaccine-strain varicella virus was demonstrated via PCR in lesions and sputum specimens. Although Down syndrome is not a primary immunodeficiency, adults with Down syndrome often have immunoglobulin subclass abnormalities. It is unknown if the humoral immunity of this subject was tested.

Meningitis

The committee identified two publications reporting disseminated VZV with meningitis after administration of a varicella vaccine. Wise et al. (2000) either did not provide evidence beyond temporality or attributed the disseminated VZV with meningitis to wild-type varicella virus. This publication did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Bryan et al. (2008) described a 21-month-old girl subsequently diagnosed with stage IV neuroblastoma, presenting with two erythematous, umbilicated papules on the right finger and lower right abdomen 5 weeks after receiving a varicella vaccine, and 4 weeks into a chemotherapy regimen consisting of cyclophosphamide, adriamycin, vincristine, cisplatin, and etoposide. The lesions evolved into vesicular patches. The lesions were positive for varicella virus by PCR. Acyclovir was initially administered followed by foscarnet therapy. The patient developed conjunctivitis, lethargy, fatigue, and photophobia 8 weeks after beginning foscarnet therapy. Varicella virus was demonstrated by PCR in lesion scrapings and the cerebrospinal fluid (CSF). Varicella virus demonstrated in lesion scrapings was indentified as vaccine-strain virus upon restriction endonuclease analysis. The strain of varicella virus in the CSF was not determined. Although vaccine-strain virus was not demonstrated in the CSF of this child, it is probable that vaccine virus was involved because of its presence in the skin and because this case likely presented well after the initiation of widespread varicella vaccination in the United States.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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Hepatitis

The committee identified eight publications reporting the development of hepatitis or hepatic pathology after administration of a varicella vaccine. Two case reports did not contribute to the weight of mechanistic evidence. Suvatte et al. (1985) did not provide evidence beyond temporality. Italiano et al. (2009) reported the isolation of vaccine-strain varicella from serum, but not from the liver, making it difficult to determine the etiology of liver pathology. In addition, Italiano et al. (2009) reported the development of toxic shock syndrome resulting from a concomitant Streptococcus pyogenes infection. Two publications describing reports submitted to passive surveillance systems, Chaves et al. (2008) and Wise et al. (2000), did not provide clinical, diagnostic, or experimental evidence of causality, including the time frame between vaccination and development of hepatic pathology beyond the additional data reported in case reports described below and thus did not separately contribute to the weight of mechanistic evidence.

Described below are three cases reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

One case, a 13-month-old boy who was subsequently diagnosed with adenosine deaminase deficiency, a severe combined immunodeficiency, was described in four publications (Galea et al., 2008; Ghaffar et al., 2000; Sharrar et al., 2001; Wise et al., 2000). The patient presented with diarrhea and respiratory distress requiring ventilation 2 weeks after receiving a varicella vaccine. Rhinovirus, enterovirus, and parainfluenza type III were demonstrated in a bronchoalveolar lavage specimen. The patient’s coagulation studies were abnormal; the serum transaminase values were elevated. A liver biopsy revealed multifocal areas of necrosis. Standard cultures were negative. The patient developed maculopapular and vesicular lesions on the extremities and trunk 4 weeks postvaccination. Varicella virus DNA was demonstrated via PCR in the skin lesions and in supernatant of a viral culture of a homogenate of the liver biopsy. The identity of the virus as vaccine strain was confirmed by restriction fragment length polymorphisms.

Ihara et al. (1992) reported one case of a 5-year-old girl with a history of acute lymphocytic leukemia. The patient was vaccinated 6 months after complete remission while receiving consolidation chemotherapy consisting of vincristine, adriamycin, and dexamethasone every 3 months. The patient presented with fever and vesicles 20 days after receiving a varicella vaccine (13 days after receiving the third course of consolidation therapy), and 5 days later the patient was still febrile, in addition to having developed jaundice. The patient’s lactate dehydrogenase, asparate aminotransferase, and alanine aminotransferase levels were 2,700 IU/L, 1,060 IU/L, and 1,690 IU/L, respectively. Varicella virus was demonstrated in vesicular fluids and

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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peripheral blood mononuclear cells, and was determined to be vaccine strain using restriction endonucleases. Analyses of serum immunoglobulins were normal; lymphocyte phenotyping, and proliferation in response to mitogens, were not performed. The weakness of this case is that a liver biopsy was not done demonstrating vaccine virus in the liver. The jaundice and very elevated liver enzymes directly reflect liver disease not normally seen after vaccination. Since vaccine virus was demonstrated in the skin lesions and since the child was immune suppressed, it is likely that the vaccine virus caused this adverse event.

One case, reported in detail in the publication by Galea et al. (2008), was a 14-month-old boy who presented with a vesicular rash 19 days after vaccination. The boy was hospitalized with a disseminated rash, elevated aspartate aminotransferase and alanine aminotransferase levels, and fever. Multinucleated giant cells consistent with varicella virus infection were revealed by a liver biopsy. However, vaccine-strain varicella virus was only demonstrated, by PCR, in a lesion. We include this case because of the pathology (giant cells) seen in the liver. The boy was subsequently diagnosed with a severe combined immunodeficiency making it likely that the vaccine virus seen in a skin lesion was also in the liver.

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). Varicella pneumonitis is associated with varicella zoster infection, and occurs more commonly in adults and immunocompromised individuals (Whitley, 2010). Furthermore, varicella pneumonitis can develop in the absence of clinical symptoms (Whitley, 2010). In addition, meningitis has been reported as a nervous system manifestation of wild-type varicella infection (Whitley, 2010). Furthermore, while rare, hepatitis has been associated with wild-type varicella zoster virus infection (Whitley, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The nine cases described above presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of disseminated Oka VZV with subsequent infection resulting in pneumonia, meningitis, or hepatitis. All of the cases described above report patients with either a genetic or acquired immunodeficiency with the possible exception of one adult with Down syndrome discussed above. Vaccine-strain varicella virus was demonstrated in the vesicular fluid, peripheral blood mononu-clear cells, liver biopsy supernatant, endotracheal fluid, tracheal aspirates, lung biopsy, and bronchoalveolar lavage fluid in the cases described above. In most cases vaccine-strain varicella virus was demonstrated in a speci-

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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men from the liver or lung. The one exception was Bryan et al. (2008) as the authors demonstrated varicella virus in the CSF of an immunodeficient patient but did not identify the strain. The committee felt that vaccine strain virus was likely the etiology of the meningitis as it would be unusual to have dermal dissemintation of vaccine virus in an immunodeficient patient who had wild-type virus in the CSF.

The latency between vaccination and disseminated Oka VZV with subsequent infection resulting in pneumonia, meningitis, or hepatitis in the publications described above ranged from 10 days to 2 months suggesting direct viral infection as the mechanism. Autoantibodies, T cells, and complement activation may also contribute to hepatitis; however, the publications did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and disseminated Oka VZV with subsequent infection resulting in pneumonia, meningitis, or hepatitis in individuals with demonstrated immunodeficiencies as strong based on nine cases presenting definitive clinical evidence.

Causality Conclusion

Conclusion 5.2: The evidence convincingly supports a causal relationship between varicella vaccine and disseminated Oka VZV with subsequent infection resulting in pneumonia, meningitis, or hepatitis in individuals with demonstrated immunodeficiencies.

VACCINE-STRAIN VIRAL REACTIVATION
WITHOUT OTHER ORGAN INVOLVEMENT

Vaccine-strain viral reactivation and dissemination as zoster limited to the skin is defined as appearance of zoster in more than the dermatome that was the site of the initial vaccination.

Epidemiologic Evidence

The committee reviewed three studies to evaluate the risk of vaccine-strain viral reactivation 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.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and vaccine-strain viral reactivation without other organ involvement.

Mechanistic Evidence

The committee identified 27 publications reporting viral reactivation without other organ involvement after vaccination against varicella. Eight publications did not provide evidence beyond temporality (Broyer and Boudailliez, 1985; Diaz et al., 1991; Emir et al., 2006; Katsushima et al., 1982; Lin et al., 2009; Minamitani et al., 1982; Naseri et al., 2003; Takahashi et al., 1985). These publications did not contribute to the weight of mechanistic evidence.

Described below are 19 publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence. The zoster in some cases seemed to involve more than the initial site of vaccination but that was only explicitly stated in two cases, one reported in two publications describing reports submitted to passive surveillance systems, Chaves et al. (2008) and Galea et al. (2008), and one reported by Chan et al. (2007).

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 VAERS or 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 981 reports of herpes zoster after vaccination submitted to VAERS from May 1995 through December 2005. Of the 981 reports, 1 was due to herpes simplex virus, 1 was due to an allergic reaction, 11 were due to varicella virus but genotyping was not performed, 10 were due to wild-type varicella virus, and 8 were due to vaccinestrain varicella virus. In addition, the authors report that of 118 specimens submitted to the National VZV Laboratory at the CDC, 24 were wild-type varicella virus, and 47 were vaccine-strain varicella virus. The latency between vaccination and presentation of herpes zoster in patients where vaccine-strain varicella virus was demonstrated ranged from 1 to 11 years. One case, reported in detail, was a 5-year-old girl who presented with a zoster-like rash on the right side of the face and right eye 25 days after receiving a varicella vaccine, diphtheria-tetanus-accellular pertussis (DTaP) vaccine, and oral polio virus vaccine. The vaccine strain of VZV was demonstrated. This section was arbitrarily assigned to the reactivation

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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section despite the early onset because of the description of the virus as “zoster-like.” This case was also reported by Galea et al. (2008).

Galea et al. (2008) identified 697 reports of herpes zoster after vaccination submitted to WAES in the first 10 years of the licensure of the varicella vaccine in the United States. Of the 697 reports, 38 were due to wild-type varicella virus and 57 were due to vaccine-strain varicella virus (some of these cases also reported meningitis). In one case a child was diagnosed with acute lymphocytic leukemia 10 days after administration of a varicella vaccine. The child developed herpes zoster 23 days, 47 days, and 116 days after vaccination. Vaccine-strain varicella virus was demonstrated by PCR. The latency between vaccination and presentation of herpes zoster in patients where vaccine-strain varicella virus was demonstrated ranged from 23 days to 7.7 years.

Sharrar et al. (2001) identified 205 reports of herpes zoster after vaccination submitted to VAERS and WAES during the first 4 years of marketing the varicella vaccine licensed in the United States. From these 205 reports 56 specimens were analyzed by PCR. Of the 56 specimens, 4 were negative, 18 were inadequate, 2 were not typed, 10 were wild-type varicella virus, and 22 were vaccine-strain varicella virus. The latency between vaccination and presentation of herpes zoster in patients where vaccine-strain varicella virus was demonstrated ranged from 47 to 1,249 days.

Wise et al. (2000) identified 251 reports of herpes zoster after vaccination submitted to VAERS from March 1995 through July 1998. Varicella virus was demonstrated via PCR in 26 of the 251 reports. Of the 26 specimens, 12 were wild-type varicella virus and 14 were vaccine-strain varicella virus. The latency between vaccination and presentation of herpes zoster in patients where vaccine-strain varicella virus was demonstrated was a median of 19 weeks.

Goulleret et al. (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 Unites States, in Europe. The authors identified 44 reports of herpes zoster after vaccination. Specimens were collected from 17 of the 44 cases. Of these 17 specimens, seven were negative for varicella virus, one was positive for varicella virus but the strain was not determined, one was wild-type varicella virus, and eight were vaccine-strain varicella virus. The latency between vaccination and presentation of herpes zoster in patients where vaccine-strain varicella virus was demonstrated ranged from 89 days to 30 months. The location of the zoster was not reported.

Chan et al. (2007) reported the case of a 9-year-old boy with chronic granulomatous disease with multiple complications from the disease who was administered a varicella vaccine at age 7 years, and who subsequently underwent bone marrow transplantation at age 8 years. He was placed

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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on long-term therapy consisting of prednisolone 5 mg and azithromycin 250 mg daily. At age 9 years (approximately 2 years after vaccination) the patient developed herpes zoster over his back and left arm. Varicella virus was demonstrated via PCR in vesicular lesions. Subsequent restriction enzyme analysis revealed the virus to be vaccine-strain varicella.

Ota et al. (2008) reported a 28-month-old boy presenting with vesicles on the anterior thorax, left forearm, left wrist, and left hand. The patient received a varicella vaccine 15 months before the development of symptoms. The patient received a dual hepatitis A and hepatitis B vaccine 2 days prior to developing herpes zoster. Similar lesions appeared in the same areas 3 months later. The patient experienced a third episode with lesions in the same areas 2 months later. Vaccine-strain varicella virus was demonstrated via PCR in vesicular fluid obtained during the first outbreak of herpes zoster. The patient’s history did not suggest an underlying immunodeficiency. Evaluation of immunoglobulin levels; antibody titers; T, B, and NK cell numbers; and proliferative responses to mitogens and antigens including VZV were found to be normal. In addition, the patient tested negative for HIV-1.

Other Cases

Described below are publications in which vaccine-strain varicella was demonstrated in individuals with viral reactivation; however, the vaccine was not that used in the United States.

Christensen et al. (1999) reported the case of a 4-year-old boy who began treatment for acute lymphocytic leukemia, received a varicella vaccine, and then developed a rash and fever 30 days after vaccination. At the time of vaccination, the patient was undergoing treatment with methotrexate and mercaptopurine, and this therapy was continued postvaccination. The patient developed herpes zoster over the left chest 70 days postvaccination. Varicella virus DNA was demonstrated via PCR in vesicle fluid, and was found to be vaccine strain by restriction endonuclease analysis.

One case, a 27-month-old girl presenting with a herpes zoster rash in a C6–C8 dermatomal distribution 16 months after receiving a varicella vaccine, was described in three publications (Sauerbrei et al., 2003, 2004; Uebe et al., 2002). The patient was vaccinated 2 days after her sister developed varicella. Vaccine-strain varicella was demonstrated via PCR in vesicular fluid. The child had a history suspicious for immunocompromise with two hospital admissions (one for fever, the other for diarrhea), molluscum contagiosum beginning at 18 months, and monthly upper respiratory infections since 21 months of age. Evaluation of the immune system did not reveal immunodeficiency. There were normal T, B, and NK cell numbers but an inverted CD4:CD8 ratio with slightly elevated CD8 T cells. Serum IgG, IgA,

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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and IgM were normal, and the patient had specific antibodies to viral antigens. Tests excluded purine nucleoside phosphorylase deficiency and HIV.

In the following three cases the vaccine was likely not that used in the United States and the distribution of zoster may have been the inoculation site. For these two reasons, these cases do not contribute to the weight of evidence.

One case, a 4-year-old boy with acute lymphocytic leukemia who developed herpes zoster in the right deltoid 22 months after administration of a varicella vaccine (source not given), was described in seven publications (Gelb et al., 1987; Gershon et al., 1984b, 1985, 1986; Hardy et al., 1991; Lawrence et al., 1988; Williams et al., 1985). The vaccine was administered 18 months after initiation of chemotherapy. Chemotherapy was suspended 1 week prior to and after administration of the vaccine. Varicella virus was cultured from vesicular fluid. Subsequent restriction endonuclease analysis demonstrated the virus to be vaccine-strain varicella. In addition to the case described above, Hardy et al. (1991) reported a 5-year-old boy with leukemia who developed herpes zoster in the right arm (possibly the vaccination site) 19 months after vaccination (source not given) and 3 months after undergoing bone marrow transplantation. Varicella virus was cultured from vesicular fluid; subsequent restriction endonuclease analysis demonstrated the virus to be vaccine-strain varicella. The patient was considered immunocompromised due to the short duration since bone marrow transplantation.

Otsuka et al. (2009) described a 3-year-old girl who presented with herpes zoster 2 years after receiving a varicella vaccine. The distribution of the zoster was not provided. The patient’s 2-year-old brother developed a fever and rash consisting of papulovesicles on the day that the patient recovered. Varicella virus DNA was demonstrated in the patient’s brother’s vesicular fluid and crust specimens; the virus was identified as vaccine-strain varicella by restriction fragment length polymorphism.

Weight of Mechanistic Evidence

Herpes zoster is characterized by vesicular lesions erupting in a dermatomal distribution upon the reactivation of latent wild-type varicella virus (Whitley, 2010). Herpes zoster afflicts approximately 20 percent of the population (Whitley, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

Cases showing definite dermal dissemination of zoster from the vaccine needed to meet three critera, namely, (1) the zoster distribution was reported to extend beyond the dermatome of the initial injection, (2) the zoster was shown to be vaccine type, and (3) the vaccine given was that currently given in the United States. Only two cases meet these criteria, one reported by Chan et al. (2007) and one reported by both Chaves et al.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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(2008) and Galea et al. (2008). This second case is somewhat less convincing because the zoster-like rash in that case developed only 25 days after the initial vaccination. The other cases reviewed, however, increased the committee’s confidence, because of the large number of zoster cases reported in the four publications describing reports submitted to passive surveillance systems. It seems certain that some of these had disseminated beyond the initial injection site. In addition, the vaccines that were not clearly that used in the United States led to disseminated zoster limited to the skin in several cases. Thus, the 18 publications described above presented clinical evidence sufficient for the committee to conclude that the vaccine was a contributing cause of viral reactivation with dermal dissemination without other organ involvement. In 13 of the publications described above it was unclear if the vaccine administered was equivalent to that currently used in the United States. In all publications described above the vaccine administered contained the Oka varicella strain described in the introduction to the chapter. Herpes zoster was reported in individuals with and without demonstrated immunodeficiencies (e.g., genetic or acquired). Vaccine-strain varicella was demonstrated in vesicular fluid in the cases described above.

The latency between vaccination and development of herpes zoster in the publications described above ranged from 23 days to 11 years suggesting viral reactivation as the mechanism.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and vaccine-strain viral reactivation without other organ involvement as strong based on cases2presenting clinical evidence.

Causality Conclusion

Conclusion 5.3: The evidence convincingly supports a causal relationship between varicella vaccine and vaccine-strain viral reactivation without other organ involvement.

VACCINE-STRAIN VIRAL REACTIVATION
WITH OTHER ORGAN INVOLVEMENT

The definition of vaccine-strain viral reactivation with organ involvement involves the finding of vaccine virus in sites other than the skin after 42 days after the initial vaccination. Vaccine virus should be found in the

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2 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.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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organ that is involved and the findings in the organ should support the presence of disease not merely minor laboratory abnormalities.

Epidemiologic Evidence

Meningitis

The committee reviewed three studies to evaluate the risk of meningitis after the administration of varicella vaccine. These three studies (Chaves et al., 2008; Goulleret et al., 2010; 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.

Encephalitis

The committee reviewed six studies to evaluate the risk of encephalitis after the administration of varicella vaccine. Five studies (Chaves et al., 2008; Galea et al., 2008; Goulleret et al., 2010; 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.

The one remaining controlled study (Donahue et al., 2009) contributed to the weight of epidemiologic evidence and is described below.

Donahue et al. (2009) conducted a retrospective cohort study in 3.25 million children (11 months to 17 years of age) enrolled at eight medical care organizations (MCOs) participating in the Vaccine Safety Datalink (VSD) from January 1991 through December 2004. The study investigated the occurrence of ischemic stroke or encephalitis (reported in hospitaliza-tions) within 12 months of varicella vaccination. The unexposed period included all other time observed outside the 12-month risk window. Children were eligible to participate if they were enrolled in the MCO for at least 12 months (or since birth). Patients with diagnoses of infantile cerebral palsy, stroke, or hemiplegia/hemiparesis at or before 11 months of age were excluded. The participants were disenrolled from the study once they experienced one of the primary outcomes, reached 18 years of age, left their MCO, or received one of the exclusionary diagnoses (leukemia/ lymphoma, HIV/AIDS, primary immune system and bone marrow disorders, leucopenia, myeloproliferative diseases, and other syndromes associated with immunodeficiency). The analyses were adjusted for MCO site, months after exposure, calendar time, and gender. The vaccination and diagnosis information were obtained from electronic databases; the authors did not review the medical charts. Approximately 1.14 million children were vaccinated and 2.09 million children were not vaccinated during the

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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study. A total of 243 children were diagnosed with encephalitis, of whom 11 were diagnosed within 12 months, and 1 was diagnosed within 90 days of receiving a varicella vaccination. None of the adjusted hazard ratios for encephalitis observed at any time within 12 months of vaccination were significantly elevated. Only one hazard ratio was listed in the study for encephalitis within 30-90 days of varicella vaccination (HR, 0.7; 95% CI, 0.1-5.2). The authors found no association between the administration of varicella vaccine and encephalitis within 12 months following vaccination.

Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between varicella vaccine and vaccine-strain viral reactivation with subsequent infection resulting in encephalitis.

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and vaccine-strain viral reactivation with subsequent infection resulting in meningitis.

Mechanistic Evidence

Meningitis

The committee identified nine publications reporting viral reactivation with subsequent infection resulting in meningitis after administration of a varicella vaccine. Wise et al. (2000) reported the isolation of wild-type varicella virus in one girl that developed herpes zoster and meningitis 21 months after administration of a varicella vaccine. This publication did not contribute to the weight of mechanistic evidence.

Described below are eight publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence. Seven case reports were strong in that vaccine virus was detected in the CSF associated with meningitis months to years after the initial vaccination.

Chaves et al. (2008) and Galea et al. (2008) described the development of herpes zoster with subsequent infection resulting in meningitis after administration of a varicella vaccine reported to VAERS and 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 material it is likely that many of the cases overlap in Chaves et al. (2008) and Galea et al. (2008).

There were two cases in the publications describing reports submitted

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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to passive surveillance systems with meningitis and vaccine virus demonstrated in the CSF. The other cases were not associated with vaccine virus in the CSF and thus did not contribute to the weight of mechanistic evidence. One case was a 4-year-old child undergoing chemotherapy for acute lymphocytic leukemia who presented with herpes zoster followed by meningitis (Chaves et al., 2008; Galea et al., 2008). The child had been given the varicella vaccine while healthy, 19 months before presentation of symptoms of meningitis. Vaccine-strain varicella was demonstrated in the CSF and herpes zoster lesions. The patient’s immune system was suppressed by the chemotherapy. Chaves et al. (2008) reported a second case. A 4-year-old previously healthy child presented with herpes zoster rash followed by meningitis. The patient had received a varicella vaccine 32 months earlier. Vaccine-strain varicella was demonstrated in the CSF.

Chaves et al. (2008) identified an additional eight cases of herpes zoster with subsequent infection resulting in meningitis after administration of a varicella vaccine. Two demonstrated vaccine-strain varicella in skin lesions but did not detect varicella virus in the CSF. Galea et al. (2008) identified an additional five cases of herpes zoster with subsequent infection resulting in meningitis after administration of a varicella vaccine. CSF specimens from these cases were negative for varicella virus. Vaccine-strain varicella virus was demonstrated in the herpes zoster lesions in two of the five cases. Wild-type varicella virus was demonstrated in the herpes zoster lesion in one of the five cases. Also, in one of the five cases enterovirus was demonstrated in the CSF. These cases did not contribute to the weight of evidence.

Iyer et al. (2009) reported a 9-year-old boy presenting with a zoster rash followed 4 days later by headache and then fatigue, as well as neck and back pain. The previously healthy child had received a varicella vaccine 8 years before development of symptoms. The CSF was negative for bacteria, enterovirus, and herpes simplex virus. DNA was amplified via PCR from vesicle fluid and the CSF, and demonstrated to be vaccine-strain varicella by identification of single-nucleotide polymorphisms. The patient was screened for immunodeficiency; a lymphocyte subset analysis was performed and was normal.

Levin et al. (2008) reported an 8-year-old boy who developed pruritic vesicles on the left shoulder followed 4 days later by headache, meningis-mus, photophobia, vomiting, and fever. The patient was diagnosed with herpes zoster and meningitis. The patient had received a varicella vaccine 7 years before presentation of symptoms. Vaccine-strain varicella was demonstrated via PCR in vesicular lesions and the CSF. The patient was screened for immunodeficiency; the patient’s immunoglobulin levels, and T cell and B cell subsets, were found to be normal and the HIV-1 test was negative.

Levin et al. (2003) describe a 1-year-old boy, subsequently diagnosed with a neuroblastoma, presenting with herpes zoster lesions on the right

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

thigh, the site of vaccination, 3 months after receiving a varicella vaccine and the start of chemotherapy. The lesions increased in number and area of involvement 4 months after the onset of herpes zoster. The patient became irritable and developed fever and erythematous papules on the scalp, face, and trunk 1 month after stem-cell infusion. Varicella virus isolated from a skin biopsy and the CSF was determined to be vaccine strain by PCR.

Three cases of meningitis were reported in which varicella was detected in the CSF but the virus was not typed. These cases follow but did not contribute to the weight of evidence. Schwab and Ryan (2004) described a 5-year-old girl who presented with headache, fever, and a pruritic rash with raised lesions that began on the face and spread to the trunk 18 months after receiving a varicella vaccine. A positive Brudzinski sign was elicited. Varicella virus was demonstrated in skin lesions by direct immunofluorescence antibody and in the CSF by PCR; the strain of virus was not identified.

Chilek et al. (2010) described a 10-year-old boy who presented with a bilateral photophobia, headache, left eye pain, and a nondermatomal vesicular rash involving the upper extremities, neck, and left eye after administration of catch up of two varicella vaccines 9 and 3 months earlier. Varicella virus was demonstrated by direct fluorescent antibody and viral culture. Testing was not done to determine if the virus was wild type or vaccine type. The patient tested positive for HIV.

Naruse et al. (1993) described a 45-month-old boy who presented with a vesicular rash, not limited to any dermatomal distribution, originating on the face and chest and spreading to the extremities 21 months after administration of a varicella vaccine. Two days later the patient developed headache and frequent vomiting. Bacterial cultures of the blood, throat swab, and CSF were negative. Varicella virus was demonstrated in the CSF by PCR; the strain of virus was not identified.

Encephalitis

The committee identified three publications reporting the development of encephalitis after administration of a varicella vaccine. One publication reported multiple cases but did not provide evidence beyond temporality (Sharrar et al., 2001). In addition, the development of encephalitis in some of the cases was attributed to other etiologies. This publication did not contribute to the weight of mechanistic evidence.

Described below is one case described in two publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

The single case was a 3-year-old girl who presented with a herpetiform rash on the right side of her face, dizziness, vomiting, somnolence, fever, and conjunctivitis 20 months after receiving a varicella vaccine (Chouliaras

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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et al., 2010; Goulleret et al., 2010). An electroencephalogram showed slow waves consistent with encephalitis. Analysis of the CSF revealed normal levels of protein and glucose, and no white blood cells. In addition, the CSF was negative for herpes simplex virus 1 and 2. The patient was diagnosed with mild encephalitis and herpes zoster ophthalmicus. Vaccine-strain varicella was demonstrated via PCR in the CSF. Analysis of serum immunoglobulins and quantification of T cell and B cell subpopulations did not reveal abnormalities of the patient’s immune system.

Weight of Mechanistic Evidence

Herpes zoster is characterized by vesicular lesions erupting in a dermatomal distribution upon the reactivation of latent wild-type varicella virus (Whitley, 2010). Herpes zoster afflicts approximately 20 percent of the population, and can be associated with central nervous system complications (Whitley, 2010). Meningitis and encephalitis have been reported as nervous system manifestations of wild-type varicella infection (Whitley, 2010). Encephalitis has been reported as a nervous system manifestation in 0.1-0.2 percent of individuals infected with wild-type varicella zoster virus (Whitley, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

In addition, six cases described above presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of vaccine-strain viral reactivation with subsequent infection resulting in meningitis or encephalitis (Chaves et al., 2008; Chouliaras et al., 2010; Galea et al., 2008; Goulleret et al., 2010; Iyer et al., 2009; Levin et al., 2003, 2008). Vaccine-strain varicella virus was demonstrated in the CSF in six cases described above (Chaves et al., 2008; Chouliaras et al., 2010; Galea et al., 2008; Goulleret et al., 2010; Iyer et al., 2009; Levin et al., 2003, 2008). In addition, vaccine-strain varicella virus was demonstrated in vesicular lesions in four of the cases described above (Chaves et al., 2008; Galea et al., 2008; Iyer et al., 2009; Levin et al., 2003, 2008).

The variation in the latency between vaccination and development of symptoms of either meningitis or encephalitis was considerable. The latency between vaccination and the development of either meningitis or encephalitis ranged from 19 months to 8 years suggesting viral reactivation as the mechanism in the cases described above.

The committee concludes the clinical and biological evidence is strong in support of an association between varicella vaccine and vaccine-strain viral reactivation with subsequent infection resulting in meningitis or encephalitis based on six cases presenting definitive clinical evidence.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 5.4: The evidence convincingly supports a causal relationship between varicella vaccine and vaccine-strain viral reactivation with subsequent infection resulting in meningitis or encephalitis.

ENCEPHALOPATHY

Epidemiologic Evidence

The committee reviewed three studies to evaluate the risk of encephalitis after the administration of varicella vaccine. These three studies (Chaves et al., 2008; Goulleret et al., 2010; 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 encephalopathy.

Mechanistic Evidence

The committee identified three publications reporting the development of encephalopathy after administration of a varicella vaccine. Two publications did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccination and development of symptoms (Chaves et al., 2008; Goulleret et al., 2010). One publication reported multiple cases, but did not provide evidence beyond temporality (Wise et al., 2000). In addition, the development of symptoms in some of the cases described by Wise et al. (2000) was attributed to other etiologies. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of encephalopathy. Viral infection and viral reactivation may contribute to the symptoms of encephalopathy; however, the publications did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and encephalopathy as lacking.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Causality Conclusion

Conclusion 5.5: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and encephalopathy.

SEIZURES

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of seizures after the administration of varicella vaccine. Three studies (Chaves et al., 2008; Klein et al., 2010; 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.

The one remaining controlled study (Black et al., 1999) contributed to the weight of epidemiologic evidence and is described below.

The study by Black et al. (1999) was described in detail in the section on disseminated Oka VZV with subsequent infection resulting in pneumonia. This retrospective cohort study reported potential adverse events following varicella vaccination, obtained from the KPMCP database. The relative risk of febrile seizures in the 1-year age group recorded during hospitalizations within 60 days of varicella vaccination (21 cases), compared to the 91–150 postvaccination control period (8 cases), was 2.27 (95% CI, 1.03–5.45; p = .04). When this analysis was adjusted for patients who received MMR vaccine in combination with varicella vaccine, the association was no longer statistically significant (relative risk [RR], 0.58; 95% CI, 0.07–3.92; p = .586).3 The relative risk of seizures in the 1-year age group recorded during clinic visits within 30 days of varicella vaccination (52 cases), compared to the 91–120 postvaccination control period (30 cases), was 1.36 (95% CI, 1.02–2.52); however, this analysis was not adjusted for combined MMR vaccination. Only statistically significant increased risks were reported in the study; analyses were not available for other age groups or comparison groups. The authors concluded that varicella vaccination is not associated with an increased risk of seizures when the results are adjusted for combined administration of MMR vaccine.

Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between varicella vaccine and seizures.

___________

3 P. M. Ray, Kaiser Permanente Vaccine Study Center, personal communication, April 22, 2010.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Mechanistic Evidence

The committee identified three publications reporting seizures developing after administration of a varicella vaccine. One publication did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccine administration and development of seizure (Chaves et al., 2008). Two publications did not provide evidence beyond temporality (Klein et al., 2010; Wise et al., 2000). In addition, Klein et al. (2010) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

Varicella infection is associated with seizures indirectly. Seizures can develop after wild-type varicella infection secondary to encephalitis and stroke (Whitley, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications described above are consistent with those leading to a diagnosis of seizure. In some instances fever may contribute to the development of seizures; however, the publications did not provide evidence linking this mechanism to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and seizures as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 5.6: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and seizures.

CEREBELLAR ATAXIA

Epidemiologic Evidence

The committee reviewed six studies to evaluate the risk of cerebellar ataxia after the administration of varicella vaccine. Five studies (Chaves et al., 2008; Goulleret et al., 2010; Sharrar et al., 2001; van der Maas et al., 2009; 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. One controlled study (Black et al., 1999) had very serious methodological limitations that precluded its inclusion in this assessment. The study by Black et al. (1999) was unable

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

to find any cases of cerebellar ataxia following varicella vaccination, so no conclusions could be drawn from this analysis.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and cerebellar ataxia.

Mechanistic Evidence

The committee identified five publications reporting cerebellar ataxia developing after administration of a varicella vaccine. Two publications did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccination and development of ataxia (Chaves et al., 2008; Goulleret et al., 2010). Three publications did not provide evidence beyond temporality (Sharrar et al., 2001; Sunaga et al., 1995; Wise et al., 2000). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

Cerebellar ataxia is associated with wild-type varicella infection with an incidence of approximately 1 in 4,000 cases among children younger than 15 years of age (Whitley, 2010). Cerebellar ataxia has been reported to present as late as 21 days after rash onset, while acute cerebellar ataxia has been reported to present within 1 week of rash onset (Whitley, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of cerebellar ataxia. Viral infection may contribute to the symptoms of cerebellar ataxia; however, evidence of this mechanism was not reported in the publications referenced above.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and cerebellar ataxia as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 5.7: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and cerebellar ataxia.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of acute disseminated encephalomyelitis (ADEM) after the administration of varicella vaccine. These two studies (Goulleret et al., 2010; 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 ADEM.

Mechanistic Evidence

The committee identified one publication reporting development of ADEM after administration of a varicella vaccine. The publication reported several cases but did not provide evidence beyond temporality (Wise et al., 2000). The publication did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

Infection with wild-type varicella zoster is associated with ADEM with an incidence of approximately 1 per 10,000 cases (Davis, 2008). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of ADEM. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of ADEM; however, the publication did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and ADEM as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 5.8: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and ADEM.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

TRANSVERSE MYELITIS

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of transverse myelitis after the administration of varicella vaccine. This one study (Wise et al., 2000) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and transverse myelitis.

Mechanistic Evidence

The committee identified two publications reporting transverse myelitis after administration of a varicella vaccine. One publication did not provide evidence beyond temporality (Wise et al., 2000). The publication did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

LaRovere et al. (2008) described a 14-year-old boy presenting with a papulovesicular rash 8 years after receiving a varicella vaccine. The patient presented with mid-scapular pain 6 days after resolution of the rash, followed 2 days later by bilateral leg paresthesias and weakness, urinary retention, and unsteady gait leading to a diagnosis of acute transverse myelitis. Antivaricella antibodies, but not varicella virus, were demonstrated in the CSF. The patient was treated with intravenous methylprednisolone and was asymptomatic 2 months after development of the symptoms.

Weight of Mechanistic Evidence

On rare occasions transverse myelitis has been associated with herpes zoster and reactivation of latent wild-type varicella viruses (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 transverse myelitis. The development of a papulovesicular rash 8 years after administration of the vaccine, and isolation of antivaricella antibodies

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

from the CSF, suggests viral reactivation as a mechanism. However, vaccine-strain varicella was not isolated, detracting from the weight of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of transverse myelitis. Autoantibodies, T cells, viral reactivation, infection, and molecular mimicry may contribute to the development of transverse myelitis; however, the publications did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and transverse myelitis as weak based on knowledge about the natural infection and one publication.

Causality Conclusion

Conclusion 5.9: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and transverse myelitis.

GUILLAIN-BARRÉ SYNDROME

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of GBS after the administration of varicella vaccine. This one study (Wise et al., 2000) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and GBS.

Mechanistic Evidence

The committee identified one publication reporting development of GBS after administration of a varicella vaccine. The publication reported several cases but did not provide evidence beyond temporality (Wise et al., 2000). The publication did not contribute to the weight of mechanistic evidence.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Mechanistic Evidence

On rare occasions GBS has been associated with herpes zoster and reactivation of latent wild-type varicella viruses (Whitley, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of GBS. Autoantibodies, complement activation, immune complexes, T cells, and molecular mimicry may contribute to the symptoms of GBS; however, the publication did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and GBS as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 5.10: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and GBS.

SMALL FIBER NEUROPATHY

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of small fiber neuropathy after the administration of varicella vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between varicella vaccine and small fiber neuropathy.

Mechanistic Evidence

The committee identified one publication reporting small fiber neuropathy after administration of a varicella vaccine. The publication did not provide evidence beyond temporality (Souayah et al., 2009). The publication did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of small fiber neuropathy. Autoanti-

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

bodies, T cells, and molecular mimicry may contribute to the symptoms of small fiber neuropathy; however, the publication did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and small fiber neuropathy as lacking.

Causality Conclusion

Conclusion 5.11: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and small fiber neuropathy.

ANAPHYLAXIS

Epidemiologic Evidence

The committee reviewed seven studies to evaluate the risk of anaphylaxis after the administration of varicella vaccine. Six studies (Chaves et al., 2008; DiMiceli et al., 2006; Ozaki et al., 2005; Sakaguchi et al., 2000b; 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.

The one remaining controlled study (Black et al., 1999) contributed to the weight of epidemiologic evidence and is described below.

The study by Black et al. (1999) was described in detail in the section on disseminated Oka VZV with subsequent infection resulting in pneumonia. This retrospective cohort study reported potential adverse events following varicella vaccination, obtained from the KPMCP database. The relative risk of allergic reactions with or without hives in the 1-year age group recorded during clinic visits within 30 days of varicella vaccination (180 cases), compared to the 91–120-day postvaccination control period (130 cases), was 1.27 (95% CI, 1.02–1.60). Only statistically significant increased risks were reported in the study; analyses were not available for other age groups or comparison groups.

Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between varicella vaccine and anaphylaxis.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Mechanistic Evidence

The committee identified eight publications describing clinical, diagnostic, or experimental evidence of anaphylaxis postvaccination against varicella vaccines that contributed to the weight of mechanistic evidence. These publications are described below.

DiMiceli et al. (2006) identified cases of anaphylaxis postvaccination in patients with a history of yeast allergy reported to VAERS from July 1990 through July 2004. One case (case 15 in the report) describes a 35-year-old woman presenting with urticaria, pruritus, oropharyngeal edema, nasal congestion, dyspnea, and tachycardia 1 hour after receiving a varicella vaccine.

Kumagai et al. (1997) identified two cases of anaphylaxis (cases 3 and 4 in the report) developing in men, ages 22 and 23, after vaccination with a varicella vaccine. One patient presented with wheezing and dyspnea, and the other presented with wheezing, urticaria, and dyspnea. In both cases the symptoms developed within 15 minutes after receipt of the vaccine. Furthermore, laboratory tests showed that both patients were positive for antigelatin IgE.

Ozaki et al. (2005) identified anaphylaxis and allergic reactions, after administration of varicella vaccines, reported to the Post-Marketing Surveillance Center of the Research Foundation for Microbial Diseases of Osaka University. The authors defined anaphylaxis as cardiovascular and/ or respiratory symptoms with an allergic reaction developing within 1 hour after receipt of the vaccine. Thirty-two cases of anaphylaxis developed and serum samples were isolated from nine patients. All nine samples were positive for antigelatin IgE.

Sakaguchi et al. (1997) reported three cases of anaphylaxis postvaccination with varicella vaccines. Case 1 describes a 4-year-old boy presenting with vomiting, urticaria, and airway obstructions with wheezing 40 minutes after vaccination. Case 2 describes a 16-month-old boy presenting with angioedema, urticaria, and airway obstruction with wheezing 20 minutes after vaccination. Case 3 describes a 22-month-old boy presenting with cough, urticaria, and wheezing 1 hour after vaccination. Laboratory tests showed all three patients were positive for antigelatin IgE.

Sakaguchi et al. (2000a) studied the relationship between antigelatin IgE and IgG and non-immediate-type reactions to gelatincontaining varicella vaccines. The authors examined sera from 33 patients that experienced immediate-type reactions after administration of a varicella vaccine as a positive control. Within 1 hour after vaccination, 18 of the patients serving as positive controls developed respiratory and cutaneous symptoms. All 18 of the patients produced antigelatin IgE and IgG antibodies.

Sakaguchi et al. (2000b) reported the incidence of anaphylaxis after

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

live viral vaccines containing gelatin. The authors subdivided systemic immediate-type reactions into three groups. Two groups, severe anaphylaxis and mild anaphylaxis, consisted of respiratory and cutaneous symptoms developing within 1 hour after vaccination. The third group consisted of cutaneous symptoms alone developing within 1 hour after vaccination. A total of 16 cases of anaphylaxis and 14 cases of systemic cutaneous symptoms developing after vaccination against varicella were identified. Of the above described cases, 27 had antigelatin IgE antibodies.

Sharrar et al. (2001) identified seven cases of anaphylaxis postvaricella vaccination reported to WAES or VAERS during the first 4 years of marketing of a gelatin-containing varicella vaccine. The four boys and three girls ranged in age from 3 to 8 years. The patients developed symptoms of urticaria, hypotension, coughing, wheezing, stridor, swollen lips, and/or itching shortly after vaccination.

Wise et al. (2000) identified 30 cases of anaphylaxis postvaricella vaccination reported to VAERS from March 1995 through July 1998. Each case presented with skin and respiratory symptoms within 4 hours after vaccination; in 11 cases, patients presented symptoms within 15 minutes after vaccination. One patient had a history of egg allergy, and presented with similar symptoms after receiving an MMR vaccine. Three patients had a history of allergies to antibiotics, atropine, or ophthalmic solution.

Weight of Mechanistic Evidence

The publications described above presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of anaphylaxis after administration of a gelatin-containing varicella vaccine. Four publications from investigators in Japan described well-documented cases of anaphylaxis occurring in individuals with documented IgE antibodies to gelatin (Ozaki et al., 2005; Sakaguchi et al., 1997, 2000a,b). Gelatin, both whole bovine and hydrolyzed gelatin, was used as a stabilizer in a number of vaccines in Japan, and it is likely that children experiencing anaphylactic reactions to the gelatin-containing varicella vaccine had developed IgE sensitization to gelatin from the administration of previous vaccines. The varicella vaccine distributed in the United States contains only hydrolyzed gelatin; the extent to which gelatin is hydrolyzed could vary from one vaccine lot to another and affect the development of anaphylaxis. Some patients are allergic to either bovine or porcine gelatin, but not both (Bogdanovic et al., 2009). Although there is considerable cross-reactivity between bovine and porcine gelatin, testing for antibody to one gelatin alone is not necessarily predictive of allergy to the other and may not be predictive of reactivity to the gelatin in varicella vaccine.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and anaphylaxis as strong based on 76 cases4presenting temporality and clinical symptoms consistent with anaphylaxis.

Causality Conclusion

Conclusion 5.12: The evidence convincingly supports a causal relationship between varicella vaccine and anaphylaxis.

ONSET OR EXACERBATION OF ARTHROPATHY

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of arthropathy (arthralgia and arthritis) after the administration of varicella vaccine. These two studies (Chaves et al., 2008; 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 onset or exacerbation of arthropathy.

Mechanistic Evidence

The committee identified three publications reporting onset or exacerbation of arthropathy (arthritis and arthralgia) after administration of a varicella vaccine. Two publications reported multiple cases but either did not provide evidence beyond temporality or did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccination and development of symptoms (Chaves et al., 2008; Wise et al., 2000). Pileggi et al. (2010) did not observe the worsening of symptoms in patients previously diagnosed with juvenile rheumatic diseases after administration of a varicella vaccine. The publications did not contribute to the weight of mechanistic evidence.

___________

4 In 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.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Weight of Mechanistic Evidence

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of arthropathy. Autoantibodies, T cells, complement activation, immune complexes, infection, viral reactivation, and viral persistence may contribute to the symptoms of arthropathy; however, the publications did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and onset or exacerbation of arthropathy as lacking.

Causality Conclusion

Conclusion 5.13: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and onset or exacerbation of arthropathy.

STROKE

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of ischemic stroke after the administration of varicella vaccine. This one controlled study (Donahue et al., 2009) contributed to the weight of epidemiologic evidence and is described below.

The study by Donahue et al. (2009) was described in detail in the section on vaccine strain viral reactivation with subsequent infection resulting in encephalitis. This retrospective cohort study investigated the occurrence of ischemic stroke or encephalitis (reported in hospitalizations obtained from the VSD) within 12 months of varicella vaccination. A total of 203 children were diagnosed with ischemic stroke, of whom one received a varicella vaccination within 3 months of diagnosis, and eight did so within 12 months. Adjusted hazard ratios (HRs) were reported for stroke within 1 month of vaccination (HR, 1.1; 95% CI, 0.1–9.2), 1–3 months of vaccination (HR, 0.7; 95% CI, 0.1–5.7), 3–6 months of vaccination (HR, 1.3; 95% CI, 0.3–5.6), 6–9 months of vaccination (HR, 1.3; 95% CI, 0.4–4.9), and 9–12 months of vaccination (HR, 0.4; 95% CI, 0.0–3.2). The authors concluded that varicella vaccination is not associated with ischemic stroke in children.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between varicella vaccine and ischemic stroke.

Mechanistic Evidence

The committee identified two publications reporting stroke after administration of a varicella vaccine. The publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Donahue et al., 2009; Wirrell et al., 2004).

Weight of Mechanistic Evidence

Infection with varicella virus has been associated with stroke with an incidence of approximately 1 in 15,000 cases (Nagel et al., 2010). Varicella virus has been shown to produce vasculopathy via direct invasion of cerebral arteries (Nagel et al., 2010). In adults, stroke associated with varicella presents after herpes zoster ophthalmicus, which is followed weeks to months later by acute contralateral hemiplegia (Nagel et al., 2010). In children, stroke follows acute hemiplegia following varicella infection (Nagel et al., 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of stroke. Direct viral infection, viral reactivation, and alterations in the coagulation cascade can lead to a hypercoagulable state that may contribute to the symptoms of stroke; however, the publications did not provide evidence linking these mechanisms to varicella vaccine.

The committee assesses the mechanistic evidence regarding an association between varicella vaccine and stroke as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 5.14: The evidence is inadequate to accept or reject a causal relationship between varicella vaccine and stroke.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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THROMBOCYTOPENIA

Epidemiologic Evidence

The committee reviewed three studies to evaluate the risk of thrombocytopenia 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 thrombocytopenia.

Mechanistic Evidence

The committee identified six publications reporting thrombocytopenia or idiopathic thrombocytopenic purpura after administration of a varicella vaccine. Chaves et al. (2008) did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccine administration and development of thrombocytopenia. Three publications did not provide evidence beyond temporality (Ferrera et al., 2009; Lee et al., 1986; Sharrar et al., 2001). One publication reported decreased platelet counts without development of unexplained bleeding, clotting, or bruising after vaccination but did not issue a diagnosis (Weibel et al., 1985). These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Wise et al. (2000) identified 31 reports, submitted to VAERS from March 1995 through July 1998, of thrombocytopenia developing after administration of a varicella vaccine. The authors did not provide evidence of causality beyond a temporal relationship of 4 to 28 days between vaccine administration and development of thrombocytopenia after vaccination for most reports. One VAERS report, identified in Wise et al. (2000), was obtained via a Freedom of Information Act request (FDA, 2010). The report describes a 14-year-old boy presenting with petechiae on the legs 1 week after administration of the first dose of a varicella vaccine. The patient experienced excessive bruising and was admitted to the hospital 9 days after administration of the second dose, and after being pinched. Laboratory

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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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 association 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 reject a causal relationship between varicella vaccine and thrombocytopenia.

CONCLUDING SECTION

Table 5-1 provides a summary of the epidemiologic assessments, mechanistic assessments, and causality conclusions for varicella vaccine.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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TABLE 5-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Varicella Vaccine

Vaccine Adverse Event Epidemiologic Assessment Studies Contributing to the Epidemiologic Assessment Mechanistic Assessment Cases Contributing to the Mechanistic Assessment Causality Conclusion
Varicella Disseminated Oka VZV without Other Organ Involvement Insufficient None Strong __a Convincingly Supports
Varicella Disseminated Oka VZV with Subsequent Infection Resulting in Pneumonia, Meningitis, or Hepatitis Limited (subsequent infection resulting in pneumonia)
Insufficient (subsequent infection resulting in meningitis or hepatitis)
1
None
Strong (in individuals with demonstrated immunodeficiencies) 9 Convincingly Supports (in individuals with demonstrated immunodeficiencies)
Varicella Vaccine-Strain Viral Reactivation without Other Organ Involvement Insufficient None Strong __a Convincingly Supports
Varicella Vaccine-Strain Viral Reactivation with Subsequent Infection Resulting in Meningitis or Encephalitis Limited (subsequent infection resulting in encephalitis)
Insufficient (subsequent infection resulting in meningitis)
1
None
Strong 6 Convincingly Supports
Varicella Encephalopathy Insufficient None Lacking None Inadequate
Varicella Seizures Limited 1 Weak None Inadequate
Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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Vaccine Adverse Event Epidemiologic Assessment Studies Contributing to the Epidemiologic Assessment Mechanistic Assessment Cases Contributing to the Mechanistic Assessment Causality Conclusion
Varicella Cerebellar Ataxia Insufficient None Weak None Inadequate
Varicella Acute Disseminated Encephalomyelitis Insufficient None Weak None Inadequate
Varicella Transverse Myelitis Insufficient None Weak 1 Inadequate
Varicella Guillain-Barre 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 Arthropathy Insufficient None Lacking None Inadequate
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.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

REFERENCES

AAP (American Academy of Pediatrics). 2009. Varicella-zoster infections. In Red book: 2009 Report of the Committee on Infectious Diseases, 28th ed., edited by L. K. Pickering, C. J. Baker, D. W. Kimberlin, and S. S. Long. Elk Grove Village, IL: American Academy of Pediatrics. Pp. 714-727.

Alpay, H., N. Yildiz, A. Onar, H. Temizer, and S. Ozcay. 2002. Varicella vaccination in children with steroid-sensitive nephrotic syndrome. Pediatric Nephrology 17(3):181-183.

Angelini, P., F. Kavadas, N. Sharma, S. E. Richardson, G. Tipples, C. Roifman, Y. Dror, and Y. Nofech-Mozes. 2009. Aplastic anemia following varicella vaccine. Pediatric Infectious Disease Journal 28(8):746-748.

Arvin, A. M. 1996. Varicella-zoster virus. Clinical Microbiology Reviews 9(3):361-381.

Arvin, A. M., and A. A. Gershon. 1996. Live attenuated varicella vaccine. Annual Review of Microbiology 50:59-100.

Austgulen, R. 1985. Immunization of children with malignant diseases with the Okastrain varicella vaccine. Postgraduate Medical Journal 61(Suppl. 4):93-95.

Bancillon, A., T. Leblanc, A. Baruchel, G. Schaison, G. Leverger, D. Mallarmey, and L. Teuliere. 1991. Study of tolerance and effectiveness of a varicella vaccine in leukemic children. Nouvelle Revue Francaise d Hematologie 33(6):555-556.

Barton, M., S. Wasfy, T. Melbourne, D. Hebert, D. Moore, J. Robinson, R. D. Marchese, and U. D. Allen. 2009. Sustainability of humoral responses to varicella vaccine in pediatric transplant recipients following a pretransplantation immunization strategy. Pediatric Transplantation 13(8):1007-1013.

Barzaga, N. G., R. H. Florese, and H. L. Bock. 2002. Reactogenicity and immunogenicity of a varicella vaccine in healthy seronegative and seropositive subjects. Southeast Asian Journal of Tropical Medicine and Public Health 33(2):259-267.

Black, S., H. Shinefield, P. Ray, E. Lewis, J. Hansen, J. Schwalbe, P. Coplan, R. Sharrar, and H. Guess. 1999. Postmarketing evaluation of the safety and effectiveness of varicella vaccine. Pediatric Infectious Disease Journal 18(12):1041-1046.

Bogdanovic, J., N. A. Halsey, R. A. Wood, and R. G. Hamilton. 2009. Bovine and porcine gelatin sensitivity in children sensitized to milk and meat. Journal of Allergy and Clinical Immunology 124(5):1108-1110.

Broyer, M., and B. Boudailliez. 1985. Varicella vaccine in children with chronic renal insufficiency. Postgraduate Medical Journal 61(Suppl. 4):103-106.

Brunell, P. A., C. F. Geiser, V. Novelli, S. Lipton, and S. Narkewicz. 1987. Varicella-like illness caused by live varicella vaccine in children with acute lymphocytic leukemia. Pediatrics 79(6):922-927.

Brunell, P. A., Z. Shehab, C. Geiser, and J. E. Waugh. 1982. Administration of live varicella vaccine to children with leukaemia. Lancet 2(8307):1069-1072.

Bryan, C. J., M. N. Prichard, S. Daily, G. Jefferson, C. Hartline, K. A. Cassady, L. Hilliard, and M. Shimamura. 2008. Acyclovir-resistant chronic verrucous vaccine strain varicella in a patient with neuroblastoma. Pediatric Infectious Disease Journal 27(10):946-948.

CDC (Centers for Disease Control and Prevention). 2006. General recommendations on immunization—recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report 55(RR15, Suppl. S):1-24, 25-47.

CDC. 2007. Prevention of varicella—recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report 56(RR4, Suppl. S):1-20, 21-40.

CDC. 2010a. National, state, and local area vaccination coverage among children aged 19-35 months—United States, 2009. Morbidity & Mortality Weekly Report 59(36):1171-1177.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

CDC. 2010b. Use of combination measles, mumps, rubella and varicella vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report 59(RR3, Suppl. S):1-11.

Chan, Y., D. Smith, T. Sadlon, J. X. Scott, and P. N. Goldwater. 2007. Herpes zoster due to Oka vaccine strain of varicella zoster virus in an immunosuppressed child post cord blood transplant. Journal of Paediatrics & Child Health 43(10):713-715.

Chaves, S. S., P. Haber, K. Walton, R. P. Wise, H. S. Izurieta, D. S. Schmid, and J. F. Seward. 2008. Safety of varicella vaccine after licensure in the United States: Experience from reports to the vaccine adverse event reporting system, 1995-2005. Journal of Infectious Diseases 197(Suppl. 2):S170-S177.

Chaves, T. D. S., M. H. Lopes, V. de Souza, S. D. dos Santos, L. M. Pereira, A. D. Reis, and E. David-Neto. 2005. Seroprevalence of antibodies against varicella zoster virus and response to the varicella vaccine in pediatric renal transplant patients. Pediatric Transplantation 9(2):192-196.

Chilek, K., S. Routhouska, and J. Tamburro. 2010. Disseminated varicella zoster virus in an immunized child as the acquired immunodeficiency syndrome-defining illness. Pediatric Dermatology 27(2):192-194.

Chouliaras, G., V. Spoulou, M. Quinlivan, J. Breuer, and M. Theodoridou. 2010. Vaccine-associated herpes zoster ophthalmicus [correction of opthalmicus] and encephalitis in an immunocompetent child. Pediatrics 125(4):e969-e972.

Christensen, C. L., A. Poulsen, B. Bottiger, M. Kirk, H. K. Andersen, and K. Schmiegelow. 1999. Complications in two children with acute lymphatic leukemia caused by vaccination against varicella zoster virus [in Danish]. Ugeskrift for Laeger 161(6):794-796.

Davis, L. E. 2008. Nervous system complications of systemic viral infections. In Neurology and general medicine. 4th ed., edited by M. J. Aminoff. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 827-850.

Diaz, P. S., D. Au, S. Smith, M. Amylon, M. Link, and A. M. Arvin. 1991. Lack of transmission of the live attenuated varicella vaccine virus to immunocompromised children after immunization of their siblings. Pediatrics 87(2):166-170.

DiMiceli, L., V. Pool, J. M. Kelso, S. V. Shadomy, and J. Iskander. 2006. Vaccination of yeast sensitive individuals: Review of safety data in the US Vaccine Adverse Event Reporting System (VAERS). Vaccine 24(6):703-707.

Donahue, J. G., B. A. Kieke, W. K. Yih, N. R. Berger, J. S. McCauley, J. Baggs, K. M. Zangwill, R. Baxter, E. M. Eriksen, J. M. Glanz, S. J. Hambidge, N. P. Klein, E. M. Lewis, S. M. Marcy, A. L. Naleway, J. D. Nordin, P. Ray, E. A. Belongia, and T. Vaccine Safety DataLink. 2009. Varicella vaccination and ischemic stroke in children: Is there an association? Pediatrics 123(2):e228-e234.

Donati, M., M. Zuckerman, A. Dhawan, N. Hadzic, N. Heaton, P. North-Lewis, and G. Mieli-Vergani. 2000. Response to varicella immunization in pediatric liver transplant recipients. Transplantation 70(9):1401-1404.

Emir, S., M. Buyukpamukcu, V. Koseoglu, G. Hascelik, C. Akyuz, T. Kutluk, and A. Varan. 2006. Varicella vaccination in children with lymphoma and solid tumours. Postgraduate Medical Journal 82(973):760-762.

Ey, J. L., S. M. Smith, and V. A. Fulginiti. 1981. Varicella hepatitis without neurologic symptoms or findings. Pediatrics 67(2):285-287.

FDA (Food and Drug Administration). 2010. Descriptive summary of VAERS report indicating probable rechallenge of petechiae following varicella vaccination discussed in Post-licensure safety surveillance for varicella vaccine. Wise, R.P., et al., 2000. Journal of the American Medical Association; 284(10):1271-1279: Sent to the Committee to Review Adverse Effects of Vaccines by the Food and Drug Administration.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Ferrera, G., V. Gajdos, S. Thomas, C. Tran, and A. Fiquet. 2009. Safety of a refrigeratorstable varicella vaccine (VARIVAX) in healthy 12- to 15-month-old children a randomized, double-blind, cross-over study. Human Vaccines 5(7):455-460.

Fleisher, G., W. Henry, M. McSorley, A. Arbeter, and S. Plotkin. 1981. Life-threatening complications of varicella. American Journal of Diseases of Children 135(10):896-899.

Galea, S. A., A. Sweet, P. Beninger, S. P. Steinberg, P. S. LaRussa, A. A. Gershon, and R. G. Sharrar. 2008. The safety profile of varicella vaccine: A 10-year review. Journal of Infectious Diseases 197(Suppl. 2):S165-S169.

Galil, K., C. Brown, F. Lin, and J. Seward. 2002. Hospitalizations for varicella in the United States, 1988 to 1999. Pediatric Infectious Disease Journal 21(10):931-934.

Gelb, L. D., D. E. Dohner, A. A. Gershon, S. P. Steinberg, J. L. Waner, M. Takahashi, P. H. Dennehy, and A. E. Brown. 1987. Molecular epidemiology of live, attenuated varicella virus vaccine in children with leukemia and in normal adults. Journal of Infectious Diseases 155(4):633-640.

Gershon, A. A., S. Steinberg, and G. Galasso. 1984a. Live attenuated varicella vaccine in children with leukemia in remission. Biken Journal, Journal of the Research Institute for Microbial Diseases 27(2-3):77-81.

Gershon, A. A., S. Steinberg, L. Gelb, G. Galasso, W. Borkowsky, P. LaRussa, and A. Ferrara. 1985. A multicentre trial of live attenuated varicella vaccine in children with leukaemia in remission. Postgraduate Medical Journal 61(Suppl. 4):73-78.

Gershon, A. A., and S. P. Steinberg. 1989. Persistence of immunity to varicella in children with leukemia immunized with live attenuated varicella vaccine. New England Journal of Medicine 320(14):892-897.

Gershon, A. A., S. P. Steinberg, and L. Gelb. 1984b. Live attenuated varicella vaccine. Efficacy for children with leukemia in remission. Journal of the American Medical Association 252(3):355-362.

Gershon, A. A., S. P. Steinberg, and L. Gelb. 1986. Live attenuated varicella vaccine use in immunocompromised children and adults. Pediatrics 78(4 Pt 2):757-762.

Ghaffar, F., K. Carrick, B. B. Rogers, L. R. Margraf, K. Krisher, and O. Ramilo. 2000. Disseminated infection with varicella-zoster virus vaccine strain presenting as hepatitis in a child with adenosine deaminase deficiency. Pediatric Infectious Disease Journal 19(8):764-766.

Goulleret, N., E. Mauvisseau, M. Essevaz-Roulet, M. Quinlivan, and J. Breuer. 2010. Safety profile of live varicella virus vaccine (Oka/Merck): Five-year results of the European Varicella Zoster Virus Identification Program (EU VZVIP). Vaccine 28 (36):5878-5882.

Guess, H. A., D. D. Broughton, L. J. Melton, and L. T. Kurland. 1986. Population-based studies of varicella complications. Pediatrics 78(4):723-727.

Haas, R. J., B. Belohradsky, and R. Dickerhoff. 1985a. Live varicella vaccination in children with acute leukemia or other malignant diseases [in German]. Klinische Padiatrie 197(6):477-480.

Haas, R. J., B. Belohradsky, R. Dickerhoff, K. Eichinger, R. Eife, H. Holtmann, O. Goetz, U. Graubner, and P. Peller. 1985b. Active immunization against varicella of children with acute leukaemia or other malignancies on maintenance chemotherapy. Postgraduate Medical Journal 61(Suppl. 4):69-72.

Hadinegoro, S. R. H., I. S. Hindra, H. H. Han, S. Gatchalian, and H. L. Bock. 2009. Reactogenicity and immunogenicity of a live-attenuated refrigerator-stable varicella vaccine (Oka strain) in healthy seronegative subjects age 10 months to 12 years. Southeast Asian Journal of Tropical Medicine and Public Health 40(5):991-999.

Hall, C. B., D. M. Granoff, D. S. Gromisch, N. A. Halsey, S. Kohl, E. K. Marcuse, M. I. Marks, G. A. Nankervis, L. K. Pickering, G. B. Scott, R. W. Steele, R. Yogev, G. Peter, K. J. Bart, C. Broome, M. C. Hardegree, R. F. Jacobs, N. E. Macdonald, W. A. Orenstein, and G. Rabinovich. 1993. The use of oral acyclovir in otherwise healthy-children with varicella. Pediatrics 91(3):674-676.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Hardy, I., A. A. Gershon, S. P. Steinberg, and P. LaRussa. 1991. The incidence of zoster after immunization with live attenuated varicella vaccine: A study in children with leukemia. New England Journal of Medicine 325(22):1545-1550.

Heath, R. B., and J. S. Malpas. 1985. Experience with the live Oka-strain varicella vaccine in children with solid tumours. Postgraduate Medical Journal 61(Suppl. 4):107-111.

Heller, L., G. Berglund, L. Ahstrom, K. Hellstrand, and B. Wahren. 1985. Early results of a trial of the Oka-strain varicella vaccine in children with leukaemia or other malignancies in Sweden. Postgraduate Medical Journal 61(Suppl. 4):79-83.

Hughes, P., P. Larussa, J. M. Pearce, M. Lepow, S. Steinberg, and A. Gershon. 1994. Transmission of varicella-zoster virus from a vaccinee with leukemia, demonstrated by polymerase chain-reaction. Journal of Pediatrics 124(6):932-935.

Ihara, T., H. Kamiya, S. Torigoe, M. Sakurai, and M. Takahashi. 1992. Viremic phase in a leukemic child after live varicella vaccination. Pediatrics 89(1):147-149.

Italiano, C. M., C. S. Toi, S. P. Chan, and D. E. Dwyer. 2009. Prolonged varicella viraemia and streptococcal toxic shock syndrome following varicella vaccination of a health care worker. Medical Journal of Australia 190(8):451-453.

Iyer, S., M. K. Mittal, and R. L. Hodinka. 2009. Herpes zoster and meningitis resulting from reactivation of varicella vaccine virus in an immunocompetent child. Annals of Emergency Medicine 53(6):792-795.

Jackson, M. A., V. F. Burry, and L. C. Olson. 1992. Complications of varicella requiring hospitalization in previously healthy children. Pediatric Infectious Disease Journal 11(6):441-445.

Jean-Philippe, P., A. Freedman, M. W. Chang, S. P. Steinbergd, A. A. Gershon, P. S. LaRussa, and W. Borkowsky. 2007. Severe varicella caused by varicella vaccine strain in a child with significant T-cell dysfunction. Pediatrics 120(5):e1345-e1349.

Kamiya, H., T. Kato, and M. Isaji. 1984. Immunization of acute leukemic children with a live varicella vaccine (Oka strain). Biken Journal, Journal of the Research Institute for Microbial Diseases 27(2-3):99-102.

Katsushima, N., N. Yazaki, and M. Sakamoto. 1982. Application of a live varicella vaccine to hospitalized children and its follow-up study. Biken Journal, Journal of the Research Institute for Microbial Diseases 25(1):29-42.

Kilgore, P. E., D. Kruszon-Moran, J. F. Seward, A. Jumaan, F. P. L. Van Loon, B. Forghani, G. M. McQuillan, M. Wharton, L. J. Fehrs, C. K. Cossen, and S. C. Hadler. 2003. Varicella in Americans from NHANES III: Implications for control through routine immunization. Journal of Medical Virology 70(Suppl. 1):S111-S118.

Klein, N. P., B. Fireman, W. K. Yih, E. Lewis, M. Kulldorff, P. Ray, R. Baxter, S. Hambidge, J. Nordin, A. Naleway, E. A. Belongia, T. Lieu, J. Baggs, and E. Weintraub. 2010. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics 126(1):e1-e8.

Konno, T., Y. Yamaguchi, and M. Minegishi. 1984. A clinical trial of live attenuated varicella vaccine (Biken) in children with malignant diseases. Biken Journal, Journal of the Research Institute for Microbial Diseases 27(2-3):73-75.

Kraft, J. N., and J. C. Shaw. 2006. Varicella infection caused by Oka strain vaccine in a heart transplant recipient. Archives of Dermatology 142(7):943-945.

Kramer, J. M., P. LaRussa, W. C. Tsai, P. Carney, S. M. Leber, S. Gahagan, S. Steinberg, and R. A. Blackwood. 2001. Disseminated vaccine strain varicella as the acquired immunodeficiency syndrome-defining illness in a previously undiagnosed child. Pediatrics 108(2):e39.

Kreth, H. W., and P. H. Hoeger. 2006. Safety, reactogenicity, and immunogenicity of live attenuated varicella vaccine in children between 1 and 9 years of age with atopic dermatitis. European Journal of Pediatrics 165(10):677-683.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
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Kumagai, T., T. Yamanaka, Y. Wataya, A. Umetsu, N. Kawamura, K. Ikeda, H. Furukawa, K. Kimura, S. Chiba, S. Saito, N. Sugawara, F. Kurimoto, M. Sakaguchi, and S. Inouye. 1997. Gelatin-specific humoral and cellular immune responses in children with immediate-and nonimmediate-type reactions to live measles, mumps, rubella, and varicella vaccines. Journal of Allergy and Clinical Immunology 100(1):130-134.

LaRovere, K. L., G. P. Raju, and M. P. Gorman. 2008. Postvaricella acute transverse myelitis in a previously vaccinated child. Pediatric Neurology 38(5):370-372.

LaRussa, P., S. Steinberg, and A. A. Gershon. 1996. Varicella vaccine for immunocompromised children: Results of collaborative studies in the United States and Canada. Journal of Infectious Diseases 174(Suppl. 3):S320-S323.

Lassker, U., T. C. Harder, M. Hufnagel, and M. Suttorp. 2002. Rapid molecular discrimination between infection with wild-type varicella-zoster virus and varicella vaccine virus. Infection 30(5):320-322.

Lawrence, R., A. A. Gershon, R. Holzman, and S. P. Steinberg. 1988. The risk of zoster after varicella vaccination in children with leukemia. New England Journal of Medicine 318(9):543-548.

Lee, S. Y., D. M. Komp, and W. Andiman. 1986. Thrombocytopenic purpura following varicella zoster vaccination. American Journal of Pediatric Hematology/Oncology 8(1):78-80.

Leung, T.-F., C.-K. Li, E. C. W. Hung, P. K. S. Chan, C.-W. Mo, R. P. O. Wong, and K.-W. Chik. 2004. Immunogenicity of a two-dose regime of varicella vaccine in children with cancers. European Journal of Haematology 72(5):353-357.

Levin, M. J., K. M. Dahl, A. Weinberg, R. Giller, A. Patel, and P. R. Krause. 2003. Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. Journal of Infectious Diseases 188(7):954-959.

Levin, M. J., R. L. DeBiasi, V. Bostik, and D. S. Schmid. 2008. Herpes zoster with skin lesions and meningitis caused by 2 different genotypes of the Oka varicella-zoster virus vaccine. Journal of Infectious Diseases 198(10):1444-1447.

Levitsky, J., H. S. Te, T. W. Faust, and S. M. Cohen. 2002. Varicella infection following varicella vaccination in a liver transplant recipient. American Journal of Transplantation 2(9):880-882.

Levy, O., J. S. Orange, P. Hibberd, S. Steinberg, P. LaRussa, A. Weinberg, S. B. Wilson, A. Shaulov, G. Fleisher, R. S. Geha, F. A. Bonilla, and M. Exley. 2003. Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. Journal of Infectious Diseases 188(7):948-953.

Lin, P., M. K. Yoon, and C. S. Chiu. 2009. Herpes zoster keratouveitis and inflammatory ocular hypertension 8 years after varicella vaccination. Ocular Immunology and Inflammation 17(1):33-35.

Liu, G. T., and D. K. Urion. 1992. Pre-eruptive varicella encephalitis and cerebellarataxia. Pediatric Neurology 8(1):69-70.

Lohiya, G.-S., L. Tan-Figueroa, S. Reddy, and S. Marshall. 2004. Chickenpox and pneumonia following varicella vaccine. Infection Control and Hospital Epidemiology 25(7):530.

Lydick, E., B. J. Kuter, B. A. Zajac, and H. A. Guess. 1989. Association of steroid therapy with vaccine-associated rashes in children with acute lymphocytic leukaemia who received Oka/Merck varicella vaccine. Niaid varicella vaccine collaborative study group. Vaccine 7(6):549-553.

Merck & Co., Inc. 2009. Proquad [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.

Meyer, P. A., J. F. Seward, A. O. Jumaan, and M. Wharton. 2000. Varicella mortality: Trends before vaccine licensure in the United States, 1970-1994. Journal of Infectious Diseases 182(2):383-390.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Minamitani, M., S. Numajiri, and Y. Imada. 1982. Application of a live varicella vaccine to the immunosuppressive children and the incidence of a case of herpes zoster after vaccination. Acta Paediatrica Japonica (Overseas Edition) 24(1):175-179.

Nagel, M. A., R. Mahalingam, R. J. Cohrs, and D. Gilden. 2010. Virus vasculopathy and stroke: An under-recognized cause and treatment target. Infectious Disorders—Drug Targets 10(2):105-111.

Naruse, H., H. Miwata, T. Ozaki, Y. Asano, J. Namazue, and K. Yamanishi. 1993. Varicella infection complicated with meningitis after immunization. Acta Paediatrica Japonica 35(4):345-347.

Naseri, A., W. V. Good, and E. T. Cunningham, Jr. 2003. Herpes zoster virus sclerokeratitis and anterior uveitis in a child following varicella vaccination. American Journal of Ophthalmology 135(3):415-417.

Ninane, J., D. Latinne, M. T. Heremans-Bracke, M. De Bruyere, and G. Cornu. 1985. Live varicella vaccine in severely immunodepressed children. Postgraduate Medical Journal 61(Suppl. 4):97-102.

Nunoue, T. 1984. Clinical observations on varicella-zoster vaccinees treated with immunosuppressants for a malignancy. Biken Journal 27(2-3):115-118.

Nyerges, G., Z. Meszner, E. Gyarmati, and S. Kerpelfronius. 1988. Acyclovir prevents dissemination of varicella in immunocompromised children. Journal of Infectious Diseases 157(2):309-313.

Oka, T., K. Iseki, R. Oka, S. Sakuma, H. Yoshioka, and M. Takahashi. 1984. Evaluation of varicella vaccine in childhood leukemia. Observation over 6 years. Biken Journal 27(2-3):103-109.

Ota, K., V. Kim, S. Lavi, E. L. Ford-Jones, G. Tipples, D. Scolnik, and R. Tellier. 2008. Vaccine-strain varicella zoster virus causing recurrent herpes zoster in an immunocompetent 2-year-old. Pediatric Infectious Disease Journal 27(9):847-848.

Otsuka, T., Y. Gomi, N. Inoue, and M. Uchiyama. 2009. Transmission of varicella vaccine virus, Japan. Emerging Infectious Diseases 15(10):1702-1703.

Ozaki, T., N. Nishimura, T. Muto, K. Sugata, S. Kawabe, K. Goto, K. Koyama, H. Fujita, Y. Takahashi, and M. Akiyama. 2005. Safety and immunogenicity of gelatin-free varicella vaccine in epidemiological and serological studies in Japan. Vaccine 23(10):1205-1208.

Pileggi, G. S., C. B. S. De Souza, and V. P. L. Ferriani. 2010. Safety and immunogenicity of varicella vaccine in patients with juvenile rheumatic diseases receiving methotrexate and corticosteroids. Arthritis Care and Research 62(7):1034-1039.

Preblud, S. R. 1986. Varicella—complications and costs. Pediatrics 78(4):728-735.

Prober, C. G., L. E. Kirk, and R. E. Keeney. 1982. Acyclovir therapy of chickenpox in immunosuppressed children—a collaborative study. Journal of Pediatrics 101(4):622-625.

Quinlivan, M., N. Sengupta, and J. Breuer. 2009. A case of varicella caused by co-infection with two different genotypes of varicelia-zoster virus. Journal of Clinical Virology 44(1): 66-69.

Ragozzino, M. W., L. J. Melton, L. T. Kurland, C. P. Chu, and H. O. Perry. 1982. Population-based study of herpes-zoster and its sequelae. Medicine 61(5):310-316.

Ross, A. H., E. Lenchner, and G. Reitman. 1962. Modification of chicken pox in family contacts by administration of gamma globulin. New England Journal of Medicine 267(8):369-376.

Sakaguchi, M., H. Miyazawa, and S. Inouye. 2000a. Sensitization to gelatin in children with systemic non-immediate-type reactions to varicella vaccines. Annals of Allergy, Asthma and Immunology 84(3):341-344.

Sakaguchi, M., T. Nakayama, H. Fujita, M. Toda, and S. Inouye. 2000b. Minimum estimated incidence in Japan of anaphylaxis to live virus vaccines including gelatin. Vaccine 19(4-5):431-436.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

Sakaguchi, M., T. Yamanaka, K. Ikeda, Y. Sano, H. Fujita, T. Miura, and S. Inouye. 1997. IgE-mediated systemic reactions to gelatin included in the varicella vaccine. Journal of Allergy and Clinical Immunology 99(2):263-264.

Sauerbrei, A., E. Rubtcova, P. Wutzier, D. Scott Schmid, and V. N. Loparev. 2004. Genetic profile of an Oka varicella vaccine virus variant isolated from an infant with zoster. Journal of Clinical Microbiology 42(12):5604-5608.

Sauerbrei, A., B. Uebe, and P. Wutzler. 2003. Molecular diagnosis of zoster post varicella vaccination. Journal of Clinical Virology 27(2):190-199.

Schwab, J., and M. Ryan. 2004. Varicella zoster virus meningitis in a previously immunized child. Pediatrics 114(2):e273-e274.

Shah, K. N., P. J. Honig, and A. C. Yan. 2007. “Urticaria multiforme”: A case series and review of acute annular urticarial hypersensitivity syndromes in children. Pediatrics 119(5):e1117-e1183.

Sharrar, R. G., P. LaRussa, S. A. Galea, S. P. Steinberg, A. R. Sweet, R. M. Keatley, M. E. Wells, W. P. Stephenson, and A. A. Gershon. 2001. The postmarketing safety profile of varicella vaccine. Vaccine 19(7-8):916-923.

Shiow, L. R., K. Paris, M. C. Akana, J. G. Cyster, R. U. Sorensen, and J. M. Puck. 2009. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a coronin-1a mutation and a chromosome 16p11.2 deletion. Clinical Immunology 131(1):24-30.

Slordahl, S. H., S. O. Lie, and D. Wiger. 1984. Vaccination of immunocompromised children against varicella [in Norwegian]. Tidsskrift for Den Norske Laegeforening 104(30): 2086-2089.

Slordahl, S. H., D. Wiger, T. Stromoy, M. Degre, E. Thorsby, and S. O. Lie. 1985. Vaccination of children with malignant disease against varicella. Postgraduate Medical Journal 61(Suppl. 4):85-92.

Sorensen, G. V., J. Helgestad, and S. Rosthoj. 2009. Varicella-associated morbidity in children undergoing chemotherapy for acute lymphoblastic leukaemia [in Danish]. Ugeskrift for Laeger 171(46):3354-3359.

Souayah, N., S. Ajroud-Driss, H. W. Sander, T. H. Brannagan, A. P. Hays, and R. L. Chin. 2009. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 27(52):7322-7325.

Sugino, H., R. Tsukino, E. Miyashiro, T. Dezawa, K. Shinohara, S. Uemura, and M. Koike. 1984. Live varicella vaccine: Prevention of nosocomial infection and protection of high risk infants from varicella infection. Biken Journal 27(2-3):63-65.

Sunaga, Y., A. Hikima, T. Ostuka, and A. Morikawa. 1995. Acute cerebellar ataxia with abnormal MRI lesions after varicella vaccination. Pediatric Neurology 13(4):340-342.

Suvatte, V., C. Wasi, and U. Kositanont. 1985. Live attenuated varicella vaccination in immunocompromised children. Asian Pacific Journal of Allergy and Immunology 3(1):16-22.

Takahashi, M., H. Kamiya, K. Baba, Y. Asano, T. Ozaki, and K. Horiuchi. 1985. Clinical experience with Oka live varicella vaccine in Japan. Postgraduate Medical Journal 61(Suppl. 4):61-67.

Takahashi, M., Y. Okuno, T. Otsuka, J. Osame, A. Takamizawa, T. Sasada, and T. Kubo. 1975. Development of a live attenuated varicella vaccine. Biken Journal 18(1):25-33.

Takahashi, M., T. Otsuka, Y. Okuno, Y. Asano, and T. Yazaki. 1974. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 2(7892):1288-1290.

Uebe, B., A. Sauerbrei, S. Burdach, and G. Horneff. 2002. Herpes zoster by reactivated vaccine varicella zoster virus in a healthy child. European Journal of Pediatrics 161(8):442-444.

Ueda, K., I. Yamada, M. Goto, T. Nanri, H. Fukuda, M. Katsuta, T. Otsuka, and M. Takahashi. 1977. Use of a live varicella vaccine to prevent the spread of varicella in handicapped or immunosuppressed children including MCLS (muco-cutaneous lymphnode syndrome) patients in hospitals. Biken Journal 20(3-4):117-123.

Suggested Citation:"5 Varicella Virus Vaccine." Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press. doi: 10.17226/13164.
×

van der Maas, N. A. T., P. E. Vermeer-de Bondt, H. de Melker, and J. M. Kemmeren. 2009. Acute cerebellar ataxia in the Netherlands: A study on the association with vaccinations and varicella zoster infection. Vaccine 27(13):1970-1973.

Waters, V., K. S. Peterson, and P. LaRussa. 2007. Live viral vaccines in a DiGeorge syndrome patient. Archives of Disease in Childhood 92(6):519-520.

Weibel, R. E., B. J. Kuter, and B. J. Neff. 1985. Live Oka/Merck varicella vaccine in healthy children. Further clinical and laboratory assessment. Journal of the American Medical Association 254(17):2425-2439.

White, C. J., B. J. Kuter, C. S. Hildebrand, K. L. Isganitis, H. Matthews, W. J. Miller, P. J. Provost, R. W. Ellis, R. J. Gerety, and G. B. Calandra. 1991. Varicella vaccine (VARIVAX) in healthy children and adolescents: Results from clinical trials, 1987 to 1989. Pediatrics 87(5):604-610.

Whitley, R. J. 2010. Varicella-zoster virus. In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. 2 vols. Vol. 2, edited by G. L. Mandell, J. E. Bennett, and R. Dolin. Philadelphia, PA: Churchill Livingstone Elsevier. Pp. 1963-1969.

Williams, D. L., A. A. Gershon, L. D. Gelb, M. K. Spraker, S. Steinberg, and A. H. Ragab. 1985. Herpes zoster following varicella vaccine in a child with acute lymphocytic leukemia. Journal of Pediatrics 106(2):259-261.

Wirrell, E., M. D. Hill, T. Jadavji, A. Kirton, and K. Barlow. 2004. Stroke after varicella vaccination. Journal of Pediatrics 145(6):845-847.

Wise, R. P., M. E. Salive, M. M. Braun, G. T. Mootrey, J. F. Seward, L. G. Rider, and P. R. Krause. 2000. Postlicensure safety surveillance for varicella vaccine. Journal of the American Medical Association 284(10):1271-1279.

Zamora, I., J. M. Simon, M. E. Da Silva, and A. I. Piqueras. 1994. Attenuated varicella virus vaccine in children with renal transplants. Pediatric Nephrology 8(2):190-192.

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Adverse Effects of Vaccines: Evidence and Causality Get This Book
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In 1900, for every 1,000 babies born in the United States, 100 would die before their first birthday, often due to infectious diseases. Today, vaccines exist for many viral and bacterial diseases. The National Childhood Vaccine Injury Act, passed in 1986, was intended to bolster vaccine research and development through the federal coordination of vaccine initiatives and to provide relief to vaccine manufacturers facing financial burdens. The legislation also intended to address concerns about the safety of vaccines by instituting a compensation program, setting up a passive surveillance system for vaccine adverse events, and by providing information to consumers. A key component of the legislation required the U.S. Department of Health and Human Services to collaborate with the Institute of Medicine to assess concerns about the safety of vaccines and potential adverse events, especially in children.

Adverse Effects of Vaccines reviews the epidemiological, clinical, and biological evidence regarding adverse health events associated with specific vaccines covered by the National Vaccine Injury Compensation Program (VICP), including the varicella zoster vaccine, influenza vaccines, the hepatitis B vaccine, and the human papillomavirus vaccine, among others. For each possible adverse event, the report reviews peer-reviewed primary studies, summarizes their findings, and evaluates the epidemiological, clinical, and biological evidence. It finds that while no vaccine is 100 percent safe, very few adverse events are shown to be caused by vaccines. In addition, the evidence shows that vaccines do not cause several conditions. For example, the MMR vaccine is not associated with autism or childhood diabetes. Also, the DTaP vaccine is not associated with diabetes and the influenza vaccine given as a shot does not exacerbate asthma.

Adverse Effects of Vaccines will be of special interest to the National Vaccine Program Office, the VICP, the Centers for Disease Control and Prevention, vaccine safety researchers and manufacturers, parents, caregivers, and health professionals in the private and public sectors.

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