The live-attenuated varicella vaccine, a routine immunization in the United States since 1995, is both safe and effective. Like wild-type varicella-zoster virus, however, vaccine Oka (vOka) varicella can establish latency and reactivate as herpes zoster, rarely leading to serious disease, particularly among immunocompromised hosts. All but one previously reported cases of reactivated vOka resulting in meningitis have been described in young children who received a single dose of varicella vaccine; less is known about vOka reactivation in older children after the 2-dose vaccine series. We present 2 adolescents with reactivated vOka meningitis, 1 immunocompetent and 1 immunocompromised, both of whom received 2 doses of varicella vaccine many years before as children. Pediatricians should be aware of the potential of vOka varicella to reactivate and cause clinically significant central nervous system disease in vaccinated children and adolescents.

Varicella-zoster virus (VZV) causes varicella (chickenpox) during primary infection and can reactivate to cause herpes zoster (HZ) (shingles). Although varicella is commonly tolerated without sequelae in immunocompetent younger children, it can result in severe disease, particularly in older or immunocompromised individuals.1  VZV was attenuated in 1974, and vaccine Oka (vOka) varicella was developed into a vaccine to prevent chickenpox.1  The Advisory Committee on Immunization Practices recommended a single dose in 1995, and a second dose was recommended in 2006.2 

Despite its success as a live-attenuated virus vaccine, vOka varicella can cause serious disease.3,4  Varicella vaccine is contraindicated in immunocompromised individuals, and 6 cases of fatal vOka disease have occurred shortly after vaccination with either the varicella59  or zoster10,11  vaccines, all among individuals who were5,6,811  or suspected to be7  immunocompromised. In addition, months to years after immunization, vaccine recipients may experience cutaneous HZ due to vOka,12  rarely leading to meningitis or encephalitis.1,3,4,1220  All3,4,1320  but one21  previously reported cases of vOka meningitis or encephalitis occurred in individuals who received a single dose of varicella vaccine during childhood. We describe vOka varicella meningitis in an additional 2 adolescents who received 2 doses of vOka as children, 1 immunocompetent and 1 immunocompromised.

VZV serology and typing for case 1 was completed at the Centers for Disease Control and Prevention National VZV Laboratory. Viral typing was completed by using a Förster Resonant Energy Transfer–based polymerase chain reaction (PCR) assay, and immunoglobulin G (IgG) was measured using whole VZV infected cell and purified glycoprotein antigen enzyme-linked immunosorbent assay. VZV typing for case 2 was completed at Columbia University through the Varicella Zoster Virus Identification Program, part of the Worldwide Adverse Experience System of Merck and Co Inc, using PCR and single nucleotide polymorphism analysis.5,22  This report was deemed exempt by the Seattle Children’s and Legacy Institutional Review Boards, and consent to publish was obtained from the patients’ parents.

A previously healthy 14-year-old boy presented with a 2-day history of malaise, anorexia, and a painful, pruritic rash and a 1-day history of severe headache. Physical examination revealed >70 papulovesicular lesions over the lateral aspect of his left thigh in an L1 to L2 dermatomal distribution, photophobia, and meningismus without focal neurologic deficits or altered mental status. The patient had no recent VZV exposure and had received 2 varicella vaccinations at 1 and 4 years of age.

Laboratory studies revealed normal peripheral blood white blood cell (WBC) and platelet counts, liver transaminases, and C-reactive protein level. Cerebrospinal fluid (CSF) had a Gram-stain result negative for organisms, glucose of 60 mg/dL, protein of 64 mg/dL, red blood cell count of 268/mm3, and WBC count of 140/mm3 with 88% lymphocytes and 10% monocytes. CSF and a scraping of a vesicular lesion resulted positive for VZV by PCR; virus from both specimens genotyped as vOka. VZV seroconversion was confirmed, and CSF tested negative for VZV IgG. The patient was HIV negative with normal numbers and percentages of T- and B-cell subsets. He was treated for 7 days with intravenous (IV) acyclovir. Pain resolved, and no new lesions developed after 3 days of treatment; headache, photophobia, and meningismus resolved after 5 days; neurologic examination was normal at discharge. Malaise resolved 2 weeks later.

A 14-year-old boy who underwent a cord blood transplant 10 months earlier for relapsed acute lymphoblastic leukemia presented with a 6-day history of abdominal rash, 5-day history of headache, and a fever. Examination revealed a 3-mm vesicular lesion on an erythematous base with central umbilication on his left upper abdomen (Fig 1) and 10 to 20 similar vesicular lesions on his right wrist and bilateral chest and back in a nondermatomal distribution. He had a WBC count of 6100/µL, an absolute neutrophil count of 3080/µL, an absolute lymphocyte count of 1641/µL, and a C-reactive protein level of 1.5 mg/dL (normal: ≤0.8 mg/dL). Head computed tomography scan appeared normal, but lumbar puncture opening pressure was elevated at 43 cm of water. CSF was Gram-stain negative for organisms, with glucose level of 65 mg/dL, protein level of 164 mg/dL, red blood cell count of 1/mm3, and WBC count of 81/mm3 with 1% neutrophils. PCR detected VZV in the CSF (14 000 000 copies per milliliter), serum (8700 copies per milliliter), and from a scraping of a vesicular skin lesion. Virus from CSF was genotyped as vOka. IV acyclovir was started at a dose of 20 mg/kg q8 hours; fevers and new lesions continued for 3 additional days.

The patient gradually improved; however, on day 12 of acyclovir, he developed a new fever, perioral numbness, slurred speech and aphasia, and right upper extremity numbness. A brain MRI demonstrated T2 prolongation in the left nucleus accumbens, anterior inferior hypothalamus, and anteroinferior putamen consistent with VZV encephalitis. The neurology service felt that his symptoms were most consistent with neurologic dysfunction secondary to acute viral infection. VZV PCR results of the CSF on day 13 of acyclovir remained positive (4500 copies per milliliter). He recovered within hours but experienced a similar episode, although without fever, 4 days later, which also quickly resolved. CSF obtained on day 20 of acyclovir remained positive for VZV (800 copies per milliliter). IV acyclovir was continued to complete 27 days of therapy.

One week after completing IV acyclovir, the patient experienced a third episode of aphasia and numbness, beginning in the right hand, progressing up the arm, and extending to the face; the episode resolved within 2 hours and was not associated with fever. Acyclovir was restarted. A brain MRI demonstrated improvement in the previously noted lesions consistent with evolving VZV meningoencephalitis. CSF VZV PCR result was negative, and acyclovir was stopped after 24 hours. Because of concern for seizure, an EEG was obtained and demonstrated intermittent slowing and excessive β activity consistent with encephalopathy. He had no further episodes.

The patient’s past medical history was remarkable for delayed immune reconstitution posttransplant, with low CD4 and CD8 T-cell counts and a normal CD19 B-cell count but a low total IgG count. He had ongoing grade IIa skin and gut graft-versus-host disease, managed with budesonide, sirolimus, and topical tacrolimus. He had received 2 doses of varicella vaccine at 1 and 10 years of age, and pretransplant, he was seropositive for VZV and received acyclovir prophylaxis through day 100 posttransplant. An immune workup postmeningitis identified adequate T-cell function but reduced mature memory and switched memory B cells. His serum VZV IgG became negative 18 months after his meningitis, and he continued acyclovir prophylaxis indefinitely.

Our 2 cases of vOka meningitis amplify a prior single case report21  and confirm that despite the expected robust immunity induced by a 2-dose series, vOka may reactivate in both immunocompetent and immunocompromised hosts.

Like wild-type virus, vOka can establish latency in sensory ganglia after immunization and may reactivate, leading to HZ.3,4,21,23  In 1 study, the rate of HZ was 70% lower in varicella-vaccinated children relative to unvaccinated children, but among vaccinated children, vOka was responsible for only half of HZ; the remaining cases were due to wild-type virus.23  vOka cases tended to occur in younger children (1–2 years of age) relative to wild-type cases (10–17 years of age),23  a finding previously noted in postlicensure surveillance.15  Classic HZ with a dermatomal distribution was noted in the majority of both vOka and wild-type cases, with half of vOka cases reactivating on the extremity of vaccination.23  Other clinical features of vaccine-related and wild-type disease were similar.23 

vOka varicella rarely results in meningitis, which is thought to occur after reactivation in a proximal dorsal root ganglion with spread to the central nervous system. vOka meningitis has been reported in both immunocompetent3,1417,1921  and immunocompromised children.3,4,13,18  Seven healthy children between 3 and 14 years of age developed a zoster-like rash before developing neurologic complaints.3,1417,19,20,21  All but one21  had received 1 dose of varicella vaccine around 1 year of age. The interval between vaccination and presentation with zoster-associated meningitis was 20 months to 11 years in those who had received single dose. The one child who had received 2 doses of vaccine at 18 months and at 12 years of age presented 2 years after the second dose. vOka DNA was detected in the CSF by PCR concurrent with neurologic symptoms in all patients. Most had CSF pleocytosis.16,17,19,21  All were treated with acyclovir and recovered without sequelae.

Previous reports of vOka meningitis also include 2 patients immunized with varicella vaccine shortly before diagnosis of neuroblastoma.13,18  HZ developed at 113  and 318  months into therapy, with progressive rash and neurologic symptoms despite acyclovir. Both children required >3 months of therapy with foscarnet plus varicella-specific IgG to clear the virus, with 1 child having VZV PCR–positive CSF for 10 weeks.13  A third case was reported in a 4-year-old undergoing chemotherapy for acute lymphoblastic leukemia who developed HZ and meningitis, vaccinated 19 months before.3,4  He was treated with IV acyclovir and recovered fully.

Our patients presented in adolescence, in contrast to the typical age of vOka HZ.23  Case 1 recovered quickly when treated with acyclovir without long-term sequelae. Case 2 presented with disseminated viremia and meningitis progressing to encephalitis. He had a normal lymphocyte count when he developed meningitis but was still receiving immunosuppression. Despite acyclovir treatment, the patient continued to have positive CSF VZV PCR results for at least 20 days and ongoing neurologic symptoms for 5 weeks. Immune workup demonstrated abnormal B-cell maturation, consistent with previous data that the B-cell compartment may take up to 5 years post–stem cell transplant to reconstitute.24  This case suggests that after transplant, patients with ongoing immunosuppression may be at risk for VZV reactivation, including vOka virus. VZV-seropositive patients at our transplant center now receive acyclovir prophylaxis until 8 months off systemic immunosuppression or 1-year posttransplant.

Children who have received the current standard schedule of 2 doses of varicella vaccine are entering adolescence and young adulthood. Ascertaining the frequency of vOka reactivation in this cohort may be important in future diagnosis and care of patients with meningitis and encephalitis.

Drs Harrington, Mató, and Englund conceptualized and drafted the initial manuscript; Drs Gershon and Schmid coordinated and supervised data collection; Drs Burroughs and Carpenter critically reviewed and revised the manuscript for important intellectual content; and all authors critically reviewed and revised the manuscript for important intellectual content, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: Dr Harrington was supported by grant K08 AI135072 from NIAID/NIH and CAMS 1017213 from the Burroughs Wellcome Fund. Supported by the National Institutes of Health (NIH).

CSF

cerebrospinal fluid

HZ

herpes zoster

IgG

immunoglobulin G

IV

intravenous

PCR

polymerase chain reaction

vOka

vaccine Oka

VZV

varicella-zoster virus

WBC

white blood cell

1
Gershon
AA
,
Gershon
MD
.
Pathogenesis and current approaches to control of varicella-zoster virus infections
.
Clin Microbiol Rev
.
2013
;
26
(
4
):
728
743
2
Marin
M
,
Güris
D
,
Chaves
SS
,
Schmid
S
,
Seward
JF
;
Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC)
.
Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP)
.
MMWR Recomm Rep
.
2007
;
56
(
RR
):
1
40
3
Chaves
SS
,
Haber
P
,
Walton
K
, et al
.
Safety of varicella vaccine after licensure in the United States: experience from reports to the vaccine adverse event reporting system, 1995-2005
.
J Infect Dis
.
2008
;
197
(
suppl 2
):
S170
S177
4
Galea
SA
,
Sweet
A
,
Beninger
P
, et al
.
The safety profile of varicella vaccine: a 10-year review
.
J Infect Dis
.
2008
;
197
(
suppl 2
):
S165
S169
5
Bhalla
P
,
Forrest
GN
,
Gershon
M
, et al
.
Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation
.
Clin Infect Dis
.
2015
;
60
(
7
):
1068
1074
6
Dutmer
CM
,
Asturias
EJ
,
Smith
C
, et al
.
Late onset hypomorphic RAG2 deficiency presentation with fatal vaccine-strain VZV infection
.
J Clin Immunol
.
2015
;
35
(
8
):
754
760
7
Leung
J
,
Siegel
S
,
Jones
JF
, et al
.
Fatal varicella due to the vaccine-strain varicella-zoster virus
.
Hum Vaccin Immunother
.
2014
;
10
(
1
):
146
149
8
Schrauder
A
,
Henke-Gendo
C
,
Seidemann
K
, et al
.
Varicella vaccination in a child with acute lymphoblastic leukaemia
.
Lancet
.
2007
;
369
(
9568
):
1232
9
Smith
C
,
Dutmer
C
,
Schmid
DS
, et al
.
A toddler with rash, encephalopathy, and hemolytic anemia
.
J Pediatric Infect Dis Soc
.
2015
;
4
(
4
):
376
380
10
Alexander
KE
,
Tong
PL
,
Macartney
K
,
Beresford
R
,
Sheppeard
V
,
Gupta
M
.
Live zoster vaccination in an immunocompromised patient leading to death secondary to disseminated varicella zoster virus infection
.
Vaccine
.
2018
;
36
(
27
):
3890
3893
11
Costa
E
,
Buxton
J
,
Brown
J
,
Templeton
KE
,
Breuer
J
,
Johannessen
I
.
Fatal disseminated varicella zoster infection following zoster vaccination in an immunocompromised patient
.
BMJ Case Rep
.
2016
;
2016
:
bcr2015212688
12
Gershon
AA
,
Takahashi
M
,
Seward
JF
. Varicella Vaccines. In:
Plotkin
SA
,
Orenstein
WA
,
Offit
PA
, eds.
Plotkin’s Vaccines
, 7th ed.
Philadelphia, PA
:
Elsevier
;
2018
:
1145
1180
13
Bryan
CJ
,
Prichard
MN
,
Daily
S
, et al
.
Acyclovir-resistant chronic verrucous vaccine strain varicella in a patient with neuroblastoma
.
Pediatr Infect Dis J
.
2008
;
27
(
10
):
946
948
14
Chouliaras
G
,
Spoulou
V
,
Quinlivan
M
,
Breuer
J
,
Theodoridou
M
.
Vaccine-associated herpes zoster ophthalmicus [correction of opthalmicus] and encephalitis in an immunocompetent child
.
Pediatrics
.
2010
;
125
(
4
).
15
Goulleret
N
,
Mauvisseau
E
,
Essevaz-Roulet
M
,
Quinlivan
M
,
Breuer
J
.
Safety profile of live varicella virus vaccine (Oka/Merck): five-year results of the European Varicella Zoster Virus Identification Program (EU VZVIP)
.
Vaccine
.
2010
;
28
(
36
):
5878
5882
16
Han
JY
,
Hanson
DC
,
Way
SS
.
Herpes zoster and meningitis due to reactivation of varicella vaccine virus in an immunocompetent child
.
Pediatr Infect Dis J
.
2011
;
30
(
3
):
266
268
17
Iyer
S
,
Mittal
MK
,
Hodinka
RL
.
Herpes zoster and meningitis resulting from reactivation of varicella vaccine virus in an immunocompetent child
.
Ann Emerg Med
.
2009
;
53
(
6
):
792
795
18
Levin
MJ
,
Dahl
KM
,
Weinberg
A
,
Giller
R
,
Patel
A
,
Krause
PR
.
Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child
.
J Infect Dis
.
2003
;
188
(
7
):
954
959
19
Levin
MJ
,
DeBiasi
RL
,
Bostik
V
,
Schmid
DS
.
Herpes zoster with skin lesions and meningitis caused by 2 different genotypes of the Oka varicella-zoster virus vaccine
.
J Infect Dis
.
2008
;
198
(
10
):
1444
1447
20
Pahud
BA
,
Glaser
CA
,
Dekker
CL
,
Arvin
AM
,
Schmid
DS
.
Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine
.
J Infect Dis
.
2011
;
203
(
3
):
316
323
21
Chen
Y-C
,
James
A
,
Kung
E
,
Madhavan
V
.
A case of herpes zoster and meningitis in a twice-vaccinated healthy adolescent
.
J Pediatr Infect Dis
.
2017
;
12
:
142
144
22
LaRussa
P
,
Lungu
O
,
Hardy
I
,
Gershon
A
,
Steinberg
SP
,
Silverstein
S
.
Restriction fragment length polymorphism of polymerase chain reaction products from vaccine and wild-type varicella-zoster virus isolates
.
J Virol
.
1992
;
66
(
2
):
1016
1020
23
Weinmann
S
,
Chun
C
,
Schmid
DS
, et al
.
Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005-2009
.
J Infect Dis
.
2013
;
208
(
11
):
1859
1868
24
Ogonek
J
,
Kralj Juric
M
,
Ghimire
S
, et al
.
Immune reconstitution after allogeneic hematopoietic stem cell transplantation
.
Front Immunol
.
2016
;
7
:
507

Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Gershon has National Institutes of Health funding to study varicella-zoster virus and a service laboratory contract with Merck for study of the safety of varicella-zoster virus vaccines. Dr Englund has received research support from Merck and GlaxoSmithKline. The other authors have indicated they have no potential conflicts of interest to disclose. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Diseases Control and Prevention.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.