untitled

Morbidity and Mortality Weekly Report

www.cdc.gov/mmwr

Recommendations and Reports June 6, 2008 / Vol. 57 / RR-5

Prevention of Herpes Zoster

Recommendations

of the Advisory Committee on

Immunization Practices (ACIP)

INSIDE: Continuing Education Examination

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Centers for Disease Control and PreventionCenters for Disease Control and Prevention

Centers for Disease Control and Prevention

MMWR

The MMWR series of publications is published by the Coordinating

Center for Health Information and Service, Centers for Disease

Control and Prevention (CDC), U.S. Department of Health and

Human Services, Atlanta, GA 30333.

Suggested Citation: Centers for Disease Control and Prevention.

[Title]. MMWR Early Release 2008;57[Date]:[inclusive page numbers].

Centers for Disease Control and Prevention

Julie L. Gerberding, MD, MPH

Director

Tanja Popovic, MD, PhD

Chief Science Officer

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Deputy Director, National Center for Health Marketing

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Editorial Board

William L. Roper, MD, MPH, Chapel Hill, NC, Chairman

Virginia A. Caine, MD, Indianapolis, IN

David W. Fleming, MD, Seattle, WA

William E. Halperin, MD, DrPH, MPH, Newark, NJ

Margaret A. Hamburg, MD, Washington, DC

King K. Holmes, MD, PhD, Seattle, WA

Deborah Holtzman, PhD, Atlanta, GA

John K. Iglehart, Bethesda, MD

Dennis G. Maki, MD, Madison, WI

Sue Mallonee, MPH, Oklahoma City, OK

Stanley A. Plotkin, MD, Doylestown, PA

Patricia Quinlisk, MD, MPH, Des Moines, IA

Patrick L. Remington, MD, MPH, Madison, WI

Barbara K. Rimer, DrPH, Chapel Hill, NC

John V. Rullan, MD, MPH, San Juan, PR

Anne Schuchat, MD, Atlanta, GA

Dixie E. Snider, MD, MPH, Atlanta, GA

John W. Ward, MD, Atlanta, GA

CONTENTS

Introduction .......................................................................... 1

Methods ...............................................................................2

Background ..........................................................................2

Biology of VZV ................................................................... 2

Clinical Features of Zoster and PHN .................................. 3

Diagnosis ..........................................................................5

Zoster Transmission ...........................................................5

Epidemiology of Zoster and Complications ....................... 6

Treatment and Nonspecific Management of Zoster

and PHN ........................................................................ 11

Prevention of Transmission from Zoster ........................... 11

Zoster Vaccine .................................................................... 11

Vaccine Composition, Dosage, and Administration ......... 11

Storage and Handling ..................................................... 12

Efficacy ............................................................................12

Immunogencity ................................................................ 14

Duration of Efficacy and of Immunity ..............................14

Safety and Adverse Events .............................................. 15

The Economic Burden of Zoster and Cost-Effectiveness of

Vaccination ......................................................................... 15

Summary of Rationale for Zoster Vaccine

Recommendations ............................................................ 17

Recommendations for Use of Zoster Vaccine ...................... 19

Routine Vaccination of Persons Aged

>60 Years ..............19

Simultaneous Administration with Other Adult Vaccines ..19

Groups for Which Vaccine is Not Licensed ....................... 19

Special Groups and Circumstances .................................. 19

Contraindications ............................................................20

Precautions ...................................................................... 21

Program Implementation Issues ......................................21

Future Research and Directions ..........................................22

Additional Information About Zoster and Zoster Vaccine ....23

Acknowledgments ..............................................................23

References .........................................................................23

Disclosure of Relationship

CDC, our planners, and our content experts wish to disclose they have

no financial interests or other relationships with the manufacturers of

commercial products, suppliers of commercial services, or commercial

supporters. This report does not include any discussion of the unlabeled

use of a product or a product under investigational use with the

exception of the discussion of off-label use of zoster vaccine by persons

who report a previous episode of herpes zoster. In addition, guidance is

provided for instances in which zoster vaccine is inadvertently

administered.

1 Vol. 57 / RR-5 MMWR

Prevention of Herpes Zoster

Recommendations of the Advisory Committee

on Immunization Practices (ACIP)

Prepared by

Rafael Harpaz, MD, Ismael R. Ortega-Sanchez, PhD, Jane F. Seward, MBBS,

Division of Viral Diseases, National Center for Immunization and Respiratory Diseases

Summary

These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the

use of a live attenuated vaccine for the prevention of herpes zoster (zoster) (i.e., shingles) and its sequelae, which was licensed

by the U.S. Food and Drug Administration (FDA) on May 25, 2006. This report summarizes the epidemiology of zoster and

its sequelae, describes the zoster vaccine, and provides recommendations for its use among adults aged >60 years in the United

States.

Zoster is a localized, generally painful cutaneous eruption that occurs most frequently among older adults and

immunocompromised persons. It is caused by reactivation of latent varicella zoster virus (VZV) decades after initial VZV

infection is established. Approximately one in three persons will develop zoster during their lifetime, resulting in an estimated

1 million episodes in the United States annually. A common complication of zoster is postherpetic neuralgia (PHN), a

chronic, often debilitating pain condition that can last months or even years. The risk for PHN in patients with zoster is

10%–18%. Another complication of zoster is eye involvement, which occurs in 10%–25% of zoster episodes and can result

in prolonged or permanent pain, facial scarring, and loss of vision. Approximately 3% of patients with zoster are hospital-

ized; many of these episodes involved persons with one or more immunocompromising conditions. Deaths attributable to zoster

are uncommon among persons who are not immunocompromised.

Prompt treatment with the oral antiviral agents acyclovir, valacyclovir, and famciclovir decreases the severity and duration

of acute pain from zoster. Additional pain control can be achieved in certain patients by supplementing antiviral agents with

corticosteroids and with analgesics. Established PHN can be managed in certain patients with analgesics, tricyclic antide-

pressants, and other agents.

Licensed zoster vaccine is a lyophilized preparation of a live, attenuated strain of VZV, the same strain used in the varicella

vaccines. However, its minimum potency is at least 14-times the potency of single-antigen varicella vaccine. In a large

clinical trial, zoster vaccine was partially efficacious at preventing zoster. It also was partially efficacious at reducing the

severity and duration of pain and at preventing PHN among those developing zoster.

Zoster vaccine is recommended for all persons aged >60 years who have no contraindications, including persons who report

a previous episode of zoster or who have chronic medical conditions. The vaccine should be offered at the patient’s first clinical

encounter with his or her health-care provider. It is administered as a single 0.65 mL dose subcutaneously in the deltoid region

of the arm. A booster dose is not licensed for the vaccine. Zoster vaccination is not indicated to treat acute zoster, to prevent

persons with acute zoster from developing PHN, or to treat ongoing PHN. Before administration of zoster vaccine, patients do

not need to be asked about their history of varicella (chickenpox) or to have serologic testing conducted to determine varicella

immunity.

Introduction

The material in this report originated in the National Center for

Immunization and Respiratory Diseases, Anne Schuchat, MD,

Infection with varicella zoster virus (VZV) causes two dis-

Director; and the Division of Viral Diseases, Larry Anderson, MD,

tinct clinical conditions. Primary VZV infection causes

Director.

varicella (i.e., chickenpox), a contagious rash illness that

Corresponding preparer: Rafael Harpaz, MD, National Center for

Immunization and Respiratory Diseases, CDC, 1600 Clifton Rd.,

typically occurs among children. A vaccine for preventing

NE, MS A-47, Atlanta, GA 30333. Telephone: 404-639-6284; Fax:

initial VZV infection has been available in the United States

404-639-8665; E-mail: r[email protected].

since 1995, and the Advisory Committee on Immuniza-

tion Practices (ACIP) recommends routine varicella

2 MMWR June 6, 2008

vaccination for all persons aged >12 months who lack evi-

dence of immunity (1–3). Varicella vaccination has dra-

matically reduced chickenpox cases among children (3).

VZV can reactivate clinically decades after initial infec-

tion to cause herpes zoster (zoster) (i.e., shingles), a local-

ized and generally painful cutaneous eruption that occurs

most frequently among older adults. Approximately 1 mil-

lion new cases of zoster occur in the United States annu-

ally. Approximately one in three persons in the general

population will develop zoster during their lifetime. A com-

mon complication of zoster is postherpetic neuralgia

(PHN), a chronic pain condition that can last months or

even years. In May 2006, a live, attenuated vaccine for pre-

vention of zoster (ZOSTAVAX

, manufactured by Merck

& Co., Inc.) was licensed in the United States for use in

persons aged >60 years. This report provides recommen-

dations for use of zoster vaccine for prevention of zoster

and its sequelae.

Methods

In Spring 2005, Merck & Co., Inc. (Whitehouse Sta-

tion, New Jersey) submitted a Biologics License Applica-

tion to the Food and Drug Administration (FDA) for an

investigational live, attenuated vaccine for prevention of

zoster on the basis of a phase 3 clinical trial. These results

were published in June 2005 (4) and presented at the ACIP

meeting later that month. In September 2005, ACIP’s

measles-mumps-rubella and varicella workgroup expanded

its membership to include experts in adult medicine and

in zoster and began review of relevant data on zoster and

the investigational vaccine. Shortly thereafter, this workgroup

reformed as the ACIP shingles workgroup and, during sub-

sequent months, held 19 conference calls to review and

discuss scientific evidence related to herpes zoster and zoster

vaccine, including the epidemiology and natural history of

zoster and its sequelae, and the safety, immunogenicity,

efficacy, financing, storage, and handling of the zoster vac-

cine. The workgroup also reviewed several economic analy-

ses on zoster prevention. Workgroup members participated

in 10 additional conference calls to develop and discuss

recommendation options for preventing zoster. When sci-

entific evidence was lacking, recommendations incorporated

expert opinions of the workgroup members.

Presentations of background materials on zoster and the

vaccine were made during ACIP meetings in October 2005

and the three meetings in 2006. Following vaccine licen-

sure on May 25, 2006, recommendation options were pre-

sented to ACIP in June 2006, and final options were

presented at the October 2006 meeting. During review by

CDC and external partners, modifications were made to

the proposed recommendations to update and clarify word-

ing in the document. As new information on the epidemi-

ology and prevention of zoster becomes available, it will be

reviewed by ACIP and recommendations will be updated

as needed.

Background

Biology of VZV

VZV is an exclusively human pathogen that infects ap-

proximately 98% of the adult population in the United

States (5). The primary infection typically occurs during

childhood and causes varicella. During its viremic phase,

cell-associated VZV gains access to epidermal cells, caus-

ing the typical varicella rash. The virus then enters sensory

nerves in mucocutaneous sites and travels through retro-

grade axonal transport to the sensory dorsal root ganglia

adjacent to the spinal cord where the virus establishes per-

manent latency in neuronal cell bodies (6–7). Latent VZV

is present in approximately 1%–7% of sensory ganglion

neurons, with <10 genomic copies per infected cell (8–10).

Seeding of dorsal root ganglia also might occur during vire-

mia. The magnitude of viremia, the number of skin lesions,

and the burden of VZV that establishes latency during pri-

mary varicella infection might be linked (11). As with other

members of the herpesvirus family, VZV is noninfectious

in its latent form but can reactivate at a later time to form

intact virions in the involved sensory neurons. These viri-

ons then migrate to the skin through axons, spread from

cell to cell, and penetrate the epidermis (12). In its full

clinical expression, zoster causes pain, which is followed by

a vesicular rash distributed across closely overlapping

dermatomes of the involved sensory nerve roots.

The triggers for reactivation of VZV have not been iden-

tified and probably involve multiple factors. However, spe-

cific components of cell-mediated immunity (CMI) have

an important role in controlling the development of zoster

by preventing reactivation within the neuron or the full

clinical expression of reactivated VZV as zoster. The

effectiveness of these protective components of CMI is well

maintained in immunocompetent persons during child-

hood and early adulthood. These CMI components are

believed to be partially or substantially maintained by

periodic immunologic boosting. “Endogenous boosting”

might occur in response to subclinical reactivation of

latent VZV or to development of zoster itself, and “exog-

enous boosting” might occur in response to exposure to

3 Vol. 57 / RR-5 MMWR

VZV circulating in the population as chickenpox (13–19).

Although virtually all adults are infected with VZV (5),

specific immunologic parameters have not been identified

to distinguish who will develop zoster. Anti-VZV antibody

levels per se are not thought to have a role in zoster preven-

tion (20). Parameters that have been monitored and corre-

late with such protection include anamnestic boost in

anti-VZV antibodies in vivo in response to VZV-based vac-

cination, and the presence of and boost in memory CD4 T

cells as measured in vitro by proliferation of peripheral blood

mononuclear cells (PBMC), by frequency of proliferating

PBMC, or by frequency of interferon-γ (IFN-γ ) releasing

PBMC, all in response to VZV-antigens (21,22). These

latter two parameters are generally assessed using a responder

cell frequency (RCF) assay and an IFN-γ enzyme-linked

immunosorbent spot-forming cell (ELISPOT) assay, respec-

tively (22). VZV-specific class I-restricted and unrestricted

cytotoxicities also have been monitored using target cell

lysis (23). Although CMI is necessary for the control of

zoster, other nonimmunologic factors also might be involved

(24).

Clinical Features of Zoster and PHN

The clinical course of acute zoster is variable. It is usually

less severe in children and younger adults. Typically, zoster

begins with a prodrome. Headache, photophobia, and

malaise might occur, with fever being less common.

Abnormal skin sensations and pain of varying severity are

the most common symptoms. These symptoms can pre-

cede the zoster rash by days to weeks (25) and rarely might

be the only clinical manifestation of VZV reactivation

(termed zoster sine herpete) (7). Pain is described as ach-

ing, burning, stabbing, or shock-like. Altered sensitivity to

touch, pain provoked by trivial stimuli, and unbearable

itching are all frequently reported.

Zoster rash is typically unilateral and does not cross the

mid-line, erupting in one or two adjacent dermatomes. The

frequency of zoster occurrence in different dermatomes has

been evaluated in certain studies. In general, thoracic, cer-

vical, and ophthalmic involvement are most common

(Figure 1) (26–28). Small numbers of lesions can occur

outside the primary or adjacent dermatome. The rash is

initially erythematous and maculopapular but progresses

to form coalescing clusters of clear vesicles containing high

concentrations of VZV (Figure 1). The vesicles form over

several days and then evolve through pustular, ulcer, and

crust stages. The rash usually lasts 7–10 days, with com-

plete healing within 2-4 weeks. However, pigmentation

changes and scarring might be permanent. Streptococcal

FIGURE 1.Thoracic distribution of zoster (A), and zoster rash

with coalescing clusters of clear vesicles (B)

or staphylococcal superinfections might complicate zoster

rash (29).

A common and potentially debilitating consequence of

zoster is PHN, a persistent pain after resolution of the rash.

Pathologic observations thought to distinguish PHN from

uncomplicated zoster include axonal and cell body degen-

eration, atrophy of the spinal cord dorsal horn, scarring of

the dorsal root ganglion, and loss of epidermal innervation

of the affected area. Certain experts believe this neuronal

damage might be caused by ongoing viral replication

(30,31). In addition, consensus is lacking regarding crite-

ria needed to distinguish the quality, duration, or underly-

ing pathophysiology of pain occurring with zoster versus

PHN. Therefore, the duration of pain used to define PHN

has been inconsistent, ranging from any duration after reso-

lution of the rash to periods from

>30 days to >6 months

after rash onset.

Regardless of definition, the pain of PHN can last for

weeks or months and occasionally persists for many years.

The nature of PHN pain varies from mild to excruciating

4 MMWR June 6, 2008

in severity, constant, intermittent, or triggered by trivial

stimuli. Approximately half of patients with zoster or PHN

describe their pain as “horrible” or “excruciating”, ranging

in duration from a few minutes to constant on a daily or

almost daily basis (32). The pain can disrupt sleep, mood,

work, and activities of daily living, adversely impacting the

quality of life and leading to social withdrawal and depres-

sion (Table 1) (31–33). Anecdotes of suicide among

patients suffering from PHN have been reported (34; Peter

Richards, MD, personal communication, 2007). Among

persons experiencing zoster, predictors of PHN include the

occurrence and severity of pain both before and after onset

of the rash, the extent of the rash, trigeminal or ophthalmic

distribution (35,36), and the occurrence of viremia (37).

In addition to PHN, zoster is associated with a variety of

other complication. Among persons with zoster, 10%–25%

have eye involvement, called herpes zoster ophthalmicus

(HZO) (38,39) (Figure 2). HZO can occur when reactiva-

tion involves the nasociliary branch of the trigeminal nerve,

sometimes preceded by the presence of zoster vesicles on

the nose (Hutchinson sign). Keratitis occurs in approxi-

mately two thirds of patients with HZO (40), often caus-

ing corneal ulceration. Other complications include

conjunctivitis, uveitis, episcleritis and scleritis, retinitis,

choroiditis, optic neuritis, lid retraction, ptosis, and glau-

coma. Extraocular muscle palsies also occur. Prolonged or

permanent sequelae of HZO include pain, facial scarring,

and loss of vision (41).

An uncommon complication of zoster is Ramsay Hunt

syndrome, a peripheral facial nerve palsy accompanied by

zoster vesicles on the ear, hard palate, or tongue (42). The

pathophysiology of this complication involves reactivation

of VZV in the geniculate ganglion of the facial nerve.

Additional signs and symptoms of Ramsey Hunt syndrome

can include pain, vertigo, hearing loss, sensitivity to sound,

tinnitus, and loss of taste. Many patients do not recover

TABLE 1. Impact of acute herpes zoster and postherpetic

neuralgia on quality of life

Life factor Impact

Physical Chronic fatigue

Anorexia and weight loss

Physical inactivity

Insomnia

Psychological Anxiety

Difficulty concentrating

Depression, suicidal ideation

Social Fewer social gatherings

Changes in social role

Functional Interferes with activities of daily living (e.g., dressing,

bathing, eating, travel, cooking, and shopping)

FIGURE 2. Case of herpes zoster ophthalmicus

Photo/MN Oxman, University of California, San Diego

completely (42). Idiopathic facial palsy (Bell’s palsy) might

be caused by inapparent VZV reactivation (42,43).

Occasionally, zoster can cause motor weakness in

noncranial nerve distributions, called zoster paresis (44,45).

The mechanism has not been determined. The weakness

develops abruptly within 2–3 weeks after onset of the rash

and can involve upper or lower extremities. Diaphragmatic

paralysis also has been described. The prognosis of zoster

paresis is good (46). Zoster also can result in autonomic

dysfunction, causing urinary retention and colon pseudo-

obstruction.

Rarely, patients will experience acute focal neurologic

deficits weeks to months after resolution of the zoster rash,

involving the trigeminal distribution contralateral to the

initial rash. This ischemic stroke syndrome, termed

granulomatous angiitis, is believed to be caused by direct

extension of VZV from the trigeminal ganglion to the

internal carotid artery or its branches, resulting in inflam-

mation (30). Mortality from this syndrome is substantial.

Other rare neurologic complications of zoster include

myelitis, aseptic meningitis, and meningoencephalitis. The

prognosis for these conditions is good, although encepha-

lomyelitis can be life threatening. Guillain-Barré syndrome

also has been reported in association with zoster (47).

In immunocompromised persons, zoster initially might

present typically. However, the rash tends to be more

severe and its duration prolonged (48,49). One specific

risk for persons with some immunosuppressive conditions

5 Vol. 57 / RR-5 MMWR

is dissemination of the zoster rash. True cutaneous dissemi-

nation generally occurs only among immunocompromised

patients, occurring in up to 37% of zoster cases in the

absence of antiviral treatment (49–54). Dissemination usu-

ally begins with a dermatomal rash; however, the rash some-

times begins with no primary dermatomal involvement (54).

Cutaneous dissemination is not life-threatening; however,

it is a marker for VZV viremia that can seed the lungs,

liver, gut, and brain and cause pneumonia, hepatitis,

encephalitis, and disseminated intravascular coagulopathy

in 10%–50% of episodes. Visceral dissemination with no

skin involvement can occur in profoundly

immunocompromised persons. Even with antiviral treat-

ment, the case fatality rate from visceral dissemination is

5%–15%, with most deaths attributable to pneumonia

(49,54,55).

The risk for neurologic zoster complications is generally

increased in immunocompromised persons. These compli-

cations, which can be aggressive and even fatal, include

myelitis, chronic encephalitis, ventriculitis, meningoen-

cephalitis, and cranial palsies (30). However, the risk for

PHN is not appreciably increased among immuno-

compromised persons who develop zoster (30).

Compared with other immunocompromised persons, the

clinical features of zoster are less severe and visceral dis-

semination less common among persons infected with

human immunodeficiency virus (HIV) (56,57). Some

zoster presentations that are unique to persons infected with

HIV include atypical skin eruptions (58,59) and an

aggressive variant of acute retinal necrosis that generally

results in blindness (60). Alveolar bone necrosis and tooth

exfoliation also have been reported (61).

Diagnosis

Zoster diagnosis might not be possible in the absence of

rash (e.g., before rash or in cases of zoster sine herpete).

Patients with localized pain or altered skin sensations might

undergo evaluation for kidney stones, gallstones, or coro-

nary artery disease until the zoster rash appears and the

correct diagnosis is made (62). In its classical manifestation,

the signs and symptoms of zoster are usually distinctive

enough to make an accurate clinical diagnosis once the rash

has appeared (63). Occasionally, zoster might be confused

with impetigo, contact dermatitis, folliculitis, scabies,

insect bites, papular urticaria, candidal infection, dermati-

tis herpetiformis, or drug eruptions. More frequently, zoster

is confused with the rash of herpes simplex virus (HSV),

including eczema herpeticum (4,31,64–66). The accuracy

of diagnosis is lower for children and younger adults in

whom zoster incidence is lower and its symptoms less

often classic.

In some cases, particularly in immunosuppressed per-

sons, the location of rash appearance might be atypical, or

a neurologic complication might occur well after resolu-

tion of the rash. In these instances, laboratory testing might

clarify the diagnosis (67–71). Tzanck smears are inexpen-

sive and can be used at the bedside to detect multinucle-

ated giant cells in lesion specimens, but they do not

distinguish between infections with VZV and HSV. VZV

obtained from lesions can be identified using tissue cul-

ture, but this can take several days and false negative

results occur because viable virus is difficult to recover from

cutaneous lesions. Direct fluorescent antibody (DFA) stain-

ing of VZV-infected cells in a scraping of cells from the

base of the lesion is rapid and sensitive. DFA and other

antigen-detection methods also can be used on biopsy

material, and eosinophilic nuclear inclusions (Cowdry type

A) are observed on histopathology. Polymerase chain reac-

tion (PCR) techniques performed in an experienced labo-

ratory also can be used to detect VZV DNA rapidly and

sensitively in properly-collected lesion material, although

VZV PCR testing is not available in all settings. A modifi-

cation of PCR diagnostic techniques has been used at a few

laboratories to distinguish wild-type VZV from the Oka/

Merck strain used in the licensed varicella and zoster

vaccines.

In immunocompromised persons, even when VZV is

detected by laboratory methods in lesion specimens, dis-

tinguishing chickenpox from disseminated zoster might not

be possible by physical examination (72) or serologically

(73–75). In these instances, a history of VZV exposure, a

history that the rash began with a dermatomal pattern,

and results of VZV antibody testing at or before the time

of rash onset might help guide the diagnosis.

Zoster Transmission

Zoster lesions contain high concentrations of VZV that

can be spread, presumably by the airborne route (76,77),

and cause primary varicella in exposed susceptible persons

(77,78–83). Localized zoster is only contagious after the

rash erupts and until the lesions crust. Zoster is less conta-

gious than varicella (78). In one study of VZV transmis-

sion from zoster, varicella occurred among 15.5% of

susceptible household contacts (78). In contrast, following

household exposure to varicella, a more recent study dem-

onstrated VZV transmission among 71.5% of susceptible

contacts (84). In hospital settings, transmission has been

6 MMWR June 6, 2008

documented between patients or from patients to health-

care personnel, but transmission from health-care person-

nel to patients has not been documented. Persons with

localized zoster are less likely to transmit VZV to suscep-

tible persons in household or occupational settings if their

lesions are covered (85).

Epidemiology of Zoster and

Complications

Risk Factors

Infection with VZV

Wild-type VZV. Because zoster reflects reactivation of

latent VZV, the primary risk factor and a necessary precon-

dition for zoster is previous VZV infection. Approximately

99.5% of the U.S. population aged >40 years has serologic

evidence of previous infection, including all evaluated sub-

groups; therefore, all older adults are at risk for zoster (5),

although many cannot recall a history of varicella (86–90).

Varicella vaccine is effective at preventing initial wild-type

VZV infection in persons not previously infected. Any wild-

type VZV infections prevented cannot reactivate as zoster.

The age at the time of initial VZV infection influences

the age at which zoster occurs. Persons acquiring an intrau-

terine or early childhood infection with VZV are at

increased risk for pediatric zoster (91–93). When VZV

infections occur before age 2 months, the risk for zoster

occurring by the age of 12 years is increased >35-fold com-

pared with the risk for VZV infections occurring after

infancy (92). Other case series suggest that the risk for

pediatric zoster also might be increased in children who

experienced varicella at older ages (94). Conversely, the risk

for zoster might be diminished in persons born in coun-

tries (95) or living in communities (96) where varicella

infection tends to occur at later ages. These observations

suggest that changes in the epidemiology of varicella caused

by varicella vaccination or by other factors can alter the

epidemiology of zoster, particularly pediatric zoster.

Oka/Merck Strain VZV. Among vaccine recipients, the

attenuated Oka/Merck strain of VZV included in varicella

vaccine also can establish a latent infection and clinically

reactivate as zoster (97). Zoster caused by Oka/Merck strain

VZV cannot be distinguished on clinical grounds from

zoster caused by wild-type VZV. The risk for zoster caused

specifically by Oka/Merck strain VZV is unknown because

recipients of varicella vaccine might have already been

infected with wild-type VZV or might have become

infected with wild-type VZV following vaccination (i.e.,

due to vaccine failure) that could also reactivate. Therefore,

the rate of all episodes of zoster among varicella vaccine

recipients define the upper bound for the risk of the subset

of episodes caused by Oka/Merck strain VZV. The risk for

zoster in immunocompromised children was approximately

65% less for those who had received the varicella vaccine

compared with those with previous wild-type varicella in-

fection (98,99). In immunocompetent children, the risk

also appears to be reduced among 1-dose vaccine recipi-

ents compared with children with a history of wild-type

varicella, although longer follow up is needed (99–101).

The risk for zoster in immunocompetent children follow-

ing 2 doses of varicella vaccine has not been studied. Col-

lectively these studies suggest that the risk for Oka/Merck

strain zoster following varicella vaccination is no higher,

and likely considerably lower, than that following wild-

type varicella infection, even though the acquisition of the

Oka/Merck VZV through vaccination generally occurs at a

young age (i.e., varicella vaccination is recommended for

children aged

>12 months [1–3]), which might be a risk

factor for pediatric zoster. As varicella vaccine recipients age,

the risk for and manifestation of Oka/Merck strain zoster

in older persons at greater risk for zoster complications can

be evaluated.

Age

Influence on zoster. Age is the most important risk fac-

tor for development of zoster (Figure 3). Virtually all stud-

ies conducted in numerous settings and with various study

designs have indicated an association between age and

increasing zoster incidence, extending to the oldest cohorts

(4,62,95,102–104). One study indicated that zoster inci-

dence increased with age by a factor of >10, from 0.74 per

1000 person years in children aged <10 years to 10.1 per

1000 person years in persons aged 80–89 years, with much

of the increase beginning at age 50–60 years (13). Approxi-

mately 50% of persons who live to age 85 years will have

experienced zoster (105,106).

The important role of age as a risk factor for zoster is

presumably related to a loss of components of VZV-

specific CMI response because of aging (i.e., immune

senescence) possibly combined with waning immunity that

might occur over time following initial varicella infection.

Loss of specific immunity allows VZV to complete the pro-

cess of reactivation and spread to the epidermis to produce

the fully expressed clinical illness (12). Although precise

correlates of protection against zoster have not been identi-

fied, certain CMI responses to VZV antigen decline with

age (21,22,107,108).

7 Vol. 57 / RR-5 MMWR

FIGURE 3. Rate* of zoster and postherpetic neuralgia (PHN)

†

by age — United States

1111

1010

20 30 40 50 60 70 >80

Zoster

PHN

Age (yrs)

*Per 1,000 person-years.

†

Defined as >30 days of pain.

Influence on PHN. Among persons experiencing zoster,

the primary risk factor for the development of PHN is age.

Several studies have indicated that the risk for PHN among

persons with zoster increases with age, particularly for per-

sons aged >50 years (13,35,62,109,110) (Figure 3). In one

study, the risk for experiencing at least 2 months of pain

from PHN increased 27.4-fold among patients aged >50

years compared with those aged <50 years (109). Approxi-

mately 80%-85% of PHN occurs in zoster patients aged

>50 years (62).

Sex

Results from a large, randomized, controlled vaccine trial

in the United States (4) indicated that the incidence of

confirmed zoster cases in a cohort of immunocompetent

persons aged >60 years was 11% higher among the women

(11.8 versus 10.7 cases per 1000 person years in women

and men, respectively). A prospective cohort study in the

Netherlands documented 38% more cases among women

than men (odds ratio = 1.38 [95% confidence interval [CI]

= 1.22–1.56) after controlling for age and other zoster risk

factors (111). Other studies (13,102–104,112) using a

variety of methods also demonstrated an age-standardized

excess of zoster among women. However, some researchers

did not find a difference by sex (36,38,105,113–115).

Women with zoster might also be at increased age-specific

risk for developing PHN compared with men (35,62).

Race

Certain studies have suggested racial differences in the

risk for zoster. In North Carolina, reported lifetime zoster

occurrences and reported incidence were lower in blacks

by 65% and 75%, respectively, compared with whites

after controlling for relevant confounders (115,116). A

study in the United Kingdom indicated that zoster risk in

patients was 54% lower among blacks after adjusting for

age, sex, country of birth, or household childhood contacts

(95). The reasons for these racial differences are unknown.

Geographic or Seasonal Variation

Most studies have not documented a seasonal pattern to

zoster incidence (13,38,92,95,105,117). Certain studies

have reported summer seasonality, particularly for exposed

skin sites. This pattern might be related to ultraviolet irra-

diation that peaks during summer months and might serve

as a trigger for zoster (28,118,119). No studies exist

regarding variation in zoster incidence by latitude. Urban/

rural status does not appear to be a risk factor for zoster

(95).

Altered Immunocompetence

Unlike other vaccine-preventable diseases, zoster epide-

miology is not directly related to exposure but to the biol-

ogy underlying the virus-host relation that allows reactivation

of latent VZV. Because CMI plays a key role in controlling

both development of zoster and the features of its clinical

expression, deficiencies in CMI, regardless of their etiol-

ogy, are risk factors for both zoster and its severe manifesta-

tions. Although the magnitude of zoster risk can be

extremely high among immunocompromised persons, the

overall population attributable risk is modest because

immunosuppression is uncommon (62,103,114).

The incidence of zoster is increased substantially in per-

sons with hematologic malignancies and solid tumors (120).

Rates are highest among children with these conditions.

The magnitude of risk depends on both the nature of the

underlying cancer and the type of treatment (121).

Although the incidence of zoster in patients with solid

tumors is <5%, this rate is many-fold higher than that in

unaffected age-matched persons (120). Patients with

Hodgkin’s disease are at particularly high risk for zoster,

with cumulative risks during the illness and its treatment

as high as 27.3% (51,53,120,122–127).

Zoster is common following hematopoietic stem cell

transplantation (HSCT); rates are 13%–55% during the

first year (54,128,129). Rates are increased following solid

organ transplants (renal, cardiac, liver, and lung) (5%–

17%). Incidence is highest during the months immedi-

ately following the procedure, and the majority of zoster

cases occur within a year of transplantation (130–132).

8 MMWR June 6, 2008

The risk for zoster and its recurrence is elevated in per-

sons infected with HIV. Zoster rates of 29.4–51.5 per 1000

person years have been reported among HIV-infected

adults, reflecting 12- to 17-fold increase compared with

HIV-negative persons (56,133–136). For HIV-infected

children, the risk is even higher (467 per 1000 person years),

especially among children who acquire VZV infection when

they are profoundly immunosuppressed (137). Most studies

have documented increasing zoster risk as CD4+

T-lymphocyte counts decline, but the risk is increased nine-

fold even among HIV-infected women with CD4+

T-lymphocyte counts >750/µL compared with HIV-

negative controls (135). However, the risk might decline at

CD4+ T-cell counts <50 cells/µL (136). Persons infected

with HIV also are at increased risk for recurrences of zoster.

Other Co-morbidities

The risk for zoster appears to be elevated in persons with

inflammatory diseases; however, for most of these condi-

tions, data are insufficient to determine how much of the

risk is attributable to the underlying disease versus its treat-

ment. Zoster has been associated with systemic lupus

erythematosus (SLE), with rates of 15–91 per 1000 per-

son years (138–143). The risk for zoster also is increased

among persons with rheumatoid arthritis (adjusted hazard

ratio = 1.9 [95% CI = 1.8–2.0]), with an incidence of

approximately 10 cases of per 1000 person years reported

(144,145). Patients with Wegener’s granulomatosis have a

reported incidence of 45 zoster cases per 1000 person years

(146), and recurrences in these patients are common. In

one study, Crohn’s disease and ulcerative colitis were both

associated with a significantly increased risk for zoster

(incident rate ratios = 1.6 and 1.2, respectively). The

increase was, in part, caused by use of immunosuppressive

medications (147). For all these conditions, zoster is gen-

erally not life-threatening, although cutaneous dissemina-

tion is more common, and deaths have been reported in

such patients (138,141,142).

Certain studies have evaluated the risk for zoster in per-

sons with other noninflammatory co-morbid conditions,

although findings have not been consistent. Two studies

have documented an association between zoster and diabe-

tes mellitus (148,149). However, this association was not

indicated in two other studies (150,151). Another study

documented an increased risk for zoster in persons who

subsequently had multiple sclerosis diagnosed (152).

Exposure to VZV/External Boosting

VZV can be transmitted from zoster lesions to cause pri-

mary varicella in susceptible persons. Although some

experts have suggested that zoster can be caused directly

by exposure to VZV from varicella or from other cases of

zoster (72,153,154), in general, zoster is not associated with

epidemics of varicella. In addition, zoster does not have a

seasonal pattern to suggest it is spread directly from vari-

cella (13,28,38,92,105,117). Theoretically, reactivation of

latent VZV might be triggered by exposure to exogenous

VZV (123,153); however, no evidence suggests that such

episodes occur more frequently than would be expected to

occur by chance.

Conversely, exposure to varicella might reduce the risk

for zoster (13). Protection might be partially maintained

by exposure to varicella circulating in the population and

the resulting exogenous boosting of VZV-specific immu-

nity (15,117,155). An analysis of surveillance data from

the United Kingdom indicated an inverse relation between

annual varicella incidence in children aged <5 years and

zoster incidence in adults aged 15–44 years (117). A case-

control study in the United Kingdom (15) documented a

graded reduction in zoster risk as a function of number of

varicella contacts over a 10-year period. Multivariate analy-

sis suggested a 74% reduction in risk for zoster among per-

sons with three to four varicella exposures compared with

those with no exposures, with a significant trend suggest-

ing some reduction with fewer than three exposures. Social

contacts with children (as a proxy for varicella exposure)

and occupational contact with sick children were protec-

tive (15). A cohort analysis based on data from a sentinel

physician network in the United Kingdom (155) suggested

that adults living with children had both increased vari-

cella exposure and a 25% decrease in zoster incidence. The

analysis estimated that this boosting effect lasted an aver-

age of 20 years (95% CI = 7–41 years). However, persons

living or interacting with children might have different

underlying health compared with persons without expo-

sure to children, which might be a confounder in these

studies. Other evidence that varicella exposure might pro-

tect against zoster includes possible effects household

exposure to varicella had against subsequent development

of zoster among children with leukemia (156). Finally, the

efficacy of the zoster vaccine (4) supports the concept that

exposure to exogenous VZV can reduce risk for zoster, pre-

sumably by boosting specific immunity against VZV.

Contrary evidence also exists that varicella exposure does

not reduce the risk for zoster. Women are at greater risk for

zoster (13,102,103,110,111) despite the fact that women

probably have more exposure to young children who expe-

rience varicella. A Japanese study indicated that the risk for

zoster in children was not diminished by repeated varicella

exposures (92).

9 Vol. 57 / RR-5 MMWR

Although a sufficient number of varicella exposures could

reduce the risk for zoster in select populations, it is unclear

whether such levels of exposure play an epidemiologically

important role in reducing the risk for zoster among the

general population of older adults who are at the highest

risk for the disease, and, if so, how long such effects would

last in the elderly.

Other Risk Factors

As with orofacial and genital flairs of HSV, zoster has been

anecdotally linked to stress. However, only two rigorous

evaluations of the role of psychological stress on zoster have

been conducted. A case-control study documented a sig-

nificant association with number of stressful life events

within 6 months of reported zoster (p = 0.012) (157). A

prospective cohort study indicated a nonsignificant asso-

ciation (p = 0.078) between zoster risk and negative life

events.

Trauma or surgery could lead to reactivation of VZV in

the affected dorsal root ganglion and increase the risk for

zoster rash in that dermatome. Such a development would

seem to be specific and easily ascertained, and certain

reports and case series describe such events (158–161). One

case-control study collected information about recent trauma

and/or surgery in patients who developed zoster and in

matched controls. The frequency of trauma in nonzoster

sites was similar between the two groups, but zoster

patients were significantly more likely than controls to

report trauma at the site of their zoster during the month

before zoster onset (adjusted OR = 12.1 [95% CI = 1.5–

97.6]; p = 0.002) (24). The basis by which these stimuli

provoke zoster is unclear, but they suggest that

nonimmunologic factors can play important roles in the

pathophysiology of zoster.

Finally, one study indicated that dietary micronutrient

intake was protective against zoster. Body mass index did

not appear to be associated with zoster risk (162). Genetic

predisposition for zoster also has been reported (163).

Population Rates of Zoster and PHN

Zoster

Zoster is not a reportable condition in the United States;

therefore, incidence has been inferred from a variety of stud-

ies. Observed rates have varied substantially on the basis of

methods for case ascertainment, access to health care, and

case definitions. The age distribution in the population

being studied also is an important consideration when com-

paring these studies because zoster can vary dramatically

across study sites. Conclusions cannot be drawn from cross-

study comparisons without adjusting for age or comparing

age-specific rates directly. Differences in the prevalence of

immunosuppression or in racial makeup also can influence

population-wide zoster incidence. In addition, the incidence

of zoster appears to have been increasing over recent decades,

even after adjusting for other factors, although this increase

has not been observed consistently.

Despite these limitations, certain analyses of zoster inci-

dence in the United States have been conducted. The inci-

dence in all studies ranged from 3.2–4.2 per 1000

population per year (age-adjusted to the 2000 U.S. popu-

lation) (62,103,104,114,164,165), translating into an

estimated 1 million cases annually. In all studies, a sub-

stantial increase in zoster incidence occurred with age and

extended to the oldest strata; for all persons aged

>60 years,

the annual incidence was approximately 10 per 1000 per-

sons (62,103,104,114,164,165), similar to the annual

incidence of 11.1 per 1000 observed during the zoster vac-

cine trial (4). On the basis of these data, an estimated 32%

of persons in the United States will experience zoster dur-

ing their lifetime (CDC unpublished data, 2007).

Certain studies provide evidence of increasing age-

specific zoster incidence in the United States

(38,62,165,166), although other studies have shown no

such trend (104). The observed increases cannot be solely

attributed to changes in the epidemiology of varicella,

because documentation of increases predated licensure of

varicella vaccine in the United States in 1995 (38) and

because age-specific increases over time also are being

reported in certain international settings, including in the

absence of varicella vaccination programs (105,167,168).

Because the basis for this increase remains unclear, predict-

ing whether the age-specific risk for zoster will continue to

increase in the future is difficult.

Recurrent Zoster

Effectively evaluating the risks for recurrent zoster

(i.e., second or subsequent episodes) in immunocompetent

persons requires large populations, long-term follow up,

adequate duration, and laboratory confirmation. Although

data are limited, certain studies suggest a recurrence rate

that is comparable to the rate of initial episodes (13,38,114).

A community-based study of clinician-diagnosed zoster was

conducted in Olmsted County, Minnesota. The observa-

tional period lasted 6 years. Of 1,669 persons that experi-

enced an episode of zoster during that period, 24 experienced

a second episode, suggesting a high incidence of zoster

recurrence and providing no evidence that an episode of

zoster protects against recurrence (62). Similar observations

were noted in an older survey-based study (169). In the

Shingles Prevention Study, two of approximately 20,000

10 MMWR June 6, 2008

vaccine placebo recipients had two episodes of zoster within

3 years of the initial episode. These cases provide the first

laboratory-confirmed evidence that zoster can recur in

immunocompetent persons, even soon after the initial

episode (4).

Zoster Hospitalizations and Deaths

Hospitalizations. Conclusions about hospitalization for

zoster should be interpreted carefully if they are derived

from administrative data. Hospital administrative data

often do not distinguish zoster episodes that were reasons

for hospitalizations from those episodes that were inciden-

tal to the hospitalization or that occurred during prolonged

hospital stay. PHN at the time of an unrelated hospitaliza-

tion also might be coded as zoster. In addition, underlying

immunosuppressive conditions might not be available or

might not be collected from administrative data. These fac-

tors preclude determination of the portion of hospitaliza-

tions that could be prevented by a live-attenuated vaccine

that is contraindicated for immunosuppressed persons.

Given these limitations, crude annual rates of zoster hos-

pitalization have ranged from 2.1 per 100,000 population

in a Northern California managed care population (170)

to 4.4 per 100,000 population in England (171). A crude

rate of 16.1 per 100,000 population was identified in an

analysis of Connecticut-wide hospitalization data that

included all zoster episodes, not just primary discharge

diagnosis (172).

In a community-based study in Olmsted County, Min-

nesota, approximately 3% of patients with zoster were hos-

pitalized for the illness (62). Although values differ

substantially, all studies indicate that zoster hospitaliza-

tion rates increase with age (170,172–174). In the Con-

necticut study, zoster hospitalization rates were

approximately 75-fold greater among persons aged >85 years

than in persons aged <30 years (172). Although precise

denominators are not available, risks for hospitalization also

increased among persons with altered immunocompetence;

approximately 30% of all persons hospitalized with zoster

episodes had one or more immunocompromising condi-

tions, primarily malignancies (82%) and HIV infection

(8%) (62,172). Central nervous system and ophthalmo-

logic complications accounted for most of the reported com-

plications among hospitalized zoster cases (172–174),

although bacterial superinfection was common in one

series (175). Another study indicated that 0.5% of patients

with confirmed zoster were hospitalized before their zoster

rash developed for prodromal pain syndromes including

suspected myocardial infarction, severe new-onset headache,

back pain, and abdominal pain resulting in appendectomy

(62).

Deaths. On the basis of clinical experience and in the

absence of zoster-related deaths in cohort studies, certain

experts believe that zoster mortality appears to be uncom-

mon, particularly among healthy persons (176). Vital

records might not distinguish deaths attributed to zoster

from incidental deaths occurring merely in the presence of

zoster, and they might not capture information on the im-

munologic status among those deaths. An Australian study

using administrative data indicated that 1% of patients hos-

pitalized with a primary zoster diagnosis died; the number

of deaths directly attributable to zoster was not validated

(174). Certain analyses have indicated that almost all zoster

deaths occur in the elderly, with a rate >10-fold higher

among persons aged >65 years (171,173,174). Immuno-

suppression also appears to be a risk factor for zoster mor-

tality. In one study, 52% of patients hospitalized with zoster

who died had one or more immunocompromising condi-

tion (e.g., malignancies, leukemia, and HIV). In that study,

the risk for death in persons with immunocompromising

conditions was 8.7%; the risk in persons without these

conditions was 3.7% (172).

PHN

Drawing conclusions from studies on the risk for PHN is

difficult because definitions for PHN vary and results are

influenced by many factors, including the source and age

of the study population. Among zoster patients treated with

a placebo in clinical trials of antiviral drugs, approximately

one third still had pain after 3 months and approximately

one fourth had pain at 6 months (177,178). However, these

trials might include a population of patients with more

severe zoster pain, thereby introducing a detection bias that

could inflate estimated risks for PHN. In a phase 3 clinical

trial of zoster vaccine (4), zoster occurred among 642

placebo recipients; the risk for pain persisting at least 30,

60, 90, 120 or 180 days among these person was 30.3%,

17.6%, 12.5%, 8.4%, and 5.1%, respectively. Results from

the trial might not reflect risks for progression to PHN in

community settings because ascertainment, diagnosis, and

antiviral treatment of zoster were standardized and thor-

ough. However, in a community-based study in Olmsted

County, Minnesota, in which almost all medical events were

captured, the risk for PHN in patients with zoster was 18%,

13%, and 10% when defining PHN as at least 30, 60, and

90 days of pain, respectively (62).

11 Vol. 57 / RR-5 MMWR

Treatment and Nonspecific Management

of Zoster and PHN

The treatment of acute zoster, the prevention of PHN

development among patients with acute zoster, and the

treatment of patients with current PHN are complex clini-

cal problems with ongoing uncertainties and active research

(31). Acyclovir, famciclovir, and valacyclovir are approved

by the FDA for treatment of zoster in immunocompetent

patients. All three are nucleoside analogs that inhibit rep-

lication of human herpes viruses, including VZV. Clinical

trials have indicated that these agents, taken orally, reduce

the duration of viral shedding and lesion formation,

reduce the time to rash healing, and decrease the severity

and duration of acute pain from zoster and the risk for pro-

gression to PHN. Because all three antiviral agents are safe

and well tolerated, many experts recommend that treat-

ment should be considered for all eligible patients with

zoster, and specifically recommend treatment for persons

aged >50 years who have moderate or severe pain, moder-

ate or severe rash, or involvement of nontruncal dermatomes

(31). In clinical trials, treatment has been initiated within

72 hours of rash onset, a biologically arbitrary time point

that often is not feasible in clinical practice. The benefits of

later treatment have not been studied (31). If treatment

cannot be initiated within 72 hours of rash onset, experts

recommend that it should be initiated as soon as possible,

particularly in the presence of new vesicle formation or of

complications.

Two clinical trials have assessed the role of corticoster-

oids in combination with acyclovir for treatment of zoster

and prevention of subsequent PHN (179,180). Patients at

risk for steroid-related toxicities (e.g., those with diabetes

mellitus or gastritis) were excluded from the trials. A 3-week

tapering course of corticosteroids diminished acute zoster

pain and decreased the time to cutaneous healing,

cessation of analgesic therapy, and return of uninterrupted

sleep and normal daily activities. However, no evidence

indicated that use of corticosteroids prevented development

of PHN. Theoretically, corticosteroids should be equally

effective in combination with valacyclovir or famciclovir;

however, combinations of these agents have not been stud-

ied in clinical trials. No evidence indicates that topical

antiviral therapy or corticosteroids without systemic

antiviral therapy have a role in treatment of zoster.

A variety of approaches have been used with varying

degrees of success for control of acute zoster pain, includ-

ing acetaminophen, nonsteroidal anti-inflammatory agents,

tricyclic antidepressants, opiates, anticonvulsants, capsaisin,

and topical anesthetics (31). In more severe instances of

pain, referral to a pain specialist, or even hospitalization

and administration of epidural analgesics, is often consid-

ered. Many of these same modalities are used with varying

degrees of success for control of chronic PHN pain

(26,181,182). Elderly persons, who already have reduced

physiologic reserve and typically take multiple medications

for pre-existing chronic conditions, might be unable to

tolerate psychotropic and other medications for manage-

ment of their acute zoster or chronic PHN pain (31,33).

Patients with uncomplicated zoster should be advised to

keep the rash clean and dry, to avoid topical antibiotics,

and, if possible, to keep the rash covered. They should alert

their physician if the rash worsens or they have fever, which

could indicate bacterial superinfection (31).

Prevention of Transmission from Zoster

Some health-care institutions might exclude personnel

with zoster from work until their lesions dry and crust (85).

Persons with localized zoster should avoid contact with

susceptible persons at high risk for severe varicella in

household and occupational settings until lesions are crusted.

Such persons include pregnant women, all premature

infants born to susceptible mothers, infants born at

<28 weeks’ gestation or who weigh <1000 g regardless of

maternal immune status, and immunocompromised per-

sons of all ages (85). Persons with opportunities for contact

with such high risk-persons in household or occupational

settings should be informed about how to recognize the

signs and symptoms of zoster. If a person susceptible to

varicella infection has close exposure to a persons with zoster,

postexposure prophylaxis with varicella vaccine or

VARIZIG

™

should be considered (3,85,183).

Zoster Vaccine

Vaccine Composition, Dosage, and

Administration

The zoster vaccine licensed in the United States

(ZOSTAVAX

, Merck & Co., Inc.) is a lyophilized prepa-

ration of the Oka/Merck strain of live, attenuated VZV,

the same strain used in the varicella vaccines (VARIVAX

PROQUAD

). The Oka strain was isolated in Japan (184)

in the early 1970s from vesicular fluid from a healthy child

who had varicella; the strain was attenuated through

sequential propagation in cultures of human embryonic

lung cells, embryonic guinea-pig cells, and human diploid

cells (WI-38). Further passage of the virus was performed

at Merck Research Laboratories in human diploid cell

12 MMWR June 6, 2008

cultures (MRC-5). The cells, virus seeds, virus bulks, and

bovine serum used in the manufacturing are all tested to

provide assurance that the final product is free of adventi-

tious agents.

Zoster vaccine, when reconstituted as directed in the

package label using the supplied diluent, is a sterile prepa-

ration for subcutaneous administration. Each 0.65-mL dose

contains a minimum of 19,400 PFU (4.29 log

) of Oka/

Merck strain of VZV when reconstituted and stored at room

temperature for up to 30 minutes. Zoster vaccine is similar

to VARIVAX

. However, its minimum potency is at least

14-times the potency of VARIVAX

, which contains a mini-

mum of 1,350 (approximately 3.13 log

) PFU.

PROQUAD

contains 3.993 log

PFU, similar in

potency to ZOSTAVAX

. Each dose of zoster vaccine also

contains additional VZV antigenic component from non-

viable Oka/Merck VZV. Additional vaccine components in

each dose include 31.16 mg of sucrose, 15.58 mg of

hydrolyzed porcine gelatin, 3.99 mg of sodium chloride,

0.62 mg of monosodium L-glutamate, 0.57 mg of so-

dium phosphate dibasic, 0.10 mg of potassium phosphate

monobasic, 0.10 mg of potassium chloride; residual com-

ponents of MRC-5 cells including DNA and protein; and

trace quantities of neomycin and bovine calf serum. The

product contains no thimerosal or other preservatives.

Zoster vaccine should be administered as a single

0.65-mL dose subcutaneously in the deltoid region of the

upper arm; a booster dose is not licensed for the vaccine.

The vaccine should not be injected intravascularly or

intramuscularly and should only be reconstituted and

injected using a sterile syringe free of preservatives, anti-

septics, and detergents, which can inactivate the vaccine

virus.

Storage and Handling

To maintain potency, lyophilized zoster vaccine must be

stored frozen at an average temperature of <5°F (<-15°C)

until it is reconstituted for injection. Any freezer that has a

separate sealed freezer door and reliably maintains an

average temperature of <5°F (<-15°C) is acceptable for stor-

ing zoster vaccine. Providers should check the adequacy of

their freezer by verifying its temperature before obtaining

vaccine. In general, the freezer compartments of dormitory

style units are incapable of reliably maintaining tempera-

tures cold enough to store zoster vaccine and are unaccept-

able for storage. For certain refrigerator/freezer models, it is

necessary to reduce the temperature to the coldest setting

to maintain zoster vaccine at the correct temperature. How-

ever, this might reduce the temperature in the refrigerator

compartment and result in freezing of any vaccines or other

pharmaceutical products being refrigerated. As a result, both

the refrigerator and freezer temperatures should be moni-

tored and the temperature recorded at least twice a day.

Any out-of-range temperature readings require immediate

and documented corrective action. When a freezer is tem-

porarily unavailable (e.g., during transport or equipment

failure), zoster vaccine should be stored in a suitable con-

tainer (i.e., the original shipping container or a compa-

rable container with a properly fitting lid) with an adequate

quantity of dry ice (i.e., a minimum of six pound per box)

so that dry ice would persist in the container if

unreconstituted vaccine must be transported back to the

freezer. Dry ice placed in a suitable container will maintain

a temperature of <5°F (<-15°C). The diluent, which does

not contain preservative or other antiviral substances that

could inactivate the vaccine virus, should be stored sepa-

rately, either at room temperature or in the refrigerator.

The vaccine should be reconstituted according to the

directions in the package label and only with the diluent

supplied. Before reconstitution, zoster vaccine should be

protected from light. Once reconstituted, the vaccine should

be used immediately to minimize loss of potency. The vac-

cine must be discarded if not used within 30 minutes after

reconstitution. Information regarding stability under con-

ditions other than those recommended is available from

the manufacturer at 800-637-2590.

Efficacy

The efficacy of zoster vaccine was evaluated in a phase 3

vaccine trial termed the Shingles Prevention Study, a double-

blind randomized, placebo-controlled trial involving

38,546 healthy adults aged >60 years who had a history of

varicella or at least 30 years of residence in the continental

United States (as a marker of previous infection). Persons

excluded from the trial included those with a history of

zoster, with allergies to components of the vaccine, with

immunocompromising conditions, or with conditions that

might have interfered with study evaluations (e.g., cogni-

tive impairment, <5 year life expectancy, dermatologic dis-

orders, chronic pain, hearing loss, or lack of mobility). The

study population ranged in age from 59–99 years (median:

69.4 years), and comprised 41.0% females, 95.4% white,

2.1% blacks, 1.3% Hispanics, and 1.2% other or unknown

race/ethnicity. On enrollment, approximately 90% of the

participants had at least one underlying chronic medical

condition.

Persons were randomized to receive a single subcutane-

ous dose of zoster vaccine or placebo; the mean duration of

13 Vol. 57 / RR-5 MMWR

follow up was 3.1 years. Active case ascertainment was con-

ducted through monthly telephone contact supplemented

by a close-out interview. Zoster cases were confirmed by

PCR testing (93%), viral culture (1%), or evaluation by a

panel of five physicians with expertise in zoster diagnosis

(6%). Patients with confirmed zoster were followed for at

least 182 days to assess the outcome of the condition,

including presence and severity of pain. Approximately 95%

of persons were followed to completion of the study. Out-

comes evaluated included incidence of zoster, incidence of

PHN (defined as pain level of three or more [on a numeri-

cal rating scale of 0-10] persisting at least 90 days after

rash onset), and burden of illness (BOI), measured using a

mean value of severity-by-duration index for each treatment

group, thus incorporating the incidence, severity, and

duration of pain and discomfort from zoster). A total of

957 confirmed cases of zoster occurred among study par-

ticipants: 315 among vaccine recipients and 642 among

placebo recipients. The proportion of vaccine and placebo

recipients that received antiviral treatment within 72 hours

of rash onset, as clinically indicated, was 64.1% and 65.9%,

respectively.

The vaccine reduced the risk for developing zoster by

51.3% (95% CI = 44.2–57.6; p<0.001 (Table 2) (4). The

vaccine was 66.5% (95% CI = 47.5–79.2; p<0.001) effi-

cacious for preventing PHN. When the definition of PHN

was changed from 30 days of pain to 182 days of pain

following rash onset, vaccine efficacy increased from 58.9%

to 72.9% (Table 3). Zoster vaccine had an independent

effect of reducing PHN among patients who developed

zoster (39% [95% CI = 7%–59%]) (Table 2). The mean

severity-by-duration of zoster was reduced by 57%

(p = 0.016) in vaccine recipients who developed PHN.

Zoster vaccine reduced BOI by 61.1% (95% CI = 51.1–

69.1; p<0.001) (Table 2). The vaccine reduced the degree

of interference in activities of daily living (ADLI) caused

by zoster, in part because of the reduction in zoster itself,

but also because of a decrease in ADLI among those vac-

cine recipients who did develop zoster (185). No evidence

indicated that vaccine recipients experiencing zoster were

protected from other sequelae such as scarring, bacterial

superinfection, palsies, or ocular or visceral complications

(186).

In general, with increasing age at vaccination, the vac-

cine retained efficacy against severity of zoster better than

against zoster itself. Thus, efficacy for the prevention of

zoster was highest among persons aged 60–69 years and

declined with increasing age (Table 2). Declines in efficacy

of preventing zoster were observed with each 5-year increase

in age throughout the age range of participants (187).

However, no significant differences were observed among

persons aged 60–69 years versus those aged

>70 years in

vaccine efficacy at reducing BOI or PHN, probably

because the independent effect of reducing PHN among

patients who developed zoster was greatest among persons

aged 70–79 years (Table 2). For persons aged >80 years,

efficacy against zoster was 18% (Table 2), but efficacy against

PHN (39%) was better retained (186). No significant dif-

ferences by sex were observed in the efficacy of the vaccine

at reducing BOI, PHN, or zoster (4). No evidence indi-

cated that the vaccine was less efficacious for prevention of

zoster (vaccine efficacy: 51.6%; 95% CI = 41.4–60.1),

PHN (vaccine efficacy: 60.9%; 95% CI = 31.3–78.7), or

for reduction in BOI (vaccine efficacy: 60.1%; 95% CI =

46.1–70.4) among subjects with functional limitations

(188).

TABLE 2. Efficacy of ZOSTAVAX

compared with a placebo, by age group — Shingles Prevention Study*

ZOSTAVAX

Placebo Efficacy

% HZ % HZ

cases cases PHN

Burden of

Age group No. HZ PHN with No. HZ PHN with HZ PHN

with HZ illness (BOI)

(yrs)

†

subjects cases cases

PHN

subjects cases cases

PHN

% (95% CI**) % (95% CI) % (95% CI) % (95% CI)

60–69 10,370 122 8 6.6 10,356 334 23 6.9 64 (56–71) 65.7 (20.4–86.7) 5 (-107–56) 65.5 (51.5–75.5)

70–79 7,621 156 12 7.7 7,559 261 45 17.2 41 (28–52) 66.8 (43.3–81.3) 55 (18–76) 55.4 (39.9–66.9)

>80 1,263 37 7 18.9 1,332 47 12 25.5 18 (-29–48) —

26 (-69–68) —

Total 19,254 315 27 8.6 19,247 642 80 12.5 51 (44–58) 66.5 (47.5–79.2) 39

††

(7–59) 61.1 (51.1–69.1)

* The analysis was performed on the Modified Intent-To-Treat (MITT) population that included all subjects randomized in the study who were followed for at least 30 days

postvaccination and did not develop an evaluable case of herpes zoster (HZ) within the first 30 days postvaccination.

†

Age strata at randomization were aged 60–69 years and >70 years.

Postherpetic neuralgia (PHN) was defined as HZ-associated pain rated as three or more, on a scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine), persisting

or appearing more than 90 days after onset of HZ rash using Zoster Brief Pain Inventory.

VE for PHN and BOI calculated for the age groups 60–69 and >70 years.

** Confidence interval.

††

Age-adjusted estimate based on the age strata (age 60–69 years and >70 years) at randomization.

Sources: Oxman MN, Levin MJ, Johnson GR, et al. Zoster Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med

2005;352:2271-84; ZOSTAVAX

. Package Insert. Merck & Co., Inc, Whitehouse Station, NJ 08889.

14 MMWR June 6, 2008

TABLE 3. Efficacy of zoster vaccine on the incidence of postherpetic neuralgia (PHN) among persons aged >60 years, by

duration of pain* — Shingles Prevention Study

Vaccine group Placebo group Efficacy

Persistence of No. confirmed Incidence No. confirmed Incidence

PHN among

all subjects

†

cases of HZ

with PHN

per 1,000

person/yr

cases of HZ

with PHN

per 1,000

person/yr

% (95% CI**)

30 days 81 1.39 196 3.39 58.9 (46.6–68.7)

60 days 45 0.77 113 1.96 60.4 (43.6–72.6)

90 days 27 0.46 80 1.38 66.5 (47.5–79.2)

††

120 days 17 0.29 54 0.93 68.7 (45.2–83.0)

182 days 9 0.16 33 0.57 72.9 (42.1–88.6)

* For the secondary end point, PHN was defined as the pain and discomfort associated with herpes zoster rated as three or more, on a scale ranging

from 0 (no pain) to 10 (pain as bad as you can imagine), persisting or appearing more than 90 days after the onset of herpes zoster rash. Efficacy

analyses were performed with the use of a follow-up interval that excluded the first 30 days after vaccination and the modified intention-to-treat

population, which excluded persons who withdrew or in whom a confirmed case of herpes zoster developed, within the first 30 days after vaccination.

Of the three persons who developed more than 1 confirmed case of herpes zoster, only the first case was included.

†

PHN was defined as the pain and discomfort associated with herpes zoster that was rated as three or more persisting or appearing more than 30, 60,

90, 120, and 182 days after the onset of herpes zoster rash.

For the total population and the subgroups stratified according to sex, the incidence of PHN in each treatment group (vaccine or placebo) was the

weighted average of the observed incidence of PHN stratified according to age group, with weights proportional to the total number of person-years of

follow-up in each age group.

Vaccine efficacy for the incidence of PHN and 95% confidence interval (CI).

** Confidence interval.

††

Vaccine efficacy for the incidence of PHN for all persons was the protocol-specified secondary end point.

Source: Oxman MN, Levin MJ, Johnson GR, et al. Zoster Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older

adults. N Engl J Med 2005;352:2271–84.

Twelve clinical lots of zoster vaccine were used in the

Shingles Prevention Study, nine of which were heat treated

to accelerate aging of the vaccine. Potency upon shipment

to study sites ranged from 21,000–62,000 PFUs/dose, but

potency and accelerated aging did not significantly influ-

ence vaccine efficacy with regard to zoster, PHN, or BOI.

Immunogencity

A substudy of the Shingles Prevention Study was con-

ducted among 1,395 persons to assess VZV-specific

immunity at baseline and 6 weeks following administra-

tion of zoster vaccine or placebo. The longer-term duration

of immunogenicity also was assessed. Anamnestic antibody

response was evaluated using gpELISA to measure increases

in VZV antibody levels after vaccination. RCF and IFN-γ

ELISPOT were used to measure the number of memory

T-cells. With all three assays, VZV-specific immunity mea-

sured 6 weeks after vaccination increased following receipt

of vaccine but not placebo. In both vaccine and placebo

recipients, immune responses were inversely related to the

risk for developing zoster; this association with protection

was greatest for anamnestic antibody response following

vaccination for which gpELISA Geometric Mean Titers

(GMTs) increased 1.7-fold (95% CI = 1.6–1.8). However,

for all three assays, no threshold level of immunity that

predicted complete protection from zoster was observed.

No clear dose response for increases in GMTs was

observed; similar increases were achieved in vaccine

recipients throughout the dosage range used in the Shingles

Prevention Study (189). Peak CMI responses were present

1–3 weeks following vaccination (187,190,191), as would

be expected for anamnestic responses that would occur in

persons with previous VZV infection. The impact of age

on CMI response to vaccination also was evaluated. RCF

and IFN-γ ELISPOT responses were greater in persons aged

60–69 years than in persons aged >70 years (p<0.01) (192).

The increase in GMTs as a measure of anamnestic anti-

body response in persons aged 50–59 years was compa-

rable to that in persons aged >60 years (193). In a

prelicensure study, subjects aged 55–70 years acquired

VZV-specific class I-restricted and unrestricted cytotoxic-

ity following vaccination with even low levels (4,000 PFUs)

of either live or heat-inactivated Oka/Merck strain of VZV

(23).

Duration of Efficacy and of Immunity

Vaccine efficacy for zoster prevention declined during the

first year following vaccination, but remained stable through

the remaining 3 years of follow up (Figure 4). Vaccine effi-

cacy for PHN prevention had a similar pattern, with an

initial decline and subsequent stabilization. After conclu-

sion of the Shingles Prevention Study, approximately 7,500

vaccine recipients will be followed to extend observation to

10 years. Because placebo recipients were offered zoster

vaccine at the conclusion of the Shingles Prevention Study,

zoster rates in these 7,500 persons will be compared with

15 Vol. 57 / RR-5 MMWR

FIGURE 4. Duration of zoster vaccine efficacy for preventing

zoster and postherpetic neuralgia (PHN)

HZ PHN

100

Vaccine efficacy

95% CI

-50

-100

0 1 2 3 4 0 1 2 3 4

Time since the start of follow-up (yrs)

historic controls. Increases in RCF and IFN-γ ELISPOT

responses persisted for 3–6 years following vaccination

(192,194).

Safety and Adverse Events

Serious Adverse Events

Adverse events were monitored in the Shingles Prevention

Study population, with more comprehensive ascertainment

in a safety substudy comprising 6,616 persons (3,345 vac-

cine recipients and 3,271 placebo recipients) (Table 4). In

the Shingles Prevention Study population, the number and

types of serious adverse events (4) during the 42 days after

receipt of vaccine or placebo were similar (1.4%). How-

ever, rates of serious adverse events in the safety substudy

were higher in vaccine recipients (1.9%) than in placebo

recipients (1.3%), with a relative risk of 1.5 (95% CI =

1.0–2.3). Nonetheless, no temporal or clinical patterns of

adverse events were observed in vaccine recipients to sug-

gest a causal relation (4,186). The incidence of death and

hospitalizations was similar in the two treatment groups

throughout the observation time (4,186).

Mild Local and Systemic Reactions

In the Shingles Prevention Study safety substudy, self-

reported injection site adverse events (e.g., erythema, pain,

swelling, warmth, and pruritis) were more common among

vaccine recipients (48.3%) than placebo recipients (16.6%)

(p<0.05) (Table 4) (4); the risk for these events was higher

in vaccine recipients aged 60–69 years (58.3%) than in

persons aged >70 years (41.3%) (189). Most injection site

adverse events were mild and resolved within 4 days (187).

Less-serious systemic adverse events, including headaches,

were more common in vaccine recipients (6.3%) than in

placebo recipients (4.9%) (p<0.05) (Table 4) (4). The risk

for fevers after vaccination did not differ between vaccine

recipients and controls.

The safety and tolerability of zoster vaccine was evalu-

ated in a separate study among persons aged 50–59 years,

including 62 persons who received the standard potency

(approximately 58,000 PFUs) and 123 persons who

received high potency (approximately 207,000 PFUs)

(195). Although the numbers of persons was small, both

vaccines were safe and well tolerated; however, injection

site reactions were more common (69.4% and 82.9%,

respectively) than those observed in person aged >60 years

in the Shingles Prevention Study (48.3%).

Vaccine Virus Rash and Transmission

Varicella-like rashes, including injection site varicella-like

lesions, generalized varicella-like rashes, and zoster-like

rashes, were evaluated in the Shingles Prevention Study

during the first 42 days of observation (Table 4). Twenty

vaccine recipients and seven placebo recipients had lesions

at the injection site (p<0.05) (4); the lesions were tested

for VZV by PCR in one of these persons in each group,

and results were negative in both. Among the vaccine

recipients, lesions occurred a median of 3–4 days after

vaccination and lasted a median of 5 days.

Generalized varicella-like rashes occurred at similar rates

in the two groups (Table 4). Zoster-like rashes were less

common in vaccine versus placebo recipients during this

42-day period (p<0.05). Oka/Merck strain VZV was not

detected in any of 10 lesion specimens from vaccine recipi-

ents available for PCR testing. In early studies conducted

as part of the manufacturer’s clinical program for develop-

ment of zoster vaccine, samples from rashes in two vacci-

nated persons were confirmed to be Oka/Merck-strain VZV

(186). Both experienced noninjection-site varicella-like

rashes; one had 21 lesions on day 17 lasting 8 days and the

other developed five lesions on day 8 that lasted 16 days.

No varicella-like rashes were documented during any clini-

cal zoster vaccine trials of laboratory-confirmed zoster

attributed to Oka/Merck strain VZV. In addition, no evi-

dence existed of transmission of vaccine virus from vaccine

recipients to contacts.

The Economic Burden of Zoster and

Cost-Effectiveness of Vaccination

The economic burden of zoster in the elderly is substan-

tial and includes direct costs attributed to health-care use

and indirect costs attributed to losses in productivity from

temporary or more permanent disability. In addition,

16 MMWR June 6, 2008

TABLE 4. Adverse events among all persons and among persons in an adverse-events substudy*

Vaccine group Placebo group Difference in risk

Event No. (%) No. (%) % (95% CI

†

)

No. in group 19,270 19,276

Day of vaccination to end of study

Death 793 (4.1) 795 (4.1) 0.01 (-1.2–1.2)

Death by age group (yrs)

60–69 218 (2.1) 246 (2.4) -0.80 (-2.0–0.4)

> 7 0 575 (6.5) 549 (6.2) 0.95 (-1.2–3.1)

Vaccine-related serious adverse event

2 (<0.1) 3 (<0.1) NC

Day of vaccination to day 42

Death 14 (0.1) 16 (0.1) -0.01 (-0.1–0.1)

>1 serious adverse events 255 (1.4) 254 (1.4) 0.01 (-0.2–0.3)

Varicella-like rash at injection site 20 (0.1) 7 (0.04) 0.07 (0.02–0.13)**

Varicella-like rash not at injection site 18 (0.1) 14 (0.1) 0.02 (-0.04–0.09)

Herpes zoster-like rash 17 (0.1) 36 (0.2) -0.10 (-0.18– -0.03)**

Rash unrelated to herpes zoster 595 (3.2) 620 (3.3) -0.13 (-0.49–0.23)

Confirmed case of herpes zoster 7 (<0.1) 24 (0.1) -0.09 (-0.16– -0.03)**

Persons in the adverse event substudy 3345 3271

Day of vaccination to end of study

Person hospitalized 1,137 (34.0) 1,115 (34.1) 0.1 (-8.8–9.0)

Hospitalization related to herpes zoster 5 (0.2) 6 (0.2) -0.1 (-0.7–0.5)

Day of vaccination to day 42

>1 serious adverse events 64 (1.9) 41 (1.3) 0.7 (0.1–1.3)**

>1 adverse events 1,929 (58.1) 1,117 (34.3) 23.7 (21.3–26.0)**

>1 systemic adverse events 820 (24.7) 768 (23.6) 1.0 (-1.0–3.1)

>1 vaccine-related systemic adverse events

209 (6.3) 160 (4.9) 1.4 (0.3–2.5)**

Documented temperature >38.3

C (>100.9

F) 27 (0.8) 27 (0.9) 0 (-0.5–0.4)

Self-reports of feeling abnormal temperature

††

231 (7.2) 190 (6.0) 1.2 (0.0–2.4)

>1 adverse event at injection site

§§

1,604 (48.3) 539 (16.6) 31.7 (28.3–32.6)**

Erythema 1,188 (35.8) 227 (7.0) 28.8 (26.9–30.6)**

Pain or tenderness 1,147 (34.5) 278 (8.5) 26.0 (24.1–27.9)**

Swelling 871 (26.2) 147 (4.5) 21.7 (20.1–23.4)**

Pruritus 237 (7.1) 33 (1.0) 6.1 (5.2–7.1)**

Warmth 57 (1.7) 11 (0.3) 1.4 (0.9–1.9)**

Hematoma 53 (1.6) 46 (1.4) 0.2 (-0.4–0.8)

R a s h 10 (0.3) 3 (0.1) 0.2 (0.0–0.5)

* The rates of death and of hospitalization are percentages of persons in each treatment group. Otherwise, percentages are rates weighted in proportion

to the number of persons with safety follow-up in each age group. NC denotes not calculated. Three persons who had withdrawn from the study because

of worsening health and subsequently died were included in the safety analysis.

†

Confidence interval.

The difference in risk (vaccine group versus placebo group) and the 95% confidence intervals (CIs) for deaths and hospitalizations are based on the

rates per 1000 persons-years of follow-up to account for differential follow-up among the study participants as a result of staggered enrollment.

Otherwise, the differences in risk and 95% CIs are based on an asymptotic method for the difference of two binomial proportions where the proportions

are weighted according to the number of persons with safety follow-up in each age group. Negative values for the difference in risk result when the rate

in the placebo group is larger than that in the vaccine group.

Events classified as possibly related to vaccination were assessed by a blinded investigator at each site.

** P<0.05 for the comparison with the placebo group.

††

A temperature of >38.3

C (>100.9

F) was not documented.

§§

None of the adverse events related to the injection site were considered to be serious adverse events.

Source: Oxman MN, Levin MJ, Johnson GR, et al. Zoster Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older

adults. N Engl J Med 2005;352:2271–4.

much of the economic burden of zoster is borne by indi- emergency department visits, and 1–5 for the number of

vidual patients as reduced quality of life because of pain medications prescribed. Approximately 1%–4% of zoster

and suffering. Certain studies provide a range of estimates episodes result in hospitalization, with a mean duration of

for health-care use among persons aged >60 years for treat- 4.8 days. (196–199). Health-care use for zoster and PHN

ment of zoster and PHN. The estimates vary widely increases substantially with the age of patients (196–198).

because of differing assumptions regarding the risk for PHN Costs associated with acute zoster have been evaluated.

and of complications resulting from zoster. Estimated health- Among patients with acute episodes of zoster, average

care use per case of zoster ranges from 1.3–3.1 for the num- expenditures ranged from $112–$287 per episode of out-

ber of outpatient visits, 0.005–0.12 for the number of patient care, $73–$180 per antiviral treatment, and

Recommendations and Reports

June 6, 2008 / Vol. 57 / RR-5

Morbidity and Mortality Weekly Report

www.cdc.gov/mmwr

Continuing Education Activity Sponsored by CDC

Prevention of Herpes Zoster Recommendations of the Advisory Committee

on Immunization Practices (ACIP)

EXPIRATION — June 6, 2010

You must complete and return the response form electronically or by mail by contact hours Certified Health Education Specialist (CHES) credit. If you

Xxxxxxxx XX, 200X, to receive continuing education credit. If you answer all return the form electronically, you will receive educational credit

of the questions, you will receive an award letter for 2.75 hours Continuing immediately. If you mail the form, you will receive educational credit in

Medical Education (CME) credit; 0.25 Continuing Education Units (CEUs); approximately 30 days. No fees are charged for participating in this continuing

2.75 contact hours Continuing Nursing Education (CNE) credit; or 3.0 education activity.

INSTRUCTIONS

By Internet

1. Read this MMWR (Vol. 57, RR-5), which contains the correct answers to

the questions beginning on the next page.

2. Go to the MMWR Continuing Education Internet site at http://

www.cdc.gov/mmwr/cme/conted.html.

3. Select which exam you want to take and select whether you want to register

for CME, CEU, CNE, or CHES credit.

4. Fill out and submit the registration form.

5. Select exam questions. To receive continuing education credit, you must

answer all of the questions. Questions with more than one correct answer

will instruct you to “Indicate all that apply.”

6. Submit your answers no later than June 6, 2010.

7. Immediately print your Certificate of Completion for your records.

By Mail or Fax

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the questions beginning on the next page.

2. Complete all registration information on the response form, including

your name, mailing address, phone number, and e-mail address.

3. Indicate whether you are registering for CME, CEU, CNE, or CHES

credit.

4. Select your answers to the questions, and mark the corresponding letters

on the response form. To receive continuing education credit, you must

answer all of the questions. Questions with more than one correct answer

will instruct you to “Indicate all that apply.”

5. Sign and date the response form or a photocopy of the form and send no

later than June 6, 2010, to

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Mail: MMWR CE Credit

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education for physicians. CDC designates this educational activity for a maximum of 2.75 hours in category 1 credit toward the AMA Physician’s Recognition

Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

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Education and Training (IACET), 1620 I Street, N.W., Suite 615, Washington, DC 20006. CDC has awarded 0.25 CEUs to participants who successfully

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education. The CDC provider number is GA0082.

depardepar

depar

tment of health and human sertment of health and human ser

tment of health and human ser

vicesvices

vices

Centers for Disease Control and PreventionCenters for Disease Control and Prevention

Centers for Disease Control and Prevention

CE-2 MMWR June 6, 2008

Goals and Objectives

This report provides recommendations on use of the licensed live-attenuated vaccine for prevention of herpes zoster (zoster) and its most frequent complication,

post-herpetic neuralgia (PHN). The recommendations were developed by CDC’s Advisory Committee on Immunization Practices. The goal of this report is to

provide recommendations on the zoster vaccine for clinicians, public health officials, and others interested in preventing zoster and PHN in the United States. Upon

completion of this educational activity, the reader should be able to 1) describe the epidemiology of zoster in the United States, 2) identify recommendations for

zoster vaccination in the United States, and 3) and describe the characteristics of zoster vaccine.

To receive continuing education credit, please answer all of the following questions.

1. Which of the following statements about herpes zoster is true?

A. It most frequently manifests in a sacral nerve dermatomal distribution.

B. It most frequently manifests in a thoracic, cervical, or ophthalmic

dermatomal distribution.

C. It most frequently presents as a disseminated rash.

2. The diagnosis of herpes zoster…

A. Can usually be made on clinical grounds alone.

B. Is made on the basis of testing antibody to varicella zoster virus.

C. Neither A nor B.

3. Which of the following statements is true regarding the epidemiology

of herpes zoster?

A. Approximately one in 10 persons acquire zoster during their lifetime.

B. After adjusting for changes in age and other factors in the population,

the rate for zoster in the United States has been stable in recent

decades.

C. Recent data suggest approximately 1 million cases of zoster occur

annually in the United States.

D. Exposure to varicella has been demonstrated to have major influence

on the rate for zoster in the population.

E. All of the above.

4. Which of the following groups are at increased risk for herpes zoster?

A. Persons at advanced age.

B. Patients with atopic dermatitis.

C. Blacks.

D. Persons that have been vaccinated with varicella vaccine.

E. All of the above.

5. The most significant burden from zoster in the U.S. population is

caused by…

A. A high number of hospitalizations.

B. A high number of deaths.

C. Blindness caused by ophthalmic zoster.

D. Impact on quality of life attributed to pain and suffering.

6. Which of the following is true regarding zoster vaccine?

A. It must be refrigerated before reconstitution.

B. It is made from a different strain of varicella zoster virus than used in

varicella vaccine.

C. It should not be administered within 28 days of inactivated influenza

vaccine.

D. It contains thimerosol.

E. None of the above.

7. Which of the following is true regarding the efficacy of zoster vaccine

in the Shingles Prevention Study?

A. The vaccine reduced overall incidence of zoster by approximtaely

51%.

B. The vaccine was most effective at preventing the post-herpatic

neuralgia (PHN) of the longest duration.

C. The vaccine was not very effective at preventing zoster in persons aged

>80 years but was much more effective at preventing PHN in these

persons.

D. Efficacy of the vaccine at preventing zoster was fairly stable over a

period of 6 years.

E. A, B, and C.

8. The Advisory Committee for Immunization Practices (ACIP)

recommends zoster vaccine for which of the following?

A. Adults aged >50 years about to undergo kidney transplantation.

B. Adults aged >60 years, with 1 booster dose 10 years later.

C. Adults aged >60 years irrespective of prior history of varicella or zoster.

D. Adults aged >60 who are experiencing zoster to prevent PHN.

E. B, C, and D.

9. Zoster vaccine is contraindicated by ACIP for which of the following

persons?

A. Persons with insulin-dependent diabetes mellitus.

B. Persons infected with human immunodeficiency virus before

progression to acquired immunodeficiency syndrome.

C. Persons that received chemotherapy for leukemia during the

preceding 3 months.

D. A, B, and C.

E. B and C.

10. In the Shingles Prevention Study, which of the following adverse

reactions occurred with significantly greater frequency in the zoster

vaccine recipients as compared with controls?

A. A generalized varicella-like rash.

B. Injection site reactions.

C. Fever.

D. All of the above.

11. What best describes your professional activities?

A. Physician.

B. Nurse.

C. Health educator.

D. Office staff.

E. Other.

12. I plan to use these recommendations as the basis for … (Indicate all

that apply.)

A. health education materials.

B. insurance reimbursement policies.

C. local practice guidelines.

D. public policy.

E. other.

MMWR Response Form for Continuing Education Credit

June 6, 2008/Vol. 57/No. RR-5

Prevention of Herpes Zoster Recommendations of the Advisory

Committee on Immunization Practices (ACIP)

13. Overall, the length of the journal report was …

A. much too long.

B. a little too long.

C. just right.

D. a little too short.

E. much too short.

14. After reading this report, I am confident I can describe the

epidemiology of zoster in the United States.

A. Strongly agree.

B. Agree.

C. Undecided.

D. Disagree.

E. Strongly disagree.

15. After reading this report, I am confident I can identify

recommendations for zoster vaccination in the United States.

A. Strongly agree.

B. Agree.

C. Undecided.

D. Disagree.

E. Strongly disagree.

16. After reading this report, I am confident I can describe the

characteristics of zoster vaccine.

A. Strongly agree.

B. Agree.

C. Undecided.

D. Disagree.

E. Strongly disagree.

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10. [ ] A [ ] B [ ] C [ ] D

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11. [ ] A [ ] B [ ] C [ ] D [ ] E

24. [ ] A [ ] B [ ] C [ ] D [ ] E

12. [ ] A [ ] B [ ] C [ ] D [ ] E

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13. [ ] A [ ] B [ ] C [ ] D [ ] E

26. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F

Signature Date I Completed Exam

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report.

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C. Undecided.

D. Disagree.

E. Strongly disagree.

18. The instructional strategies used in this report (text, tables, and figures)

helped me learn the material.

A. Strongly agree.

B. Agree.

C. Undecided.

D. Disagree.

E. Strongly disagree.

19. The content was appropriate given the stated objectives of the report.

A. Strongly agree.

B. Agree.

C. Undecided.

D. Disagree.

E. Strongly disagree.

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C. Undecided.

D. Disagree.

E. Strongly disagree.

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A. Strongly agree.

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E. Strongly disagree.

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$3,221–$7,206 per hospitalization (2006 dollars). Addi-

tional costs associated with managing non-PHN complica-

tions (e.g., ocular, neurologic, and cutaneous) ranged from

$1,158–$11,255 per complication, and from $566–

$1,914 per episode of PHN. Among the subset of patients

with PHN persisting from 30 days to 12 months, annual-

ized health-care costs, including costs of the acute episode,

ranged from $2,159 to $5,387 (200,201). Although indi-

rect costs from death can occur with zoster, these costs

result mostly from losses in work time caused by tempo-

rary or more permanent disability. Patients with zoster

(including those progressing to PHN) lose an average of

>129 hours of work per episode (197,198), including losses

of 12 or more hours of work time and 69 hours of leisure

time during the first 30 days (196). Data on the national

economic impacts of zoster and its complications on

quality of life have not been reported.

Five studies have estimated the cost-effectiveness of a

1-dose routine vaccination program of immunocompetent

persons aged >60 years (196,197,199,202,203) (Table 5).

One of these studies has not been published (196). All five

studies used a Markov cohort model (105), followed a cost-

utility analytic approach that included a societal perspec-

tive (204,205), and used quality-adjusted life-year (QALY)

scores to assess the incremental impact of the vaccine

program on quality of life. Costs and health benefits were

measured in 2005–2006 U.S. dollars, and a 3% discount

rate was used to adjust health outcomes and costs. Model

assumptions varied regarding duration of vaccine protec-

tion, the efficacy of the vaccine for preventing PHN among

vaccine recipients who developed zoster, costs associated

with vaccine adverse events, and costs attributed to losses

in work productivity. None of the five models incorporated

costs for losses in leisure time. Assuming a routine vaccina-

tion program with 100% coverage, the estimated QALYs

gained ranged from 0.0016 (0.6 days) to 0.0087 (3 days).

At a vaccine cost of $150 per dose, the societal costs of

routinely vaccinating immunocompetent persons aged >60

years range from $27,000 to $112,000 per QALY gained.

In the sensitivity analyses, variables with the strongest

influence on outcomes include vaccine costs, duration of

vaccine efficacy, risks for PHN as a complication, and costs

and QALY scores for zoster and its complications.

Although costs per QALY gained are most appropriately

used to prioritize among competing programs for purposes

of resource allocation, policymakers often decide whether

or not to support programs by comparing their cost per

QALY against a standard threshold. A threshold suggested

by the World Health Organization is three times the gross

domestic product per capita, which would be $94,431 for

the United States (206). Alternatively, policymakers often

decide about supporting programs by comparing their cost

per QALY with the values for other widely accepted inter-

ventions. Compilations of such cost effectiveness data have

been published and maintained in on-line registries

(207,208). The estimated cost per QALY for zoster vacci-

nation covers a wide range that appears acceptable in com-

parison to either standard thresholds or to other established

interventions, but it is at the intermediate-to-high end of

that range.

Summary of Rationale for Zoster

Vaccine Recommendations

The availability of a safe and effective vaccine for zoster

offers an opportunity to decrease the burden of this disease

and its complications among persons with high levels of

risk. In the United States, the vaccine is licensed for use

among persons aged >60 years, and routine vaccination of

this population is recommended for several reasons. First,

zoster causes substantial morbidity in the United States,

with approximately 1,000,000 new cases occurring annu-

ally (62). Many of these cases cause debilitating pain, and

when PHN develops, the pain can last for months or even

years. Other complications include involvement of the eye

that can threaten sight, bacterial superinfections, and dis-

figuring facial scarring. Second, although effective antiviral

medications for treatment of zoster are available, adminis-

tration must be initiated within 72 hours of rash onset for

maximum benefit. Many patients might not obtain such

rapid diagnosis and treatment, and even when they do, the

treatment is only partially effective at alleviating the symp-

toms and shortening their duration. Third, available treat-

ments for PHN often do not completely alleviate the pain

and might be poorly tolerated by the older patients (31,33).

Finally, available evidence suggests the cost-effectiveness of

zoster vaccine is within the range of some other public

health interventions.

In a large, placebo-controlled clinical trial, the zoster vac-

cine reduced BOI attributed to zoster by 61.1 % and the

incidence of PHN by 66.5 %. The vaccine reduced the

overall incidence of zoster by 51.3 % and substantially

reduced its associated pain (4). Although the vaccine was

more efficacious in persons aged 60–69 years, substantial

efficacy against zoster was observed in persons aged

>70 years, and PHN was prevented in older age groups.

Prevention of zoster and its sequelae is particularly impor-

tant among the oldest persons because they experience the

highest incidence of zoster and PHN, they might be least

18 MMWR June 6, 2008

TABLE 5. Economic burden and projected cost-effectiveness of a herpes zoster vaccination program, by selected studies* —

United States

Study No. 1

†

Study No. 2 Study No. 3 Study No. 4 Study No. 5

Costs

Acute zoster

Outpatient care $246–$312

$214 (SD** = $52.7) $287 ($221–$422) $112 ($56–$224) $289 ($178–$527)

Antiviral medicines $73–$135 $155 NA

††

$180 ($135–$238) NA

Hospitalization $6,815 (SD = $11,608) $8,521 $7,206 ($6,529–$8,401) $6,884 $3,221 ($130–$5,200)

Out-of-pocket

§§

$7–$20 NA NA NA N/A

Complications (nonpostherpetic

neuralgia [PHN])

¶¶

Ocular $1,158 (SD = $2,231) $1,827 (SD= $2,844) $11,255 ($9,255–$13,255) NA NA

Neurologic $1,642 (SD = $3,483) $2,623 (SD= $3,965) NA NA NA

Cutaneous $1,851 (SD = $1,838) $3,739 (SD= $5,684) NA NA NA

PHN***

Outpatient care and prescriptions $903–$1071 $1,914 (SD= $2,667) $566 ($483–$673) $996 NA

Out-of-pocket $29–$118 NA NA NA NA

Productivity losses per case

†††

$1,062 $2,437 $782 (0–$1,000) $744 ($185–$1,934) NA

Cost-Effectiveness

Outcomes prevented per million person-years

Zoster 58,000 66,000 NA NA NA

Complications (non-PHN) 7,000 8,500 NA NA NA

PHN 32,000 20,000 NA NA NA

Premature deaths 5 37 NA NA NA

Resource-use averted per million person-years

Outpatient visits 285,000 274,000 NA NA NA

Emergency department visits 28,000 8,700 NA NA NA

Hospitalization days 6,000 8,900 NA NA NA

Prescription fills 176,000 354,000 NA NA NA

QALYs gained per person-year

§§§

0.0087 0.0057 0.0021 0.0016 NA

Vaccine cost per dose

¶¶¶

$150 ($50–$200) $150 $145 ($50–$150) $200 ($50–$500) $170 ($123–$245)

Cost per QALY****

,§§§

$55,000 $27,000 $112,000 $100,000 $50,000

* Study No. 1: Ortega-Sanchez IR. Projected cost-effectiveness of vaccinating US elderly to prevent shingles. Oral presentation to the Advisory Committee for Immunization

Practices (ACIP) Meeting, June 2006; Study No. 2: Pellissier JM, Brisson M, Levin MJ. Evaluation of the cost-effectiveness In the United States of a vaccine to prevent herpes

zoster and postherpetic neuralgia in older adults. Vaccine 2007;25:8326–37; Study No. 3: Rothberg MB, Virapongse A, Smith KJ. Cost-effectiveness of a vaccine to prevent

herpes zoster and postherpetic neuralgia in older adults. Clin Infect Dis 2007;44:1280–8; Study No. 4: Hornberger J, Robertus K. Cost-effectiveness of a vaccine to prevent

herpes zoster and postherpetic neuralgia in older adults. Ann Intern Med 2006;145:317–25; Study No. 5: Ho A, Coplan PM, Lee A, et al. Cost-effectiveness of vaccination against

herpes zoster in the elderly population. Canadian J Anesthesia (Suppl 1): 26394. Studies used a Markov cohort model. Except for Study 5, which considered vaccinating

immunocompetent persons aged >65 years, studies No. 1–4 evaluated a routine vaccination program of immunocompentent persons aged >60 years. Baseline for comparison

in all studies was “no vaccination.” Study No. 5 measured medical costs of zoster in 2002 U.S. dollars and Studies No. 1–4 measured age-specific costs in 2005–2006 U.S. dollars.

†

For rates of zoster incidence and medical costs, Study No. 1 used data mainly from MedStat. For rates of zoster incidence and complications, the study used:Yawn BP, Saddier

S, Wollan P, Sauver JS, Kurland M, Sy L. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin

Proc 2007;82:1341–9. For quality-of-life scores with zoster, out-of-pocket, and productivity costs, the study used:Lieu TA, Ortega-Sanchez IR, Ray GT, et al. Community and

patient values for preventing zoster. Pharmacoeconomics 2008;26:235–49.

For incidence of zoster, Study No. 5 used data mainly from: Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older

adults. N Engl J Med 2005;352:2271–84; CDC. Prevention of varicella: updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR

2007;56(No. RR-4). Medical costs from 1995 were updated to 2002 U.S. dollars.

Ranges in medical costs described age-specific costs for zoster or PHN cases among persons aged >60 years. High and low medical costs also were used for sensitivity analysis.

** SD = Standard deviation. In addition to reported mean costs, SD values were used for sensitivity analysis.

††

NA = not available.

§§

Out-of-pocket costs are monetary expenses associated with zoster or PHN as reported by patients and include medical and nonmedical payments, over-the-counter medications,

travel expenses, and other monetary expenses.

¶¶

Study Nos. 1–3 included costs of frequent non-PHN complications observed <30 days after zoster reactivation (i.e., ocular, neurologic, and cutaneous complications).

*** Study Nos. 1 and 2 used costs attributable to PHN cases lasting >90 days, and study No. 4 used cost attributable to PHN cases lasting 182 days ($166 per month). Although

Study No. 3 assumed that 43%–56% of PHN cases lasted >12 months, attributable costs were not explicitly defined.

†††

Productivity losses (i.e., indirect costs) in cases of zoster and PHN were related to monetary value of time of work missed or income lost. Losses from leisure time or unpaid

activities were not included. Although zoster can cause death, no productivity costs associated with premature deaths were included.

§§§

Source of quality-of-life values to estimate quality-adjusted live years (QALYs) differed across studies. Source of quality-of-life values to estimate quality-adjusted life years

(QALYs) differed across studies. For all five studies, quality-of-life values are based on published data with valuation by representative samples of community members. In

addition, study No. 1 also used published quality-of-life values using valuation by zoster patients, yielding values of QALYs gained per person-year of 0.019 and cost per QALY

of $23,000.

¶¶¶

Range in vaccine costs were used for sensitivity analyses. Study No. 4 reported an aggregated cost for the vaccine and vaccine administration equal to $200. Except for Study

No. 5, vaccine administration costs also were included (i.e., $3.50 in Study No. 3, $18 in Study No. 2, and $15–$30 in Study No. 1).

**** Estimates of cost per QALY saved assumed that PHN cases were avoided only through the prevention of zoster cases.When PHN cases were prevented in persons with zoster

for whom the vaccine failed to prevent zoster (i.e., burden of illness), a societal cost of $35,000 per QALY saved was estimated by Study No. 1.

able to seek medical attention for zoster and PHN and to to treat PHN, they might have the least reserve to tolerate

request treatment of ongoing pain, they might be least able zoster and its complications, and they are most likely to

to tolerate the medications and procedures commonly used suffer social and psychological consequences from PHN.

19 Vol. 57 / RR-5 MMWR

Recommendations for Use of

Zoster Vaccine

Routine Vaccination of Persons Aged

>60 Years

ACIP recommends routine vaccination of all persons aged

>60 years with 1 dose of zoster vaccine. Persons who report

a previous episode of zoster and persons with chronic medical

conditions (e.g., chronic renal failure, diabetes mellitus,

rheumatoid arthritis, and chronic pulmonary disease) can

be vaccinated unless those conditions are contraindications

or precautions. Zoster vaccination is not indicated to treat

acute zoster, to prevent persons with acute zoster from

developing PHN, or to treat ongoing PHN. Before routine

administration of zoster vaccine, it is not necessary to ask

patients about their history of varicella (chickenpox) or to

conduct serologic testing for varicella immunity.

Simultaneous Administration with Other

Adult Vaccines

Immunogenicity of zoster vaccine and trivalent inacti-

vated influenza vaccine is not compromised when the two

vaccines are administered simultaneously (186). However,

no data exist on administration of zoster vaccine with other

vaccines routinely recommended for persons aged >60 years,

which are all inactivated. In general, the simultaneous

administration of most widely used live, attenuated and

inactivated vaccines has not resulted in impaired immune

response or an increased rate of adverse events (209). There-

fore, zoster vaccine can be administered with other

indicated vaccines during the same visit (e.g., Td, Tdap,

and pneumococcal polysaccharide vaccines). Each vaccine

must be administered using a separate syringe at a differ-

ent anatomic site. If simultaneous administration is not

possible, zoster vaccine can be administered at any time

before or after an inactivated vaccine, but at least 4 weeks

before or after another live, attenuated vaccine (209).

Groups for Which Vaccine is Not

Licensed

Vaccination of Persons Aged <60 Years

The vaccine is not licensed for persons aged <60 years,

and no recommendation exists for routine vaccination of

persons aged <60 years. In the clinical trial, the zoster vac-

cine was evaluated among persons aged >60 years. The vac-

cine was most effective and well tolerated in the youngest

persons (Table 1) (4). Although the vaccine would

probably be safe and effective in persons aged <60 years,

data are insufficient to recommend vaccination of these

persons at this time.

Vaccination of Persons Who Have Received

Varicella Vaccine

Zoster vaccination is not recommended for persons of

any age who have received varicella vaccine. However, health-

care providers do not need to inquire about varicella vacci-

nation history before administering zoster vaccine because

virtually all persons currently or soon to be in the recom-

mended age group have not received varicella vaccine. In

the United States, varicella vaccination began in 1995. Since

that time, few adults aged >40 years would have been sus-

ceptible to varicella and thus eligible to receive varicella

vaccine (5). The number of persons eligible for zoster vac-

cination who have received varicella vaccine is extremely

small and will remain so for at least a decade.

Special Groups and Circumstances

Persons with a Reported History of Zoster

Persons with a reported history of zoster can be vacci-

nated. Repeated zoster has been confirmed in immuno-

competent persons soon after a previous episode (4).

Although the precise risk for and severity of zoster as a func-

tion of time following an earlier episode are unknown, some

studies suggest it may be comparable to the risk in persons

without a history of zoster (62,169). Furthermore, no labo-

ratory evaluations exist to test for the previous occurrence

of zoster, and any reported diagnosis or history might be

erroneous (4,64,65). Although the safety and efficacy of

zoster vaccine have not been assessed in persons with a his-

tory of zoster, different safety concerns are not expected in

this group.

Persons Anticipating Immunosuppression

The risk for zoster and its severe morbidity and mortal-

ity is much greater among persons who are immunosup-

pressed. Review of vaccination status for zoster and other

vaccines should be a key component of the medical assess-

ment for immunocompetent patients aged >60 years who

might be anticipating initiation of immunosuppressive treat-

ments or who have diseases that might lead to immunode-

ficiency. Such patients without a history of zoster vaccination

should receive 1 dose of zoster vaccine at the first possible

clinical encounter while their immunity is intact. Zoster

vaccine should be administered at least 14 days before ini-

tiation of immunosuppressive therapy, although some

20 MMWR June 6, 2008

experts advise waiting 1 month after zoster vaccination to

begin immunosuppressive therapy if delay is possible (210).

Persons Receiving Antiviral Medications

Licensed antiviral medications active against members of

the herpesvirus family include acyclovir, famciclovir, and

valacyclovir. These agents might interfere with replication

of the live, VZV-based zoster vaccine. All three agents have

relatively short serum half-lives and are quickly cleared from

the body. Persons taking chronic acyclovir, famciclovir, or

valacyclovir should discontinue these medications at least

24 hours before administration of zoster vaccine, if pos-

sible (209). These medications should not be used for at

least 14 days after vaccination, by which time the immu-

nologic effect should be established (209).

Persons Receiving Blood Products

Zoster vaccine can be administered to persons at any time

before, concurrent with, or after receiving blood or other

antibody-containing blood product because persons with

a history of varicella indefinitely maintain high levels of

antibody to VZV, and the levels are comparable to those

found in donated blood and antibody-containing blood

products (e.g., whole blood, packed red blood cells, and

plasma immune globulin, hyperimmune globulin, and

intravenous immune globulin) (192,211).

Nursing Mothers

Most live vaccines, including varicella vaccine, are not

secreted in breast milk (209,212). Therefore, breast feed-

ing is not a contraindication for zoster vaccination. However,

this situation will be extremely rare in the target age group

for this vaccine.

Contraindications

Allergy to Vaccine Components

Zoster vaccine is contraindicated for persons who have a

history of anaphylactic reaction to any component of the

vaccine, including gelatin and neomycin. Neomycin allergy

is usually manifested as a contact dermatitis, which repre-

sents a delayed-type immune response. A history of con-

tact dermatitis to neomycin is not a contraindication for

receiving zoster vaccine (209).

Immunocompromised Persons

Zoster vaccine should not be administered to persons with

primary or acquired immunodeficiency including:

• Persons with leukemia, lymphomas, or other malignant

neoplasms affecting the bone marrow or lymphatic

system. However, patients whose leukemia is in remis-

sion and who have not received chemotherapy (e.g.,

alkylating drugs or antimetabolites) or radiation for at

least 3 months can receive zoster vaccine (209).

• Persons with AIDS or other clinical manifestations of

HIV, including persons with CD4+ T-lymphocyte val-

ues <200 per mm

or <15% of total lymphocytes.

• Persons on immunosuppressive therapy, including

high-dose corticosteroids (>20 mg/day of prednisone

or equivalent) lasting two or more weeks. Zoster vacci-

nation should be deferred for at least 1 month after

discontinuation of such therapy (209). Short-term cor-

ticosteroid therapy (<14 days); low-to-moderate dose

(<20 mg/day of prednisone or equivalent); topical (e.g.,

nasal, skin, inhaled); intra-articular, bursal, or tendon

injections; or long-term alternate-day treatment with

low to moderate doses of short-acting systemic corti-

costeroids are not considered to be sufficiently immu-

nosuppressive to cause concerns for vaccine safety.

Persons receiving this dose or schedule can receive zoster

vaccine. Therapy with low-doses of methotrexate (<0.4

mg/Kg/week), azathioprine (<3.0 mg/Kg/day), or 6-

mercaptopurine (<1.5 mg/Kg/day) for treatment of

rheumatoid arthritis, psoriasis, polymyositis, sarcoido-

sis, inflammatory bowel disease, and other conditions

are also not considered sufficiently immunosuppres-

sive to create vaccine safety concerns and are not

contraindications for administration of zoster vaccine.

• Persons with clinical or laboratory evidence of other

unspecified cellular immunodeficiency. However, per-

sons with impaired humoral immunity (e.g.,

hypogammaglobulinemia or dysgammaglobulinemia)

can receive zoster vaccine.

• Persons undergoing hematopoietic stem cell transplan-

tation (HSCT). The experience of HSCT recipients with

VZV-containing vaccines (e.g., zoster vaccine) is lim-

ited. Physicians should assess the immune status of

the recipient on a case-by-case basis to determine the

relevant risks. If a decision is made to vaccinate with

zoster vaccine, the vaccine should be administered at

least 24 months after transplantation (209).

• Persons receiving recombinant human immune media-

tors and immune modulators, especially the antitumor

necrosis factor agents adalimumab, infliximab, and

etanercept. The safety and efficacy of zoster vaccine

administered concurrently with these agents is

unknown. If it is not possible to administer zoster vac-

cine to patients before initiation of therapy, physicians

should assess the immune status of the recipient on a

case-by-case basis to determine the relevant risks and

21 Vol. 57 / RR-5 MMWR

benefits. Otherwise, vaccination with zoster vaccine

should be deferred for at least 1 month after discon-

tinuation of such therapy.

Pregnancy

Zoster vaccine is not recommended for use in pregnant

women, although these women are unlikely to be in the

vaccine target age group. The effects of the live, attenuated

VZV-based zoster vaccine on the fetus are unknown.

Women should avoid becoming pregnant for 4 weeks fol-

lowing zoster vaccination. Having a pregnant household

member is not a contraindication to zoster vaccination. If a

pregnant woman is vaccinated or becomes pregnant within

1 month of vaccination, she should be counseled about

potential effects on the fetus. Wild-type VZV poses a small

risk to the fetus (3), and the fetal risk from the attenuated

zoster vaccine is probably even lower. Furthermore, virtu-

ally all persons receiving the vaccine will have preexisting

VZV immunity, which is expected to limit viral replica-

tion and presumably further reduce fetal risk. In most cir-

cumstances, the decision to terminate a pregnancy should

not be based on whether zoster vaccine was administered

during pregnancy. Merck & Co., Inc., in collaboration with

CDC, has established a pregnancy registry to monitor the

maternal-fetal outcomes of pregnant women who are inad-

vertently administered live-attenuated VZV-based vaccines

within 1 month of pregnancy (telephone: 800-986-8999).

Patients and health-care providers should report any expo-

sure to zoster vaccine during pregnancy to this registry.

Precautions

Moderate to Severe Illness

Zoster vaccination of persons who have severe acute ill-

ness should be postponed until recovery. The decision to

delay vaccination depends on the severity of symptoms and

the etiology of the disease. Zoster vaccine can be adminis-

tered to persons who have mild acute illnesses with or

without fever (209).

Program Implementation Issues

Following Good Adult Vaccination Practices

Zoster vaccine should be offered to patients aged >60

years at the first available clinical encounter with their pro-

vider. The average adult in this age group has 5–8 clinical

encounters with their provider annually (213). Strategies

to promote zoster vaccination include linking delivery of

zoster vaccine to delivery of other indicated adult vaccines

(e.g., influenza) and preventive-health interventions (214–

217), standing orders so that patients will automatically

be offered indicated vaccines rather than requiring case-

by-case physicians’ orders (218), and practice-based audits

and/or physician-reminder systems (218). Residents of

nursing homes and other long-term–care facilities who are

at least aged 60 years and without contraindications should

be included in routine zoster vaccination activities. When

administering zoster vaccine, health-care providers should

review the patient’s vaccination status for all indicated adult

vaccines (219,220).

ACIP recommends that health-care providers keep per-

manent documentation of all administered vaccines, includ-

ing zoster vaccine, in the vaccine recipient’s permanent

medical record (209). The type of the vaccine, manufac-

turer, anatomic site, route of delivery, date of administra-

tion, lot number, and name of the administering facility

should be recorded. To help avoid the administration of

unnecessary doses, every patient should be given a record

of the vaccination.

Administration Errors

The zoster vaccine, ZOSTAVAX

, is a live, attenuated

vaccine containing Oka/Merck strain VZV. The vaccine is

similar to the varicella vaccine, VARIVAX

, except the mini-

mum PFU-content of the ZOSTAVAX

is at least 14-fold

higher than the minimum PFU-content of VARIVAX

Opportunities for administration errors are possible.

For providers who serve both children and adults, physi-

cal separation of products, careful visual inspection and

reading of labels, and preparation of vaccine for patient use

only at time of vaccination can help prevent errors. If a

provider mistakenly administers high-potency zoster vac-

cine to a child indicated for varicella vaccine, the level of

protection against varicella would probably be at least the

same as for conventional doses of varicella vaccine. This

erroneous dose should count as a single valid dose of vari-

cella vaccine. If the erroneous dose was administered in lieu

of the first dose of varicella vaccine, a second dose of vari-

cella vaccine is required. Administration errors involving

zoster vaccine should be reported to VAERS whether or

not an adverse event occurs.

Early clinical trials for prevention of varicella were con-

ducted in susceptible children using a formulation of live-

attenuated Oka/Merck strain VZV at doses of 17,430 PFU,

approaching the range of PFU in zoster vaccine (>19,400

PFU). This high-dose formulation was well tolerated and

efficacious (221). The more recently licensed live, attenu-

ated Oka-strain VZV vaccine (PROQUAD

) prepared in

22 MMWR June 6, 2008

combination with measles, mumps, and rubella vaccine

(MMRV) is formulated with a broad range of titers that

extend to over 60,000 PFU (222,223).

Varicella vaccine (VARIVAX

) is not indicated for pre-

vention of zoster. MMRV vaccine (PROQUAD

) is not

licensed for use in persons aged >13 years. If a provider

mistakenly administers varicella vaccine to persons indi-

cated for zoster vaccine, no specific safety concerns exists,

but the dose should not be considered valid and the

patient should be administered a dose of zoster vaccine dur-

ing that same visit. If the error is not immediately detected,

a dose of zoster vaccine should be administered as soon as

possible but not within 28 days of the varicella vaccine

dose to prevent potential interference of 2 doses of live

attenuated virus.

Risk for Transmission of Oka/Merck Strain

after Receiving Zoster Vaccine

Persons having close household or occupational contact

with persons at risk for severe varicella need not take any

precautions after receiving zoster vaccine except in rare

instances in which a varicella-like rash develops, when stan-

dard contact precautions are adequate. Although transmis-

sion of Oka/Merck strain VZV has been documented

following varicella vaccination, such transmission is rare and

has only been documented when the vaccine recipient first

developed a varicella-like rash. Rates of varicella-like rash

appear to be less common following zoster vaccination than

following varicella vaccination (4), and transmission of the

Oka/Merck strain VZV from recipients of zoster vaccine

has not been detected. The risk for transmitting the

attenuated vaccine virus to susceptible persons should be

weighed against the risk for developing wild-type zoster

that could be transmitted to a susceptible person. If a sus-

ceptible, immunocompromised person is inadvertently

exposed to a person who has a vaccine-related rash,

VARIZIG

™

need not be administered because disease as-

sociated with this type of transmission is expected to be

mild. Acyclovir, valacyclovir, and famciclovir are active

against live-attenuated Oka/Merck strain VZV and can be

used in the unlikely situations in which a severe illness

develops in the susceptible contact.

Reporting of Adverse Events after

Vaccination

As with any newly licensed vaccine, surveillance for rare

adverse events associated with administration of zoster vac-

cine is important for assessing its safety in widespread use.

Vaccine safety surveillance in the age group for which zoster

vaccine is recommended (aged >60 years) will present chal-

lenges because of the high prevalence of chronic conditions,

the frequent use of multiple medications, and the common

occurrence of medical events. Coincident adverse events can

be anticipated following zoster vaccination, but many of

these could be caused by the vaccine as well. All clinically

significant adverse events should be reported to VAERS even

if causal relation to vaccination is not certain. VAERS

reporting forms and information are available electronically

at http://www.vaers.hhs.gov or by telephone (800-822-

7967). Web-based reporting is also available, and provid-

ers are encouraged to report electronically at https://

secure.vaers.org/VaersDataEntryintro.htm.

Future Research and Directions

Key questions remain regarding optimal implementation

of zoster vaccination and preventing zoster and its compli-

cations. Areas that need particular focus include:

• Surveillance for zoster and its complications. Zoster is

not a notifiable condition. Other strategies will be

needed to monitor zoster and its complications include

using administrative databases, population-based sur-

veys, or active surveillance in sentinel sites. Because the

primary disease burden associated with zoster is pain,

capturing this condition will be particularly challeng-

ing using any surveillance strategy.

• Durability of protection against zoster and its compli-

cations afforded by the zoster vaccine. In a persistence

substudy ongoing at 12 of 22 of the original zoster

vaccine study sites, follow up of vaccine recipients will

be extended to an observation time of 10 years. How-

ever, no concurrent randomized placebo group exists

to which these vaccine recipients can be compared, and

results will be compared against historic controls. Large

administrative databases also will be important in evalu-

ating changes in vaccine effectiveness over time. These

and other available data will help to determine changes

in vaccine policy (e.g. a booster dose). However, both

of these approaches might be confounded by secular

changes in the incidence of zoster.

• Increased understanding of the epidemiology of zoster.

Better knowledge of age-adjusted changes in the inci-

dence of zoster and risk factors for any such changes

will help determine the long-term effectiveness of the

zoster vaccine and clarify whether changes in VZV cir-

culation caused by varicella vaccination might be

affecting zoster incidence. A better understanding of

the epidemiology and risk factors for zoster might also

lead to changes in policy regarding use of zoster vac-

cine (e.g., targeting the vaccine to selected risk groups

23 Vol. 57 / RR-5 MMWR

that are not now covered by the vaccine recommenda-

tions or lowering the targeted age group). Additional

information is needed to define risks for zoster in vari-

cella-vaccinated adults attributed to Oka/Merck strain

VZV from the vaccine itself or to wild-type VZV from

breakthrough varicella. Although studies involving both

immunocompromised and immunocompetent children

provided evidence that the risks for zoster are lower in

varicella-vaccinated children than in children with natu-

rally acquired varicella (3,99,100,224), characteriza-

tion of these risks in older adults will involve longer

follow up.

• Better prevention and treatment strategies for zoster

and PHN. Although licensure of zoster vaccine repre-

sents an important milestone in prevention of zoster,

the vaccine remains only partially efficacious and is not

licensed for all populations and age groups at risk.

Although available treatments for zoster and PHN have

improved, treatment of these conditions remains inad-

equate. Improved prevention and treatment strategies,

including better vaccines, are needed to reduce the dis-

ease burden of zoster. ZOSTAVAX

or other active or

inactive formulations of zoster vaccine should be evalu-

ated in additional cohorts of persons (e.g., persons aged

50–59 years and immunosuppressed persons at the

highest risk for zoster and its complications). Patients

infected with HIV, with or without AIDS, could

benefit substantially from the prevention of zoster. A

better understanding of immunologic correlates of pro-

tection against zoster would help facilitate the devel-

opment and evaluation of such new zoster prevention

strategies.

• The epidemiology of zoster in persons with a history of

varicella vaccination. Available data suggest that chil-

dren vaccinated with varicella vaccines are at reduced

risk for Oka/Merck strain zoster as compared with the

risk for zoster from wild-type VZV in children with a

history of chickenpox. However, this evidence does not

extend to vaccine recipients as they become older. Nor

does it include decades of time after vaccination, par-

ticularly in the absence of circulating VZV that could

externally boost immunity. Data also are lacking

regarding the risk for zoster from wild-type VZV in

vaccinated persons with a history of breakthrough vari-

cella. These issues should be addressed in future stud-

ies to develop zoster vaccination policy for cohorts of

vaccine recipients as they age.

• Safety of zoster vaccination. Postlicensure studies to

evaluate further the safety of the zoster vaccine are

under development and will be conducted by the manu-

facturer. Clinical trials have been completed to assess

the safety and immunogenicity of simultaneous admin-

istration of zoster vaccine and formulations of influ-

enza vaccine. In addition, independent studies are being

developed by CDC to monitor safety through VAERS

and the CDC Vaccine Safety Datalink.

Additional Information About

Zoster and Zoster Vaccine

Additional information about zoster and zoster vaccine

is available from several sources, and new information will

be available in the future. Updated information about

zoster, PHN, and zoster vaccine is available at http://

www.cdc.gov/vaccines/vpd-vac/shingles/default.htm.

Acknowledgments

Gregory S. Wallace, MD, Mary Mulholland, MA, Immunization

Services Division, National Center for Immunization and Respiratory

Diseases, CDC, assisted in writing the section on vaccine storage and

handling. Meredith Reynolds, PhD, Division of Viral Diseases, National

Center for Immunization and Respiratory Diseases, CDC, assisted with

compiling and preparing data on economics. Aisha O. Jumaan, PhD,

MPH, Division of Viral Diseases, National Center for Immunization

and Respiratory Diseases, CDC, assisted in writing material related to

the risk of postherpetic neuralgia. Sandra S. Chaves, M.D., M.Sc.,

assisted in preparing the section on adverse events from zoster vaccine.

Jessica Leung, MPH, and Adriana Lopez, Division of Viral Diseases,

National Center for Immunization and Respiratory Diseases, CDC,

helped with graphs and tables.

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Advisory Committee on Immunization Practices Shingles Work Group

Chair: John Treanor, MD, Rochester, New York.

Members: Members: William L. Atkinson, MD, MPH, Atlanta, Georgia; Jeffrey I. Cohen, MD, Bethesda, Maryland; Robert H. Dworkin, PhD,

Rochester, New York; Sandra Gambescia, Atlanta, Georgia; Paul M. Gargiullo, PhD, Atlanta, Georgia; Anne A. Gershon, MD, New York, New York; John

W. Glasser, PhD, MPH, Atlanta, Georgia; Dalya Güris, MD, MPH, Atlanta, Georgia; Penina Haber, MPH, Atlanta, Georgia; Rafael Harpaz, MD, MPH,

Atlanta, Georgia; Beth F. Hibbs, MPH, Atlanta, Georgia; John K. Iskander, MD, MPH, Atlanta, Georgia; Samuel L. Katz, MD, Durham, North Carolina;

Philip R. Krause, MD, Bethesda Maryland; Phillip S. LaRussa, MD, New York, New York; Myron J. Levin, MD, Denver, Colorado; Tracy A. Lieu, MD,

MPH, Boston, Massachusetts; Mona E. Marin, MD, MPH, Atlanta, Georgia; Kathleen M. Neuzil, MD, MPH, Seattle Washington; Kristin Nichol, MD,

MPH, MBA, Minneapolis, Minnesota; Ismael R. Ortega- Sánchez, PhD, Atlanta, Georgia; Gregory A. Poland, MD, Rochester, Minnesota; Sara

Rosenbaum, JD, Washington, DC; Tammy A. Santibanez, PhD; William Schaffner, MD, Nashville, Tennessee; Kenneth E. Schmader, MD, Durham, North

Carolina; D. Scott Schmid, PhD, Atlanta, Georgia; Jane Seward, MBBS, MPH, Atlanta, Georgia; Heather Stafford, Philadelphia, Pennsylvania; Ray

Strikas, MD, Washington, DC; Gregory S. Wallace, MD, Atlanta, Georgia; Barbara Watson, MB ChB, Philadelphia, Pennsylvania.

Advisory Committee on Immunization Practices Membership List, June 2007

Chairman: Jon S. Abramson, MD, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Executive Secretary: Larry K. Pickering, MD, CDC, Atlanta, Georgia.

Members: Ban Mishu Allos, MD, Vanderbilt University School of Medicine, Nashville, Tennessee; Carol Baker, MD, Baylor College of Medicine,

Houston, Texas; Robert L. Beck, JD, Palmyra, Virginia; Janet R. Gilsdorf, MD, University of Michigan, Ann Arbor, Michigan; Harry Hull, MD, Minnesota

Department of Health, Minneapolis, Minnesota; Susan Lett, MD, MPH, Massachusetts Department of Public Health, Jamaica Plain, Massachusetts;

Tracy Lieu, MD, MPH, Harvard Pilgrim Health Care and Harvard Medical School, Boston, Massachusettes; Dale L. Morse, MD, New York State

Department of Health, Albany, New York; Julia Morita, MD, Chicago Department of Public Health, Chicago, Illinois; Kathleen Neuzil, MD, MPH,

University of Washington, Seattle, Washington; Patricia Stinchfield, Children’s Hospitals and Clinics, St. Paul, Minnesota; Ciro Valent Sumaya, MD,

MPH, Texas A&M University System Health Science Center, College Station, Texas; John J. Treanor, MD, University of Rochester, Rochester, New York;

and Robin J. Womeodu, MD, University of Tennessee Health Science Center, Memphis, Memphis, Tennessee.

Ex-Officio Members: James Cheek, MD, Indian Health Service, Albuquerque, New Mexico; Wayne Hachey, DO, Department of Defense, Falls Church,

Virginia; Geoffrey S. Evans, MD, Health Resources and Services Administration, Rockville, Maryland; Bruce Gellin, MD, National Vaccine Program

Office, Washington, DC; Linda Murphy, Centers for Medicare and Medicaid Services, Baltimore, Maryland; George T. Curlin, MD, National Institutes

of Health, Bethesda, Maryland; Norman Baylor, PhD, U.S. Food and Drug Administration, Rockville, Maryland; and Kristin Lee Nichol, MD, Department

of Veterans Affairs, Minneapolis, Minnesota.

Liaison Representatives: American Academy of Family Physicians, Jonathan Temte, MD, Madison, Wisconsin, and Doug Campos-Outcalt, MD, Phoenix,

Arizona; American Academy of Pediatrics, Keith Powell, MD, Akron, Ohio, and Carol Baker, MD, Houston, Texas; America’s Health Insurance Plans,

Andrea Gelzer, MD, Hartford, Connecticut; American College Health Association, James C. Turner, MD, Charlottesville, Virginia; American College of

Obstetricians and Gynecologists, Stanley Gall, MD, Louisville, Kentucky; American College of Physicians, Kathleen M. Neuzil, MD, Seattle, Washington;

American Medical Association, Litjen Tan, PhD, Chicago, Illinois; American Pharmacists Association, Stephan L. Foster, PharmD, Memphis, Tennessee;

Association of Teachers of Preventive Medicine, W. Paul McKinney, MD, Louisville, Kentucky; Biotechnology Industry Organization, Clement Lewin,

PhD, Cambridge, Massachusetts; Canadian National Advisory Committee on Immunization, Monica Naus, MD, Vancouver, British Columbia; Healthcare

Infection Control Practices Advisory Committee, Steve Gordon, MD, Cleveland, Ohio; Infectious Diseases Society of America, Samuel L. Katz, MD,

Durham, North Carolina; London Department of Health, David Salisbury, MD, London, United Kingdom; National Association of County and City

Health Officials, Nancy Bennett, MD, Rochester, New York, and Jeffrey S. Duchin, MD, Seattle, Washington; National Coalition for Adult Immunization,

David A. Neumann, PhD, Alexandria, Virginia; National Foundation for Infectious Diseases, William Schaffner, MD, Nashville, Tennessee; National

Immunization Council and Child Health Program, Romeo S. Rodriquez, Mexico City, Mexico; National Medical Association, Patricia Whitley-Williams,

MD, New Brunswick, New Jersey; National Vaccine Advisory Committee, Gary Freed, MD, Swiftwater, Pennsylvania, and Peter Paradiso, PhD, Collegeville,

Pennsylvinia; Society for Adolescent Medicine, Amy B. Middleman, MD, Houston, Texas; Pharmaceutical Research and Manufacturers of America,

Damian A. Araga, Swiftwater, Pennsylvania.

MMWR

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