Zoster

349

23

Herpes zoster, also known as zoster, or shingles, is caused by 

the reactivation of varicella-zoster virus (VZV). The term “herpes 

zoster” was first used by encyclopedist Celsus in c. 25 BCE to 

c. 50 AD. Clinical observations of the relationship between

varicella and herpes zoster were made in 1888 by James von

Bokay, when children who never had varicella (chickenpox)

developed varicella after contact with a person with herpes

zoster (shingles). In 1954, Thomas Weller used cell culture to

isolate VZV from vesicular fluid of patients with varicella or

zoster. However, it was not until 1965 that Edgar Hope-Simpson

hypothesized that herpes zoster was due to the reactivation of

latent VZV. The first vaccine to reduce the risk of herpes zoster

was licensed in the United States in 2006.

Varicella-Zoster Virus (VZV)

VZV is a DNA virus and is a member of the herpesvirus family. 

Like other herpesviruses, VZV persists in the body as a latent 

infection after the primary (first) infection; VZV persists in 

sensory nerve ganglia. Primary infection with VZV results in 

varicella (chickenpox). Latent infection can reactivate resulting 

in herpes zoster (or shingles). 

The virus has a short survival time in the environment. 

Pathogenesis

Herpes zoster is the result of reactivation of latent VZV 

infection. During the primary (first) infection (i.e. varicella), VZV 

travels to the sensory ganglia where it resides permanently. In 

this latent form, replication is suppressed by the host immune 

system and VZV is noninfectious but can reactivate to form 

intact virions in the involved sensory neurons. Reactivated 

virions travel to epithelial cells resulting in a rash within the 

dermatome innervated by the sensory nerve. The immunologic 

mechanism that controls latency of VZV is not well understood. 

However, factors associated with increased risk of developing 

herpes zoster disease include aging, immunosuppression, 

intrauterine exposure to VZV, and having had varicella at 

younger than age 18 months.

Clinical Features

A vesicular eruption of zoster generally occurs unilaterally in 

the distribution of a sensory nerve or dermatome and does 

not cross the mid-line. Zoster can occur in any dermatome but 

occurs most often in the trunk or face. Two to four days prior to 

the eruption, there may be pain and paresthesia in the involved 

area. Zoster rash are initially red macules and papules but 

progresses to form clusters of vesicular lesions before crusting 

over. The rash lasts for 7–10 days with healing in 2–4 weeks. 

Jessica Leung, MPH; Theresa Harrington, MD, MPH&TM; and Kathleen Dooling, MD, MPH

Herpes Zoster

● Caused by reactivation of

varicella-zoster virus (VZV)

● Observed relationship between

varicella and herpes zoster in

1888

● Hypothesis formed in 1965

that herpes zoster was due to

reactivation of latent VZV

● First vaccine to reduce risk of

herpes zoster licensed in the

U.S. in 2006

Varicella-Zoster Virus (VZV)

● DNA virus

● Member of herpesvirus family

● Persists as latent infection

Zoster Pathogenesis

● Result of reactivation of latent

VZV infection

● Immunologic mechanism

for VZV latency not well

understood

● Risk factors: Aging,

immunosuppression,

intrauterine exposure to VZV,

history of varicella at younger

than age 18 months

Zoster Clinical Features

● Variable and usually less severe

in children and younger adults

● Vesicular eruption occurring

most often in the trunk or face

● Rash lasts for 7–10 days with

healing in 2–4 weeks

● Immunocompromised

persons experience more

systemic symptoms

https://www.cdc.gov/vaccines/pubs/pinkbook/herpes-zoster.html Aug 2021
350

Zoster

 23

In healthy persons there are few systemic symptoms. In 

immunocompromised persons, zoster may disseminate, causing 

generalized skin lesions and central nervous system, pulmonary, 

and hepatic involvement.

Complications

The most common and debilitating complication from zoster 

is postherpetic neuralgia (PHN). PHN is pain that persists in 

the area of the initial rash occurrence after the lesions have 

resolved. Treatment of persons with PHN is complex, with 

varying degrees of success in controlling the chronic pain. 

PHN can last for weeks or months and occasionally may last 

a year or longer after the resolution of the rash. In addition 

to PHN, other complications from zoster include ophthalmic 

involvement, bacterial superinfection, cranial and peripheral 

nerve palsies, and visceral involvement, all of which often 

result in severe sequelae.

Laboratory Testing

The diagnosis of zoster is usually made clinically. In some 

cases where disease is atypical, such as in persons with altered 

immunocompetence, laboratory testing can be performed, 

although a positive result does not differentiate zoster from 

varicella. Polymerase chain reaction (PCR) to detect VZV DNA 

is the most useful test for confirming cases of zoster. The ideal 

samples for PCR testing are swabs of unroofed vesicular lesions 

and scabs from crusted lesions. Direct fluorescent antibody 

(DFA) and Tzanck smear are not recommended due to limited 

sensitivity. Serologic methods have limited use for laboratory 

confirmation of herpes zoster. Although not widely available, 

there is a serologic test, VZV IgG avidity test, which may be used 

to distinguish primary infection from reactivation or reinfection. 

Epidemiology

Occurrence

Zoster occurs worldwide. In the United States, about 1 in 3 

people will develop zoster in their lifetime. Although zoster can 

occur at any age, the incidence increases with advancing age 

due to waning immunity. Approximately 50% of persons who 

live to age 85 years will have experienced zoster. 

Reservoir

VZV, which is the same virus that causes both varicella and 

zoster, is an exclusively human pathogen. No animal or insect 

source or vector is known to exist. 

Transmission

VZV transmission occurs person-to-person by direct contact 

with vesicular fluid or inhalation of aerosols from vesicular 

fluid of skin lesions of persons with acute varicella or zoster. 

Zoster Complications

● Postherpetic neuralgia (PHN)

most common

● Ophthalmic involvement,

bacterial superinfection, cranial

and peripheral nerve palsies,

and visceral involvement

Zoster Epidemiology

● Reservoir

■ Human

● Transmission

■ Person-to-person

■ Direct contact with vesicular

fluid or inhalation of aerosols

● Temporal pattern

■ No temporal pattern

● Communicability

■ From rash onset until

lesions crust

■ 1/5 as infectious as varicella
Zoster

351

23

Transmission may also occur from infected respiratory tract 

secretions of patients with varicella that might also be 

aerosolized. Skin lesions are considered the major source of 

transmissible VZV. Transmission of VZV would cause varicella, 

not zoster, in a VZV-naïve person. 

Temporal Pattern

Zoster has no seasonal variation and occurs throughout 

the year. 

Communicability

A person with localized zoster is contagious beginning from 

rash onset until their lesions crust. Persons are less likely to 

transmit if their lesions are completely covered. Zoster is about 

1/5 as infectious as varicella. 

Secular Trends in the United States

An estimated 1 million episodes of zoster occur annually in the 

United States. The lifetime risk of zoster is estimated to be at 

least 32%. Increasing age and cellular immunosuppression are 

the most important risk factors; 50% of persons living until age 

85 years will develop zoster. Rates of zoster are decreasing in 

the United States in children younger than age 18 years and in 

older adults.

Among adults age 60 years or older in 2017, 34.9% had ever 

received a herpes zoster vaccine. 

Zoster Vaccines

RZV (Shingrix) vaccine is a recombinant subunit vaccine and is 

currently the only zoster vaccine licensed and available for use 

in the United States. ZVL (Zostavax) vaccine, a live, attenuated 

zoster vaccine, was also available for use in the United States 

from 2006 until 2020, when its production for U.S. distribution 

was discontinued.

Characteristics

RZV vaccine contains recombinant glycoprotein E in 

combination with a novel adjuvant (AS01B). The lyophilized 

antigen component is reconstituted with the adjuvant 

suspension component. RZV vaccine is administered by 

intramuscular injection. Each dose of RZV vaccine contains 

DOPC and ASO1B as adjuvants. It contains no antibiotic 

or preservative.

Zoster Secular Trends 

in the United States

● Estimated 1 million zoster 

episodes occur annually in U.S.

● Lifetime risk 32%

● Increasing age and cellular 

immunosuppression most 

important risk factors

Zoster Vaccines

● RZV (Shingrix)

Zoster Vaccine Characteristics

● Contains novel adjuvant

● Administered by 

intramuscular injection
352

Zoster

 23

Vaccination Schedule and Use

RZV vaccine is licensed for use in persons age 50 years or older. 

RZV vaccine is recommended for immunocompetent adults 

age 50 years or older, including those who have previously 

received ZVL or varicella vaccine. Persons with a previous history 

of shingles may also be vaccinated. Adults 50 years or older do 

not need to be screened for history of varicella infection prior to 

vaccination. RZV vaccine is administered as 2-dose series. Dose 

2 is administered between 2 and 6 months after dose 1. If more 

than 6 months have elapsed between doses, the RZV vaccine 

series does not need to be restarted. However, a second dose 

given less than 4 weeks after the first dose should be repeated.

Because estimates of efficacy against both herpes zoster and 

PHN are higher for RZV than for ZVL, and because ZVL efficacy 

wanes substantially during the 4 years following receipt when 

compared to RZV, the Advisory Committee on Immunization 

Practices (ACIP) issued a preferential recommendation for RZV 

over ZVL in 2017, when both vaccines were in use. 

Persons who have received ZVL vaccine should be revaccinated 

with a 2-dose series of RZV vaccine. Intervals shorter than 

5 years between administration of ZVL vaccine and RZV 

vaccine have not been studied; however there are no data or 

theoretical concerns suggesting that RZV vaccine administered 

sooner than 5 years after ZVL would be less safe or effective. 

Because ZVL vaccine has been shown to be less efficacious 

when administered at age 70 years or older, providers might 

consider the age at which ZVL vaccine was administered when 

considering the interval between the two vaccines. Based on 

expert opinion, RZV vaccine should not be given less than 2 

months after receipt of ZVL vaccine.

RZV vaccine may be administered concomitantly (at different 

anatomic sites) with other adult vaccines, including PPSV23 

(Pneumovax 23) and annual seasonal influenza vaccine. 

Evaluation of coadministration with most other adult vaccines 

is ongoing, but there is currently no evidence of efficacy or 

safety concerns.

Immunogenicity and Vaccine Efficacy

Efficacy of RZV was evaluated in a two-part, phase III multicenter 

clinical trial enrolling more than 30,000 participants. Efficacy for 

prevention of herpes zoster after more than 3 years was 96.6% 

for participants age 50 through 59 years, 97.4% for participants 

age 60 through 69 years, and 91.3% for participants age 70 

years or older. Efficacy for prevention of PHN was 91.2% for 

participants age 50 years or older and 88.8% for participants 

age 70 years or older in a pooled analysis.

Zoster Vaccination Schedule 

● 2-dose series at 0, 2–6 months 

in persons age 50 years or older

Zoster Vaccine Use 

● Immunocompetent persons 

age 50 years or older indicated 

for vaccination, including:

■ Persons who have 

previously received ZVL or 

varicella vaccine

■ Persons with a previous 

history of shingles

Zoster Vaccine Efficacy

● Phase III multicenter clinical 

trial efficacy:

■ 96.6% for participants age 50 

through 59 years

■ 97.4% for participants age 60 

through 69 years

■ 91.3% for participants age 70 

years or older
Zoster

353

23

Postexposure Prophylaxis

Exposure to a person with either varicella or herpes zoster 

does not cause zoster in the exposed susceptible person, but 

rather varicella. Zoster vaccine has no role in the postexposure 

management of varicella or zoster and should not be used 

for that purpose. Persons without evidence of immunity who 

are exposed to varicella or herpes zoster are recommended 

to receive varicella vaccine within 3 days, and possibly up to 

5 days, after exposure. For persons exposed to varicella or 

herpes zoster who cannot receive varicella vaccine, varicellazoster immune globulin (VariZIG) can prevent varicella from 

developing or lessen the severity of the disease. 

Varicella Immunity

Evidence of immunity to varicella includes any of the following: • Documentation of age-appropriate vaccination: ■ Preschool-aged children (age 12 months or older): 

1 dose 

■ School-aged children, adolescents, and adults: 2 doses

• Laboratory evidence of immunity: commercial assays can 

be used to assess disease-induced immunity, but they lack 

adequate sensitivity to reliably detect vaccine-induced 

immunity (i.e., they may yield false negative results). 

• Laboratory confirmation of disease. • Birth in the United States before 1980 (except for health 

care personnel, pregnant women, and immunocompro-

mised persons for whom birth in the United States before 

1980 should not be considered evidence of immunity). 

Persons born outside the United States should meet one of 

the other criteria for varicella immunity.

• A health care provider diagnosis or verification of varicella 

disease: verification of history or diagnosis of typical 

disease can be done by any healthcare provider (e.g., 

school or occupational clinic nurse, nurse practitioner, 

physician assistant, physician). For persons reporting a 

history of or presenting with atypical and/or mild cases, 

assessment by a physician or designee is recommended, 

and one of the following should be sought: a) an epide-

miologic link to a typical varicella case, or b) evidence 

of laboratory confirmation if laboratory testing was 

performed at the time of acute disease. When such docu-

mentation is lacking, a person should not be considered 

as having a valid history of disease, because other diseases 

may mimic mild or atypical varicella. 

• History of herpes zoster based on health care provider 

diagnosis or verification of disease history.
354

Zoster

 23

Contraindications and Precautions 

to Vaccination

As with other vaccines, a history of a severe allergic reaction 

(anaphylaxis) to a vaccine component or following a prior 

dose is a contraindication to further doses. Moderate or severe 

acute illness (with or without fever) in a patient is considered a 

precaution to vaccination, although persons with minor illness 

may be vaccinated. 

Persons with chronic medical conditions should receive RZV 

vaccine unless a contraindication or precaution exists.

Although RZV vaccine is approved for all persons age 50 years 

or older, immunocompromised persons, including those on 

moderate- to high- doses of immunosuppressive therapy, were 

excluded from efficacy studies. Therefore, ACIP has not yet 

made recommendations regarding use of RZV vaccine in those 

persons. However, ACIP recommends RZV vaccine for persons 

taking low-dose immunosuppressive therapy (e.g., less than 20 

mg/day of prednisone or equivalent, or using inhaled or topical 

steroids), or who are anticipating immunosuppression or have 

recovered from an immunocompromising illness.

Adults age 50 years or older with a history of herpes zoster 

should receive RZV vaccine. If a patient is experiencing an acute 

episode of herpes zoster, vaccination should be delayed until 

the acute stage of the illness has resolved and symptoms abate.

Vaccination in Pregnancy

There are no available data to establish whether RZV vaccine 

is safe in pregnant or lactating women, and there is currently 

no ACIP recommendation for use of RZV vaccine in these 

populations. Consider delaying vaccination until after delivery 

and lactation.

Vaccine Safety

The most common solicited adverse reactions from two 

placebo-controlled clinical studies involving 29,305 subjects 

were injection-site pain (78%), myalgia (45%), and fatigue 

(45%). Serious adverse events were examined in eight studies; 

overall, rates of serious adverse events were similar in vaccine 

and placebo groups. Injection-site and systemic grade 3 (i.e., 

side effects that are severe or medically significant but not 

immediately life-threatening) solicited adverse events were 

surveyed in eight studies. Among 9,963 subjects, 16.5% of 

vaccine recipients, compared with 3.1% of placebo recipients, 

reported any grade 3 adverse event. Grade 3 injection-site 

reactions (pain, redness, and swelling) were reported by 

9.4% of vaccine recipients and 0.3% of placebo recipients. 

Zoster Vaccine Contraindications 

and Precautions 

● Contraindication

■ Severe allergic reaction 

to vaccine component or 

following a prior dose

● Precaution

■ Moderate or severe 

acute illness

■ Pregnancy

Zoster Vaccine Safety

● Injection site pain

■ 78%

● Myalgia

■ 45%

● Fatigue

■ 45%
Zoster

355

23

Grade 3 solicited systemic events (myalgia, fatigue, headache, 

shivering, fever, and gastrointestinal symptoms) were reported 

by 10.8% of vaccine recipients and 2.4% of placebo recipients. 

Grade 3 local reactions were reported with equal frequency 

following doses 1 and 2, but Grade 3 systemic reactions were 

reported more frequently after dose 2. Data informing whether 

a person will experience a more severe reaction after the 

second dose, if they had a moderate or severe reaction after 

the first dose, are lacking.

Before vaccination, providers should counsel recipients about 

expected systemic and local reactogenicity. Recipients should 

be encouraged to complete the series even if they experienced 

a grade 1 to 3 reaction after the first dose.

RZV vaccine does not cause varicella as it is a recombinant 

vaccine and does not contain live virus.

In a postmarketing observational study, an increased risk 

of Guillain-Barré syndrome (GBS) was observed during the 

42 days following vaccination with Shingrix in adults 65 

years of age and older. Based on this evaluation, FDA has 

determined that there is an association of GBS with Shingrix, 

but that available evidence is insufficient to establish a causal 

relationship. FDA has concluded that revision to the Warnings 

and Precautions section of the Prescribing Information for 

Shingrix to include a warning about GBS is warranted. FDA 

has determined that the benefits of vaccination with Shingrix 

continue to outweigh its risks. 

The vaccination recommendations for Shingrix remain the 

same. CDC and collaborators will continue safety monitoring of 

Shingrix in the Vaccine Adverse Event Reporting System (VAERS) 

and the Vaccine Safety Datalink (VSD).

Vaccine Storage and Handling

Before reconstitution, both lyophilized antigen component 

vials and adjuvant suspension component vials should be 

stored refrigerated between 2°C and 8°C (36°F and 46°F) and 

protected from light. After reconstitution, use immediately 

or store refrigerated between 2°C and 8°C (36°F and 46°F). 

Discard if not used within 6 hours of reconstitution or if 

frozen. Manufacturer package inserts contain additional 

information. For complete information on best practices and 

recommendations, please refer to CDC’s Vaccine Storage and 

Handling Toolkit, www.cdc.gov/vaccines/hcp/admin/storage/

toolkit/storage-handling-toolkit.pdf. 
356

Zoster

 23

Surveillance and Reporting of Zoster 

Zoster is not a nationally notifiable condition in the United 

States. For information on guidance for state and local health 

department staff who are involved in surveillance activities for 

vaccine-preventable diseases, please consult the Manual for the 

Surveillance of Vaccine-Preventable Diseases, www.cdc.gov/

vaccines/pubs/surv-manual/chapters.html .

Acknowledgements

The editors would like to acknowledge Jennifer Hamborsky, 

Valerie Morelli, Ginger Redmon, Cindy Weinbaum, and 

Skip Wolfe for their contributions to this chapter.

NOTES
Zoster

357

23

Selected References

CDC. Immunization of health-care personnel. Recommendations 

of the Advisory Committee on Immunization Practices (ACIP). 

MMWR 2011;60(RR-7):1–45.

CDC. Prevention of herpes zoster. Recommendations of the 

Advisory Committee on Immunization Practices. MMWR

2008;57(No.RR-5).

CDC. Recommendations of the Advisory Committee on 

Immunization Practices for Use of Herpes Zoster Vaccines. 

MMWR 2018;67(No. 3):103–8.

CDC. Update on Recommendations for use of Herpes Zoster 

Vaccine. MMWR 2014;66(33):729–31.

Cunningham A, Lal H, Kovac M, et al. Efficacy of the herpes 

zoster subunit vaccine in adults 70 years of age or older. NEJM

2016;375(11):1019–32.

Galetta K, Gilden D. Zeroing in on zoster: A tale of many 

disorders produced by one virus. J Neurol Sci 2015;358(1-

2):38–45.

Grading of Recommendations, Assessment, Development, 

and Evaluation (GRADE): Recombinant Zoster Vaccine (RZV) 

and Herpes Zoster Live-Attenuated Vaccine (ZVL). www.cdc.

gov/vaccines/acip/recs/grade/herpes-zoster.html, accessed 

August 28, 2020.

Harpaz R, Leung J. The Epidemiology of Herpes Zoster in the 

United States During the Era of Varicella and Herpes Zoster 

Vaccines: Changing Patterns Among Children. Clin Infect Dis 

2019;69(2):345–7.

Harpaz R, Leung J. The Epidemiology of Herpes Zoster in the 

United States During the Era of Varicella and Herpes Zoster 

Vaccines: Changing Patterns Among Older Adults. Clin Infect Dis

2019;69(2):341–4.

Hesse E, Shimabukuro T, Su J, et al. Postlicensure Safety 

Surveillance of Recombinant Zoster Vaccine (Shingrix) - United 

States, October 2017-June 2018. MMWR 2019 Feb 1;68(4):91–4.

Lal H, Cunningham A, Godeaux O, et al. Efficacy of an 

adjuvanted herpes zoster subunit vaccine in older adults. NEJM 

2015;372(22):2087–96.

Nagel M, Bubak A. Varicella Zoster Virus Vasculopathy. J Infect Dis

2018;218(Suppl_2):s107–12.

NOTES
358

Zoster

 23

Oxman M, Levin M, Johnson G, et.al. A Vaccine to prevent herpes 

zoster and postherpetic neuralgia in older adults. NEJM 2005; 

352(12): 2271–84.

Schmader K, Levin M, Gnann J, et al. Efficacy, safety, and 

tolerability of herpes zoster vaccine in persons aged 50-59 years. 

Clin Inf Dis 2012;54(7):922–8.

Tseng H, Bruxvoort K, Ackerson B, et al. The epidemiology of 

herpes zoster in immunocompetent, unvaccinated adults ≥50 

years old: incidence, complications, hospitalization, mortality, 

and recurrence. J Infect Dis. 2019;222(5):798–806.

U.S. Food and Drug Administration. FDA requires a warning 

about Guillain-Barre Syndrome (GBS) be included in the 

prescribing information for Shingrix. https://www.fda.gov/

vaccines-blood-biologics/safety-availability-biologics/

fda-requires-warning-about-guillain-barre-syndrome-gbs-beincluded-prescribing-information-shingrix. Accessed 

April 9, 2021.

Zhang Y, Luo G, Huang Y, et al. Risk of Stroke/Transient 

Ischemic Attack or Myocardial Infarction with Herpes Zoster: A 

Systematic Review and Meta-Analysis. J Stroke Cerebrovasc Dis

2017;26(8):1807–16.

NOTES