Impact of Vaccination

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S224 • JID 2008:197 (Suppl 2) • Reynolds et al.

S U P P L E M E N T A R T I C L E

The Impact of the Varicella Vaccination Program

on Herpes Zoster Epidemiology in the United States:A Review

Meredith A. Reynolds, Sandra S. Chaves, Rafael Harpaz, Adriana S. Lopez, and Jane F. Seward

Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention,

Atlanta, Georgia

Speculation that a universal varicella vaccination program might lead to an increase in herpes zoster (HZ)

incidence has been supported by modeling studies that assume that exposure to varicella boosts immunity

and protects against reactivation of varicella-zoster virus (VZV) as HZ. Such studies predict an increase inHZ incidence until the adult population becomes predominantly composed of individuals with vaccine-induced

immunity who do not harbor wild-type VZV. In the United States, a varicella vaccination program was

implemented in 1995. Since then, studies monitoring HZ incidence have shown inconsistent findings: 2 studies

have shown no increase in overall incidence, whereas 1 study has shown an increase. Studies from Canada

and the United Kingdom have shown increasing rates of HZ incidence in the absence of a varicella vaccination

program. Data suggest that heretofore unidentified risk factors for HZ also are changing over time. Further

studies are needed to identify these factors, to isolate possible additional effects from a varicella vaccination

program. Untangling the contribution of these different factors on HZ epidemiology will be challenging.

Herpes zoster (HZ) is caused by reactivation of the

varicella-zoster virus (VZV) after primary VZV infec-

tion. Some have speculated that a universal varicella

vaccination program might alter the epidemiology of

HZ if exposure to varicella boosts immunity and pre-

vents VZV reactivation. Studies modeling the impact

of a varicella vaccination program have predicted that

HZ incidence would increase, perhaps as early as 5–7

years after the implementation of a vaccination pro-

gram. Such an increase would last ∼30–50 years, until

the adult population was predominantly composed of

vaccinated individuals with no disease history [1, 2].

Over this period, the burden of the increased incidence

Potential conflicts of interest: none reported.

Financial support: supplement sponsorship is detailed in the Acknowledgments.

The findings and conclusions in this report are those of the authors and do not

necessarily represent the views of the Centers for Disease Control and Prevention,

US Department of Health and Human Services.

Reprints or correspondence: Dr. Meredith A. Reynolds, National Center for

Immunization and Respiratory Diseases, Centers for Disease Control and

Prevention, 1600 Clifton Rd. NE, MS A-47, Atlanta, GA 30333 ([email protected]).

The Journal of Infectious Diseases 2008;197:S224–7

This article is in the public domain, and no copyright is claimed.

0022-1899/2008/19705S2-0034

DOI: 10.1086/522162

of HZ may counteract most or all of the benefits of

varicella vaccination [1]. The longer-term burden of

HZ in the population is expected to be lower. However,

models may not accurately predict what occurs in a

population.

Understanding HZ epidemiology in populations with

and without varicella vaccination programs is important

and may assist countries considering implementing var-

icella and/or HZ vaccination programs. In the United

States, a varicella vaccination program was implemented

in 1995, and dramatic declines in the incidence of var-

icella ensued [3]. In this article, we review the HZ data

available in the United States after a decade of experience

with a national varicella vaccination program and sum-

marize the literature relevant to this issue.

HZ PATHOGENESIS AND

COMPLICATIONS

HZ is characterized by a painful vesicular rash with a

dermatomal distribution. After initial infection, VZV

establishes latency in the sensory ganglia. Although the

mechanism of VZV reactivation is not fully understood,

one important modulator is cell-mediated immunity



Herpes Zoster Epidemiology • JID 2008:197 (Suppl 2) • S225

(CMI). Declines in VZV-specific CMI, because of aging or im-

munosuppression, increase the likelihood of VZV reactivation

[4, 5].

HZ causes acute and chronic morbidity, with complications

occurring in 15%–40% of cases [6]. The most common com-

plication is postherpetic neuralgia (PHN), the persistence of

pain after resolution of the HZ rash. Among persons with HZ,

the risk of PHN increases with age, with rates increasingsharply around 60 years of age [7–12]. Studies have found a wide range

in crude annual rates of hospitalization for HZ, from 2.1 to

16.1/100,000 population, which in part reflects differences in

inclusion criteria [13–15].

HZ EPIDEMIOLOGY IN THE PRE–VARICELLA-

VACCINATION ERA

In the United States, before the introduction of the varicella

vaccine, virtually everyoneу40 years of age was at risk for HZ,

since 199.5% of adults in this age group showed serological

evidence of VZV infection [16]. In US studies conducted be-

tween 1949 and 2003, HZ incidence ranged from 1.2 to 6.5

cases/1000 person-years [17–21]. As demonstrated in the

United States and elsewhere, the risk of HZ is greatest for those

with immunosuppression and increases significantly with age,

particularly among those у50 years of age [17, 19–21]. Other

risk factors described include race (lower risk for African Amer-

icans, compared with whites) [4, 5], sex (higher risk for female

adults, as found in many studies) [4, 8, 22–24], psychological

stress (higher risk for those with recent stressful life events)

[25], exposure to varicella (lower risk for those exposed to

varicella or to children) [1, 26], and varicella vaccination (lowerrisk for those vaccinated, compared with persons with varicella)

[27, 28].

Evidence from population-based studies suggests that rates of

HZ were increasing in the United States before the introduction

of the varicella vaccination program. A study conducted in Roch-

ester, Minnesota, found an increase in HZ incidence rates (age

standardized to the 1970 US white population) from 112 cases/

100,000 person-years during 1945–1949 to 150 cases/100,000

person-years during 1955–1959 [19]. With the exception of a

sizeable peak in 1949, the increase in incidence over time during

this period was linear and was seen for all age groups and for

both sexes. Donahue et al. [17] studied HZ incidence amongpatients enrolled in a health maintenance organization (HMO)

from July 1990 to June 1992 and found an annual HZ incidence

rate (age standardized to the 1970 US white population) of 287

cases/100,000 person-years [17], which is more than twice the

rate reported by Ragozzino et al. [19] for 1945–1959 (131 cases/

100,000 person-years). Donahue et al. speculated that HZ inci-

dence may have increased over this period. However, drawing

this conclusion on the basis of these 2 studies is unwarranted,

given that the studies involved very different settings, health care

systems, populations, and methods of ascertaining data.

HZ EPIDEMIOLOGY IN THE POST–VARICELLA-

VACCINATION ERA

Since implementation of the varicella vaccination program, HZ

epidemiology has been studied by use of medical record data

from several HMOs and statewide survey methods. Three stud-

ies have been reported: 2 reported no change in HZ incidence,

and 1 reported an increase in HZ incidence. Among patients

enrolled in a large HMO in Seattle, Washington, where baseline

HZ data were available from 1992 to 1996 (when varicella

vaccine coverage was !10%), age-adjusted overall or age-spe-

cific incidence rates of HZ did not change between 1992 and

2002. During this period, varicella incidence declined 65% [20].

In another study of HMO patients in Washington and Oregon,

covering the period 1997–2003, overall HZ incidence rates were

stable. Significant increases in incidence rates were found in

the subgroup of children 10–17 years of age, but these increases

were attributable to the increased use of oral steroids [29]. In

Massachusetts, varicella and HZ incidence have been measured

for several years via an annual statewide telephone survey. From

1999 to 2003, as varicella incidence declined 66%, age-stan-

dardized rates of HZ incidence increased from 2.77 to 5.25

cases/1000 person-years [21].

DISCUSSION

In theory, universal varicella vaccination has the potential to

change the epidemiology of HZ. However, to date, the data

available in the United States do not provide conclusive evi-

dence that such a change is occurring. The only study that usedpre–vaccine-era baseline data for comparison found no increase

in HZ incidence in the first 7 years after the introduction of

the varicella vaccine in the United States, although this time

frame may not have been adequate for detection of an effect

[20]. Two studies that examined trends in HZ incidence in the

post–varicella-vaccine era had conflicting findings: one found

that HZ incidence was stable [29], and the other found that

the incidence rate increased [21].

Studies from Canada and the United Kingdom have reported

increases in HZ incidence rates that were not associated with

a varicella vaccination program. Law et al. [30] examined data

from hospital and physician claim files that included Interna-

tional Classification of Diseases, 9th Revision, Clinical Modifi-

cation codes for HZ in Manitoba, Canada, and found that age-

and sex-adjusted annual HZ incidence rates for the entire

population had increased steadily from 2.34 cases/1000 pop-

ulation in 1980 to 3.46 cases/1000 population in 1997. The rate

of increase for the period 1979–1993 was significantly greater

than that for the period 1994–1997. Similarly, Russell et al. [24]

found that HZ incidence rates had increased in Alberta, Canada,



S226 • JID 2008:197 (Suppl 2) • Reynolds et al.

throughout the period 1986–2002, with the increase evident

before the varicella vaccination program was introduced in

2001. The rate of increase in HZ incidence was higher among

those 45–59 and 185 years of age. Data from the Royal College

of General Practitioners for England and Wales were used to

examine trends in overall rates of HZ consultations over time

and indicated that these rates have slowly increased in the

United Kingdom, from 315 to 382 cases/100,000 person-yearsfrom 1979 to 1997. In this study, age-standardized rates were

not presented [15].

In the United States, few data were available on trends in

HZ incidence rates before the introduction of varicella vaccine.

One early study suggested that HZ incidence rates were in-

creasing before the initiation of the varicella vaccination pro-

gram [19]. Increasing incidence rates in the United States and

in other countries before the introduction of varicella vacci-

nation programs cannot be explained by known major risk

factors for HZ, such as age and immune status. Until the risk

factors responsible for changing HZ incidence rates indepen-

dent of vaccination programs are determined, studies cannot

control for these factors. In addition, until these factors can be

taken into account, we cannot adequately assess the possibility

of additional effects from a varicella vaccination program that

are due to changes in opportunities for external boosting.

The roles that external boosting (exposure to exogenous VZV

via contact with individuals with infection) and internal boost-

ing (reactivation of endogenous VZV) may play in maintaining

VZV immunity are poorly understood. Although studies of

both immunocompetent and immunocompromised popula-

tions have reported that exposure to people with varicella dis-

ease is associated with a lower risk of HZ [1, 26, 27, 31], many questions remain. In a case-control study, Thomas et al. [26]

found that persons with у5 exposures to varicella during the

previous 10 years had a lower risk of developing HZ. However,

these levels of exposure may exceed those typically experienced

by the general population, especially among adults. If the

amount of exposure to varicella required to produce a mean-

ingful external boosting effect is not usually experienced by

most in a population, then reductions in exposure after the

implementation of a successful varicella vaccination program

would not be expected to impact HZ incidence in the general

population (despite a possible significant impact on some select

subgroups of the population with unusually high levels of exposure).

In the study by Thomas et al. [26], social contact with chil-

dren outside the household also was found to be protective

against HZ, although much less so than exposure to varicella.

Other studies have found that exposure to varicella in the

household is associated with reduced risk of HZ among vac-

cinated children with leukemia [27, 31]. After using a com-

bination of epidemiological data and mathematical modeling,

Brisson et al. [1] reported that adults living with children had

up to twice as much exogenous exposure to varicella than did

those who were not living with children and that this exposure

was protective against HZ. The average period of immunity

conferred by exposure to varicella was estimated to be 20 years.

Few data exist pertaining to the role of internal boosting in

VZV reactivation. Some authors have noted that, during clinical

trials conducted during the prevaccine era, increases in antibody levels in serially monitored vaccine recipients exceeded the in-

creases that might have been expected from external exposure

alone [32]. Although some suggest that this result is evidence

of internal boosting [32], others disagree on the basis of the

argument that drawing any firm conclusions regarding internal

boosting while external exposure persists is impossible [33].

Determining the possible impact of a varicella vaccination

program on HZ incidence is complicated further by the intro-

duction of the HZ vaccine, which was licensed recently and

recommended provisionally in the United States, by the Ad-

visory Committee on Immunization Practices, for immuno-competent adults у60 years of age [34]. HZ vaccine, which

reduced the incidence of HZ by 51.3% and of PHN by 66.5%

among participants in the vaccine clinical trial, is likely to lead

to a decline in HZ incidence [12]. Separating the possible effects

of the varicella and HZ vaccines on HZ epidemiology will be

extremely challenging.

In countries using the varicella vaccine, future HZ incidence

rates in the population will be a function of multiple factors,

including but not limited to (1) whether HZ incidence rates

among persons with a history of disease will change as a func-

tion of decreased opportunities for external boosting (thus far,

data are inconclusive) or of changes in internal boosting; (2)

the HZ incidence rate among varicella vaccine recipients with

no history of varicella disease (data, not reviewed here, show

reduced risk among vaccine recipients) [27, 28, 35]; (3) the

HZ incidence rate among varicella vaccine recipients who also

harbor wild-type VZV; (4) a reduction in the proportion of

children infected with VZV during infancy (a potent risk factor

for pediatric HZ); (5) changes in the proportion of the pop-

ulation who are not at risk for HZ (which is likely to increase

with implementation of a varicella vaccination program); and

(6) the coverage and effectiveness of both the varicella and the

newly licensed HZ vaccines.Any factors that increase HZ incidence also may shift its age

distribution downward. Since the risk for progression of HZ

to PHN is strongly linked to age, reduced VZV circulation as

a result of a varicella vaccination program may have paradoxical

effects on the actual burden of HZ. Indeed, given the complex

and unpredictable nature of the interactions between varicella

and HZ, it will be very important to monitor and analyze the

epidemiology of these 2 illnesses that have substantial public



Herpes Zoster Epidemiology • JID 2008:197 (Suppl 2) • S227

health impacts, to ensure that vaccination programs are re-

sulting in the intended benefits.

Acknowledgments

Supplement sponsorship. This article was published as part of a sup-

plement entitled “Varicella Vaccine in the United States: A Decade of Pre-

vention and the Way Forward,” sponsored by the Research Foundation forMicrobial Diseases of Osaka University, GlaxoSmithKline Biologicals, the

Sabin Vaccine Institute, the Centers for Disease Control and Prevention,

and the March of Dimes.

References

1. Brisson M, Gay NJ, Edmunds WJ, Andrews NJ. Exposure to varicella

boosts immunity to herpes-zoster: implications for mass vaccination

against chickenpox. Vaccine 2002; 20:2500–7.

2. Ferguson NM, Anderson RM, Garnett GP. Mass vaccination to control

chickenpox: the influence of zoster. Proc Natl Acad Sci USA 1996;93:

7231–5.

3. Seward JF, Watson BM, Peterson CL. Varicella disease after introduction

of varicella vaccine in the United States, 1995–2000. JAMA 2002;287:606–11.

4. Thomas SL, Hall AJ. What does epidemiology tell us about risk factors

for herpes zoster? Lancet Infect Dis 2004; 4:26–33.

5. Schmader KE. Epidemiology of herpes zoster. In: Arvin AM, Gershon

AA, eds. Varicella-zoster virus: virology and clinical management. 1st

ed. Cambridge, UK: Cambridge University Press, 2000:220–45.

6. Pellissier J. A model-based approach for analyzing Zostavax cost-ef-

fectiveness. In: Proceedings of the National Centre for Immunisation

Research and Surveillance (NCIRS) Varicella Zoster Workshop. Sydney:

NCIRS, 2006. Available at: http://www.ncirs.usyd.edu.au/newsevents/

j_pellissier_modelling_vzv.pdf. Accessed 6 April 2007.

7. Kost RG, Straus SE. Postherpetic neuralgia—pathogenesis, treatment,

and prevention. N Engl J Med 1996; 335:32–42.

8. Chidiac C, Bruxelle J, Daures JP, et al. Characteristics of patients with

herpes zoster on presentation to practitioners in France. Clin Infect

Dis 2001; 33:62–9.

9. Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster

and potential cost-effectiveness of vaccination in England and Wales.

Vaccine 2001; 19:3076–90.

10. Haanpaa M, Laippala P, Nurmikko T. Allodynia and pinprick hypes-

thesia in acute herpes zoster, and the development of postherpetic

neuralgia. J Pain Symptom Manage 2000; 20:50–8.

11. Scott FT, Leedham-Green ME, Barrett-Muir WY, et al. A study of

shingles and the development of postherpetic neuralgia in East London.

J Med Virol 2003; 70(Suppl 1):S24–30.

12. 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.

13. Coplan P, Black S, Rojas C, et al. Incidence and hospitalization rates

of varicella and herpes zoster before varicella vaccine introduction: a

baseline assessment of the shifting epidemiology of varicella disease.

Pediatr Infect Dis J 2001; 20:641–5.

14. Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster

hospitalizations: the pre–varicella vaccine era. J Infect Dis 2000;181:

1897–905.

15. Brisson M, Edmunds WJ, Law B, et al. Epidemiology of varicella-zoster

virus in Canada and the United Kingdom. Epidemiol Infect 2001;127:

305–14.

16. Kilgore PE, Kruszon-Moran D, Seward JF, et al. Varicella in Americans

from NHANES III: implications for control through routine immu-

nization. J Med Virol 2003; 70(Suppl 1):S111–8.

17. Donahue JG, Choo PW, Manson J, Platt R. The incidence of herpes

zoster. Arch Intern Med 1995; 155:1605–9.

18. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the

management of herpes zoster. Clin Infect Dis 2007; 44(Suppl 1):S1–26.

19. Ragozzino MW, Melton LJ III, Kurland LT, Chu CP, Perry HO. Pop-

ulation-based study of herpes zoster and its sequelae. Medicine 1982;

61:310–6.

20. Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil K, Seward JF. Incidence

of herpes zoster, before and after varicella-vaccination–associated de-

creases in the incidence of varicella, 1992–2002. J Infect Dis 2005;191:

2002–7.

21. Yih WK, Brooks DR, Lett SM, et al. The incidence of varicella and

herpes zoster in Massachusetts as measured by the Behavioral Risk

Factor Surveillance System (BRFSS) during a period of increasing var-

icella vaccine coverage, 1998–2003. BMC Public Health 2005; 5:68.

22. Chant KG, Sullivan EA, Burgess MA, et al. Varicella-zoster virus in-

fection in Australia. Aust N Z J Public Health 1998; 22:413–8 (erratum:

Aust N Z J Public Health 1998; 22:630).

23. Cooper M. The epidemiology of herpes zoster. Eye 1987; 1:413–21.

24. Russell ML, Schopflocher DP, Svenson L, Virani SN. Secular trends in

the epidemiology of shingles in Alberta. Epidemiol Infect 2007;135:908–13.

25. Schmader K, Studenski S, MacMillan J, Grufferman S, Cohen HJ. Are

stressful life events risk factors for herpes zoster? J Am Geriatr Soc

1990; 38:1188–94.

26. Thomas SL, Wheeler JG, Hall AJ. Contacts with varicella or with chil-

dren and protection against herpes zoster in adults: a case-controlstudy.

Lancet 2002; 360:678–82.

27. Hardy I, Gershon AA, Steinberg SP, LaRussa P. The incidence of zoster

after immunization with live attenuated varicella vaccine: a study in

children with leukemia. Varicella Vaccine Collaborative Study Group.

N Engl J Med 1991; 325:1545–50.

28. White CJ, Kuter BJ, Ngai A, et al. Modified cases of chickenpox after

varicella vaccination: correlation of protection with antibody response.

Pediatr Infect Dis J 1992; 11:19–23.

29. Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H. Inci-dence of herpes zoster, 1997–2002. Epidemiol Infect 2005; 133:245–53.

30. Law BJ, Chateau D, Walld R, Roos L. Temporal trends in the annual

population-based incidence of herpes zoster by age and gender: Man-

itoba, 1979–1998. Can J Infect Dis Med Microbiol 2004; 15:357–8.

31. Gershon AA, LaRussa P, Steinberg S, Mervish N, Lo SH, Meier P. The

protective effect of immunologic boosting against zoster: an analysis

in leukemic children who were vaccinated against chickenpox. J Infect

Dis 1996; 173:450–3.

32. Krause PR, Klinman DM. Varicella vaccination: evidence for frequent

reactivation of the vaccine strain in healthy children. Nat Med 2000;

6:451–4.

33. Seward J, Jumaan A, Schmid S. Varicella vaccine revisited. Nat Med

2000; 6:1298–300.

34. Advisory Committee on Immunization Practices, Centers for Disease

Control and Prevention (CDC). Provisional recommendations for the

use of zoster vaccine. Atlanta: CDC, 2006. Available at: http://www

.cdc.gov/vaccines/recs/provisional/downloads/zoster-11-20-06.pdf.

Accessed 16 April 2007.

35. Guess HA, Broughton DD, Melton LJ, Kurland LT. Epidemiology of

herpes zoster in children and adolescents: a population-based study.

Pediatrics 1985; 76:512–7.

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