Varicella Prevention in the United States: A Review of Successes and Challenges Mona Marin, H.

Cody Meissner and Jane F. Seward Pediatrics 2008;122;e744 DOI: 10.1542/peds.2008-0567

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/122/3/e744.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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REVIEW ARTICLE

Varicella Prevention in the United States: A Review of Successes and Challenges

Mona Marin, MDa, H. Cody Meissner, MDb, Jane F. Seward, MBBS, MPHa
a

National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; bTufts University School of Medicine, Boston, Massachusetts

The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. In 1995, the United States was the rst country to introduce a universal 1-dose childhood varicella vaccination program. In 2006, the US varicella vaccine policy was changed to a routine 2-dose childhood program, with catchup vaccination for older children. The objective of this review was to summarize the US experience with the 1-dose varicella vaccination program, present the evidence considered for the policy change, and outline future challenges of the program. METHODS. We conducted a review of publications identied by searching PubMed for the terms varicella, varicella vaccine, and herpes zoster. The search was limited to US publications except for herpes zoster; we reviewed all published literature on herpes zoster incidence. RESULTS. A single dose of varicella vaccine was 80% to 85% effective in preventing

www.pediatrics.org/cgi/doi/10.1542/ peds.2008-0567 doi:10.1542/peds.2008-0567

Dr Marin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The ndings and conclusions in this article 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. Key Words varicella, chickenpox, varicella epidemiology, varicella vaccine, varicella vaccination program Abbreviations HZ herpes zoster VZVvaricella-zoster virus VEvaccine effectiveness CI condence interval MMRmeasles-mumps-rubella MMRVmeasles-mumps-rubella-varicella gpELISA glycoprotein enzyme-linked immunosorbent assay
Accepted for publication Apr 29, 2008 Address correspondence to Mona Marin, MD, Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS A-47, Atlanta, GA 30333. E-mail: mmarin@cdc.gov PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2008 by the American Academy of Pediatrics

disease of any severity and 95% effective in preventing severe varicella and had an excellent safety prole. The vaccination program reduced disease incidence by 57% to 90%, hospitalizations by 75% to 88%, deaths by 74%, and direct inpatient and outpatient medical expenditures by 74%. The decline of cases plateaued between 2003 and 2006, and outbreaks continued to occur, even among highly vaccinated school populations. Compared with children who received 1 dose, in 1 clinical trial, 2-dose vaccine recipients developed in a larger proportion antibody titers that were more likely to protect against breakthrough disease and had a 3.3-fold lower risk for breakthrough disease and higher vaccine efcacy. Two studies showed no increase in overall herpes zoster incidence, whereas 2 others showed an increase.

CONCLUSIONS. A decade of varicella prevention in the United States has resulted in a dramatic decline in disease; however, even with high vaccination coverage, the effectiveness of 1 dose of vaccine did not generate sufcient population immunity to prevent community transmission. A 2-dose varicella vaccine schedule, therefore, was recommended for children in 2006. Data are inconclusive regarding an effect of the varicella vaccination program on herpes zoster epidemiology. Pediatrics 2008;122: e744e751

program.1,2 One dose of vaccine was recommended for children aged 12 months through 12 years, and 2 doses were recommended for susceptible adolescents and adults. Use of the vaccine dramatically decreased varicella morbidity and mortality37; however, for additional improvement of disease control, a second dose of varicella vaccine was added to the childhood immunization schedule in 2006.8,9 This review summarizes the burden of varicella in the prevaccine era, experience with the 1-dose vaccination program, the evidence considered for changing to a 2-dose schedule, and the remaining challenges associated with the national varicella vaccination program. To obtain this information, we reviewed publications identied using the National Library of Medicines PubMed on-line search utility and the search terms varicella, varicella vaccine, and herpes zoster (HZ). The search was limited to US publications, except for HZ; we reviewed all published literature on HZ incidence. BURDEN OF VARICELLA IN THE PREVACCINE ERA Disease Incidence Before introduction of varicella vaccine, an estimated 4 million cases of varicella (1516 per 1000 population) occurred annually in the United States, a number approximating the birth cohort.10,11 More than 90% of the cases occurred among individuals aged 15 years, with the highest age-specic incidence among children aged 5 to 9
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N 1995, THE United States became the rst country to introduce a universal childhood varicella vaccination

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years. By the early 1990s, the highest age-specic incidence had shifted to children aged 1 to 4 years, likely as a result of increased use of child care facilities,12,13 and the incidence of varicella increased among infants 12 months of age.10,11 Varicella rarely occurred among individuals aged 40 years. National seroprevalence data for 1988 1994 were consistent with incidence data: 95.5% of adults aged 20 to 29 years and 99.6% of adults aged 40 years had varicella-zoster virus (VZV)-specic antibodies.14 Hospitalization Varicella may result in serious complications, hospitalizations, and deaths. In the 8 years before vaccine licensure, an estimated 10 632 hospitalizations were attributable to varicella annually, with signicant variation by year (range: 8198 16 586; rate: 2.3 6.3 per 100 000 population).15 A higher burden from hospitalizations was found when a varicella-related code in any, rather than the principal, discharge diagnosis eld was included (range: 13 91217 899; rate: 4.8 7.1 per 100 000 population).5,6,16 Children aged 5 years accounted for 43% to 44% of hospitalizations, and individuals aged 20 years accounted for 32% to 33%.6,15 Compared with varicella-infected children aged 5 to 9 years, infants aged 12 months and adults aged 20 years had 6- and 13-fold higher risks, respectively, for hospitalization.15 The most common varicella complications resulting in hospitalization were skin and soft tissue infections, pneumonia, dehydration, and encephalitis.15 Most hospitalized individuals were healthy (70%) or had comorbid conditions not considered to place them at higher risk for severe varicella (19%).15 Only 11% had immunocompromising conditions (eg, HIV infection, malignancy, severe defect of T cell immunity, organ recipient, chemotherapy treatment). Mortality During 1970 1994, the average annual number of deaths for which varicella was recorded as the primary cause was 105 (rate: 0.4 deaths per 1 million population).17 Varicella was a contributory cause in 40 additional deaths a year (1990 1994).7 During 1990 1994, adults aged 20 years had a 25-fold higher risk for death from varicella compared with children aged 1 4 years (case-fatality rate: 21.3 and 0.8 per 100 000 cases, respectively).17 The percentage of varicella-related deaths among individuals aged 20 years shifted from 80% during 1970 1974 to 46% during 1990 1994. During 1990 1994, 89% of varicella-related deaths among children and 75% among adults occurred in individuals who were not immunocompromised.17 The most common complications that led to death were pneumonia, central nervous system complications (including encephalitis), secondary bacterial infection, and hemorrhagic conditions. EXPERIENCE WITH THE 1-DOSE VACCINATION PROGRAM Epidemiology After implementation of the varicella vaccination program in 1995, vaccine coverage among US children aged

19 to 35 months increased nationally from 27% in 1997 to 89% in 2006,18 with no coverage gaps by race or ethnicity,19 and varicella-related morbidity and mortality were dramatically reduced.37 National data on incidence are not available because varicella was not nationally reportable until 2005; however, in 2 communities where active surveillance was instituted in 1995 (Antelope Valley, CA, and West Philadelphia, PA), varicella incidence declined 76% to 78% by 2000 (vaccine coverage: 82% 84%)3 and 90% by 2005 (vaccine coverage: 92%94%)4 compared with 1995. In 2005, the decline was greatest (90%95%) among children aged 1 to 9 years; however, age-specic incidence rates for all age groups were signicantly lower than in 1995, including rates among infants 12 months and adults, indicating indirect vaccination or herd-immunity effects as a result of reduction in exposure. Similar trends were reported from states with consistent passive reporting systems (Michigan, Illinois, Texas, and West Virginia): in 2005, reported cases had declined 53% to 94% (vaccine coverage: 81%93%) compared with cases reported during 19931995 (Fig 1A).20 States with the lowest decline in incidence reported that efforts to enhance varicella surveillance may have led to more complete reporting, which could have resulted in underestimation of the decline in incidence. In the postvaccine era, the number and rate of varicella-related hospitalizations and associated costs have declined 75% to 88%.5,6 Zhou et al5 found that hospitalization rates declined 88% during 1994 2002 (Fig 1B), with a decline in all age groups studied: 100% among infants, 91% to 92% among individuals aged 20 years, and 78% among adults aged 20 to 49 years. The greater decline in hospitalizations among children relative to adults led to an increase in the percentage of varicella-related hospitalizations among adults (40% of hospitalizations occurred among individuals aged 20 years in 2002, compared with 21% during 1994 1995).5 The reduction in varicella-related hospitalizations and cases was associated with an estimated 74% reduction ($62.8 million) in direct inpatient and outpatient medical expenditures in 2002 compared with 1994.5 Varicella-related deaths also have decreased. When considering deaths for which varicella was designated as the underlying cause, mortality rates decreased 66% from 1990 1994 to 1999 2001 (Fig 1C) when the ageadjusted mortality rate was 0.14 per 1 million population.7 This overall reduction is considered an underestimation of the impact because it includes deaths among individuals aged 50 years, for whom the validity of reporting varicella deaths is low.21 Among individuals aged 50 years, the decline in mortality was 74% for all age groups, with the greatest declines among children aged 1 to 4 years (92%) and 5 to 9 years (89%).7 Vaccine Performance Postlicensure studies have assessed varicella vaccine effectiveness (VE) in child care, school, household, and community settings, commonly during outbreak investigations.2238 VE has been estimated against all and against combined moderate and severe varicella. Most investigations2227,29,30,3238 found VE for prevention of all
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2600.00 2025.00 1450.00 875.00

Vaccine recommended

Incidence Hospitalizations Mortality

Rate per 1 million population

300.00 29.50

20.50

11.50

2.50 0.48 0.36 0.24 0.12 0.00

1990 1991 1992 1993 1994 1995

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Year
FIGURE 1 Varicella incidence, hospitalization, and mortality rates: United States, 1990 2005. A, Varicella incidence: incidence of reported varicella cases from 4 states (Illinois, Michigan, Texas, and West Virginia) that maintained consistent and adequate surveillance during 1990 1995; B, hospitalization: varicella was the primary diagnosis code; data are for individuals aged 50 years; C, mortality rates: varicella was the underlying cause of death.

varicella among children to be lower than that described in the single, placebo-controlled clinical trial (98% after 2 years of follow-up)39; however, VE was similar to that described in nonplacebo-controlled prelicensure trials (70%90%),4042 with some lower (44% and 56%)28,31 and higher (100%)24 estimates. The median and mean VE for preventing all disease from 20 published estimates were 84.5% and 81%, respectively.43 Although the denitions of moderate and severe varicella varied across studies,* varicella vaccine was highly effective in preventing combined moderate and severe disease2225,2733,35,37,38,44 with median and mean VE from 16 published estimates of 97% (range: 86%100%) and 96%, respectively.43 VE was 100% against severe disease when measured separately.30,3335,38,44 Risk Factors for Vaccine Failure Several potential risk factors for vaccine failure have been identied in VE studies, but ndings have not been consistent. Younger age at vaccination (dened as 14, 16, or 18 months), time since vaccination (dened as 3, 5, or 5 years), and a history of asthma or eczema have been associated with vaccine failure in some outbreak investigations2629,31,36 but not in others22,27,28,32,33,36;
*Usually, moderate varicella was dened as either 250 to 500 lesions or 50 to 500 lesions and severe varicella as 500 lesions or any hospitalization or complication.

however, the independent association of individual risk factors with vaccine failure was assessed in only a few studies. A retrospective cohort study that controlled for other potential risk factors demonstrated a 1.4-fold higher risk (95% condence interval [CI]: 1.11.9) for breakthrough disease among children who were vaccinated before 15 months of age.45 This study did not demonstrate an association between breakthrough disease and asthma but did nd an increased risk for breakthrough disease when varicella vaccine was administered within 28 days of measles-mumps-rubella (MMR) vaccine or when an oral corticosteroid prescription was issued within 3 months before breakthrough disease. A case-control study found VE in the rst year after vaccination signicantly lower among children who were vaccinated at age 15 months (73%) than among children who were vaccinated at age 15 months (99%), but the difference was not maintained through years 7 to 8 after vaccination.37 In contrast, 2 prospective cohort studies found neither decreased immunogenicity nor increased risk for breakthrough disease among children who were vaccinated at age 12 to 14 months compared with 15 to 23 months.46,47 A meta-analysis of published reports on varicella outbreaks suggested waning immunity by demonstrating lower VE with increasing time since vaccination, but the information was insufcient to

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estimate how quickly VE decreased over time.48 Last, a study that used active surveillance data and controlled for the effects of age at vaccination, age at infection, and year of infection found that children who were vaccinated 5 years previously had a 2.6-fold higher risk (95% CI: 1.25.8) for moderate or severe breakthrough varicella than those who were vaccinated 5 years before.49 In this, as in most studies of breakthrough disease, cases were predominantly clinically diagnosed. Safety Through December 31, 2006, with 55 million vaccine doses distributed, varicella vaccine has demonstrated an excellent safety prole. Postlicensure safety surveillance through the US Vaccine Adverse Event Reporting System and Mercks Worldwide Adverse Experience System indicate that rash, fever, and injection-site reactions are the most frequently reported adverse events, accounting for approximately two thirds of all reports.5052 Severe adverse events (5% of reports received by the Vaccine Adverse Events Reporting System or 2.6 per 100 000 doses distributed) were uncommon. Reports conrmed by isolate analysis to be attributable to vaccine strain were extremely rare and included cases of pneumonia, hepatitis, and severe disseminated varicella infection (all among patients with serious medical conditions that were undiagnosed at the time of vaccination) and cases of HZ and meningitis. Five instances of vaccine virus strain transmission from immunocompetent vaccine recipients to susceptible contacts have been documented.50,51,5355 Hospitalization from HZ, meningitis with concurrent HZ, and secondary transmission cases of varicella occurred among healthy individuals. Other serious adverse events (thrombocytopenia, acute cerebellar ataxia, and acute hemiparesis) have been reported among vaccinated individuals but not laboratory conrmed as attributable to vaccine strain VZV. Related to measles-mumps-rubella-varicella (MMRV) vaccine, preliminary postlicensure analysis indicated that the risk for febrile seizure was twofold higher 7 to 10 days after vaccination among children who were 12 to 23 months of age and received MMRV vaccine compared with those who received MMR vaccine and varicella vaccine at the same visit.56 RATIONALE FOR VACCINE POLICY CHANGE In 2006, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommended a universal 2-dose childhood varicella vaccination program.8,9 The rst dose is recommended routinely at age 12 to 15 months and the second at 4 to 6 years. The second dose may be administered earlier provided that 3 months have elapsed since the rst dose. For individuals who previously received 1 dose of varicella vaccine, a second, catchup vaccination was recommended. The policy change was based on available evidence on disease epidemiology, immune response to vaccination, VE, and economic analysis related to the 1and 2-dose schedules, as reviewed next. Despite progress in controlling varicella in the United

States,4,5,7 incidence data from recent years suggested that the limit of control with a 1-dose vaccination program had been reached. The decline in numbers of varicella cases reached a plateau between 2003 and 2006 (Fig 1A). Although severe cases were reduced by 95%, the 85% VE afforded by 1 vaccine dose did not provide sufcient herd immunity to interrupt community transmission of VZV, especially in settings with high contact rates, such as schools. Outbreaks continued to be reported, although they were fewer in number and smaller than in the prevaccine era. During the mature phase of the 1-dose program, outbreaks occurred among highly vaccinated (96%100%) school populations, there were index cases and contributors to disease transmission who had been previously vaccinated, and VE in preventing all disease ranged between 72% and 87%.22,32,34,36 These outbreaks, which proved difcult to control because most students were already vaccinated according to existing recommendations, placed a nancial and resource burden on state health departments.34 In communities with high vaccination coverage, breakthrough varicella cases constituted 50% of the reported cases.4 Although breakthrough cases commonly present with no or mild temperature elevation and a median of 50 skin lesions (commonly maculopapular lesions, papules that may not progress to vesicles),5759 1 in 4 such cases present with clinical features similar to those in unvaccinated children.60 Mild breakthrough cases may not be recognized and, if not excluded from child care or school settings, can create opportunities for transmission to individuals who are at risk for severe varicella, including those with contraindications to vaccination. As overall disease incidence declines, the VZV exposure risk decreases, leading to susceptible unvaccinated and vaccinated children aging into adolescence and adulthood. Accumulation of susceptible individuals may result in disease and outbreaks later in life, when varicella is more likely to be severe. Because the greatest decline in varicella incidence has occurred in children 10 years, the peak incidence for varicella cases in active surveillance areas has shifted from ages 3 to 6 years in 1995 to 9 to 11 years in 2005. The median age at infection increased for both vaccinated and unvaccinated individuals, although incidence rates for all age groups were lower.4 Implementation of middle and high school requirements is an important strategy for vaccinating adolescents who may have missed out on varicella exposure. Epidemiologic data were consistent with immunologic ndings, suggesting that 15% to 20% of children did not develop antibody levels (as measured by sensitive glycoprotein enzyme-linked immunosorbent assay (gpELISA) or uorescent-antibody-to-membrane-antigen assays) sufcient to protect them fully against varicella.41,6163 Children with a 6-week postvaccination antibody titer of 5 gpELISA U/mL were 3.5 times more likely to experience breakthrough varicella than those with a titer of 5 gpELISA U/mL.62 Among children with 6-week postvaccination antibody titers of 5 and 5 gpELISA U/mL, VE was 83.5% (95% CI: 76.9% 89.5%)
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TABLE 1 Humoral and Cellular Immune Response to 1 and 2 Doses of Varicella Vaccines Among Children Aged 12 Months to 12 Years
Immune Response 6 wk After Dose 1 Varicella Vaccine VZV IgG gpELISA 5 U/mL GMT VZV IgG gpELISA U/mL Mean stimulation index 85.7% 12.544 28.6 6.265
44

6 wk After Dose 2 and 3 mo Between Doses MMRV 91.2% 13.067

67

6 wk After Dose 2 at Age 46 y Varicella Vaccine 99.4% 212.466 58.6 6.569

66

Varicella Vaccine 99.6% 142.644 36.9 9.165

44

MMRV 99.2% 58867

67

MMRV 98.9%66 31766

Mean stimulation indices from different laboratories and from different studies should not be compared directly.

and 95.5% (95% CI: 94.2%96.8%), respectively.62 Titers of 5 gpELISA U/mL were induced in 76% to 86% of children who received a single dose of vaccine.44,64 Fluorescent-antibody-to-membrane-antigen assay demonstrated seroconversion (titers 1:4) in 76% of children at 16 weeks after vaccination.63 A second dose of varicella vaccine among children produces an improved humoral and cellular immune response (Table 1) that correlates with improved protection against disease.44,6569 A postlicensure randomized clinical trial indicated that, compared with 1 dose, 2 doses of varicella vaccine administered 3 months apart provided higher antibody levels (as measured by the proportion of individuals with titers of 5 gpELISA U/mL and by geometric mean titers) and greater protection against disease.44 A comparable improved immune response was documented when the second dose of vaccine was administered as part of the combination MMRV vaccine67 or when the 2 doses were administered 3 to 5 years apart as either formulation.66,69 VZV-specic lymphocyte proliferation responses, measured by the mean stimulation index, a marker of cell-mediated immunity, were signicantly higher for recipients of 2 vaccine doses administered either 3 months or 3 to 5 years apart.65,68,69 In the 1 postlicensure clinical trial, the risk for breakthrough disease was 3.3-fold lower among children who received 2 doses of varicella vaccine than among those who received 1 dose.44 Using historic estimates for the attack rate among unvaccinated children, VE for the 10-year observation period was also signicantly higher after 2 doses (98.3% [95% CI: 97.3%99.0%] vs 94.4% [95% CI: 92.9%95.7%]; P .001). The economic impact of a 2- versus 1-dose vaccination program was evaluated using a cost/benet analysis with the assumption that the second dose would reduce varicella disease following the rst dose by 79%.70 This analysis found that, compared with no vaccination, both 1- and 2-dose programs were cost saving from the societal perspective; however, compared with the 1-dose program, the incremental second dose, costing $109 000 per quality-adjusted life-year, was not cost saving. Several scientic and programmatic issues were considered in recommending that the second dose be administered routinely at age 4 to 6 years: (1) current epidemiology of varicella, with low incidence and no outbreaks reported among preschool-aged children and peak incidence and outbreaks among older elementary and middle school students; (2) similar immune response to the second dose administered 3 months or 3 to
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5 years after the rst dose; (3) some evidence of waning immunity or secondary vaccine failure,49 which supports later administration of the second dose; and (4) the benet (in terms of simplicity of the vaccination schedule and vaccine uptake) of having the second dose of varicella vaccine recommended at the same age as the second dose of MMR vaccine ideally through administration of the combination MMRV vaccine. However, MMRV vaccine has had limited availability in the United States since June 2007 because of manufacturing constraints unrelated to vaccine safety or efcacy and is not expected to be widely available before 2009.56 REMAINING CHALLENGES As varicella disease has reached low levels, and as the 2-dose vaccination program is implemented, conrming each case will become increasingly important; however, varicella in 2-dose vaccine recipients may be considerably modied, presenting challenges for laboratory conrmation. Rapid diagnostic tests for detecting DNA by using polymerase chain reaction or direct uorescent antibody assay (DFA) are the methods of choice for conrming varicella cases. Monitoring levels and duration of vaccine-induced immunity and understanding humoral and cellular correlates of protection are also important. Commercial assays lack the sensitivity required for detecting vaccine-induced immunity in every sample; therefore, such testing is not recommended. A major concern since the beginning of the varicella vaccination program has been the impact of varicella vaccination on the incidence of HZ. Some studies suggested that exposure of individuals with latent wild-type VZV infection (as a result of natural infection) to individuals with varicella reduces the risk for HZ, presumably by externally boosting VZV immunity.7176 The relative importance of boosting VZV immunity by exposure to exogenous virus versus endogenous reactivation is unknown. Nonetheless, mathematical models71,76 predict that by decreasing varicella exposures, the varicella vaccination program might increase the risk for HZ in the short- and medium-term (during the rst 30 50 years of the vaccination program). In the long-term, as vaccinated cohorts age into older adulthood, the incidence of HZ is expected to decline to levels lower than in the prevaccine era because of the reduced tendency of vaccine virus strain, compared with wild-type virus, to reactivate.77,78 One model estimated that individuals who were aged 10 to 44 years at the introduction of the program will be most affected by not experiencing boosting from exposure to children with varicella.71 Their

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lifetime risk for HZ was projected to increase to 50% compared with 33% in the prevaccine era. For addressing this concern, a number of studies assessed the incidence of HZ in the United States in the pre- and postvaccine eras. Results so far are inconclusive. In a study in a health maintenance organization in Seattle, the age-adjusted incidence of HZ remained stable during 19922002 as the incidence of varicella decreased 65%.79 Data from 2 health maintenance organizations in Oregon and Washington for 19972002 showed no statistically signicant increase in HZ incidence rates except among children aged 10 to 17 years (relative risk: 1.12 [95% CI: 1.051.18]); these increases were attributed to increased use of oral steroids.80 An analysis of incidence data from a national database81 found an overall incidence of HZ in 2000 and 2001 in the range reported before vaccine introduction.82 A study that used statewide telephone survey data during 1998 2003 in Massachusetts demonstrated an overall 90% increase in HZ, whereas varicella incidence declined 66%.83 A population-based study found a 22% increase in the incidence of HZ between 1996 and 2001.84 In interpreting these ndings, it should be noted that some studies showed a rising trend in HZ incidence in the absence of a vaccination program.8587 Because risk factors other than age and immune status for HZ are largely unknown, understanding the secular trends and separating the potential impact of the varicella vaccination program on HZ epidemiology will be challenging, especially among adults aged 60 years, the age group now recommended for zoster vaccine.88 A denitive answer may not be available in the short-term. The VZV vaccine strain has the potential to establish latency and later reactivate to cause vaccine virus strain HZ.89 Several studies have evaluated the risk for vaccine virus strain HZ after vaccination of immunocompromised and healthy children.7779,90,91 In a study of children who had leukemia and were followed for a mean of 4.1 years (range: 6 months to 10 years), HZ incidence was 3.0 times lower among vaccinated children compared with age- and chemotherapy protocolmatched children who had experienced natural varicella (0.80 vs 2.46 per 100 person-years).77 Data for healthy children are more limited but also suggest that the risk for vaccine virus strain HZ after a single dose of varicella vaccine is lower than that after wild-type varicella infection.78,79,91 The risk for HZ among individuals who received 2 doses of varicella vaccine or who experienced breakthrough varicella and therefore became latently infected with both vaccine and wild-type VZV is unknown. CONCLUSIONS The US varicella vaccination program has dramatically reduced varicella incidence and related complications, hospitalizations, and deaths. Varicella vaccine has an excellent safety prole and high performance, but 85% effectiveness of 1 dose of vaccine has proved insufcient to prevent transmission, especially in highcontact settings such as schools. After consideration of the disease epidemiology after implementation of the 1-dose vaccination program as well as the improved

immune response to a second vaccine dose, a 2-dose varicella vaccine schedule was recommended for children in 2006. For evaluation of the epidemiologic impact of the 2-dose policy on varicella and HZ, ongoing surveillance that includes laboratory conrmation, monitoring vaccine-induced immunity and identifying correlates of protection, and increasing our understanding of risk factors for HZ are needed. NOTE Detailed data on the varicella vaccination program in the United States can be found in the supplement Varicella Vaccine in the United States, a Decade of Prevention and the Way Forward.92 REFERENCES
1. Centers for Disease Control and Prevention. Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1996; 45(RR-11):136 2. American Academy of Pediatrics, Committee on Infectious Diseases. Recommendations for the use of live attenuated varicella vaccine [published correction appears in Pediatrics. 1995;96(1 pt 1):preceding 151, following 171]. Pediatrics. 1995;95(5):791796 3. Seward JF, Watson BM, Peterson CL, et al. Varicella disease after introduction of varicella vaccine in the United States, 19952000. JAMA. 2002;287(5):606 611 4. Guris D, Jumaan AO, Mascola L, et al. Changing varicella epidemiology in active surveillance sites: United States, 19952005. J Infect Dis. 2008;197(suppl 2):S71S75 5. Zhou F, Harpaz R, Jumaan AO, Winston CA, Shefer A. Impact of varicella vaccination on health care utilization. JAMA. 2005; 294(7):797 802 6. Davis MM, Patel MS, Gebremariam A. Decline in varicellarelated hospitalizations and expenditures for children and adults after introduction of varicella vaccine in the United States. Pediatrics. 2004;114(3):786 792 7. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality due to varicella after implementation of varicella vaccination in the United States. N Engl J Med. 2005;352(5):450 458 8. Marin M, Guris D, Chaves SS, Schmid S, Seward JF. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007; 56(RR-4):1 40 9. American Academy of Pediatrics, Committee on Infectious Diseases. Prevention of varicella: recommendations for use of varicella vaccines in children, including a recommendation for a routine 2-dose varicella immunization schedule. Pediatrics. 2007;120(1):221231 10. Wharton M. The epidemiology of varicella-zoster virus infections. Infect Dis Clin North Am. 1996;10(3):571581 11. Gershon AA, Takahashi M, Seward JF. Varicella vaccine. In: Plotkin SA, Orenstein WA, Oft PA, eds. Vaccines. 5th ed. Philadelphia, PA: Sanders; 2007:915958 12. Yawn BP, Yawn RA, Lydick E. Community impact of childhood varicella infections. J Pediatr. 1997;130(5):759 765 13. Finger R, Hughes JP, Meade BJ, Pelletier AR, Palmer CT. Age-specic incidence of chickenpox. Public Health Rep. 1994; 109(6):750 755 14. Kilgore PE, Kruszon-Moran D, Seward JF, et al. Varicella in Americans from NHANES III: implications for control through routine immunization. J Med Virol. 2003;70(suppl 1): S111S118 15. Galil K, Brown C, Lin F, Seward J. Hospitalizations for varicella

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PEDIATRICS Volume 122, Number 3, September 2008

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Varicella Prevention in the United States: A Review of Successes and Challenges Mona Marin, H. Cody Meissner and Jane F. Seward Pediatrics 2008;122;e744 DOI: 10.1542/peds.2008-0567
Updated Information & Services References including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/122/3/e744.full.h tml This article cites 87 articles, 27 of which can be accessed free at: http://pediatrics.aappublications.org/content/122/3/e744.full.h tml#ref-list-1 This article has been cited by 12 HighWire-hosted articles: http://pediatrics.aappublications.org/content/122/3/e744.full.h tml#related-urls This article, along with others on similar topics, appears in the following collection(s): Infectious Diseases http://pediatrics.aappublications.org/cgi/collection/infectious_ diseases_sub Vaccine/Immunization http://pediatrics.aappublications.org/cgi/collection/vaccine:im munization_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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