Published online September 1, 2008
PEDIATRICS Vol. 122 No. 3 September 2008, pp. e744-e751 (doi:10.1542/peds.2008-0567)
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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 and Jane F. Seward, MBBS, MPHa

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


   ABSTRACT
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BURDEN OF VARICELLA IN...
 EXPERIENCE WITH THE 1-DOSE...
 RATIONALE FOR VACCINE POLICY...
 REMAINING CHALLENGES
 CONCLUSIONS
 NOTE
 REFERENCES
 
OBJECTIVE. In 1995, the United States was the first 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 identified 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 disease of any severity and >95% effective in preventing severe varicella and had an excellent safety profile. 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 efficacy. 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 sufficient 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.

Key Words: varicella • chickenpox • varicella epidemiology • varicella vaccine • varicella vaccination program

Abbreviations: HZ—herpes zoster • VZV—varicella-zoster virus • VE—vaccine effectiveness • CI—confidence interval • MMR—measles-mumps-rubella • MMRV—measles-mumps-rubella-varicella • gpELISA—glycoprotein enzyme-linked immunosorbent assay

In 1995, the United States became the first country to introduce a universal childhood varicella vaccination 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 mortality3–7; 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 identified using the National Library of Medicine's 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
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Disease Incidence
Before introduction of varicella vaccine, an estimated 4 million cases of varicella (15–16 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-specific incidence among children aged 5 to 9 years. By the early 1990s, the highest age-specific 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)-specific antibodies.14

Hospitalization
Varicella may result in serious complications, hospitalizations, and deaths. In the 8 years before vaccine licensure, an estimated 10632 hospitalizations were attributable to varicella annually, with significant variation by year (range: 8198–16586; rate: 2.3–6.3 per 100000 population).15 A higher burden from hospitalizations was found when a varicella-related code in any, rather than the principal, discharge diagnosis field was included (range: 13912–17899; rate: 4.8–7.1 per 100000 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 100000 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
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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.3–7 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-specific incidence rates for all age groups were significantly 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 1993–1995 (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.


Figure 1
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  		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.

 
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 age-adjusted 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.22–38 VE has been estimated against "all" and against "combined moderate and severe" varicella. Most investigations22–27,29,30,32–38 found VE for prevention of all 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 non–placebo-controlled prelicensure trials (70%–90%),40–42 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 definitions of moderate and severe varicella varied across studies,* varicella vaccine was highly effective in preventing combined moderate and severe disease22–25,27–33,35,37,38,44 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.30,33–35,38,44

Risk Factors for Vaccine Failure
Several potential risk factors for vaccine failure have been identified in VE studies, but findings have not been consistent. Younger age at vaccination (defined as <14, <16, or ≤18 months), time since vaccination (defined as ≥3, >5, or ≥5 years), and a history of asthma or eczema have been associated with vaccine failure in some outbreak investigations26–29,31,36 but not in others22,27,28,32,33,36; 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% confidence interval [CI]: 1.1–1.9) 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 find 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 first year after vaccination significantly 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 insufficient to 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: 1.2–5.8) 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 profile. Postlicensure safety surveillance through the US Vaccine Adverse Event Reporting System and Merck's 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.50–52 Severe adverse events (5% of reports received by the Vaccine Adverse Events Reporting System or 2.6 per 100000 doses distributed) were uncommon. Reports confirmed 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.50,51,53–55 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 confirmed 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


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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 first 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 first 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 1- and 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 sufficient 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 difficult to control because most students were already vaccinated according to existing recommendations, placed a financial 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),57–59 ~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 findings, suggesting that ~15% to 20% of children did not develop antibody levels (as measured by sensitive glycoprotein enzyme-linked immunosorbent assay (gpELISA) or fluorescent-antibody-to-membrane-antigen assays) sufficient to protect them fully against varicella.41,61–63 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%) 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.44,65–69 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-specific lymphocyte proliferation responses, measured by the mean stimulation index, a marker of cell-mediated immunity, were significantly 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 significantly higher after 2 doses (98.3% [95% CI: 97.3%–99.0%] vs 94.4% [95% CI: 92.9%–95.7%]; P < .001).


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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

 
The economic impact of a 2- versus 1-dose vaccination program was evaluated using a cost/benefit analysis with the assumption that the second dose would reduce varicella disease following the first 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 ~$109000 per quality-adjusted life-year, was not cost saving.

Several scientific 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 5 years after the first dose; (3) some evidence of waning immunity or secondary vaccine failure,49 which supports later administration of the second dose; and (4) the benefit (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 efficacy and is not expected to be widely available before 2009.56


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As varicella disease has reached low levels, and as the 2-dose vaccination program is implemented, confirming each case will become increasingly important; however, varicella in 2-dose vaccine recipients may be considerably modified, presenting challenges for laboratory confirmation. Rapid diagnostic tests for detecting DNA by using polymerase chain reaction or direct fluorescent antibody assay (DFA) are the methods of choice for confirming 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.71–76 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 first 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 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 1992–2002 as the incidence of varicella decreased 65%.79 Data from 2 health maintenance organizations in Oregon and Washington for 1997–2002 showed no statistically significant increase in HZ incidence rates except among children aged 10 to 17 years (relative risk: 1.12 [95% CI: 1.05–1.18]); 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 findings, it should be noted that some studies showed a rising trend in HZ incidence in the absence of a vaccination program.85–87 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 definitive 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.77–79,90,91 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 protocol–matched 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.


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The US varicella vaccination program has dramatically reduced varicella incidence and related complications, hospitalizations, and deaths. Varicella vaccine has an excellent safety profile and high performance, but ~85% effectiveness of 1 dose of vaccine has proved insufficient to prevent transmission, especially in high-contact 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 confirmation, monitoring vaccine-induced immunity and identifying correlates of protection, and increasing our understanding of risk factors for HZ are needed.


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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


   FOOTNOTES
 
Accepted 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{at}cdc.gov

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 findings 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.

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

* Usually, moderate varicella was defined as either 250 to 500 lesions or 50 to 500 lesions and severe varicella as >500 lesions or any hospitalization or complication. Back


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