Wild-type Varicella Research Articles

Abstract TMP8: Varicella Zoster Virus Infection in Children With Arterial Ischemic Stroke: The Chicken or the Egg?

Introduction: Serologic evidence of varicella zoster virus (VZV) infection has been associated with childhood arterial ischemic stroke (AIS). Questions of causality persist: does VZV infection cause AIS, or does AIS reactivate VZV? The Vascular effects of Infection in Pediatric Stroke (VIPS II) study aimed to examine this relationship. Methods: This North American 22-center prospective cohort study enrolled 205 children (28 days-18 years) with AIS (2017-2022). Blood samples were hyperacute (≤72hrs; n=194), acute (4-7 days; n=180) and convalescent (1-6 weeks; n=73). A virology research lab used ELISA to measure VZV IgM and IgG titers. A pediatric virologist (CG) interpreted the results and classified the evidence of infection. Low-level IgG seropositivity is consistent with prior vaccination/infection. Highly elevated IgM in hyperacute/acute samples indicated reactivation coincident with stroke . Rising IgG titers between hyperacute and convalescent samples, occasionally with a high IgM in convalescent sample, indicated reactivation after the stroke . Results: Median age (IQR) was 11.6 years (5.3, 15.6). All 205 cases were low-level IgG positive; 160 (78%) reported prior VZV vaccination and 3 reported remote chicken pox. Serologies for 15 (7.3%; 95% CI 4.1, 11.8%) indicated VZV reactivation coincident with stroke; prior VZV vaccination reported in 14 and unknown in one. Stroke etiology amongst these 15 was definite arteriopathy in 4 (27%), possible arteriopathy in 4 (27%), cardioembolic in 5 (33%), and idiopathic in 2 (13%) (compared to 37%, 37%, 10%, 14%, respectively, for the other 190). Among 73 with convalescent samples, 17 (23%) had VZV reactivation after stroke. All cases of VZV reactivation were asymptomatic zoster sine herpete (herpes zoster without rash). Conclusions: While stroke triggered VZV reactivation in 23% of cases, 7.3% had evidence of zoster sine herpete at the time of their stroke, implying a causal role. We could not distinguish antibodies to vaccine virus versus wild-type; these zoster cases could represent reactivation of vaccine virus or a break-through wild-type varicella infection. Either scenario would be unexpected in this current era of routine childhood VZV vaccination and low rates of pediatric chicken pox or zoster.

Unvaccinated: An unrecognized risk factor for stroke (P14-5.030)

<h3>Objective:</h3> Review the under-recognized risk for childhood stroke for unvaccinated children. <h3>Background:</h3> Approximately thirty five percent of pediatric strokes may be attributed to focal cerebral arteriopathy (FCA). FCA is a unifocal and unilateral stenosis of a large intracranial artery of the anterior circulation. Cases have been associated with varicella infection in the year prior to stroke. Acute ischemic strokes caused by FCA have a 25% recurrence risk in one year and therefore need to be monitored closely. Literature suggests that patients with FCA may benefit from treatment with steroids, in addition to anti-thrombotic therapy, making early diagnosis essential for optimizing outcomes. We present a case of FCA in the setting of recent varicella infection. <h3>Design/Methods:</h3> n/a <h3>Results:</h3> A 14-year-old unvaccinated female presented to the emergency department with left facial droop, left hemiparesis and speech disturbance. Symptoms started four days prior, worsening on day of arrival. NIH Stroke Scale on presentation was 2 for aphasia. CT head was normal. MRI brain showed restricted diffusion involving the right internal capsule and deep grey matter. MRA showed right internal carotid artery narrowing. Given delayed presentation, she was out of the window for acute interventions and was transferred for higher level of care. History was notable for varicella 7 months ago and COVID-19 5 months ago. Vessel wall imaging showed narrowing in the right internal carotid and A1, consistent with FCA. Patient was started on pulse dose steroids and aspirin. <h3>Conclusions:</h3> We present a case arterial ischemic stroke secondary to FCA in a patient with history of varicella infection. Wild type varicella infection has been associated with FCA up to 12 months post-infection and under-vaccination is associated with over 8-fold increase in risk of childhood stroke. Incidence of strokes related to varicella infection has decreased with the availability of vaccinations, highlighting the importance of childhood vaccines. <b>Disclosure:</b> Dr. Gupta has nothing to disclose. Dr. Pearson has nothing to disclose.

Insights on the Impact of External and Internal Boosting on Varicella-Zoster Virus Reactivation Based on Evidence From the First Decade of the United States Universal Varicella Vaccination Program.

Since the licensure of the varicella vaccine in the United States in 1995 and the implementation of the universal varicella vaccination program, varicella infection rates, and associated morbidity and mortality rates have decreased. However, controversy exists over whether universal vaccination has resulted in an increased incidence of herpes zoster (HZ). In 1965, Dr. Hope-Simpson hypothesized that exogenous exposures to the wild-type varicella-zoster virus (wt-VZV) provide immune boosts that inhibit HZ; therefore, reducing the amount of circulating wt-VZV may have the negative effect of increasing the incidence of HZ. A historical review of data from the Centers for Disease Control and Prevention-sponsored Antelope Valley Varicella Active Surveillance Project, along with other studies, is provided to investigate the exogenous boosting hypothesis in the first decade post-vaccine licensure. These data indicated that adoption of universal varicella vaccination led to (1) significant HZ incidence rate increases among children, adolescents, and adults with a history of wild-type varicella and (2) decline in varicella vaccine efficacy after the initial post-licensure period. These effects were likely due to reduced exogenous exposures from children shedding wt-VZV. Appropriate methodologies for ongoing research are also discussed, both in studies during the first decade post-licensure and more recent work.

The Impact of Varicella Vaccination on the Incidence of Varicella and Herpes Zoster in the United States: Updated Evidence From Observational Databases, 1991-2016.

Universal childhood vaccination against varicella began in the United States as a 1-dose schedule in 1996, changing to a 2-dose schedule in 2006. The exogenous boosting hypothesis, which postulates that reexposure to circulating wild-type varicella delays the onset of herpes zoster, predicts a transient increase in the incidence of herpes zoster, peaking in adults 15-35 years after the start of varicella vaccination. This was a retrospective study of administrative claims data from the MarketScan Commercial and Medicare databases between 1991-2016. Outcome measures were the incidences of herpes zoster per 100 000 person-years, by calendar year and age category, and the annual rates of change in herpes zoster by age category, in an interrupted time series regression analysis, for the periods of 1991-1995 (prevaccine), 1996-2006 (1-dose vaccination period), and 2007-2016 (2-dose vaccination period). The annual incidences of herpes zoster increased throughout the period of 1991-2012 in all adult age categories, with a plateau in 2013-2016 that was most evident in the ≥65 age group. In 1991-1995, the herpes zoster incidences increased at annual rates of 4-6% in age categories 18-34, 35-44, 45-54, and 55-64 years. In the same age categories during 1996-2006 and 2007-2016, the herpes zoster incidences increased at annual rates of 1-5%. Although the annual incidence of herpes zoster in adults has continued to increase, the rates of change decreased during both the 1- and 2-dose vaccination periods. The hypothesized increase in herpes zoster predicted from modelling of the exogenous boosting hypothesis was not observed.

Severe Herpes Zoster Following Varicella Vaccination in Immunocompetent Young Children.

Varicella vaccination is now virtually universal in North America, as well as in some European and Asian countries. Since varicella vaccine is a live attenuated virus, the virus replicates in the skin after administration and can travel via sensory nerves or viremia to become latent in the dorsal root ganglia. In some immunized children, virus reactivates within a few months to a few years to cause the dermatomal exanthem known as herpes zoster (shingles). Herpes zoster caused by vaccine virus often reactivates within the same dermatome as the site of the original varicella vaccine injection. We present evidence that occasional cases of herpes zoster following varicella vaccination in immunocompetent children can be as severe as herpes zoster following wild-type varicella. Analysis of the virus in one case disclosed that the vaccine virus causing herpes zoster was a wild-type variant with a mutation in ORF0. With regard to dermatomal localization of the viral eruption, we predict that herpes zoster of the lumbar dermatomes in children is likely to be caused by vaccine virus, because herpes zoster in those dermatomes is rare in children after wild-type varicella. One of the children with herpes zoster subsequently developed asthma, a known risk factor for herpes zoster, but none of the children had an autoimmune disease. Although postherpetic neuralgia is exceedingly rare, children who develop herpes zoster following varicella vaccination are at risk (albeit low) of developing meningoencephalitis and should be carefully observed for a few weeks.

Trends in U.S. Community hospitalizations due to herpes zoster: 2001–2015

BackgroundIn 2007, based on decisions by the U.S. Advisory Committee on Immunization Practices, the CDC recommended a booster dose at 4–6 years in the varicella vaccine schedule. In 2008, a herpes zoster vaccine was recommended for use in persons age ≥60 years. The purpose of this study was to examine trends in herpes zoster hospitalization rates and assess the impact of both policy recommendations using U.S. hospital discharge data. MethodsNationwide Inpatient Sample discharge data from 2001 to 2015 were used to identify primary or secondary herpes zoster diagnoses. Trends in annual total and age-specific herpes zoster hospitalization rates and average length of stay were examined. Average annual rates for the pre (2001–2005) and post (2012–2015)-zoster vaccine policy eras were compared. Absolute change in herpes zoster hospitalizations were calculated. ResultsThe rate difference of U.S. herpes zoster hospitalizations in the post vs. pre-zoster vaccine policy era was −1.9 per 100,000 population (6,200 fewer hospitalizations in 2015 than expected). Key age group rate differences: 0–3 years (−0.4 per 100,000; 50 fewer), 4–6 years (−0.6 per 100,000; 50 fewer), 7–14 years (−1.3 per 100,000; 400 fewer), 50–59 years (0.7 per 100,000; 300 more), 60–69 years (−2.5 per 100,000; 900 fewer), 70–79 years (−10.2 per 100,000; 2,000 fewer), 80+ years (−29.9 per 100,000; 3,600 fewer). ConclusionsReduction of wild-type varicella due to the 2-dose varicella vaccination recommendation may have impacted declining herpes zoster hospitalization rates among children ≤14 years. The 2008 herpes zoster vaccine may have impacted declining herpes zoster hospitalization rates for adults age ≥60 years despite vaccination coverage <31% by 2015.

2478. Impact of 20 Years of Varicella Vaccination on the Epidemiology of Herpes Zoster in the United States: An Interrupted Time Series Analysis

BackgroundThe mechanism for reactivation of varicella zoster virus as herpes zoster (HZ) is not well understood. One hypothesis postulates that re-exposure to circulating wild-type varicella can boost individual immunity and prevent reactivation (“Exogenous Boosting,” EB). The validity of this hypothesis has been debated and the evidence to evaluate it is limited. Dynamic transmission model outcomes of impact and cost-effectiveness of universal varicella vaccination (UVV) are sensitive to EB characterization and assumptions, occasionally leading to conclusions that UVV programs may not be cost-effective and could lead to temporary increases in HZ incidence. The goal of this study was to use data from 20 years of UVV in the United States from 1996 to 2016 to evaluate whether the hypothesized increases in HZ incidence have been realized.MethodsThis is a retrospective study of de-identified administrative claims data from the US MarketScan® databases between 1991 and 2016. The incidence of HZ was analyzed by calendar year and age category using interrupted time series (ITS) analysis implemented through a negative binomial generalized linear regression model over three time periods: pre-UVV (1991–1995); 1 dose UVV (1996–2006); and 2 dose UVV (2007–2016). The ITS approach (Bernal et al., IJE, 2017) is an effective way to evaluate the impact of public health interventions implemented at specific time points.ResultsHZ incidence in the pre-UVV period increased at annual rates between 3.67% and 12.38%, with the highest increases in the 0–17 and 65+ age groups. The rate of HZ increase was lower in the 1 dose UVV period compared with the pre-UVV period for all age groups except for minor increases in the 18–35 (0.52%) and 55–65 (0.14%) groups. During the 2 dose UVV period, the rate of increase in HZ was lower in all groups than in the pre-UVV period, with the largest reductions in the 0–17 (−22.58%), 65+(−10.68%), and 18–<35 (−3.57%) age groups.ConclusionThis evaluation of the impact of UVV on rates of change in HZ does not support the hypothesis of an increase in HZ incidence due to UVV. While overall HZ incidence rates have been increasing year on year, the rate of that increase has been declining in both UVV periods. Our findings have implications on the assumptions used in economic evaluations of UVV programs. Disclosures L. Wolfson, Merck & Co., Inc.: Employee and Shareholder, Salary. V. Daniels, Merck & Co., Inc.: Employee and Shareholder, Salary. Y. T. Chen, Merck & Co., Inc.: Employee and Shareholder, Salary. W. Ou, Merck & Co., Inc.: Employee and Shareholder, Salary.

Administrative Data to Explore the Role of Family History as a Risk Factor for Herpes Zoster

We used administrative data to study the impact of family history on the risk of herpes zoster (HZ). Our HZ cases and our HZ family history were both ascertained on the basis of medically attended diagnoses, without reliance on self-report or recall bias. Family history was associated with HZ risk among both siblings and parents. The strength of the association differed when the index child was latently infected with vaccine-strain vs wild-type varicella zoster virus.

Cycling probe technology to quantify and discriminate between wild-type varicella-zoster virus and Oka vaccine strains

Rapid differentiation between wild-type varicella zoster virus (VZV) and Oka-vaccine (vOka) strains is important for monitoring side reactions of varicella vaccination. To develop a high-throughput molecular diagnostic method for the differentiation of wild-type VZV and vOka strains based on cycling probe technology. The primers were designed to amplify common sequences spanning a single nucleotide polymorphism (SNP) in gene 62 of VZV. DNA–RNA chimeric probes (cycling probes) were designed to detect the SNP at nucleotide 105705. The cycling probe real-time PCR assays for VZV wild-type and vOka strains specifically amplified plasmids containing target sequences that ranged between 10 and 1×106 copies per reaction. The inter- and intra-assay coefficients of variation were less than 5%. After initial validation studies, the clinical reliability of this method was evaluated using 38 swab samples that were collected from patients suspected of being zoster. Compared to the loop mediated isothermal amplification method, which is defined as the gold standard, cycling probe real-time PCR was highly sensitive and specific. The cycling probe real-time PCR technology is a reliable tool for differentiating between wild-type VZV and vOka strains in clinical samples.

COMMENTARY

COMMENTARY

Serologic Analysis of the IgG Antibody Response in Children With Varicella Zoster Virus Wild-type Infection and Vaccination

In contrast to varicella zoster virus (VZV) primary infection, VZV vaccination does not seem to provide lifelong immunity against varicella. Because more people get vaccinated every year, the development of sensitive serological test systems for the detection of protective anti-VZV IgG will become important in the future. We have previously developed a novel VZV line assay based on 5 different recombinant VZV antigens. In this study, we compared this novel assay with a commercially available glycoprotein enzyme immunoassay (RIDASCREEN VZV IgG) in detecting anti-VZV IgG of children with previous varicella infection and VZV vaccination. One hundred twenty-five children were included in this study, 72 with a history of varicella infection and 53 with VZV vaccination. Both assays detected anti-VZV IgG antibodies in both study groups with similar sensitivities. The VZV line assay revealed striking differences in the anti-VZV IgG composition against the VZV open reading frames, 4, 14 and 49, between both study groups, indicating that wild-type varicella infection causes a more diverse immune response against VZV than does vaccination. The exploitation of these results enabled the discrimination of both study groups with a sensitivity of 0.93 and a specificity of 0.83, indicating that the serologic differentiation of children with previous varicella infection and VZV vaccination might be possible. The VZV line assay enables the detection of anti-VZV IgG with sensitivities comparable to glycoprotein enzyme immunoassays and might be suitable for the serologic discrimination between children with a history of varicella infection and VZV vaccination.

Chickenpox in childhood is associated with decreased atopic disorders, IgE, allergic sensitization, and leukocyte subsets

Wild-type varicella zoster infection (WTVZV) up to 8 yr of age has been shown to protect against atopic dermatitis (AD) and asthma. We sought to determine whether WTVZV in childhood protects against atopic disorders, allergic sensitization or decreases serum Immunoglobulin E (IgE) levels. We conducted a retrospective, practice-based study of outpatient pediatric practices in NY. One hundred children with WTVZV up to 8 yr of age and 323 children who received varicella vaccine (VV) were randomly selected. WTVZV up to 8 yr of age is associated with decreased odds of subsequent asthma (exact logistic regression; OR = 0.12, 95% CI = 0.03-0.57, p = 0.003), allergic rhinoconjunctivitis (OR = 0.16, 95% CI = 0.05-0.49, p = 0.0003), and AD (OR = 0.57, 95% CI = 0.33-0.96, p = 0.02), but not food allergies (p = 0.78); decreased total serum IgE levels [mixed linear model, LSM (95% CI): 129.09 (33.22-501.63) vs. 334.21 (102.38-1091.04) IU/ml; p = 0.02] remained significant at all time intervals after WTVZV (<5, 5-10, and >10) compared with VV (p = 0.003-0.03). WTVZV was associated with decreased allergic sensitization (logistic regression, OR = 0.11, 95% CI = 0.03-0.38, p = 0.0004). WTVZV is also associated with persistently decreased numbers of peripheral blood lymphocytes (p < 0.0001) for up to 12 yr (p = 0.0003-0.047), monocytes (p = 0.002) for up to 16 yr (p < 0.001) and basophils at ages 4-6, 10-12, and 14-16 (p < 0.03). WTVZV up to 8 yr of age protects against atopic disorders, which is likely mediated by suppression of IgE production and allergic sensitization, as well as altered leukocyte distributions.

Association between varicella zoster virus infection and atopic dermatitis in early and late childhood: A case-control study

Wild-type varicella zoster virus infection (WTVZV) early in childhood has been shown to protect against the development of asthma and atopy. To determine whether WTVZV in childhood protects against atopic dermatitis (AD). This retrospective, practice-based, case-control study randomly sampled 256 children and adolescents (age 1-18 years) with AD and 422 age-matched healthy controls from 2005 to 2007. Observations were made before the a priori hypothesis. (1) A single episode of WTVZV in childhood is associated with decreased odds ratio (OR) of developing AD (conditional logistic regression; OR, 0.55; 95% CI, 0.34-0.89; P = .01). (2) When using intervals for age corresponding to bimodal distribution of age of WTVZV infection, the effects of WTVZV infection are significant when occurring at age 0 to 8 years (OR, 0.56; 95% CI, 0.35-0.90; P = .02), but not at 8 to 18 years (OR, 0.50; 95% CI, 0.19-1.31; P = .16). Considering 5-year intervals has similar findings. (3) WTVZV is associated with decreased odds of moderate AD (multinomial logistic regression; OR, 0.08, 95% CI, 0.04-0.15; P < .0001) or severe AD (OR, 0.04; 95% CI, 0.01-0.13; P < .0001). (4) WTVZV in children is associated with prolonged AD-free survival (Kaplan-Meier; median, 15.3 years; 95% CI, 10.9-18.0) compared with controls (median, 7.5 years; 95% CI, 4.8-11.9; log-rank test, P < .0001). (5) Children with WTVZV, compared with vaccine, who eventually develop AD require fewer pediatrician sick visits for management of AD (logistic regression; OR, 0.17; 95% CI, 0.06-0.51; P = .001). WTVZV in childhood protects up to 10 years of age against AD, delays onset of AD symptoms, and decreases AD severity and office visits.

An Outbreak of Varicella in Elementary School Children With Two-Dose Varicella Vaccine Recipients—Arkansas, 2006

In June 2006, the Advisory Committee on Immunization Practices (ACIP) expanded its June 2005 recommendation for a second dose of varicella vaccine during outbreaks to a recommendation for routine school entry second dose varicella vaccination. In October 2006, the Arkansas Department of Health was notified of a varicella outbreak among students where some received a second dose during an outbreak-related vaccination campaign in February 2006. The outbreak was investigated using a school-wide parental survey with a follow-up survey of identified case patients. Vaccination status was verified using state and local immunization records. Limited laboratory testing confirmed circulation of wild-type varicella, including varicella in 2-dose vaccine recipients. Vaccination information was available for 871 (99%) of the 880 children. Varicella vaccination coverage was 97% (2-dose, 39%; 1-dose, 58%). A review of the February vaccination clinic found no deficiencies; lot numbers did not differ between cases and noncases. Varicella was confirmed by PCR in 5 (42%) of 12 lesion specimens and by IgM in 1 (6%) of 16 serum specimens. Varicella was reported in 84 children, including 25 (30%) two-dose and 53 (63%) one-dose recipients. Attack rates among 2-dose recipients (10.4%) and 1-dose recipients (14.6%) were not significantly different (RR: 0.72, 95% CI: 0.44-1.15). All 2-dose recipients and 80% of 1-dose recipients reported having 50 or fewer skin lesions. This outbreak is the first to document varicella in both 1- and 2-dose vaccine recipients; both groups had mild disease. The vaccine effectiveness of 1 and 2 doses were similar.

Varicella Zoster Virus (Wild-Type) Infection, but not Varicella Vaccine, in Late Childhood Is Associated With Delayed Asthma Onset, Milder Symptoms, and Decreased Atopy

Varicella zoster virus (VZV) infection, early in life, has been shown to have a protective role against the development of asthma and atopy in children. It is unknown whether VZV infection in late childhood and adolescence also has an asthma protective effect. We studied whether VZV infection in late childhood and adolescence, or administration of the live attenuated varicella vaccine, provides a similar protective effect. In the present study, we use a retrospective chart review of a pediatric practice (N = 62) to analyze the effect of wild-type (WT) VZV infection or recombinant varicella vaccine in children (age 3–21 years) diagnosed with asthma. We found (1) asthma onset occurred 9.4 ± 4.4 years after WT VZV infection (4.4 ± 2.2) by age 13.9 ± 6.5 years, but only 3.0 ± 1.7 years after recombinant vaccine (3.2 ± 3.0 years) at age 5.0 ± 3.6 years (P = 0.05); (2) asthma classifications were 61.5% intermittent, 15.4% mild persistent, and 23.1% moderate persistent after WT VZV infection, but were 30.0% inte...

Case for varicella surveillance in Australia

Case for varicella surveillance in Australia

Persistent Humoral Immune Defect in Highly Active Antiretroviral Therapy–Treated Children With HIV-1 Infection: Loss of Specific Antibodies Against Attenuated Vaccine Strains and Natural Viral Infection

In the pre-highly active antiretroviral therapy era, a loss of specific antibodies was seen. Our objective with this study was to describe the loss of specific antibodies during treatment with highly active antiretroviral therapy. In a prospective, single-center, cohort study of 59 children with HIV-1 infection, we investigated the long-term effect of highly active antiretroviral therapy on the titers and course of specific antibodies against measles, mumps, and rubella vaccine strains compared with wild-type varicella zoster virus, cytomegalovirus, and Epstein-Barr virus. During highly active antiretroviral therapy, age-adjusted CD4+ T cells and B cells increased, whereas total immunoglobulin levels declined. Although these children were preimmunized before the start of highly active antiretroviral therapy, only 24 (43%) had antibodies against all 3 measles, mumps, and rubella. Antibodies against measles, mumps, and rubella were lost in 14 (40%), 11 (38%), and 5 (11%) children who were seropositive at baseline. We also observed loss of varicella zoster virus immunoglobulin G in 7 (21%) of 34, cytomegalovirus immunoglobulin G in 3 (7%) of 45, but none of 53 Epstein-Barr virus-seropositive children. During highly active antiretroviral therapy, primary vaccination in 3 patients and 15 revaccinations in those with negative serology demonstrated incomplete seroconversion. Humoral reactivity in children with HIV-1 infection remains abnormal during highly active antiretroviral therapy. Despite immune reconstitution, antibodies against live-attenuated vaccine and wild-type natural virus strains disappear over time in up to 40% of children with HIV-1 infection.

Universal Varicella Vaccination: Efficacy Trends and Effect on Herpes Zoster

In 1995, the Varicella Active Surveillance Project (VASP) was established in Antelope Valley (California), a geographically distinct high-desert community of 300,000 residents, as one of three sites in the nation in a cooperative agreement with the Centers for Disease Control and Prevention (CDC) to collect baseline demographic and clinical data and to monitor trends in varicella (chickenpox) following introduction of varicella vaccine. Herpes zoster (shingles) was added to the active surveillance January 1, 2000. The universal varicella program has proven effective in terms of reducing the number of reported verified varicella cases by 85%, from 2,934 in 1995 to 412 in 2002. Prior to this dramatic reduction, immunologic boosting due to exogenous exposures to wild-type varicella-zoster virus (VZV) in the community (1) caused mean serum anti-VZV levels among vaccines to increase with time after vaccination and (2) served as a mechanism that helped suppress the reactivation of herpes zoster (HZ), especially among individuals with a previous history of wild-type varicella. That immunologic boosting might play a significant role in both varicella and the closely related HZ epidemiology is evidenced by (1) a decline in vaccine efficacy by over 20%, from 95.7% (95% C.I., 82.7% to 98.9%) in 1999 to 73.9% (95% C.I., 57.9% to 83.8%) in 2001 and (2) an unexpectedly high cumulative (2000 to 2003) true incidence rate of 223 (95% C.I. 180-273) per 100,000 person-years (p-y) among children <10 years old with a previous history of varicella. Because capture-recapture methods demonstrate a likely lower bound of 50% underreporting, the actual rate is likely double or 446 per 100,000 p-y, approaching the HZ rate reported among older adults. Other recent studies based on VASP data have mitigated against discovery of the above trends that challenge several initial assumptions inherent to the universal varicella program, namely, (1) a single dose confers long-term immunity and (2) there is no immunologically mediated link between varicella and HZ incidence. As vaccinated children replace those with a prior history of wild-type varicella in the <10 age group, increasing HZ incidence among this cohort will be of less concern in the near future. However, previous scientific studies, including the present preliminary results from active surveillance indicate that HZ may be increasing among adults. It may be difficult to design booster interventions that are cost-effective and meet or exceed the level of protection provided by immunologic boosting that existed naturally in the community in the prelicensure era.

Vaccine Effectiveness During a Varicella Outbreak Among Schoolchildren: Utah, 2002–2003

In the context of a chickenpox outbreak involving 2 Utah elementary schools, we conducted an investigation to assess vaccine effectiveness, describe illness severity, and examine risk factors for breakthrough varicella (ie, varicella in those who have been vaccinated). All parents were asked to complete a questionnaire about their child's medical history. Parents of children with recent varicella were interviewed, and vaccination records were verified. Lesions were submitted for polymerase chain reaction testing. Questionnaires were returned for 558 (93%) of 597 students in school A and 924 (97%) of 952 students in school B. A total of 83 schoolchildren (57 unvaccinated and 26 vaccinated) had varicella during the October 2002 through February 2003 outbreak period. An additional 17 cases occurred among household contacts, including infants and adults. Polymerase chain reaction analysis recovered wild-type varicella. Vaccine effectiveness was 87%. With 1 notable exception, vaccinated children tended to have milder illness. Risk factors for breakthrough varicella included eczema, vaccination > or =5 years before the outbreak, and vaccination at < or =18 months of age. Restricting analysis to children vaccinated > or =5 years before the outbreak, those vaccinated at < or =18 months of age were more likely to develop breakthrough varicella (relative risk: 9.3; 95% confidence interval: 1.3-68.9). The vaccine, administered by >100 health care providers to 571 children during a 7-year time period, was effective. Risk factors for breakthrough varicella suggest some degree of biological interaction between age at vaccination and time since vaccination.

Cost–benefit analysis of universal varicella vaccination in the U.S. taking into account the closely related herpes–zoster epidemiology

Many models concur that universal varicella vaccination of children is beneficial from the perspective of reducing societal costs. Yet, the majority of such cost analyses have been modeled under the assumption that varicella vaccination has no adverse effect on the closely related herpes–zoster (HZ) epidemiology. Historical models have assumed that asymptomatic endogenous reactivation is the chief mechanism of boosting that suppresses the reactivation of HZ and that immunity wanes due to the aging process. Recent studies suggest instead that periodic exogenous exposures to wild-type varicella are the predominant factor influencing the curve of increasing HZ incidence rate with advancing age among individuals <50, after which an age-related decline dominates in the elderly. Based on a realistic age-structured model, we compare differences in outcomes of the number of HZ cases and direct medical costs associated with the population existing in 2000 and as it ages (according to the mortality given in the 2000 U.S. census) during the following 50 years with and without implementation of universal varicella vaccination. Under universal varicella vaccination, we assume that 15 years post-licensure, the boosting mechanism known as asymptomatic endogenous reactivation principally serves to limit HZ incidence to 550 per 100,000 person-years in unvaccinated individuals <50 with a previous history of natural varicella—since there has been a vaccine-induced decline in exogenous boosting. We estimate universal varicella vaccination has the impact of an additional 14.6 million (42%) HZ cases among adults aged <50 years during a 50 year time span at a substantial medical cost burden of US$ 4.1 billion or US$ 80 million annually utilizing an estimated mean healthcare provider cost of US$ 280 per HZ case.