Challenges in confirming a varicella outbreak in the two-dose vaccine era

Background

A second dose of varicella vaccine was recommended for U.S. children in 2006. We investigated a suspected varicella outbreak in School District X, Texas to determine 2-dose varicella vaccine effectiveness (VE).

Methods

A varicella case was defined as an illness with maculopapulovesicular rash without other explanation with onset during April 1–June 10, 2011, in a School District X student. We conducted a retrospective cohort in the two schools with the majority of cases. Lesion, saliva, and environmental specimens were collected for varicella-zoster virus (VZV) PCR testing. VE was calculated using historic attack rates among unvaccinated.

Results

In School District X, 82 varicella cases were reported, including 60 from Schools A and B. All cases were mild, with a median of 14 lesions. All 10 clinical specimens and 58 environmental samples tested negative for VZV. Two-dose varicella vaccination coverage was 66.4% in Schools A and B. Varicella VE in affected classrooms was 80.9% (95% CI: 67.2–88.9) among 1-dose vaccinees and 94.7% (95% CI: 89.2–97.4) among 2-dose vaccinees in School A, with a second dose incremental VE of 72.1% (95% CI: 39.0–87.3). Varicella VE among School B students did not differ significantly by dose (80.1% vs. 84.2% among 1-dose and 2-dose vaccinees, respectively).

Conclusion

Laboratory testing could not confirm varicella as the etiology of this outbreak; clinical and epidemiologic data suggests varicella as the likely cause. Better diagnostics are needed for diagnosis of varicella in vaccinated individuals so that appropriate outbreak control measures can be implemented.     

Neurological complications of varicella in childhood: Case series and a systematic review of the literature

Although varicella has usually an uncomplicated course in early childhood, several neurological complications may occur. We conducted a study to review the type and the rate of varicella neurological complications in a case series of hospitalized immunologically healthy children over nearly a 8 year period. We also systematically reviewed data from the literature to estimate the rate of varicella neurological complications. In our case reports, the proportion of neurological complications among all those hospitalized for varicella was of 21.7% (CI 17.9-26%). The pooled prevalence of neurological complications resulting from the systematic review of the literature identifies the likelihood of such complications in the range of 13.9-20.4%. Although neurological complications of chickenpox do not frequently result in permanent sequelae, they represent significant determinants of prolonged hospital stay and of other indirect costs. The obtained results may be useful for estimating costs associated with hospitalization from varicella in cost-benefit analysis for immunization.     

Varicella breakthrough infection and effectiveness of 2-dose varicella vaccine in China

Background2-dose varicella vaccination has been available in Ningbo city, China since 2014 in the private sector. This study aimed to evaluate the breakthrough varicella infection rate, and to examine overall and incremental effectiveness of 2-dose varicella vaccination among Chinese children.MethodsA retrospective investigation was done among native children born from 2008 to 2013 in active surveillance area in Ningbo, China. Between 2009 and 2016, demographic information and data on varicella vaccination were collected by Ningbo’s Immunization Information System, and information of varicella infections were obtained from China Information System for Disease Control and Prevention. The logistic regression was conducted to estimate varicella vaccine effectiveness (VE).ResultA total of 107,324 local children were enrolled in the cohort analysis and 95.11% of these children with no varicella disease history received at least 1-dose varicella vaccine from 2009 to 2016. The total breakthrough varicella infection rate (BVR) was 0.37% for all the vaccinated children and 0.04% for 2-dose vaccination. The annual BVR ranged from 0.01% to 0.49% for 1-dose of varicella vaccine and from 0.01% to 0.02% for 2-dose. The infection rates both in the unvaccinated children and the 1-dose children were decreasing after 2-dose vaccination implemented in 2014 (Unvaccinated: P < 0.001 for trend; 1-dose: P = 0.003 for trend). The VE against all varicella was 50.3% (95% CI: 39.8%–59.0%) for 1-dose (P < 0.001) and 98.7% (95% CI: 98.1%–99.1%) for 2-dose (P < 0.001), and the incremental VE was 97.4% (95% CI: 96.2%–98.2%) compared with 1-dose (P < 0.001).ConclusionThe 2-dose regimen provided excellent protection to prevent all varicella, and the universal 2-dose regimen of varicella vaccine should be recommended to prevent the varicella disease among children in China.     

Long-term safety and efficacy of varicella vaccination in children with juvenile idiopathic arthritis treated with biologic therapy

ObjectiveTo evaluate the long-term safety and efficacy of varicella vaccination in children with juvenile idiopathic arthritis (JIA) treated with biologics.MethodsWe performed a prospective study with long term follow up. Six patients with JIA treated with biologics, received 2 doses of varicella vaccine. Before vaccination, JIA was stable on therapy and peripheral blood lymphocyte populations were within normal limits. After vaccination, children were followed for disease activity, infections and production of protective antibodies.ResultsThere were no serious side effects after vaccination and no varicella infection. Disease activity remained stable. Five patients (83%) produced protective antibodies against varicella virus 6 weeks after the second vaccination. One patient with low level of protective antibodies got mild varicella infection 4 months after the second vaccination.ConclusionVaricella vaccination appears to be safe in our group of six JIA patients treated with biologics. Vaccination does not always protect against varicella infection.     

Single-dose varicella vaccine effectiveness in Brazil: A case-control study

BackgroundVaricella vaccine was introduced into the Brazilian Immunization Program in October 2013, as a single-dose schedule administered at 15 months of age. Its effectiveness had not yet been assessed in the country.MethodsA matched case-control study was carried out in São Paulo and Goiânia (Southeast and Midwest regions, respectively), Brazil. Suspected cases, were identified through a prospective surveillance established in the study sites. All cases had specimens from skin lesion collected for molecular laboratory testing. Cases were confirmed by either clinical or PCR of skin lesions and classified as mild, moderate, and severe disease.Two neighborhood controls were selected for each case. Cases and controls were aged 15–32 months and interviewed at home. Evidence of prior vaccination was obtained from vaccination cards. Univariate and multivariate logistic regression models were used, and odds ratio and its respective 95% confidence intervals were estimated. Vaccine effectiveness was estimated by comparing de odds of having received varicella vaccine among cases and controls.ResultsA total of 168 cases and 301 controls were enrolled. Moderate and severe illness, was found in 33.3% and 9.9% of the cases. Effectiveness of a single dose varicella vaccine was 86% (95%CI 72–92%) against disease of any severity and 93% (95%CI 82–97%) against moderate and severe disease. Out of 168 cases, 81.8% had positive PCR results for wild-type strains, and 22.0% were breakthrough varicella cases. Breakthrough cases were milder compared to non-breakthrough cases (p < .001).ConclusionsEffectiveness of single dose varicella vaccine in Brazil is comparable to that in other countries where breakthrough varicella cases have also been found to occur. The goal of the varicella vaccination program, along with disease burden and affordability should be taken into consideration when considering the adoption of a second dose of varicella vaccine into national immunization programs.     

烟台市15岁以下儿童水痘发病特征及危险因素分析

目的 分析烟台市15岁以下儿童水痘发病特征及危险因素,为烟台市水痘防控工作提供理论依据。方法 收集2011-2015年烟台市15岁以下儿童水痘的发病特征进行描述性分析;采取病例对照研究方法,对水痘危险因素进行调查分析。结果 2011-2015年烟台市15岁以下儿童水痘发病占病例总数的48.73%,10~14岁年龄组所占构成比最高(占39.33%);发病率呈逐年下降趋势,4~6岁下降幅度最大,达48.80%,其他年龄组均有不同程度的下降。发病高峰为每年的11-1月份和4-6月份,分别占42.60%和31.34%。所有地区均有水痘病例报告,城市高于农村。儿童水痘病例以轻型和中型为主,97.78%的病例无并发症。86.74%的水痘病例无水痘疫苗免疫史。分析结果显示,水痘病人接触史、带状疱疹病人接触史、医院就诊史可能是水痘发病的危险因素,接种水痘疫苗是水痘发病的保护因素。结论 做好水痘病例的管理及加强水痘疫苗接种可有效预防水痘的发生。     

Report of varicella outbreak in a low vaccination coverage group of otherwise healthy children in Italy: the role of breakthrough and the need of a second dose of vaccine

We describe an outbreak of varicella at a preschool center in Southern Italy, in the period January–May 2009, among children with a vaccination coverage of 53.9% for one dose.     

The impact of two-dose varicella vaccination on varicella and herpes zoster incidence in South Korea using a mathematical model with changing population demographics

BackgroundIn South Korea, one-dose varicella vaccination was introduced to the National Immunization Program in 2005, but varicella outbreaks have continued to occur. Therefore, a two-dose vaccination strategy is considered.MethodsWe developed an age-structured deterministic compartment model using Korean population projection data. The impact of adding a second dose of varicella vaccine on varicella and herpes zoster (HZ) epidemiology was assessed under four different vaccine effectiveness (VE) scenarios (base, moderate, lowest, highest) and the optimal timing of the second vaccine dose (18 months, 4, 5, or 6 years of age) was examined over the period 2020–2065.ResultsA two-dose vaccination schedule reduced the cumulative varicella incidence by > 90% compared to no vaccination, regardless of the VE. The additional reduction attributable to a second dose compared to a single dose was greatest (82%) with the lowest VE scenario. A second dose at 6 years of age reduced the varicella incidence at a population level, whereas a second dose at 18 months of age reduced the varicella incidence primarily in the target birth cohorts. Routine vaccination at the age of 18 months with a catch-up vaccination of 6-year-olds was the optimal strategy for birth cohort and population-level control. HZ incidence continued to increase under no vaccination scenario, which represents the effect of aging population. Under a two-dose scenario, the additional increase in HZ incidence attributable to the reduced exogenous boosting was small relative to a one-dose scenario and a further reduction in HZ cases was observed.ConclusionA two-dose varicella vaccination schedule would significantly reduce varicella and HZ incidence in the long term. A second dose at the age of 18 months with a catch-up vaccination of 6-year-olds would be optimal for controlling varicella in South Korea.     

北京市小学生水痘疫苗应急接种效果及影响因素评价

目的 评价北京市小学生水痘疫苗应急接种效果及其影响因素.方法 对2007年5-7月北京市4个区(县)49起小学水痘疫情应急接种进行前瞻性观察.将应急接种前发生水痘病例的班级和同楼层或同排平房无病例班级的全体7882名学生作为观察对象;收集水痘病史、疫苗接种史、病例个案等资料,采用描述流行病学方法评价水痘疫苗应急接种保护效果.结果 水痘疫苗应急接种总体保护率为85.26%.首例水痘病例既往有疫苗接种史、疫情发现及时、病例数少、距首例病例发病时间短的水痘疫苗应急接种保护效果较好;分别对水痘疫苗应急接种前已发生病例班级和同楼层或同排平房无病例班级的应急接种效果进行分析,疫苗保护率分别为84.26%和87.06%.首例病例既往有水痘疫苗接种史的应急接种保护率分别为92.09%和93.06%,均高于首例病例既往无疫苗接种史的学校.应急接种前仅发生1例病例的疫曲接种保护率分别为83.09%和93.02%,均高于应急接种前已发生2～3例病例的学校.首例病例发病后<5 d完成消毒、隔离和应急接种等综合措施的疫苗保护率分别为86.60%和92.73%,均高于首例病例发病后<5 d完成消毒、隔离、但≥5 d完成应急接种的学校.此外,学校教室为平房、无校车或食堂、无住宿、学生间无搭伴包车或就餐的学校应急接种后疫苗保护率较高.结论 北京市小学生水痘疫苗应急接种具有较高的保护率,有利于控制水痘疫情.     

北京市房山区儿童水痘自然免疫现状横断面调查

目的 掌握北京市房山区儿童水痘自然免疫现状,为今后有效开展水痘预防与控制提供流行病学依据.方法 采用横断面调查的方法,选取有代表性的1～14岁健康儿童作为研究对象,进行问卷调查和血样采集,采用酶联免疫吸附法检测血清水痘IgG抗体.结果 648名儿童水痘抗体阳性率为44.1%;抗体阳性率在不同性别、户籍间差别无统计学意义(P＞0.05),在不同年龄和地区间儿童水痘抗体阳性率差别有统计学意义(P＜0.01),3～5岁年龄组、山区儿童水痘抗体阳性率最低,分别为30.6%和34.4%.结论 该地区儿童水痘抗体阳性率偏低,尚不能形成有效的免疫屏障,山区和3～5岁儿童是重点保护地区和人群,需采取有效措施加强这一薄弱环节的水痘预防管理与控制工作.     

The first case of Nocardia transvalensis infection in varicella in a previously immunocompetent child

A child referred to Infectious Disease Unit for varicella complicated by pneumonia with pleural effusion. Due to not improvement, laboratory search was extended to uncommon pathogens, revealing Nocardia transvalensis infection.It is likely that varicella induced immunodepression, facilitating opportunistic infection in an otherwise healthy and immunocompetent child. To our knowledge, our report is the first case of Nocardia infection in varicella.     

Evaluation of Australia's varicella vaccination program for children and adolescents

Objective

This paper examines how the monovalent varicella vaccine for children, with an adolescent catch-up dose, was introduced into Australia's National Immunisation Program (NIP), focusing on programme implementation.

Methods

Semi-structured interviews were conducted with key informants involved in programme implementation. Key themes from interviews were identified through content analysis. Childhood coverage was assessed using data from the Australian Childhood Immunisation Register (ACIR) with adolescent coverage obtained from state/territory immunisation programmes. Seroprevalence data were analysed from national serosurveys conducted before and after programme commencement.

Results

Implementation challenges for both parents and providers included: (a) parental report of previous infection as an exclusion criterion; (b) introducing a vaccine on its own at 18 months of age; and (c) adding the adolescent dose into existing school-based vaccination programmes with parental reported exclusion criteria. Despite these challenges, coverage rapidly reached 83% by 24 months of age and 30–33% for the adolescent catch-up dose. When considered in conjunction with estimated pre-vaccination natural immunity in both target groups (20% and 83%, respectively) coverage can be considered high. The serosurvey under-estimated coverage in 2-year-old children but was useful to assess trends in population immunity.

Conclusion

The introduction of a single dose of monovalent varicella vaccine at 18 months of age and a school-based catch-up programme at 11–13 years of age successfully achieved high coverage, notwithstanding some challenges. Reported natural infection has been an exclusion criterion for vaccination, but as the programme matures and circulation of wild-type virus decreases, the need for this warrants consideration. There is a need for sensitive laboratory assays to measure vaccine-induced immunity at a population level.     

水痘疫苗接种儿童水痘IgG水平的横断面研究

[目的] 观察儿童1剂水痘疫苗（VarV）免疫的持续效果及其影响因素,初探加强免疫方案。[方法] 采集≤12岁接种1剂水痘疫苗的健康儿童手指末梢血629份,用定量酶联免疫吸附试验（ELISA）测定水痘IgG水平,同时调查VarV记录和水痘患病史。[结果] 儿童水痘IgG浓度值呈偏态分布,P₂₅为40.19 mIU/mL,P₅₀为96.42 mIU/mL,P₇₅为290.82 mIU/mL,抗体对数值为（2.02±0.69） mIU/mL（95%CI：1.97～2.07）。不同接种年限和不同年龄组抗体浓度值差异有统计学意义（F=2.723,P=0.006和F=3.933,P=0.002）。儿童水痘IgG阳性率为69.0%,本地儿童抗体阳性率显著高于外来儿童（χ²=3.934,P=0.047）。抗体阳性率按VarV接种年限呈U形分布,拐点在接种后4年。[结论] 水痘疫苗接种后4年IgG浓度值降到低点,易受水痘感染。建议儿童在接种第一剂满3年后,加强1剂VarV免疫以获更有效免疫保护。     

Attitudes towards varicella vaccination in parents and paediatric healthcare providers in Hungary

BackgroundVaricella vaccination is important in prevention of childhood infection. Aim of this cross-sectional study was to survey attitudes and determinants of support or refusal of varicella vaccination in parents and in paediatric healthcare professionals, mainly health visitors in Hungary prior to the introduction of this vaccine in National Immunization Program in 2019.MethodsBetween October 2018 and February 2019, 1042 parents and 198 healthcare professionals completed a self-administered anonymous questionnaire regarding sociodemographic background, knowledge and attitudes towards varicella vaccination, and reasons for non-vaccination.ResultsFrom the participating parents 53.3% have vaccinated at least one of their children. Vaccination rate was significantly higher in families with <3 children, living in the capital, among those who have seen complications of varicella and among parents with university degree. Most important positive determinant was recommendation of the vaccine by healthcare professionals: 77.8% of parents accepted vaccination when recommended by the paediatrician, despite the cost of the vaccine, whereas only 17.3% of parents vaccinated their children when the vaccine was not recommended by paediatrician. Most important reasons for non-vaccination was finding the vaccine unnecessary, concerns regarding side effects, and not believing in the vaccine’s effectiveness. Among paediatric healthcare professionals, support rate of universal varicella vaccination was 76.3%. Support rate was higher among those who have seen complications of varicella more often and those who consider varicella a severe infection. Reasons of professionals who do not support universal varicella vaccination were similar to those of vaccine hesitant parents. Practice of intentional exposure of non-immune child to infected ones still exist.ConclusionsEducational programs are needed for parents and health visitors to address concerns regarding vaccination. Paediatricians are the most trusted source of information for parents hence they have a significant responsibility and parents likely follow their recommendations.     

上海市部分地区儿童水痘疫苗免疫后流行病学效果观察

[目的]观察水痘疫苗接种情况和接种水痘疫苗1~7年后的水痘发病情况。[方法]在本市部分地区选择接种组和未接种组儿童,采用统一调查问卷调查水痘疫苗接种情况和水痘发病情况。[结果]调查地区儿童水痘疫苗累积接种率为4.12%,12岁以下人群为26.90%。1999~2005年接种组总发病率为1.00%,未接种组为4.35%,水痘疫苗接种保护率为77.0%;各年接种组发病率分别为1.62%、2.06%、0.29%、0.43%和0.66%,疫苗接种保护率在67.9%~90.3%之间;接种进口和国产水痘疫苗后水痘发病率分别为0.8%和1.0%,疫苗接种保护率分别为81.6%和75.3%。[结论]本市儿童水痘疫苗接种率呈上升趋势。水痘疫苗对接种者具有较好的保护率,进口和国产水痘疫苗的保护率相似。     

Development of varicella vaccine in Japan and future prospects

In Japan, Dr. Michiaki Takahashi (1928–2013) successfully developed the first live attenuated varicella vaccine in the world. The virus used for this vaccine was varicella-zoster virus isolated from the vesicular fluid of a child with typical varicella and it was named the Oka strain after the family name of the child. In 1974, a patient with nephrosis developed varicella in the Pediatric Ward, and uninfected pediatric patients received varicella vaccine immediately. As a result, there were no cases of varicella in the other children and all of the vaccinated children acquired immunity to the disease. These results were published in the Lancet, demonstrating the safety and efficacy of varicella Oka strain vaccine for the first time. When clinical studies were conducted at the start of vaccine development, most of the subjects were pediatric patients with a high risk of contracting severe varicella. Therefore, the development process was different from that for other vaccines, since clinical studies are generally performed in healthy individuals.This vaccine was approved in Japan in 1986, and voluntary single-dose vaccination for children aged 1 year or older was started in 1987. However, the vaccination coverage rate remained low and the number of patients with varicella did not decrease significantly. Due to its voluntary status, the cost of vaccination was borne by the child's family and this was considered to be a reason for the low coverage rate. Moreover, although the vaccine achieved a good antibody response, the number of cases of breakthrough varicella (BV) was relatively high and showed an increasing trend that was also a concern. In order to increase the coverage rate and reduce BV, the Japanese government changed the varicella vaccination policy from voluntary to routine vaccination in October 2014. At the same time, a two-dose schedule was introduced that involved administration of the vaccine twice at an interval of at least 3 months up to the age of 3 years.At present, cases of varicella are only monitored at the pediatric sentinel clinics in Japan. Therefore, we need to establish a system to survey all patients, in order to demonstrate the efficacy of varicella vaccine based on detailed surveillance data. We also need to investigate the optimum timing of the second dose of the vaccine and the necessity for further booster vaccination. A combined live vaccine containing varicella vaccine has not yet been approved in Japan. Because of the greater convenience of combined vaccines, development and introduction of such a vaccine in the future would be desirable. Routine varicella vaccination is also expected to eventually reduce the occurrence of herpes zoster, although there are no supporting epidemiological data. The prevalence of herpes zoster has attracted attention, but it is necessary to develop a surveillance system for this disease. In March 2016, use of varicella vaccine to prevent herpes zoster in adults aged 50 years or older was approved in Japan, and the results of this policy change need to be assessed.     

Effectiveness of post-exposure prophylaxis during varicella outbreaks among primary and middle school students in Shanghai: An analysis of three-year surveillance data

ObjectivesTo evaluate the effectiveness of post-exposure prophylaxis conducted during varicella outbreaks among students in Shanghai.MethodsSurveillance data were collected from September 1, 2013 to December 31, 2016 involving 3524 susceptible students in 109 primary and middle school classes where emergency vaccinations (EVs) had been administered. Students were divided into two groups according to their prior vaccination (PV) varicella vaccine status. A secondary attack rate was used to compare EV and non-EV groups using a chi-squared test. Stratification analyses were performed, adjusting for the EV administration date, the vaccination coverage rate, and the number of cases prior to the EV.ResultsThe effectiveness rate was 92.2% (95% confidence interval (CI): 37.1–99.0%) when EV was applied within 3 days following the outbreak onset date, and 95.2% (95% CI: 79.9–98.8%) when vaccination coverage was ≥80% among students with PV. When students with PV received an EV for varicella within 3 days, the effectiveness rate was 100%.ConclusionsEV showed high protective effectiveness for varicella during outbreaks, especially if administered within 3 days of an outbreak and in conjunction with a high coverage rate.     

中国1～12岁健康儿童接种1剂水痘减毒活疫苗保护效果的系统评价与证据质量分析

目的 系统评价1～12岁健康儿童接种1剂水痘减毒活疫苗保护效果（VE）,探索运用GRADE（Grades of Recommendation, Assessment, Development, and Evaluation）证据质量评级方法评价疫苗效果观察性研究。方法 检索2019年以前关于中国1～12岁健康儿童1剂水痘减毒活疫苗VE的文献,采用纽卡斯尔-渥太华量表进行文献质量评价,采用Meta分析计算水痘疫苗VE,对研究类型、是否为暴发疫情、文献质量、年龄分亚组计算VE。采用GRADE方法评价整合证据质量。结果 共纳入32篇文献,合并后VE值为75%（95% CI：68%～80%）,亚组分析暴发疫情VE（66%,95% CI：57%～73%）低于非暴发疫情［85%（95% CI：78%～89%）］,<6岁儿童VE［84%（95% CI：77%～89%）］高于≥6岁儿童VE［60%（95% CI：51%～68%）］,不同研究类型、不同文献质量的VE差异无统计学意义。整合证据评级VE证据质量为“极低”,分别在偏倚风险和不一致性方面降一级,在间接性、不精确性和发表偏倚方面未降级。结论 中国1～12岁健康儿童1剂次水痘减毒活疫苗可提供中等水平保护,但≥6岁儿童VE明显降低,建议对<6岁儿童开展2剂次水痘疫苗接种。GRADE的证据质量评级方法可用于疫苗效果的观察性研究,建议制定观察性研究技术指南,提高证据体的整体质量。     

Administration of live attenuated varicella vaccine to children with cancer before starting chemotherapy

From July 1985 to February 1987, of 46 consecutive children with cancer (26 male, 20 female; median age, 4 years) with no prior history of chickenpox, the initial 30 patients were randomized either to receive or not to receive live attenuated varicella vaccine (LAVV) before chemotherapy was started and the remaining 16 patients were all immunized without randomization. Before immunization, Varicella zoster (VZ) antibodies were detected by immunofluorescence and ELISA in 11 (34%) of 32 vaccinated children and two (14%) of 14 controls, indicating previous infection. A booster effect was evident in 70% of them and no side effects were noted. Ten (28%) of 32 vaccinees were excluded from the analysis because of early death due to cancer (1–4 weeks). Seroconversion was demonstrated in ten (77%) of 13 vaccinees, with high antibody titres. Only three of them lost their antibodies 2 years after immunization, as disclosed by serological follow-up. Eight out of 13 vaccinees had household contacts with VZ and none became infected. Zoster immunoglobulin (ZIG) was never given. Among controls, seven out of 14 were exposed to VZ and four (57%) became infected. Mild side effects were observed in four (12.5%) out of 32 vaccinees (three with papulovesicular rash, 6—30 lesions, and one with a 3-day intermittent fever). Local reactions, zoster and spreading of vaccinal virus did not occur. LAVV proved to be safe and effective when administered before starting chemotherapy to children with cancer and no history of varicella.