Tick-borne encephalitis

蜱传脑炎
  • 文章类型: Journal Article
    越来越多的研究表明,病毒性脑膜炎和脑膜脑炎,即使是那些患有轻度脑膜炎的人,会导致残留的后遗症。
    我们旨在调查病毒性脑膜炎和脑膜脑炎/脑炎患者的长期结局,以及长期后遗症对患者社会和职业日常生活的影响。
    总共50名患者(12%的脑炎,58%的脑膜脑炎和30%的脑膜炎)和21名对照者参加了研究。最常见的原因是蜱传脑炎(TBE)病毒。2年后最重要的持续体征和症状是主观认知障碍(36%),疲劳和/或白天过度嗜睡(31%),夜间睡眠受到干扰(31%)和头痛(13%),以及在认知努力后感觉更快疲惫(53%)。与急性期的疾病严重程度无关,近三分之一的患者报告说,由于长期后遗症,社会和/或职业生活受到轻度损害,与健康对照相比,健康状况评估中的得分仍然显着降低。
    无论急性疾病的严重程度如何,尽管在2年内不断改善,67%的患者仍有持续的体征和症状,但这些仅与约30%的患者的日常社交或职业生活有关。
    UNASSIGNED: An increasing number of studies demonstrate that viral meningitis and meningoencephalitis, even those with a mild course of meningitis, can result in residual sequelae.
    UNASSIGNED: We aimed to investigate the long-term outcome in both viral meningitis and meningoencephalitis/encephalitis patients and impact of long-term sequelae on patients\' social and professional daily lives in a prospective observational study with a follow-up period of 20 months.
    UNASSIGNED: A total of 50 patients (12% encephalitis, 58% meningoencephalitis and 30% meningitis) and 21 control persons participated in the study. The most common cause was the tick-borne encephalitis (TBE) virus. The most important persistent signs and symptoms after 2 years were subjective cognitive impairment (36%), fatigue and/or excessive daytime sleepiness (31%), disturbed nighttime sleep (31%) and headaches (13%), as well as feeling more rapidly exhausted after cognitive effort (53%). Independent of disease severity in the acute phase, almost one third of patients still reported mildly impaired social and/or professional life due to the long-term sequelae, with scores in the health status assessment still significantly lower compared to healthy controls.
    UNASSIGNED: Regardless of the severity of the acute illness and despite constant improvement within 2 years, 67% of patients still had persistent signs and symptoms, but these were only relevant to everyday social or professional life in about 30% of these patients.
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  • 文章类型: Journal Article
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  • 文章类型: Journal Article
    BackgroundTick传脑炎(TBE)是一种严重的,疫苗可预防的中枢神经系统病毒感染。儿童和青少年的症状通常比成人轻,虽然严重的疾病确实发生。更好地了解疾病负担和疫苗介导的保护持续时间对于疫苗接种建议很重要。为了估计TBE疫苗接种覆盖率,瑞士0-17岁人群的疾病严重程度和疫苗有效性(VE)。方法使用瑞士国家疫苗接种覆盖率调查(SNVCS)估计2005年至2022年之间的疫苗接种覆盖率。一个全国性的,评估疫苗摄取的重复横断面研究。使用瑞士疾病监测系统的数据确定2005年至2022年TBE的发生率和严重程度,并使用病例对照分析计算VE。将TBE案例与SNVCS控件进行匹配。结果在研究期间,疫苗接种覆盖率大幅增加,从4.8%(95%置信区间(CI):4.1-5.5%)到50.1%(95%CI:48.3-52.0%)。无论年龄如何,TBE病例的报告临床症状相似。与未接种疫苗相比,未完全(1-2剂量)和完全(≥3剂量)接种疫苗的病例中神经系统受累的可能性较小。对于不完全的疫苗接种,VE为66.2%(95%CI:42.3-80.2),而完整疫苗接种的VE为90.8%(95%CI:87.7-96.4).疫苗有效性仍然很高,83.9%(95%CI:69.0-91.7)自上次疫苗接种以来长达10年。结论即使小于5岁的儿童也会经历严重的TBE。不完整和完整的疫苗接种可防止疾病的神经系统表现。完整的疫苗接种为TBE提供长达10年的持久保护。
    BackgroundTick-borne encephalitis (TBE) is a severe, vaccine-preventable viral infection of the central nervous system. Symptoms are generally milder in children and adolescents than in adults, though severe disease does occur. A better understanding of the disease burden and duration of vaccine-mediated protection is important for vaccination recommendations.AimTo estimate TBE vaccination coverage, disease severity and vaccine effectiveness (VE) among individuals aged 0-17 years in Switzerland.MethodsVaccination coverage between 2005 and 2022 was estimated using the Swiss National Vaccination Coverage Survey (SNVCS), a nationwide, repeated cross-sectional study assessing vaccine uptake. Incidence and severity of TBE between 2005 and 2022 were determined using data from the Swiss disease surveillance system and VE was calculated using a case-control analysis, matching TBE cases with SNVCS controls.ResultsOver the study period, vaccination coverage increased substantially, from 4.8% (95% confidence interval (CI): 4.1-5.5%) to 50.1% (95% CI: 48.3-52.0%). Reported clinical symptoms in TBE cases were similar irrespective of age. Neurological involvement was less likely in incompletely (1-2 doses) and completely (≥ 3 doses) vaccinated cases compared with unvaccinated ones. For incomplete vaccination, VE was 66.2% (95% CI: 42.3-80.2), whereas VE for complete vaccination was 90.8% (95% CI: 87.7-96.4). Vaccine effectiveness remained high, 83.9% (95% CI: 69.0-91.7) up to 10 years since last vaccination.ConclusionsEven children younger than 5 years can experience severe TBE. Incomplete and complete vaccination protect against neurological manifestations of the disease. Complete vaccination offers durable protection up to 10 years against TBE.
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  • 文章类型: Journal Article
    背景:蜱传脑炎(TBE)病毒感染中枢神经系统,并可能导致严重的神经系统并发症或死亡。这项研究评估了免疫原性,安全,1岁及以上日本参与者的TBE疫苗耐受性。
    方法:此阶段3,多中心,单臂,在日本成人(≥16岁)和儿童(1-<16岁)人群中进行了开放标签研究.参与者在3次访问中每次接受单次0.5mL(成人)或0.25mL(儿科)剂量的TBE疫苗。主要终点是剂量3后4周血清阳性(中和试验[NT]滴度≥1:10)的参与者比例。次要和探索性终点包括剂量2后4周的NT血清阳性率,剂量2和3后4周的免疫球蛋白G(IgG)血清阳性率,NT几何平均滴度(GMT),IgG几何平均浓度(GMC),几何平均倍数上升。主要的安全终点是局部反应的频率,系统性事件,不良事件(AE),严重的AE。
    结果:在100名成人和65名儿科参与者中,99.0%和100.0%完成了研究,分别。剂量3后,98.0%的成人和100.0%的儿科参与者达到NT血清阳性;剂量2后的血清阳性为93.0%和92.3%,分别。在这两个年龄组中,剂量2和3后IgG血清阳性率分别≥90.0%和≥96.0%;剂量3后4周GMT和GMC最高。反应性事件的严重程度通常为轻度至中度,持续时间短。15.0%(成人)和43.1%(儿童)的参与者报告了不良事件。没有危及生命的AE,导致停药的不良事件,即时AE,相关AE,或报告死亡。没有严重的AE被认为与TBE疫苗有关。
    结论:TBE疫苗在1岁及以上的日本参与者中引发了强烈的免疫反应。3-剂量方案是安全和良好的耐受性,研究结果与该TBE疫苗的已知安全性一致.
    结果:gov:NCT04648241。
    BACKGROUND: Tick-borne encephalitis (TBE) virus infects the central nervous system and may lead to severe neurological complications or death. This study assessed immunogenicity, safety, and tolerability of TBE vaccine in Japanese participants 1 year of age and older.
    METHODS: This phase 3, multicenter, single-arm, open-label study was conducted in Japanese adult (≥ 16 years) and pediatric (1-< 16 years) populations. Participants received a single 0.5-mL (adult) or 0.25-mL (pediatric) dose of TBE vaccine at each of 3 visits. The primary endpoint was the proportion of participants who were seropositive (neutralization test [NT] titer ≥ 1:10) 4 weeks after Dose 3. Secondary and exploratory endpoints included NT seropositivity rates 4 weeks after Dose 2, immunoglobulin G (IgG) seropositivity 4 weeks after Doses 2 and 3, NT geometric mean titers (GMTs), IgG geometric mean concentrations (GMCs), and geometric mean fold rises. Primary safety endpoints were frequencies of local reactions, systemic events, adverse events (AEs), and serious AEs.
    RESULTS: Among 100 adult and 65 pediatric participants, 99.0 % and 100.0 % completed the study, respectively. NT seropositivity was achieved in 98.0 % adult and 100.0 % pediatric participants after Dose 3; seropositivity after Dose 2 was 93.0 % and 92.3 %, respectively. In both age groups, IgG seropositivity was ≥ 90.0 % and ≥ 96.0 % after Doses 2 and 3, respectively; GMTs and GMCs were highest 4 weeks after Dose 3. Reactogenicity events were generally mild to moderate in severity and short-lived. AEs were reported by 15.0 % (adult) and 43.1 % (pediatric) of participants. No life-threatening AEs, AEs leading to discontinuation, immediate AEs, related AEs, or deaths were reported. No serious AEs were considered related to TBE vaccine.
    CONCLUSIONS: TBE vaccine elicited robust immune responses in Japanese participants 1 year of age and older. The 3-dose regimen was safe and well tolerated, and findings were consistent with the known safety profile of this TBE vaccine.
    RESULTS: gov: NCT04648241.
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  • 文章类型: Journal Article
    蜱传脑炎(TBE)病毒的自然传播周期通过与栖息地特征紧密相关的蜱和关键宿主之间的复杂相互作用而增强。已知野生动物宿主物种的多样性及其相对丰度会影响蜱传疾病的传播。因此,在当前全球生物多样性丧失的背景下,我们探讨了栖息地丰富度与欧洲人类TBE病例模式之间的关系,以评估生物多样性在疾病风险缓解中的作用。
    我们使用欧洲监测系统(TESSy)在2017年至2021年间报告的来自15个国家的官方流行病学数据,评估了879个欧洲地区的人类TBE病例分布。我们通过二项回归研究了TBE存在与栖息地丰富度指数(HRI1)之间的关系。我们使用2017年至2021年在特伦托省和贝卢诺省的227个城市收集的数据,在地方尺度上验证了我们的发现。意大利北部有两个已知的TBE病灶。
    我们的结果表明,在我们数据集中的欧洲地区,HRI对人类TBE病例的存在概率具有显着的抛物线效应,和一个重要的,HRI对意大利北部TBE局部存在的负面影响。在两个空间尺度上,在HRI值较高的地区,TBE风险降低。
    据我们所知,尚未努力探索生物多样性与TBE风险之间的关系,可能是由于缺乏高分辨率,关于关键寄主物种丰度或密度的大规模数据。因此,在这项研究中,我们认为栖息地丰富度是脊椎动物寄主多样性的代表。结果表明,在高度多样化的栖息地中,TBE风险降低。因此,生物多样性的丧失可能会增加人类和野生动物的TBE风险。这种关联与支持以下假设相关:维持高度多样化的生态系统可以减轻疾病风险。
    UNASSIGNED: The natural transmission cycle of tick-borne encephalitis (TBE) virus is enhanced by complex interactions between ticks and key hosts strongly connected to habitat characteristics. The diversity of wildlife host species and their relative abundance is known to affect transmission of tick-borne diseases. Therefore, in the current context of global biodiversity loss, we explored the relationship between habitat richness and the pattern of human TBE cases in Europe to assess biodiversity\'s role in disease risk mitigation.
    UNASSIGNED: We assessed human TBE case distribution across 879 European regions using official epidemiological data reported to The European Surveillance System (TESSy) between 2017 and 2021 from 15 countries. We explored the relationship between TBE presence and the habitat richness index (HRI1) by means of binomial regression. We validated our findings at local scale using data collected between 2017 and 2021 in 227 municipalities located in Trento and Belluno provinces, two known TBE foci in northern Italy.
    UNASSIGNED: Our results showed a significant parabolic effect of HRI on the probability of presence of human TBE cases in the European regions included in our dataset, and a significant, negative effect of HRI on the local presence of TBE in northern Italy. At both spatial scales, TBE risk decreases in areas with higher values of HRI.
    UNASSIGNED: To our knowledge, no efforts have yet been made to explore the relationship between biodiversity and TBE risk, probably due to the scarcity of high-resolution, large-scale data about the abundance or density of critical host species. Hence, in this study we considered habitat richness as proxy for vertebrate host diversity. The results suggest that in highly diverse habitats TBE risk decreases. Hence, biodiversity loss could enhance TBE risk for both humans and wildlife. This association is relevant to support the hypothesis that the maintenance of highly diverse ecosystems mitigates disease risk.
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  • 文章类型: Multicenter Study
    目的:我们的目的是研究蜱传脑炎患者神经元和神经胶质细胞损伤的生物标志物与疾病严重程度之间的相关性。
    方法:前瞻性纳入立陶宛和瑞典诊断的115例蜱传脑炎患者,住院后不久获得脑脊液(CSF)和血清样本。使用预定义的标准,病例被归类为轻度,中度或重度蜱传脑炎。此外,脊髓神经麻痹(脊髓炎)和/或颅神经病变的存在。脑细胞生物标志物胶质纤维酸性蛋白(GFAP)的浓度,YKL-40,S100B,神经颗粒素,在CSF中分析了神经丝光(NfL)和tau,此外,NFL,在血清中测量GFAP和S100B水平。采用Jonckheere-Terpstra检验对连续变量进行分组比较,采用Spearman偏相关检验对年龄进行校正。
    结果:脑脊液和血清GFAP和NfL浓度与疾病严重程度相关,独立于年龄,神经麻痹的存在。标记神经颗粒素,检测CSF中的YKL-40、tau和S100B,血清中的S100B,但它们的浓度与疾病严重程度无关.
    结论:CSF和血清中NfL和GFAP增加的神经元细胞损伤和星形胶质细胞活化与更严重的疾病有关,独立于年龄。CSF中的GFAP和NfL浓度增加以及血清中的NfL也指示脊髓和/或颅神经损伤。NfL和GFAP是tick传脑炎的有希望的预后生物标志物,未来的研究应该集中在确定这些生物标志物与长期后遗症之间的关联。
    Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis.
    One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate or severe tick-borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL-40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere-Terpstra test was used for group comparisons of continuous variables and Spearman\'s partial correlation test was used to adjust for age.
    Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL-40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity.
    Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick-borne encephalitis, and future studies should focus on determining the association between these biomarkers and long-term sequelae.
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  • 文章类型: Journal Article
    目的:蜱传脑炎(TBE)是由蜱传脑炎病毒(TBEV)引起的感染,导致中枢神经系统炎症的症状。TBE在拉脱维亚和其他欧洲国家流行。TBE疫苗通常在拉脱维亚使用,但是疫苗有效性估计是有限的。
    方法:里加·斯特拉丁什大学的研究人员在全国范围内对TBEV感染进行了主动监测。血清和脑脊液进行TBEV特异性IgG和IgM抗体的ELISA检测。通过访谈和病历审查收集疫苗接种史。利用监测和人口调查的数据,使用筛选方法估计疫苗有效性(95%置信区间)和避免的病例.
    结果:2018-2020年有587例实验室鉴定的TBE病例;98.1%(576/587)未接种疫苗,1.5%(9/587)未知或部分接种疫苗,和0.3%(2/587)完全接种疫苗(三剂主要系列和适当定时的加强剂)。TBE导致1.7%(10/587)的TBE死亡。从普通人群中92.0%(13,247/14,399)的人群中确定了TBE疫苗史:38.6%(5113/13,247)未接种疫苗,26.3%(3484/13,247)完全接种疫苗,35.1%(4650/13,247)接受了部分疫苗接种。TBE疫苗对TBE的有效性为99.5%(98.0-99.9),99.5%(97.9-99.9)反对TBE住院,99.3%(94.8-99.9)对中度/重度TBE,99.2%(94.4-99.9)的TBE住院时间>12天。从2018年到2020年,疫苗接种避免了906例TBE病例,包括20人死亡。
    结论:TBE疫苗在预防TBE方面非常有效,中度和重度疾病,和长期住院。为了防止危及生命的TBE,在TBE流行的拉脱维亚和其他欧洲地区,应增加TBE疫苗的吸收和依从性。
    OBJECTIVE: Tick-borne encephalitis (TBE) is an infection by the tick-borne encephalitis virus (TBEV) that results in symptoms of central nervous system inflammation. TBE is endemic in Latvia and other European countries. TBE vaccines are commonly used in Latvia, but vaccine effectiveness estimates are limited.
    METHODS: Study staff at Rīga Stradinš University conducted nationwide active surveillance for TBEV infections. Serum and cerebrospinal fluid were ELISA-tested for TBEV-specific IgG and IgM antibodies. Vaccination history was collected by interview and medical record review. Utilizing data from surveillance and population surveys, vaccine effectiveness (with 95% CIs) and cases averted were estimated using the screening method.
    RESULTS: There were 587 laboratory-identified TBE cases from 2018 to 2020; 98.1% (576/587) were unvaccinated, 1.5% (9/587) were unknown or partially vaccinated, and 0.3% (2/587) were fully vaccinated (three-dose primary series and appropriately timed boosters). TBE resulted in the death of 1.7% (10/587) of TBE cases. TBE vaccine history was ascertained from 92.0% (13 247/14 399) people from the general population: 38.6% (5113/13 247) were unvaccinated, 26.3% (3484/13 247) were fully vaccinated, and 35.1% (4650/13 247) were partially vaccinated. TBE vaccine effectiveness was 99.5% (98.0-99.9) against TBE, 99.5% (97.9-99.9) against TBE hospitalization, 99.3% (94.8-99.9) against moderate/severe TBE, and 99.2% (94.4-99.9) against TBE hospitalization >12 days. From 2018 to 2020, vaccination averted 906 TBE cases, including 20 deaths.
    CONCLUSIONS: TBE vaccine was highly effective in preventing TBE, moderate and severe disease, and prolonged hospitalization. To prevent life-threatening TBE, TBE vaccine uptake and compliance should be increased in Latvia and other European regions where TBE is endemic.
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  • 文章类型: Randomized Controlled Trial
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  • 文章类型: Journal Article
    在德国,蜱传脑炎(TBE)感染主要发生在南部地区。尽管最近发病率有所增加,TBE疫苗接种覆盖率仍然很低,需要针对TBE的额外预防策略。我们于2018年至2020年在德国南部进行的病例对照研究绘制了滴答保护策略的知识/应用,并确定了TBE风险因素。我们计算了赔率比(OR),95%置信区间(CI)。我们采访了581例病例和975例匹配的对照。大多数参与者回忆起一生的蜱叮咬,主要是在走路的时候,园艺,或者徒步旅行.然而,只有45%的病例在暴露时间内发现了蜱虫;另有12%的病例报告了未经巴氏消毒的牛奶摄入量。虽然壁虱保护知识令人满意,应用程序落后。风险因素包括养狗(OR=2.45,95%CI:1.85−3.24),步行≥4×/周(OR=2.11,95%CI:1.42−3.12),园艺≥4×/周(OR=1.83,95%CI:1.11−3.02),和花园接近<250米的森林(OR=2.54,95%CI:1.82−3.56)。应用≥2种蜱保护策略(OR=0.52,95%CI:0.40−0.68)和保持草坪修剪(OR=0.63,95%CI:0.43−0.91)与TBE呈负相关。2020年(可能与大流行有关),报告的病例比以前有更多的步行,可能解释了创纪录的高病例数。我们的研究结果为TBE预防目标提供了指导。森林附近有花园的人,频繁的户外活动,或者狗可以特别受益于有针对性的信息,包括疫苗接种和预防蜱叮咬。
    In Germany, tick-borne encephalitis (TBE) infections mainly occur in southern regions. Despite recent increases in incidence, TBE vaccination coverage remains low, necessitating additional preventive strategies against TBE. Our case-control study in Southern Germany from 2018 to 2020 mapped knowledge/application of tick-protective strategies and identified TBE risk factors. We calculated odds ratios (OR), with 95% confidence intervals (CI). We interviewed 581 cases and 975 matched controls. Most participants recalled lifetime tick bites, mainly while walking, gardening, or hiking. However, only 45% of cases noticed ticks during exposure time; another 12% reported unpasteurized milk intake. While tick-protection knowledge was satisfactory, application lagged behind. Risk factors included dog ownership (OR = 2.45, 95% CI: 1.85−3.24), walks ≥ 4×/week (OR = 2.11, 95% CI: 1.42−3.12), gardening ≥ 4×/week (OR = 1.83, 95% CI: 1.11−3.02), and garden proximity < 250 m of forests (OR = 2.54, 95% CI: 1.82−3.56). Applying ≥2 tick-protective strategies (OR = 0.52, 95% CI: 0.40−0.68) and keeping lawns mowed (OR = 0.63, 95% CI: 0.43−0.91) were inversely associated with TBE. In 2020 (likely pandemic-related), cases reported significantly more walks than previously, potentially explaining the record high case numbers. Our findings provide guidance on targets for TBE prevention. Persons with gardens near forests, frequent outdoor activities, or dogs could particularly benefit from targeted information, including on vaccination and preventing tick bites.
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  • 文章类型: Journal Article
    在接种疫苗的人中,蜱传脑炎(TBE)的严重程度存在差异。我们,因此,分析了住院接种和未接种TBE的患者中严重和轻度疾病的发生,并确定了针对这些疾病形式的疫苗接种的现场有效性(FE)。
    该研究涵盖了2000年至2018年在奥地利住院的所有TBE患者。在巢式病例对照研究中比较了接种疫苗以及年龄和性别匹配的未接种疫苗的患者的临床诊断。FE是根据未接种疫苗和接种疫苗人群的疫苗接种覆盖率和发病率计算的。
    在1545例TBE住院患者中,206人接种了疫苗。在那些,观察到较高比例的严重TBE,尤其是儿童。FE在所有年龄段都很高,对所有形式的疾病都很高。严重TBE的比例较高,可以解释为较低的FE对严重比对轻度疾病,在儿童中尤其明显的差异(FE,重度疾病为82.7%,轻度疾病为94.7%)。
    TBE疫苗接种的FE是优异的。在接种TBE的人中观察到的较高比例的严重疾病并不反映与疫苗接种相关的较高风险,而是由于对严重TBE的FE略低。因为这种效果在儿童中更明显,我们建议调整免疫计划.
    There are discrepant observations on the severity of tick-borne encephalitis (TBE) in vaccinated persons. We, therefore, analyzed the occurrence of severe and mild disease in hospitalized vaccinated and nonvaccinated patients with TBE and determined the field effectiveness (FE) of vaccination against these forms of disease.
    The study covered all patients hospitalized with TBE in Austria from 2000 to 2018. Clinical diagnoses in vaccinated and age- and sex-matched nonvaccinated patients were compared in a nested case-control study. FE was calculated based on vaccination coverage and incidences in the nonvaccinated and vaccinated population.
    Of 1545 patients hospitalized with TBE, 206 were vaccinated. In those, a higher proportion of severe TBE was observed, especially in children. FE was high in all age groups and against all forms of disease. The higher proportion of severe TBE can be explained by a lower FE against severe than against mild disease, a difference especially pronounced in children (FE, 82.7% for severe vs 94.7% for mild disease).
    The FE of TBE vaccination is excellent. The observed higher proportion of severe disease in vaccinated persons with TBE does not reflect a higher risk associated with vaccination but is rather due to a somewhat lower FE against severe TBE. Because this effect was more pronounced in children, we recommend adapting the immunization schedule.
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