BackgroundTick-borne encephalitis (TBE) is a vaccine-preventable disease involving the central nervous system. TBE became a notifiable disease on the EU/EEA level in 2012.AimWe aimed to provide an updated epidemiological assessment of TBE in the EU/EEA, focusing on spatiotemporal changes.MethodsWe performed a descriptive analysis of case characteristics, time and location using data of human TBE cases reported by EU/EEA countries to the European Centre for Disease Prevention and Control with disease onset in 2012-2020. We analysed data at EU/EEA, national, and subnational levels and calculated notification rates using Eurostat population data. Regression models were used for temporal analysis.ResultsFrom 2012 to 2020, 19 countries reported 29,974 TBE cases, of which 24,629 (98.6%) were autochthonous. Czechia, Germany and Lithuania reported 52.9% of all cases. The highest notification rates were recorded in Lithuania, Latvia, and Estonia (16.2, 9.5 and 7.5 cases/100,000 population, respectively). Fifty regions from 10 countries, had a notification rate ≥ 5/100,000. There was an increasing trend in number of cases during the study period with an estimated 0.053 additional TBE cases every week. In 2020, 11.5% more TBE cases were reported than predicted based on data from 2016 to 2019. A geographical spread of cases was observed, particularly in regions situated north-west of known endemic regions.ConclusionA close monitoring of ongoing changes to the TBE epidemiological situation in Europe can support the timely adaption of vaccination recommendations. Further analyses to identify populations and geographical areas where vaccination programmes can be of benefit are needed.

• Keywords
• European Union, Tick-borne encephalitis, epidemiology, public health, surveillance, vaccination,
• MeSH
• Encephalitis, Tick-Borne * epidemiology   prevention & control   MeSH
• Humans MeSH
• Vaccination MeSH
• Viral Vaccines * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe epidemiology   MeSH
• Germany epidemiology   MeSH
• Names of Substances
• Viral Vaccines * MeSH

Tick-borne encephalitis (TBE) virus is a major cause of central nervous system infections in endemic countries. Here, we present clinical and laboratory characteristics of a large international cohort of patients with confirmed TBE using a uniform clinical protocol. Patients were recruited in eight centers from six European countries between 2010 and 2017. A detailed description of clinical signs and symptoms was recorded. The obtained information enabled a reliable classification in 553 of 555 patients: 207 (37.3%) had meningitis, 273 (49.2%) meningoencephalitis, 15 (2.7%) meningomyelitis, and 58 (10.5%) meningoencephalomyelitis; 41 (7.4%) patients had a peripheral paresis of extremities, 13 (2.3%) a central paresis of extremities, and 25 (4.5%) had single or multiple cranial nerve palsies. Five (0.9%) patients died during acute illness. Outcome at discharge was recorded in 298 patients. Of 176 (59.1%) patients with incomplete recovery, 80 (27%) displayed persisting symptoms or signs without recovery expectation. This study provides further evidence that TBE is a severe disease with a large proportion of patients with incomplete recovery. We suggest monitoring TBE in endemic European countries using a uniform protocol to record the full clinical spectrum of the disease.

• Keywords
• central paresis, meningomyelitis, peripheral paresis, tick-borne encephalitis, vaccine-preventable disease,
• Publication type
• Journal Article MeSH

BACKGROUND: The castor bean tick Ixodes ricinus is an important vector of several clinically important diseases, whose prevalence increases with accelerating global climate changes. Characterization of a tick life-cycle is thus of great importance. However, researchers mainly focus on specific organs of fed life stages, while early development of this tick species is largely neglected. METHODS: In an attempt to better understand the life-cycle of this widespread arthropod parasite, we sequenced the transcriptomes of four life stages (egg, larva, nymph and adult female), including unfed and partially blood-fed individuals. To enable a more reliable identification of transcripts and their comparison in all five transcriptome libraries, we validated an improved-fit set of five I. ricinus-specific reference genes for internal standard normalization of our transcriptomes. Then, we mapped biological functions to transcripts identified in different life stages (clusters) to elucidate life stage-specific processes. Finally, we drew conclusions from the functional enrichment of these clusters specifically assigned to each transcriptome, also in the context of recently published transcriptomic studies in ticks. RESULTS: We found that reproduction-related transcripts are present in both fed nymphs and fed females, underlining the poorly documented importance of ovaries as moulting regulators in ticks. Additionally, we identified transposase transcripts in tick eggs suggesting elevated transposition during embryogenesis, co-activated with factors driving developmental regulation of gene expression. Our findings also highlight the importance of the regulation of energetic metabolism in tick eggs during embryonic development and glutamate metabolism in nymphs. CONCLUSIONS: Our study presents novel insights into stage-specific transcriptomes of I. ricinus and extends the current knowledge of this medically important pathogen, especially in the early phases of its development.

• Keywords
• Ixodes ricinus, Life stage, Reference gene validation, Tick development, Transcriptome assembly,
• MeSH
• Ixodes genetics   growth & development   MeSH
• Nymph growth & development   MeSH
• Reproduction genetics   MeSH
• Life Cycle Stages MeSH
• Gene Expression Profiling * MeSH
• Feeding Behavior MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Tick-borne encephalitis (TBE) is a serious acute neuroinfection of humans caused by a tick-borne flavivirus. The disease is typically seasonal, linked to the host-seeking activity of Ixodes ricinus (predominantly nymphs), the principal European tick vector species. To address the need for accurate risk predictions of contracting TBE, data on 4,044 TBE cases reported in the Czech Republic during 2001-2006 were compared with questing activity of I. ricinus nymphs monitored weekly at a defined location for the same 6-year period. A time shift of 21 days between infected tick bite and recorded disease onset provided the optimal model for comparing the number of cases of TBE with numbers of questing nymphs. Mean annual distribution of TBE cases and tick counts showed a similar bimodal distribution. Significantly, the ratio of TBE cases to questing nymphs was highest in the summer-autumn period even though the number of questing nymphs peaked in the spring-summer period. However, this pattern changed during a period of extreme meteorological events of flooding and abnormally high temperatures, indicating that changes in climate affect the incidence of TBE. Previous studies failed to link human behavior with changes in incidence of TBE but showed extrinsic temperature impacts arbovirus replication. Hence, we hypothesize the apparent discrepancy between peak nymphal tick activity and greatest risk of contracting TBE is due to the effect of temperature on virus replication in the tick vector. Relative proportions of questing nymphs and the numbers of weeks in which they were found were greater in summer-autumn compared with spring-summer at near-ground temperatures >5°C and at standard day and weekly average temperatures of >15°C. Thus, during the summer-autumn period, the virus dose in infected tick bites is likely greater owing to increased virus replication at higher microclimatic temperatures, consequently increasing the relative risk of contracting TBE per summer-autumn tick bite. The data support the use of weather-based forecasts of tick attack risk (based on daytime ambient temperature) supplemented with weekly average temperature (as a proxy for virus replication) to provide much-needed real-time forecasts of TBE risk.

• Keywords
• Ixodes ricinus, TBEV, arbovirus, climate change, seasonality, tick-borne encephalitis,
• MeSH
• Arachnid Vectors physiology   virology   MeSH
• Incidence MeSH
• Ixodes physiology   virology   MeSH
• Encephalitis, Tick-Borne epidemiology   transmission   virology   MeSH
• Humans MeSH
• Weather MeSH
• Seasons MeSH
• Temperature MeSH
• Encephalitis Viruses, Tick-Borne genetics   isolation & purification   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH

Tick-borne encephalitis (TBE) is peculiar due to its unstable dynamics with profound inter-annual fluctuations in case numbers - a phenomenon not well understood to date. Possible reasons - apart from variable human contact with TBE foci - include external factors, e.g. climatic forcing, autonomous oscillations of the disease system itself, or a combined action of both. Spectral analysis of TBE data from six regions of central Europe (CE) revealed that the ostensibly chaotic dynamics can be explained in terms of four superposed (quasi-)periodical oscillations: a quasi-biennial, triennial, pentennial, and a decadal cycle. These oscillations exhibit a high degree of regularity and synchrony across CE. Nevertheless, some amplitude and phase variations are responsible for regional differences in incidence patterns. In addition, periodic changes occur in the degree of synchrony in the regions: marked in-phase periods alternate with rather off-phase periods. Such a feature in the disease dynamics implies that it arises as basically diverging self-oscillations of local disease systems which, at intervals, receive synchronizing impulses, such as periodic variations in food availability for key hosts driven by external factors. This makes the disease dynamics synchronized over a large area during peaks in the synchronization signal, shifting to asynchrony in the time in between.

• Keywords
• Central Europe, disease dynamics, spectral analysis, tick-borne encephalitis, time-series, wildlife cycle,
• MeSH
• Incidence MeSH
• Ticks growth & development   MeSH
• Encephalitis, Tick-Borne epidemiology   MeSH
• Humans MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Tick-borne encephalitis virus (TBEV) is a human-pathogenic flavivirus that is endemic in large parts of Europe and Asia and causes severe neuroinvasive illness. A formalin-inactivated vaccine induces strong neutralizing antibody responses and confers protection from TBE disease. CD4+ T cell responses are essential for neutralizing antibody production, but data on the functionalities of TBEV-specific CD4+ T cells in response to vaccination or infection are lacking. This study provides a comprehensive analysis of the cytokine patterns of CD4+ T cell responses in 20 humans after TBE vaccination in comparison to those in 18 patients with TBEV infection. Specifically, Th1-specific cytokines (IFN-γ, IL-2, TNF-α), CD40 ligand and the Th1 lineage-specifying transcription factor Tbet were determined upon stimulation with peptides covering the TBEV structural proteins contained in the vaccine (C-capsid, prM/M-membrane and E-envelope). We show that TBEV-specific CD4+ T cell responses are polyfunctional, but the cytokine patterns after vaccination differed from those after infection. TBE vaccine responses were characterized by lower IFN-γ responses and high proportions of TNF-α+IL-2+ cells. In vaccine-induced responses-consistent with the reduced IFN-γ expression patterns-less than 50% of TBEV peptides were detected by IFN-γ+ cells as compared to 96% detected by IL-2+ cells, indicating that the single use of IFN-γ as a read-out strongly underestimates the magnitude and breadth of such responses. The results provide important insights into the functionalities of CD4+ T cells that coordinate vaccine responses and have direct implications for future studies that address epitope specificity and breadth of these responses.

• MeSH
• Cell Lineage immunology   MeSH
• CD4-Positive T-Lymphocytes drug effects   immunology   MeSH
• Cytokines biosynthesis   immunology   MeSH
• Adult MeSH
• Epitopes immunology   MeSH
• Encephalitis, Tick-Borne immunology   prevention & control   virology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antibodies, Viral blood   immunology   MeSH
• Aged MeSH
• T-Lymphocytes, Helper-Inducer drug effects   immunology   MeSH
• Vaccination * MeSH
• Viral Vaccines administration & dosage   immunology   MeSH
• Encephalitis Viruses, Tick-Borne immunology   pathogenicity   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cytokines MeSH
• Epitopes MeSH
• Antibodies, Viral MeSH
• Viral Vaccines MeSH

Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), and 2'-C-methylcytidine (2'-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 μM for 7-deaza-2'-CMA, 7.1 ± 1.2 μM for 2'-CMA, and 14.2 ± 1.9 μM for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 μM). The anti-TBEV effect of 2'-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2'-CMA showed no detectable cellular toxicity (CC50 > 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2'-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2'-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.

• MeSH
• Adenosine analogs & derivatives   chemistry   pharmacology   MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Cell Line MeSH
• Cytidine analogs & derivatives   chemistry   pharmacology   MeSH
• Humans MeSH
• Nucleosides chemistry   pharmacology   MeSH
• Swine MeSH
• Virus Replication drug effects   MeSH
• Tubercidin analogs & derivatives   chemistry   pharmacology   MeSH
• Encephalitis Viruses, Tick-Borne drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 2'-C-methyladenosine MeSH Browser
• 2'-C-methylcytidine MeSH Browser
• 7-deaza-2'-C-methyladenosine MeSH Browser
• Adenosine MeSH
• Antiviral Agents MeSH
• Cytidine MeSH
• Nucleosides MeSH
• Tubercidin MeSH

UNLABELLED: This study of 170 children in the Czech Republic examines the clinical course and sequelae for tick-borne encephalitis. Evaluated were demographic and epidemiological data, signs and symptoms at admission, clinical course during hospital stay and laboratory findings. Cerebrospinal fluid was analysed for white blood cells, protein, impairment of blood-cerebrospinal fluid (CSF) barrier and tick-borne encephalitis virus (TBEV)-specific antibodies. Subjective complaints and objective neurological deficits were investigated. Tick bites were reported in 74 % of the children. The illness had a biphasic clinical course in 58 % of cases. The second phase was characterized by headache in 98 %, high fever in 86 % (more than 38.5 °C), vomiting in 64 % and meningeal signs in 92 % of children. Meningitis (77 %) dominated over meningoencephalitis (13 %). Inflammatory changes in CSF were found in 90 % of children. Immunoglobulin M (IgM) antibodies against TBEV in serum were found early in the infection in 99 %. IgM positivity lasted up to 1,126 days. Neurocognitive abnormalities were found in 19 (11 %) of children. Acquired aphasia, lasting tremor of the upper extremities, speech impairment, inversion of sleep and wakefulness, abnormal hyperkinetic movements and vertigo were found to be permanent but not progressing. Severe sequelae persisted in two children (1 %) while in three (2 %) were classified as mild or moderate. CONCLUSION: Tick-borne encephalitis in children has a benign course with minimal sequelae. Meningitis with biphasic course is the prevalent involvement and the duration of IgM antibodies in serum and index of positivity are not decisive for postencephalitic disorders.

• MeSH
• Child MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Immunoglobulin G blood   MeSH
• Immunoglobulin M blood   MeSH
• Encephalitis, Tick-Borne cerebrospinal fluid   diagnosis   MeSH
• Infant MeSH
• Comorbidity MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Antibodies, Viral blood   MeSH
• Encephalitis Viruses, Tick-Borne immunology   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Immunoglobulin G MeSH
• Immunoglobulin M MeSH
• Antibodies, Viral MeSH

Tick-borne diseases represent major public and animal health issues worldwide. Ixodes ricinus, primarily associated with deciduous and mixed forests, is the principal vector of causative agents of viral, bacterial, and protozoan zoonotic diseases in Europe. Recently, abundant tick populations have been observed in European urban green areas, which are of public health relevance due to the exposure of humans and domesticated animals to potentially infected ticks. In urban habitats, small and medium-sized mammals, birds, companion animals (dogs and cats), and larger mammals (roe deer and wild boar) play a role in maintenance of tick populations and as reservoirs of tick-borne pathogens. Presence of ticks infected with tick-borne encephalitis virus and high prevalence of ticks infected with Borrelia burgdorferi s.l., causing Lyme borreliosis, have been reported from urbanized areas in Europe. Emerging pathogens, including bacteria of the order Rickettsiales (Anaplasma phagocytophilum, "Candidatus Neoehrlichia mikurensis," Rickettsia helvetica, and R. monacensis), Borrelia miyamotoi, and protozoans (Babesia divergens, B. venatorum, and B. microti) have also been detected in urban tick populations. Understanding the ecology of ticks and their associations with hosts in a European urbanized environment is crucial to quantify parameters necessary for risk pre-assessment and identification of public health strategies for control and prevention of tick-borne diseases.

• Keywords
• Europe, Ixodes ricinus, tick-borne pathogens, ticks, urban habitats,
• Publication type
• Journal Article MeSH
• Review MeSH

UNLABELLED: Tick-borne encephalitis (TBE) virus is an important human-pathogenic flavivirus endemic in large parts of Europe and Central and Eastern Asia. Neutralizing antibodies specific for the viral envelope protein E are believed to mediate long-lasting protection after natural infection and vaccination. To study the specificity and individual variation of human antibody responses, we developed immunoassays with recombinant antigens representing viral surface protein domains and domain combinations. These allowed us to dissect and quantify antibody populations of different fine specificities in sera of TBE patients and vaccinees. Postinfection and postvaccination sera both displayed strong individual variation of antibody titers as well as the relative proportions of antibodies to different domains of E, indicating that the immunodominance patterns observed were strongly influenced by individual-specific factors. The contributions of these antibody populations to virus neutralization were quantified by serum depletion analyses and revealed a significantly biased pattern. Antibodies to domain III, in contrast to what was found in mouse immunization studies with TBE and other flaviviruses, did not play any role in the human neutralizing antibody response, which was dominated by antibodies to domains I and II. Importantly, most of the neutralizing activity could be depleted from sera by a dimeric soluble form of the E protein, which is the building block of the icosahedral herringbone-like shell of flaviviruses, suggesting that antibodies to more complex quaternary epitopes involving residues from adjacent dimers play only a minor role in the total response to natural infection and vaccination in humans. IMPORTANCE: Tick-borne encephalitis (TBE) virus is a close relative of yellow fever, dengue, Japanese encephalitis, and West Nile viruses and distributed in large parts of Europe and Central and Eastern Asia. Antibodies to the viral envelope protein E prevent viral attachment and entry into cells and thus mediate virus neutralization and protection from disease. However, the fine specificity and individual variation of neutralizing antibody responses are currently not known. We have therefore developed new in vitro assays for dissecting the antibody populations present in blood serum and determining their contribution to virus neutralization. In our analysis of human postinfection and postvaccination sera, we found an extensive variation of the antibody populations present in sera, indicating substantial influences of individual-specific factors that control the specificity of the antibody response. Our study provides new insights into the immune response to an important human pathogen that is of relevance for the design of novel vaccines.

• MeSH
• Adult MeSH
• Epitopes immunology   MeSH
• Encephalitis, Tick-Borne immunology   MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Antibodies, Neutralizing blood   MeSH
• Viral Envelope Proteins immunology   MeSH
• Antibodies, Viral blood   MeSH
• Aged MeSH
• Viral Vaccines administration & dosage   immunology   MeSH
• Encephalitis Viruses, Tick-Borne immunology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Epitopes MeSH
• glycoprotein E, Flavivirus MeSH Browser
• Antibodies, Neutralizing MeSH
• Viral Envelope Proteins MeSH
• Antibodies, Viral MeSH
• Viral Vaccines MeSH