Human Tick-borne Encephalitis Research Articles

Spatiotemporal heterogeneity and potential drivers of human tick-borne encephalitis in the south of Russian Far East

The south of the Russian Far East is distinguished by diversity of natural conditions for the presence of vectors and circulation of pathogens, primarily tick-borne infections. Despite the relatively low proportion of tick-borne encephalitis in the structure of tick-borne infections and the rather low incidence rate compared to other Russian regions, the disease here has epidemiological significance, which is associated with its severe course. Therefore, it is important to identify local areas of greatest epidemic manifestation of the disease and potential drivers influencing the spread of tick-borne encephalitis. This study uses data on population incidence in the municipal districts of Khabarovsk Krai, Amur Oblast, Jewish Autonomous Oblast and Zabaikalsky Krai between 2000 and 2020. Based on Kulldorf spatial scanning statistics, a temporally stable cluster of virus circulation in the population in the southwest of Zabaikalsky Krai was identified, which existed during 2009-2018. Regression modeling using zero-inflated negative binomial regression based on a set of environmental and socio-economic predictors allowed to identify variables determining the probability of infection: the share of forest, the amount of precipitation in the warm period, population density, as well as variables reflecting population employment and socio-economic well-being. Despite the fact that tick-borne encephalitis is a natural focal disease and may be characterized by natural periods of increased incidence, the influence of the social component can have a strong impact on the epidemiological manifestation. The identified spatio-temporal differences within the study region and potential drivers must be taken into account when developing a set of preventive measures.

High habitat richness reduces the risk of tick-borne encephalitis in Europe: A multi-scale study

BackgroundThe 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. MethodsWe 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. FindingsOur 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. InterpretationTo 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.

Genetic polymorphisms in innate immunity genes influence predisposition to tick-borne encephalitis

Tick-borne encephalitis (TBE) is a neuroviral disease that ranges in severity from a mild febrile illness to a severe and life-threatening meningoencephalitis or encephalomyelitis. There is increasing evidence that susceptibility to tick-borne encephalitis virus (TBEV)-induced disease and its severity are largely influenced by host genetic factors, in addition to other virus- and host-related factors. In this study, we investigated the contribution of selected single nucleotide polymorphisms (SNPs) in innate immunity genes to predisposition to TBE in humans. More specifically, we investigated a possible association between SNPs rs304478 and rs303212 in the gene Interferon Induced Protein With Tetratricopeptide Repeats 1 (IFIT1), rs7070001 and rs4934470 in the gene Interferon Induced Protein With Tetratricopeptide Repeats 2 (IFIT2), and RIG-I (Retinoic acid-inducible gene I) encoding gene DDX58 rs311795343, rs10813831, rs17217280 and rs3739674 SNPs with predisposition to TBE in population of the Czech Republic, where TBEV is highly endemic. Genotypic and allelic frequencies for these SNPs were analyzed in 247 nonimmunized TBE patients and compared with 204 control subjects. The analysis showed an association of IFIT1 rs304478 SNP and DDX58 rs3739674 and rs17217280 SNPs with predisposition to TBE in the Czech population indicating novel risk factors for clinical TBE but not for disease severity. These results also highlight the role of innate immunity genes in TBE pathogenesis.

TBE in Belgium

In 2018, the two first human tick-borne encephalitis (TBE) cases with possible/probable autochthonous infection were diagnosed at the National Reference Centre (NRC) of Arbovirus (The Institute of Tropical Medicine, Antwerp, Belgium). Every year, some imported cases of TBE are also detected, infected in other European countries such as Germany, Scandinavia, Austria, Kyrgyzstan or Slovenia and Russia.

Potential drivers of human tick-borne encephalitis in the Örebro region of Sweden, 2010–2021

Incidence of tick-borne encephalitis (TBE) has increased during the last years in Scandinavia, but the underlying mechanism is not understood. TBE human case data reported between 2010 and 2021 were aggregated into postal codes within Örebro County, south-central Sweden, along with tick abundance and environmental data to analyse spatial patterns and identify drivers of TBE. We identified a substantial and continuing increase of TBE incidence in Örebro County during the study period. Spatial cluster analyses showed significant hotspots (higher number of cases than expected) in the southern and northern parts of Örebro County, whereas a cold spot (lower number of cases than expected) was found in the central part comprising Örebro municipality. Generalised linear models showed that the risk of acquiring TBE increased by 12.5% and 72.3% for every percent increase in relative humidity and proportion of wetland forest, respectively, whereas the risk decreased by 52.8% for every degree Celsius increase in annual temperature range. However, models had relatively low goodness of fit (R2 < 0.27). Results suggest that TBE in Örebro County is spatially clustered, however variables used in this study, i.e., climatic variables, forest cover, water, tick abundance, sheep as indicator species, alone do not explain this pattern.

Dairy milk from cow and goat as a sentinel for tick-borne encephalitis virus surveillance.

Tick-borne encephalitis (TBE) is one of the most severe human tick-borne diseases in Europe. It is caused by the tick-borne encephalitis virus (TBEV), which is transmitted to humans mainly via bites of Ixodes ricinus or I. persulcatus ticks. The geographical distribution and abundance of I. ricinus is expanding in Sweden as has the number of reported human TBE cases. In addition to tick bites, alimentary TBEV infection has also been reported after consumption of unpasteurized dairy products. So far, no alimentary TBEV infection has been reported in Sweden, but knowledge about its prevalence in Swedish ruminants is scarce. In the present study, a total of 122 bulk tank milk samples and 304 individual milk samples (including 8 colostrum samples) were collected from dairy farms (n=102) in Sweden. All samples were analysed for the presence of TBEV antibodies by ELISA test and immunoblotting. Participating farmers received a questionnaire about milk production, pasteurization, tick prophylaxis used on animals, tick-borne diseases, and TBE vaccination status. We detected specific anti-TBEV antibodies, i.e., either positive (>126 Vienna Units per ml, VIEU/ml) or borderline (63-126 VIEU/ml) in bulk tank milk from 20 of the 102 farms. Individual milk samples (including colostrum samples) from these 20 farms were therefore collected for further analysis. Our results revealed important information for detection of emerging TBE risk areas. Factors such as consumption of unpasteurized milk, limited use of tick prophylaxis on animals and a moderate coverage of human TBE vaccination, may be risk factors for alimentary TBEV infection in Sweden.

Prevalence of anti-tick-borne encephalitis virus (TBEV) antibodies in Swiss blood donors in 2014-2015.

Disease morbidity of tick-borne encephalitis (TBE) has been increasing over the last decades. Since the 1990s, however, no extensive seroprevalence studies on TBE in humans have been performed in Switzerland. Here we assessed the prevalence of anti-TBE virus (TBEV) antibodies among different groups of the Swiss blood donor population. The study was carried out from July 2014 to January 2015. Blood donors participating in the study (n=9,328) were asked to fill in a questionnaire relating to vaccination against or infection with different flaviviruses, and blood samples were collected. All samples were screened for the presence of anti-TBEV IgG antibodies using ELISA testing. Seropositivity rates in different groups of blood donors were compared using Chi square tests with Bonferroni correction. In 2014 and 2015, 24.6% of healthy Swiss blood donors indicated vaccination against TBE. Among vaccinated blood donors, antibody prevalence was significantly higher in younger (<40y: 85.3%) than older individuals (≥40 to <55y: 80.0%, ≥55y: 76.7%; p=0.005). In non-vaccinated individuals, antibody prevalence was significantly higher in younger (<40y: 10.0%) than older (≥40 to <55y: 4.0%, ≥55y: 3.9%; p<0.005), male (6.8%) than female (3.7%, p<0.0001), and blood donors from endemic (7.0%) than border (6.2%) or non-endemic regions (4.2%, p<0.001). Possible asymptomatic infection, as defined by positive IgG ELISA results in blood donors indicating no vaccination against TBEV, was found in 5.6%. Our data importantly complement the knowledge on TBEV vaccination rates and estimate the frequency of subclinical TBE in Switzerland.

Байкальский тракт как место высокого риска заражения трансмиссивными «клещевыми» инфекциями

The results of long-term monitoring of the taiga ticke I. persulcatus abundance and its infection rate with tick-borne encephalitis virus and bacteria of genus Anaplasma, Borrelia, Ehrlichia and Rickettsia in forests along the Baikalian highway (road No 25К-011 Irkutsk region, Russia). The ticks’ abundance varied in space and time from complete lack on the registration route up to 339 ticks per flag-hour. The dynamics during study period (2005-2022) had three waves of ups and downs. The maximum of long-term average seasonal activity occurred at second and third decade of May. The average numbers of ticks increased as distance from the city grew. The analysis with the help of multiplex test system for four infections (tick-borne encephalitis virus, Anaplasma, Borrelia, Ehrlichia) showed marker at least of one pathogen in 57 % of specimens, different mixes of two and more co-infections – in 16.3 %. From 10 variants of co-infections found in this sample, the most prevalent were combinations of Borrelia, Ehrlichia and Anaplasma (74.7 % of double and 7.5 % triple «mixes»). Least often, the ticks were co-infected with tick-borne encephalitis virus in combination with Ehrlichia and Anaplasma (0.5 % each). In average the ticks most often contained the genetic material of Rickettsia (68.1±2.94 % of tested samples) and Borrelia, (48.3±1.30 %), then, in descending order, – Anaplasma, (13.5±0.88 %), Ehrlichia (9.5±0.76 %) and tick-borne encephalitis virus (3.0±0.47 %). Despite the low proportion of ticks with the virus in natural foci, 68.5 % of the persons, bit by infected ticks on the territories along Baikalian highway, became ill with tick-borne encephalitis. Conversely, with a wide prevalence of Rickettsia and Borrelia in ticks, the tick-borne rickettsiosis was diagnosed in 3.1 % of the victims and borrelioses – in 28.4 %. No significant differences have been revealed between the infection rate of adult ticks and nymphs, and between males and females, except for Borrelia, which more often have been found in females than in males (51.9 % versus 45.7 %). The tendencies of the pathogens prevalence in time and different plots of territory studied and risks for human infection have been revealed. It was shown than more than a half of human tick-borne encephalitis, tick-borne borrelioses and tick-borne rickettsiosis contracting occurs in the closest suburbs of Irkutsk – up to the 30th km of the highway, where the ticks’ abundance is lower, than in more distant areas, in other words are more to do with human behavioral factor than with the vector’s activity.

New directions in the experimental therapy of tick-borne encephalitis

Tick-borne encephalitis (TBE) is a potentially fatal disease common in much of Europe and Asia. There is no specific therapy for the treatment of TBE patients. However, several efforts are being made to develop small molecules that specifically interfere with the life cycle of TBE virus. In particular, recently various nucleoside analogues that can inhibit the viral replicase, such as the RNA-dependent RNA polymerase or viral methyltransferases, have been explored. In addition, human or chimeric (i.e., structural chimeras that combine mouse variable domains with human constant domains) monoclonal antibodies with promising potential for post-exposure prophylaxis or early therapy have been developed. This review summarizes the latest directions and experimental approaches that may be used to combat TBE in humans.

TBE in Belgium

In 2018, the two first human tick-borne encephalitis (TBE) cases with possible/probable autochthonous infection were diagnosed at the National Reference Centre (NRC) of Arbovirus (The Institute of Tropical Medicine, Antwerp, Belgium). Every year, some imported cases of TBE are also detected, infected in other European countries such as Germany, Scandinavia, Austria, Kyrgyzstan or Slovenia and Russia.

Envelope E protein of dengue virus and phospholipid binding to the late endosomal membrane

Flaviviruses include many significant human pathogens, comprising dengue, West Nile, Yellow fever, Japanese encephalitis, Zika and tick-borne encephalitis viruses and many others, affecting millions of people in the world. These viruses have produced important epidemics in the past, they continue to do it and they will undoubtedly continue to do so in the future. Flaviviruses enter into the cells via receptor-mediated endocytosis by fusing its membrane with the endosomal membrane in a pH-dependent manner with the help of the envelope E protein, a prototypical class II membrane fusion protein. The envelope E protein has a conserved fusion peptide at its distal end, which is responsible in the first instance of inserting the protein into the host membrane. Since the participation of other segments of the E protein in the fusion process should not be ruled out, we have used atomistic molecular dynamics to study the binding of the distal end of domain II of the envelope E protein from Dengue virus (DENV) with a complex membrane similar to the late-endosome one. Our work shows that not only the fusion peptide participates directly in the fusion, but also two other sequences of the protein, next to the fusion peptide it in the three-dimensional structure, are jointly wrapped in the fusion process. Overall, these three sequences represent a new target that would make it possible to obtain effective antivirals against DENV in particular and Flaviviruses in general.

New and Confirmed Foci of Tick-Borne Encephalitis Virus (TBEV) in Northern Germany Determined by TBEV Detection in Ticks.

Tick-borne encephalitis (TBE) is a tick-transmitted, virus-induced neurological disease with potentially fatal outcomes in humans and animals. Virus transmission takes places in so-called tick-borne encephalitis virus (TBEV) microfoci, which constitute small areas of sustained virus circulation. In southern Germany, TBEV has been endemic for decades; however, a northward expansion of risk areas, based on disease incidence in the human population, has been observed in recent years. The present study investigated TBEV occurrence in questing ticks at eight locations in the federal state of Lower Saxony, northwestern Germany, chosen due to reported associations with human TBE cases (N = 4) or previous virus detection (N = 4). A total of 20,056 ticks were collected in 2020 and 2021 and tested for TBEV RNA in pools of ten nymphs or five adults by quantitative reverse transcription-PCR (RT-qPCR). Positive results were confirmed by RT amplification of the viral E gene. In total, 18 pools from five different sampling locations were positive for TBEV RNA. One previously unknown transmission focus was detected, while ongoing virus circulation was confirmed at the four further locations. Phylogenetic analysis showed that two different virus strains with different origins circulate in the locations identified as natural foci.

Spatial and temporal distribution patterns of tick-borne diseases (Tick-borne Encephalitis and Lyme Borreliosis) in Germany.

BackgroundIn the face of ongoing climate warming, vector-borne diseases are expected to increase in Europe, including tick-borne diseases (TBD). The most abundant tick-borne diseases in Germany are Tick-Borne Encephalitis (TBE) and Lyme Borreliosis (LB), with Ixodes ricinus as the main vector.MethodsIn this study, we display and compare the spatial and temporal patterns of reported cases of human TBE and LB in relation to some associated factors. The comparison may help with the interpretation of observed spatial and temporal patterns.ResultsThe spatial patterns of reported TBE cases show a clear and consistent pattern over the years, with many cases in the south and only few and isolated cases in the north of Germany. The identification of spatial patterns of LB disease cases is more difficult due to the different reporting practices in the individual federal states. Temporal patterns strongly fluctuate between years, and are relatively synchronized between both diseases, suggesting common driving factors. Based on our results we found no evidence that weather conditions affect the prevalence of both diseases. Both diseases show a gender bias with LB bing more commonly diagnosed in females, contrary to TBE being more commonly diagnosed in males.ConclusionFor a further investigation of of the underlying driving factors and their interrelations, longer time series as well as standardised reporting and surveillance system would be required.

Canine Tick-Borne Encephalitis: Clinical Features, Survival Rate and Neurological Sequelae: A Retrospective Study of 54 Cases (1999-2016).

Tick-borne encephalitis (TBE) is one of the most important infectious diseases of the central nervous system in dogs from endemic areas. While in humans survival rate and long-term outcomes are well described, these data are lacking in veterinary literature. The aim of the present paper is to characterize the clinical aspects of TBE and to investigate fatality rate, long-term outcome and the long-term neurological sequelae in a population of dogs infected with TBE. We performed a retrospective analysis of 54 dogs diagnosed with TBE at the veterinary hospital of the University of Zurich between 1999 and 2016. Medical data such as signalment, clinical presentation, results of diagnostic procedures, treatment and outcome were collected and analyzed. Statistical analysis including a cox proportional hazard model using a backward stepwise regression approach was performed. In 62% of the TBE cases unspecific signs were described before the onset of neurological signs, resembling a biphasic appearance that is well known in human TBE. Case fatality rate was 33% and all dogs died within the first 4 months after diagnosis. Long-term neurological sequalae were detected in 17% of the TBE cases. For each day of clinical signs before hospital entry the odds of sequalae increased by a factor of 1.88 (CI 1.04–3.15). Older dogs and dogs presented with seizure activity had an increased hazard risk of death (Hazard ration = 1.2, p = 0.03; and 9.38, p = 0.001, respectively). In conclusion, despite TBE being a life-threatening disease with severe clinical signs, the survival rate in our study was 67%. However, long-term sequalae can be of concern especially in dogs with longer clinical course.

Flavivirus NS1 and Its Potential in Vaccine Development.

The Flavivirus genus contains many important human pathogens, including dengue, Japanese encephalitis (JE), tick-borne encephalitis (TBE), West Nile (WN), yellow fever (YF) and Zika (ZIK) viruses. While there are effective vaccines for a few flavivirus diseases (JE, TBE and YF), the majority do not have vaccines, including WN and ZIK. The flavivirus nonstructural 1 (NS1) protein has an unusual structure–function because it is glycosylated and forms different structures to facilitate different roles intracellularly and extracellularly, including roles in the replication complex, assisting in virus assembly, and complement antagonism. It also plays a role in protective immunity through antibody-mediated cellular cytotoxicity, and anti-NS1 antibodies elicit passive protection in animal models against a virus challenge. Historically, NS1 has been used as a diagnostic marker for the flavivirus infection due to its complement fixing properties and specificity. Its role in disease pathogenesis, and the strong humoral immune response resulting from infection, makes NS1 an excellent target for inclusion in candidate flavivirus vaccines.

TBE in Belgium

In 2018, the two first human tick-borne encephalitis (TBE) cases with possible/probable autochthonous infection were diagnosed at the National Reference Centre (NRC) of Arbovirus (The Institute of Tropical Medicine, Antwerp, Belgium). Every year, some imported cases of TBE are also detected, infected in other European countries such as Germany,1 Scandinavia, Austria, Kyrgyzstan or Slovenia2 and Russia.

Mapping geographical areas at risk for tick-borne encephalitis (TBE) by analysing bulk tank milk from Swedish dairy cattle herds for the presence of TBE virus\u2013specific antibodies

BackgroundThe vector-borne human viral zoonosis tick-borne encephalitis (TBE) is of growing concern in Sweden. The area where TBE is considered endemic has expanded, with an increasing geographical distribution of Ixodes ricinus as the tick vector and a rising number of reported TBE cases in humans. Efforts to map TBE risk areas have been carried out by sentinel monitoring, mainly based on individual sampling and analysis of wild and domestic animals, as well as ticks, for tick-borne encephalitis virus (TBEV). However, the interpretation of the geographical distribution has been hampered by the patchy and focal nature of TBEV occurrence. This study presents TBEV surveillance data based on antibody analysis of bulk tank milk collected from dairy herds located throughout Sweden before (May) and after (November) the vector season. A commercial TBEV antibody ELISA was modified and evaluated for use in this study.ResultsThe initial comparative TBEV antibody analysis revealed a good correlation between milk and serum antibody levels from individually sampled cows. Also, the TBEV-antibody levels for the mean-herd serum showed good comparability with TBEV antibody levels from bulk tank milk, thus indicating good predictability of seroprevalence when analysing bulk tank milk from a herd.Analyses of bulk tank milk samples collected from 616 herds in May and 560 herds in November showed a geographical distribution of TBEV seropositive herds that was largely consistent with reported human TBE cases. A few TBEV-reactive herds were also found outside known locations of human TBE cases.ConclusionSerological examination of bulk tank milk from dairy cattle herds may be a useful sentinel surveillance method to identify geographical presence of TBEV. In contrast to individual sampling this method allows a large number of animals to be monitored. TBEV seropositive herds were mainly found in coastal areas of southern Sweden similar to human TBE cases. However, some antibody-reactive herds were found outside known TBE areas at the time of the study.

Получение стабильной формы стандартного образца содержания антител IgG человека к вирусу клещевого энцефалита

To ensure a long-term stability of the reference IgG antibodies to tick-borne encephalitis is an urgent task. The shelf life of immunoglobulin isolated from human immune blood plasma can be increased by freeze-drying an antibody solution stabilized with L-proline and glycine at a concentration of 12.5 g/L each and adjusting the pH value to 5.0± 0.5. The proposed method was used to obtain 3 batches of a reference sample with a shelf life from 30 to 48 months. During this time, the tested samples retained constant potency, fragmentation, absobance (400 nm) and dissolution time, which allows predicting its further stability during storage. The proposed method can also be helpful for obtaining stable antibody lyophilisates for use as standards in the analysis of the specific activity of human immunoglobulins against tick-borne encephalitis. reference standard, human tick-borne encephalitis immunoglobulin, L-proline, glycine, lyophilization, specific activity, production technology The work was carried out in accordance with the state assignment "Improvement of Quality Control Methods for Human Immunoglobulins".

The Red Fox (Vulpes vulpes) as Sentinel for Tick-Borne Encephalitis Virus in Endemic and Non-Endemic Areas.

Tick-borne encephalitis (TBE) is one of the most important viral zoonosis caused by a neurotropic arbovirus (TBEV). In Germany, TBE is classified as a notifiable disease with an average of 350 autochthonous human cases annually. The incidence-based risk assessment in Germany came under criticism because every year, a number of autochthonous human TBE cases have been detected outside of the official risk areas. Therefore, it is necessary to find additional parameters to strengthen TBEV surveillance. The aim of this study was to examine red foxes as sentinels for TBE. Thus far, there are no published data about the sensitivity and specificity for serological methods testing fox samples. Hence, we aimed to define a system for the screening of TBEV-specific antibodies in red foxes. A total of 1233 fox sera were collected and examined by ELISA and IIFA and confirmed by micro-NT. The overall seroprevalence of antibodies against TBEV in red foxes from Germany confirmed by micro-NT was 21.1%. The seroprevalence differed significantly between risk (30.5%) and non-risk areas (13.1%), with good correlations to local TBE incidence in humans. In conclusion, serological monitoring of red foxes represents a promising surrogate marker system and may even determine unexpected TBEV foci in regions currently regarded as non-risk areas.

Operational TBE incidence forecasts for Austria, Germany, and Switzerland 2019–2021

In spring 2019, forecasts of the incidence of tick-borne encephalitis (TBE) for the next 2 years, i.e. 2019 and 2020, were made for the first time. For this purpose, negative binomial regression models with 4–5 predictors were fitted to the time series of annual human TBE incidences from Austria, Germany, and Switzerland. The most important predictor for TBE incidences is the fructification index of the European beech (Fagus sylvatica) 2 years prior as a proxi for the intensity of the TBE virus transmission cycle. These forecasts were repeated in spring 2020 after the updated predictors and the confirmed TBE cases for 2019 became available. Forecasting TBE incidences for 2020 and 2021 results in 156 ± 19 and 131 ± 23 TBE cases for Austria, 663 ± 95 and 543 ± 112 TBE cases for Germany as well as 472 ± 56 and 350 ± 62 TBE cases for Switzerland. The newly implemented operational TBE forecasts will be verified every year with confirmed TBE cases. An initial verification for 2019 demonstrates the high reliability of the forecasts.