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Tick-borne encephalitis virus (TBEV) is a pathogen that causes febrile infectious diseases and neurological damage to humans. TBEVs are prevalent from Europe to Far Eastern Asia, including Northeastern China. The understanding of TBEV phylogeny in China has been limited owing to insufficient genomic data on Chinese TBEV strains. Here, six TBEV strains were isolated from ticks collected in Inner Mongolia. The transmission electron microscopy revealed spherical particles with an enveloped structure of 50–60 nm in diameter. Phylogenetic analysis showed that, two strains were classified as the Siberian subtype, while the remaining four were identified as the Far Eastern subtype. Migration analyses based on TBEV ORF and envelope (E) protein sequences revealed that Chinese TBEV strains were migrated from Russia and/or Kazakhstan into China. Hulun Buir and Mudanjiang, the northeastern region of China, are considered hotspots with multiple import and export routes of Chinese TBEV strains. These results promote the understanding of TBEV genetic variations and phylogeny in China and suggest the importance of improving investigation of TBEV prevalence, which would instrumental for vaccine design strategies and better preparation for controlling TBEV infection in humans. • Isolation of six TBEV strains from Inner Mongolia ticks reveals Siberian and Far Eastern subtypes. • TBEV migration from Russia and Kazakhstan to China, with hotspots in Hulun Buir and Mudanjiang. • TBEV surveys in China benefit the understanding of TBV phylogeny and the designing of vaccine. [ABSTRACT FROM AUTHOR]

Abstract Background In the South of Kazakhstan, Almaty Oblastʼ (region) is endemic for tick-borne encephalitis, with 0.16–0.32 cases/100,000 population between 2016–2018. The purpose of this study was to determine the prevalence and circulating subtypes of tick-borne encephalitis virus (TBEV) in Almaty Oblastʼ and Kyzylorda Oblastʼ. Methods In 2015 we investigated 2341 ticks from 7 sampling sites for the presence of TBEV. Ticks were pooled in 501 pools and isolated RNA was tested for the presence of TBEV by RT-qPCR. For the positive samples, the E gene was amplified, sequenced and a phylogenetic analysis was carried out. Results A total of 48 pools were TBEV-positive by the RT-qPCR. TBEV-positive ticks were only detected in three districts of Almaty Oblastʼ and not in Kyzylorda Oblastʼ. The positive TBEV pools were found within Ixodes persulcatus, Haemaphysalis punctata and Dermacentor marginatus. These tick species prevailed only in Almaty Oblastʼ whereas in Kyzylorda Oblastʼ Hyalomma asiaticum and D. marginatus are endemic. The minimum infection rates (MIR) in the sampling sites were 4.4% in Talgar, 2.8% in Tekeli and 1.1% in Yenbekshikazakh, respectively. The phylogenetic analysis of the generated sequences indicates that TBEV strains found in Almaty Oblastʼ clusters in the Siberian subtype within two different clades. Conclusions We provided new data about the TBEV MIR in ticks in Almaty Oblastʼ and showed that TBEV clusters in the Siberian Subtype in two different clusters at the nucleotide level. These results indicate that there are different influences on the circulating TBEV strains in south-eastern Kazakhstan. These influences might be caused by different routes of the virus spread in ticks which might bring different genetic TBEV lineages to Kazakhstan. The new data about the virus distribution and vectors provided here will contribute to an improvement of monitoring of tick-borne infections and timely anti-epidemic measures in Kazakhstan.

In this review, the manifestations of the tick-borne encephalitis (TBE) evolution in different aspects, which are traced over the 80 years since the discovery of TBE virus, are highlighted and systematized. The evolution of infection is expressed in a change in the properties of the etiological agent (changing of the genetic structure of the pathogen populations in certain territories, phenomenon of changing in the dominant subtype, changing in virulence), the epidemiology and ecology of TBE (period of marked increase in incidence, changing in the endemicity of territories, level of population immunity, the appearance of foci TBE in suburban areas and cities, changing in the range of certain types of ticks and the appearance of «tick-mutants»), as well as the clinical picture of TBE (phenomenon of pathomorphosis, growing relevance of mixed infections transmitted by ticks). The analysis of the possible causes of evolutionary transformations is carried out, among which the main ones are natural factors (climate change), anthropogenic factors, namely disturbance of natural landscapes due to human activities and environmental pollution by some pesticides, and additional ones -impact of vaccination. Purpose of the article: characteristics of the main manifestations and probable causes of the evolution of TBE over 80 years. Conclusions: The review for the first time provides information about the main issues of this problem, identifies changes and transformations that affect pathogens and vectors, and, as a result, entails changes in the epidemiology and clinical picture of this disease, which are traced in different territories.

Relevance.Тhe Ural Federal district (Ural Federal district) is a highly endemic tick-borne viral encephalitis (TBEV) territories in the Russian Federation. The epidemiological situation on the TBEV is studied in Sverdlovsk and Chelyabinsk regions and slightly shown in the Kurgan region. There is no information about the evolution TBEV, the structure of immunity population, vaccine prevention in the Kurgan region. The article presents the dynamics epidemiological situation on TBEV in the Kurgan region over a 30-year period.Materials and methods: Used expedition reports, viral encephalitis named after the Academy of medical Sciences of the USSR for 1983–2007, as well as materials of medical institutions of the Kurgan region 2007–2017. For population immunity used: hemagglutination test (HAI-test), neutralization test (NT). To identify specific antibodies – IgG, IgM, antigen of TBEV, sets of reagents of ELISA from «Vector-Best» were used. To immunotypicalli and genotypically Strains and isolates RNA of TBEV isolated in 1983–2007, used precipitation in agar (RDPA) and by RT-PCR technique in real time with genotypespecific probes.Results and discussions: Kurgan region is a highly TBEV endemic area. the morbidity rate – 18,3 per 100 thousand people 1983. Maximum elevation – 44.1 in 1996 to and decrease to 13.5 in 2000–2012. The immune part of the population according hemagglutination tests, on epidemiologically significant territories is 15–20%, (66% NT), in the regions with sporadic incidence is 8%, (21–50% NT), in non-endemic territories – 3%. At the present stage, the region marked the expansion of nosoareal TBEV due to the previously less significant Eastern regions. In Kurgan region vaccination coverage against TBE 39.3%. The clinical efficacy of vaccination was manifested in an increase in fever forms of TBE disease and a decrease in meningeal and focal forms of the disease. In the period 2004–2012 the number of vaccinated patients was 20.3% of the total number of patients.Сonclusions. Evolution of tick-borne encephalitis manifested the expansion of nosoareal TBEV, increase seasonal activity of ticks, the TBEV Siberian subtype is absolutely dominating.

Relevance. Modern inactivated culture vaccines against tick-borne encephalitis (TBE) with at least 70% of the population living in the natural foci of the FE give a high epidemiological effect. Unresolved issues are the simplification of the cumbersome vaccination scheme, the optimal number of revaccinations, the protective titer of antibodies against the Siberian subtype of the TBE virus dominant in Russia.Goal of this work is to study the state of postvaccinal immunity in the population of the highly endemic area of the Trans-Urals.Materials and methods. 1381 blood serum of the population vaccinated from 3 to 13 times with vaccines was studied: unconcentrated culture inactivated from strain No. 205 of the TBE virus produced by «Virion», Tomsk, «EnceVir» produced by «Microgen», Tomsk, produced by Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products of Russian.To identify specific antibodies – IgG, IgM, antigen of TBE virus, sets of reagents of ELISA from «Vector-Best» were used. Neutralizing activity of sera was determined by the index of neutralization index with 4 strains of the Siberian subtype of TBE virus.Results. The immune layer among the vaccinated population in 10 districts of the Kurgan region, which differ in epidemiological tension, ranges from 69.9% to 94.6%. The intensity of humoral immunity varied according to IgG titers in ELISA from 1: 100 – 1: 200 to 1: 3200 (rarely 1: 6400). The duration and intensity of immunity depends on the number of vaccinations and the number of missed remote revaccinations. Preservation and intensity of immunity with reliability P = 95%, higher in persons vaccinated 6–10 times compared with the group of vaccinated 3 times. In persons who had 4–8 booster dose of vaccine, the immunity persisted for 15–19–36 years with an IgG titer of not more than 1: 100. The neutralizing activity of the sera of vaccinated individuals with antibody titers from 1:100 to 1: 6400 was studied for the Siberian subtype of BCE. The degree of protection of the vaccinated population against the doses of the virus found in individual mites is determined. From the doses of the virus, 57% of the vaccinated population are most often found in mites, and from the dose of 105– 8%. Recommendations are proposed on the tactics of revaccination of the population, depending on the level of immunity.

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a causative agent of a severe neurological disease. There are three main TBEV subtypes: the European (TBEV-Eu), Far Eastern (TBEV-FE), and Siberian (TBEV-Sib). Currently, three lineages within TBEV-Sib have been recorded. In this study, the genetic and biological characteristics of a new original strain, TBEV-2871, isolated in the Novosibirsk province of Western Siberia, Russia were investigated. The strain has low neuroinvasiveness in mice. Phylogenetic analysis demonstrated that TBEV-2871 belongs to TBEV-Sib, but does not cluster with any of the TBEV-Sib lineages. The TBEV-2871 strain has 88–89% nucleotide sequence identity with the other TBEV-Sib strains, 84–86% nucleotide sequence identity with the TBEV-FE and TBEV-Eu subtypes and is genetically close to the subtype division border. The TBEV-2871 polyprotein sequence includes 43 unique amino acid substitutions, 30 of which are recorded at positions that are conserved among all TBEV subtypes. Strain TBEV-2871 and two similar but not identical isolates found in Kemerovo province, Western Siberia are separated into a new lineage tentatively named Obskaya after the name of Ob riber, in the vicinity of which the TBEV-2871 was first found. A molecular evolution investigation demonstrated that within TBEV-Sib, the Obskaya lineage likely separated 1535 years ago, which is even earlier than the Baltic lineage. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis is widespread in Eurasia and transmitted by Ixodes ticks. Classification of its causative agent, tick-borne encephalitis virus (TBEV), includes three subtypes, namely Far-Eastern, European, and Siberian (TBEV-Sib), as well as a group of 886-84-like strains with uncertain taxonomic status. TBEV-Sib is subdivided into three phylogenetic lineages: Baltic , Asian , and South-Siberian . A reason to reconsider TBEV-Sib classification was the analysis of 186 nucleotide sequences of an E gene fragment submitted to GenBank during the last two years. Within the South-Siberian lineage, we have identified a distinct group with prototype strains Aina and Vasilchenko as an individual lineage named East-Siberian . The analysis of reclassified lineages has promoted a new model of the evolutionary history of TBEV-Sib lineages and TBEV-Sib as a whole. Moreover, we present arguments supporting separation of 886-84-like strains into an individual TBEV subtype, which we propose to name Baikalian (TBEV-Bkl). [ABSTRACT FROM AUTHOR]

The first tick-borne encephalitis (TBE) cases in Kotka, Finland appeared in 2010. Altogether ten human cases have been diagnosed by 2014. Four had long-lasting sequelae. We collected 195 Ixodes ricinus ticks, nine rodents, and eleven shrews from the archipelago of Kotka in 2011. Three Siberian subtype TBE virus (TBEV) strains were isolated from the ticks and three mammals were positive for TBEV antibodies. The archipelago of Kotka is a newly emerged TBE focus of Siberian subtype TBEV circulating notably in I. ricinus . The patients had on average longer hospitalization than reported for the European subtype infection. [ABSTRACT FROM AUTHOR]

Background: Tick-borne encephalitis virus (TBEV) is a causative agent of acute central nervous system disease in humans. It has three subtypes, far eastern (FE), Siberian (Sib) and European (Eu) subtypes, which are distributed over a wide area of Europe and Asia. The objective of this study was to develop a simple and rapid assay for the detection of TBEV RNA by using reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) method that can differentiate the three subtypes of TBEV and can be used for clinical diagnosis and epidemiological study. Methods: Primers for TBEV-specific and subtype-specific RT-LAMP assay were designed to target the consensus sequence in NS1 of all subtypes and the consensus sequence in the E gene of each subtype, respectiveluy. In vitro transcribed RNA of Oshima strain that belongs to FE subtype was serially diluted and used to examine the sensitivity of the assay. Cross-reactivity of subtype-specific RT-LAMP assay was tested by using the RNA of Oshima and Sofjin (FE), IR-99 (Sib) and Hochosterwitz (Eu) strains. RNA extracted from the mixtures of TBEV and ticks, and of TBEV and human blood, and the mouse tissues infected with TBEV, were evaluated in the assay. Positive amplification was observed by real-time monitoring of turbidity and by visual detection of color change. Results: The sensitivity of TBEV-specific RT-LAMP assay was 102 copies of target RNA per reaction volume. FEspecific RT-LAMP assay amplified viral genes of Oshima and Sofjin strains but not of IR-99 and Hochosterwitz strains, and of Japanese encephalitis virus. RT-LAMP assay for Sib and for Eu specifically amplified viral genes of IR-99 and Hochosterwitz strains, respectively. We also showed that tick or human blood extract did not inhibit the amplification of viral gene during the assay. Furthermore, we confirmed that the TBEV RT-LAMP could detect virus RNA from peripheral and central nervous system tissues of laboratory mice infected with TBEV. Conclusion: TBEV RT-LAMP assay offers a sensitive, specific, rapid and easy-to-handle method for the detection of TBEV RNA in tick samples and this may be applied in the clinical samples collected from TBE-suspected patients. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis virus (TBEV) causes one of the most important inflammatory diseases of the central nervous system, namely severe encephalitis in Europe and Asia. Since the 1980s tick-borne encephalitis is known in Mongolia with increasing numbers of human cases reported during the last years. So far, however, data on TBEV strains are still sparse. We herein report the isolation of a TBEV strain from Ixodes persulcatus ticks collected in Mongolia in 2010. Phylogenetic analysis of the E-gene classified this isolate as Siberian subtype of TBEV. The Mongolian TBEV strain showed differences in virus titers, plaque sizes, and growth properties in two human neuronal cell-lines. In addition, the 10,242 nucleotide long open-reading frame and the corresponding polyprotein sequence were revealed. The isolate grouped in the genetic subclade of the Siberian subtype. The strain Zausaev (AF527415) and Vasilchenko (AF069066) had 97 and 94 % identity on the nucleotide level. In summary, we herein describe first detailed data regarding TBEV from Mongolia. Further investigations of TBEV in Mongolia and adjacent areas are needed to understand the intricate dispersal of this virus. [ABSTRACT FROM AUTHOR]

Background In many European countries (including Finland, Estonia, Latvia and Russia) two subtypes of tick-borne encephalitis virus (TBEV) occur with overlapping geographic distribution yet with apparently different severity and persistence of symptoms. However, it has not usually been possible to distinguish these infections in the laboratory, as TBEV RNA or sequences have rarely been retrieved from patients seeking medical care in the second phase of infection when the neurological symptoms occur, and serological tests have so far not been able to discriminate between the subtype-specific responses. Objectives The aim of this study was to assess the applicability of a μ-capture enzyme immunoassay (EIA) based on TBEV prME subviral particles produced in mammalian cells from Semliki-Forest virus replicons (SFV-prME EIA) to distinguish reactivity to European and Siberian strains of TBEV. Study design Altogether 54 TBEV IgM positive acute human serum samples and 6 positive cerebrospinal fluid (CSF) samples from different regions of Finland were tested in EIA with subtype-specific antigens and TBEV-IgM subtype-specific index ratios were determined. Results All 30 samples from patients whose transmission had occurred in foci where only Siberian subtype of TBEV is occurring had an index ratio of more than 1.8, whereas all 30 acute TBE samples from an area where only European subtype circulates had an index ratio below 1.5. Conclusions We conclude that the assay is a useful tool to distinguish between acute infections of European and Siberian strains of TBEV, and should help in further studies of the clinical outcome of these two subtypes. [ABSTRACT FROM AUTHOR]

Abstract: Western Siberia is the region with the highest known incidence of tick-borne encephalitis (TBE) in the world, with 40 to >80 cases/100,000 population. Few data are available on the circulation of TBE virus (TBEV) strains in the region. In the present study, a total of 468 pooled ticks (Ixodes persulcatus) collected in 7 areas around Kemerovo, Western Siberia, were tested for the presence of TBEV RNA by real-time RT-PCR. Positive tick pools were further investigated by conventional PCR and the nucleotide sequences of the partial TBEV E protein genes were compared to known nucleotide sequences of (Siberian) TBEV strains. In 4 of the 7 areas tested, TBEV RNA-positive ticks were found. Seven out of 28 tick pools were positive in real-time RT-PCR. Assuming only one tick of each pool to be positive, the overall minimal infection rate (MIR) was 1.5% (7/468), ranging from 0% up to 4% for positive regions. Molecular characterization of the E protein of 6 of the 7 positive pools exhibited a sequence variability of 1.4–2.6% in comparison to the nucleotide (nt) sequence of the Aina strain of the Siberian subtype of TBEV. The phylogenetic analysis of the nt sequences clearly indicates that two clusters of the Siberian subtype of TBEV seem to circulate simultaneously in the Kemerovo region. The pathogenicity of the respective virus variants, however, warrants further examination. [Copyright &y& Elsevier]

• Tick-borne encephalitis virus, Siberian subtype (TBEV-Sib) exhibits high diversity. • A novel Bosnia lineage was described within TBEV-Sib in addition to known lineages. • Each TBEV-Sib lineage has a certain pattern of geographic distribution. • TBEV-Sib spread across Eurasia was not linear and included multiple introductions. • Average substitutions rate in TBEV-Sib ORFs was 3.0 × 10-5 substitutions/site/year. The tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is currently subdivided into three main subtypes—the European (TBEV-Eu), the Far-Eastern (TBEV-FE), and the Siberian (TBEV-Sib). The TBEV-Sib is the most common subtype and found in all regions where TBEV was detected, except for Central and Western Europe. Currently, four genetic lineages have been described within TBEV-Sib. In this study, detailed analysis of TBEV-Sib genetic diversity, geographic distribution, phylogeography and divergence time of different TBEV-Sib genetic lineages based on E gene fragments, complete genome sequences, and all currently available data in the GenBank database was performed. As a result, a novel Bosnia lineage within the TBEV-Sib was identified. It was demonstrated that the Zausaev lineage is the most widely distributed among the TBEV-Sib lineages, and was detected in all studied regions except the Far East. The Vasilchenko lineage was found from Western Siberia to the Far East. The Baltic lineage is presented from Europe to Western Siberia. The Obskaya lineage was found only in Western Siberia. TBEV strains from a newly described Bosnia lineage were detected in Bosnia, the Crimean peninsula, Kyrgyzstan and Kazakhstan. The greatest divergence of the TBEV-Sib genetic variants was observed in Western Siberia. Within the TBEV-Sib, the Obskaya lineage diverged from the common ancestor the earliest, after that the Bosnia lineage was separated, then the Baltic lineage, and the Zausaev and Vasilchenko lineages diverged most recently. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis (TBE) virus, which is usually divided into European, Far Eastern and Siberian subtypes, is a serious public health problem in several European and Asian countries. Vaccination is the most effective measure to prevent TBE; cross-subtype protection elicited by the TBE vaccines is biologically plausible since all TBE virus subtypes are closely related. This manuscript systematically explores available data on the cross-subtype immunogenicity elicited by the currently available Western vaccines based on the European subtype. Completed immunization course of 3 doses of both Western vaccines determined very high seroconversion/seropositivity rates against both Far Eastern and Siberian subtypes among previously flavivirus-naïve subjects. All but one study found no statistically significant difference in titers of neutralizing antibodies against strains belonging to homologous and heterologous subtypes. Pooled analysis of randomized controlled trials on head-to-head comparison of immunogenicity of Western and Russian TBE vaccines did not reveal differences in seroconversion rates against Far Eastern isolates in either hemagglutination inhibition (risk ratio = 0.98, p = 0.83) or enzyme-linked immunosorbent (risk ratio = 0.95, p = 0.44) assays after 2 vaccine doses. This suggests that, in regions where a heterogeneous TBE virus population circulates, vaccines based on the European subtype may be used alongside vaccines based on the Far Eastern subtype. Studies on the field effectiveness of TBE vaccines and investigation of vaccination failures, especially in countries where different subtypes co-circulate, will further elucidate TBE vaccination-induced cross-subtype protection.