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Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, can cause serious infection of the central nervous system in humans, resulting in potential neurological complications and fatal outcomes. TBEV is primarily transmitted to humans through infected tick bites, and the viral agent circulates between ticks and animals, such as deer and small mammals. The occurrence of the infection aligns with the seasonal activity of ticks. As no specific antiviral therapy exists for TBEV infection, treatment approaches primarily focus on symptomatic relief and support. Active immunization is highly effective, especially for individuals in endemic areas. The burden of TBEV infections is increasing, posing a growing health concern. Reported incidence rates rose from 0.4 to 0.9 cases per 100,000 people between 2015 and 2020. The Baltic and Central European countries have the highest incidence, but TBE is endemic across a wide geographic area. Various factors, including social and environmental aspects, improved medical awareness, and advanced diagnostics, have contributed to the observed increase. Diagnosing TBEV infection can be challenging due to the non-specific nature of the initial symptoms and potential co-infections. Accurate diagnosis is crucial for appropriate management, prevention of complications, and effective control measures. In this comprehensive review, we summarize the molecular structure of TBEV, its transmission and circulation in natural environments, the pathogenesis of TBEV infection, the epidemiology and global distribution of the virus, associated risk factors, clinical manifestations, and diagnostic approaches. By improving understanding of these aspects, we aim to enhance knowledge and promote strategies for timely and accurate diagnosis, appropriate management, and the implementation of effective control measures against TBEV infections.

BACKGROUND: Southern Sweden is endemic for tick borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. The aim of this study was to describe cases of vaccine failures, and to optimize future vaccination recommendations. METHODS: Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in the county of Stockholm during 2006-2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least two doses. Clinical data were extracted from medical records. RESULTS: A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group the median age was 62 years (6-83). Forty-three (81%) patients were over 50 years of age and two were children. Approximately half of the patients had comorbidities with diseases affecting the immune system accounting for 26% of all cases.Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases. CONCLUSION: To our knowledge, this is the largest documented cohort of TBE-vaccine failures. Vaccine failure after five TBE-vaccine doses is rare. Our data provides rationale for adding an extra priming dose to the age group 50 years and older.

Information on febrile illness caused by tick-borne encephalitis virus (TBEV) without central nervous system involvement is limited. We characterized 98 patients who had TBEV RNA in their blood but no central nervous system involvement at the time of evaluation. Median duration of illness was 7 days; 37 (38%) patients were hospitalized. The most frequent findings were malaise or fatigue (98%), fever (97%), headache (86%), and myalgias (54%); common laboratory findings were leukopenia (88%), thrombocytopenia (59%), and abnormal liver test results (63%). During the illness, blood leukocyte counts tended to improve, whereas thrombocytopenia and liver enzymes tended to deteriorate. At the time of positive PCR findings, 0/98 patients had serum IgG TBEV and 7 serum IgM TBEV; all patients later seroconverted. Viral RNA load was higher in patients with more severe illness but did not differ substantially in relation to several other factors. Illness progressed to tick-borne encephalitis in 84% of patients within 18 days after defervescence.

The rising awareness and increasing number of case reports of tick-borne encephalitis (TBE) in dogs indicate that the virus might be an important tick-borne pathogen in dogs, especially in endemic areas. Therefore, the aim of the present study was to investigate the prevalence rate of TBEV RNA and TBEV-specific antibodies in clinical samples of dogs living in a highly endemic region of Lithuania and to evaluate the main risk factors for severe disease course and death. The blood samples (n = 473) of dogs were collected in two veterinary clinics in central Lithuania. Tick-borne encephalitis virus (TBEV) RNA was detected in 18.6% (88/473; CI 95% 15.2–22.4) and TBEV-specific antibodies were found in 21.6% (102/473; CI 95% 17.9–25.6) of dog blood serum samples after confirmation with a virus neutralization test. The death/euthanasia rate was 18.2% (16/88; CI 95% 10.8–27.8) in PCR-positive dogs. Male dogs were more likely to develop neurological symptoms (p = 0.008). Older dogs (p = 0.003), dogs with the presence of neurological symptoms (p = 0.003), and dogs with the presence of TBEV-specific antibodies (p = 0.024) were more likely to experience worse outcomes of the disease. The results of the present study demonstrate that TBEV is a common and clinically important pathogen in dogs in such endemic countries as Lithuania.

A reliable surveillance strategy of tick-borne encephalitis virus (TBEV) is necessary to ensure adequate disease control measures. However, current approaches assessing geographical TBEV circulation are ineffective or have significant limitations. In this study we investigated a total of 1363 goat and 312 sheep bulk tank milk samples for the presence of TBEV. Samples were collected from systematically selected farms in Lithuania every 4–5 days from April to November in 2018 and 2019. To validate results, we additionally tested 2685 questing ticks collected in the vicinity of milk collection sites. We found 4.25% (95% CI 3.25–5.47) and 4.48% (95% CI 2.47–7.41) goat and sheep milk samples to be positive for TBEV, respectively. Furthermore, geographical distribution of TBEV in milk samples coincided with the known TBE endemic zone and was correlated with incidence of TBE in humans in 2019. When sampling time coincides, TBEV detection in milk samples is as good a method as via flagged ticks, however bulk milk samples can be easier to obtain more frequently and regularly than tick samples. The minimal infectious rate (MIR) in ticks was 0.34% (CI 95% 0.15–0.64). Therefore, our results confirm that testing milk serves as a valuable tool to investigate the spatial distribution of TBEV at higher resolution and lower cost.

•RA patients showed lower IgG-anti-TBEV compared to HC.•In RA, IgG-anti-TBEV are influenced by age at, time since last TBEV vaccination and disease duration.•Higher IgG-anti-TBEV responses in RA patients who had received booster vaccination.•Lower natural killer cell responses in RA patients.•Immunological benefits are suggested for timely boosters. Inactivated vaccines, such as tick-borne-encephalitis-virus-(TBEV) vaccine, have been discussed as less immunogenic in elderly and in immunocompromised patients. In this controlled cross-sectional cohort study, the antibody and cellular responses after TBEV-vaccination were investigated in 36 rheumatoid arthritis (RA) patients and 112 healthy controls (HC) by evaluating IgG-anti-TBEV concentration, neutralization and relative avidity index (RAI). Cellular reactivity was assessed by IFNgamma-producing spot-forming-units (SFU) by ELISPOT assay and flow cytometry. RA patients showed lower IgG-anti-TBEV compared to HC, which were influenced by age at and time since last TBEV vaccination and disease duration. High-responders regarding cellular immunity and avidity were less frequent in RA compared to HC. RA patients who had received booster vaccinations were more likely to demonstrate higher IgG-anti-TBEV responses compared to those who had not. In conclusion, RA patients showed a negative effect of age on anti-TBEV-IgG and immunological benefits of timely booster vaccination are suggested.

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Tick-borne encephalitis virus (TBEV) infection may cause acute central nervous system inflammation varying in clinical manifestations and severity. A possible correlation of TBEV-specific antibody and cell-mediated immune responses, shortly after infection, with clinical manifestations, severity and long-term outcome has been poorly investigated. In a cohort of thirty early tick-borne encephalitis (TBE) patients, we assessed the magnitude, specificity and functional properties of TBEV-specific T-cell and antibody responses. These responses early during disease were assessed in view of clinical manifestations, severity and long-term outcome. TBEV-specific T-cell responses to C, E, NS1, and NS5 proteins were significantly lower in patients with severe acute illness than in patients with mild TBE. Lower T-cell responses to E, NS1, and NS5 proteins also correlated with the development of meningoencephalomyelitis. Virus-specific antibody titres early after infection did not correlate with disease severity, clinical manifestations, or long-term outcome in this study, possibly due to the small number of patients of which matching serum and peripheral blood mononuclear cells were available. The findings suggest that virus-specific T cells afford a certain degree of protection against the development of severe TBEV-induced disease.

Abstract Background Southern Sweden is endemic for tick-borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. Our aim in this study was to describe cases of vaccine failures and to optimize future vaccination recommendations. Methods Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in Stockholm County during 2006–2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least 2 doses. Clinical data were extracted from medical records. Results A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group, the median age was 62 years (6–83). Forty-three (81%) patients were aged >50 years and 2 were children. Approximately half of the patients had comorbidities, with diseases affecting the immune system accounting for 26% of all cases. Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases. Conclusions To our knowledge, this is the largest documented cohort of TBE vaccine failures. Vaccine failure after 5 TBE vaccine doses is rare. Our data provide rationale for adding an extra priming dose to those aged ≥50 years. This 10-year retrospective study includes 53 patients (median age 62 years, 6-83) with TBE vaccination failure. Forty-four (81%) patients were aged ≥50 years. Based on our data, we propose adding an extra priming dose for individuals aged ≥50 years.

During February 2018-January 2019, we conducted large-scale surveillance for the presence and prevalence of tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) in sentinel animals and ticks in the United Kingdom. Serum was collected from 1,309 deer culled across England and Scotland. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. A focus in the Thetford Forest area had the highest proportion (47.7%) of seropositive samples. Ticks collected from culled deer within seropositive regions were tested for viral RNA; 5 of 2,041 ticks tested positive by LIV/TBEV real-time reverse transcription PCR, all from within the Thetford Forest area. From 1 tick, we identified a full-length genomic sequence of TBEV. Thus, using deer as sentinels revealed a potential TBEV focus in the United Kingdom. This detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis.