Summary & Conclusion:
The TBE-Virus (TBEV) is circulating throughout Europe and Asia from the United Kingdom and the polar circle to northern Italy and eastwards through Russia and China to Japan. Due to a lack of systematic testing over time, disease incidences as well as detailed TBEV-distribution or emergence remain elusive. Systematic surveillance is urgently needed to address the question if TBE is spreading or increasing anywhere.
|Citation: Mahmood S, Erber W, Yi Z, Dobler G, Schmitt HJ. The Changing Epidemiology of Tick-Borne Encephalitis (TBE). VacciReview. 2022;6(1):1-14. https://doi.org/10.33442/vr220601.
Academic Editor: Heinz-Josef Schmitt.
Received: February 22, 2022
Publisher’s Note: GHP stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Copyright: © 2022 by the authors. GHP. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Keywords: TBE; epidemiology; disease risk; disease trends; TBE trends
Tick-borne encephalitis (TBE) is a serious infection of the brain, spinal cord and/or the meninges, either solitary or in combination. Case fatality rates vary between 0.5%–2% in Europe and up to 20% in Russia . Around 40% of survivors in Europe suffer from permanent sequelae . Non-CNS manifestations of TBEV-infections have also been observed, but this has not been systematically studied yet . The causative agent of TBE is the TBE virus (TBEV) belonging to the family Flaviviridae, genus Flavivirus. While some AIDS-medications have been reported to exhibit substantial in-vitro activity against the TBEV  and one single patient with severe TBE was “cured” after receiving an influenza medication , no specific therapy against TBE is licensed. Therefore, vaccination against the disease is recommended in endemic areas by local and international authorities . Until recently, it was believed that TBE was confined to central Europe, the Baltics, parts of Scandinavia, Russia, and parts of Asia . However, since about 1990 there has been increasing evidence the TBEV is also circulating in Japan, South Korea, Mongolia, and Kazakhstan in the East, as well as in The Netherlands, France, and in the United Kingdom in the West [7, 8].
With decreasing costs over time, recent studies on TBE epidemiology used modern and more sensitive methods like polymerase chain reaction (PCR) to detect the TBEV in ticks or enzyme-linked immunosorbent assay (ELISA) testing for anti-TBEV-antibodies in reservoir animals or in humans . Thus, it remains unknown if the current emergence of “new” TBE-endemic areas is a result of spreading of the TBEV to new areas or if it is due to the use of improved and more frequently applied diagnostic tools. Here we use the database of the German National Consulting Laboratory for TBE supplemented with a targeted literature review (1) to summarize current evidence on the emergence of the TBEV to new areas; (2) to detect different epidemiological patterns of the disease; (3) to examine disease trends; and (4) to synthesize all data as basis for public health decisions.
2. Materials and Methods
The literature database of the National Consulting Laboratory for TBE in Germany routinely checks the international literature on the epidemiology of TBE. It was used here to identify articles on areas where TBE/TBEV were newly detected over the last 20 years. In addition, a targeted search of relevant articles was conducted in PubMed and Google Scholar to identify publications reporting TBE cases in previously non-endemic areas.
For the review here, TBEV isolations from ticks, serosurveillance data from animals, as well as reports on human TBE cases were considered. In addition, the number of TBE cases over time in Austria was obtained from the Center for Virology at the Medical University of Vienna, which acts as the National Reference Laboratory for flaviviruses. For Germany the annual number of TBE cases was collected from the website of the national public health authority, the Robert Koch Institute (RKI) (https://survstat.rki.de/Content/Query/Create.aspx). Annual TBE incidences in Estonia, Latvia, Finland, Norway and Sweden were obtained from the literature including the recently published “The TBE Book”. For Austria, Estonia and Latvia cases reported from 1979 to 2020 were available, and data since 1991 were used for state-level comparisons (https://www.virologie.meduniwien.ac.at/wissenschaft-forschung/virus-epidemiologie/virusepidemiologische-information/2021/). Germany has had laboratory-based mandatory reporting since 2001. Therefore, data since 2001 were considered for both overall and state-level analysis (RKI, SurvStat). For Finland, Norway and Sweden data were available from 1995, 1994, and 1979, respectively. Population data (to calculate incidences) of different states/regions/counties were collected from publicly accessible websites including the Statistics Austria (Statistik Austria), the Federal Statistical Office Germany (Statistisches Bundesamt), and the Statistics Estonia (Eesti Statistika).
For analysis of TBE within states/counties, the Stata 14 software (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP) was used. Incidences were expressed as number of cases per 100,000 population. Linear regression was done for trend analysis. For the comparison of any changes as well as for the appearance or disappearance of TBE in Bavaria and Baden-Württemberg, the mean incidences of different counties of these two states were calculated for the periods 2001–2005 and 2014–2018. Due to unavailability of longitudinal population data at county level, census data of 2011 were collected for Bavaria and Baden-Württemberg, and incidences were calculated with the assumption that the total population for these counties did not change significantly over time.
To demonstrate the change of mean incidences in maps, geospatial data of Bavaria and Baden-Württemberg showing all counties of these two states were obtained from the DIVA-GIS website (https://www.diva-gis.org/). For analyzing geospatial data of these two states, ArcGIS
v.10.7 was used. The definitions of “cases emerged” and “cases disappeared” for county-level comparisons for Bavaria and Baden-Württemberg were as follows: Cases emerged: zero TBE cases were reported during 2001–2005, but TBE cases were reported throughout 2014–2018. Cases disappeared: TBE cases were reported during 2001–2005, but zero TBE cases were reported throughout 2014–2018.
3.1 TBE emergence
TBEV circulation over the past decades can be visualized by published maps used to document TBE-endemic areas as a basis for the recommendation to get vaccinated against the disease in Europe (Figure 1). From a few restricted endemic areas in 1999, the TBEV today is known to circulate in Europe and Asia in a belt reaching from the United Kingdom  and France  in the West to Japan [12-14] in the East and from the arctic circle in Norway  and Russia down to Northern Italy , Bulgaria , Kazakhstan , China and Korea [19, 20] in the south. Comprehensive literature searches revealed circulation of TBEV in ticks in some newly emerging countries (see below), but no similar data from the past were found for a comparison. Therefore, it remains unknown if the TBEV “newly emerged” or if it was simply “first detected” in most of the regions now newly known to harbor the virus.
|Figure 1.||Known areas of TBEV circulation in 1999 and 2013 (data from: Baxter Austria), and 2016 (from: Pfizer), and 2020 (from: The TBE Book, 2020; based on references from the respective countries).|
Based on the literature review, the epidemiological situation in countries/areas with recently emerging TBE cases can be summarized as follows:
- From the literature review, 6 countries with “definite newly emerging” TBE areas were identified, i.e. Denmark, The Netherlands, The United Kingdom, France, Norway, and Japan. In addition, there were recent reports indicating TBEV circulation based on serosurveys in animals from the three South European areas Spain , Turkey , Greece , and for the first time outside of Eurasia in Tunisia, Northern Africa [24, 25]. TBE is not a reportable disease in Denmark, but as microbiological confirmation of TBE is accomplished in one central laboratory only, confirmed and published cases from this institution represent all known cases in the country. Consistently, in Denmark 0–8 TBE cases were reported annually between 1997 and 2019, all from Bornholm Island except in 2009, when a severe case of TBE was diagnosed in a forest worker from a small forested area, Tokkekøb Hegn on Zealand just north of Copenhagen. With 4 more cases outside Bornholm and all from Northern Zealand, there currently appears to be limited circulation of the TBEV in Denmark outside Bornholm . A study of TBEV among roe deer (Capreolus capreolus) in Denmark revealed that there was an increase in the rate of seropositivity along the coast of all major islands and in mainland Denmark when comparing data from the early 2000s to data from 2013–2014 . When seropositivity data of roe deer from 2002–2003 were compared to 1958–1962, in the later period seropositive roe deer were found in Bornholm and Jutland islands compared to only Bornholm in 1958–1962 .
- Autochthonous TBE had never been reported from The Netherlands before May 2016. The few cases reported until then were considered disease importations from known endemic countries. However, a serological survey of 297 blood samples from roe deer found a 2% seropositivity rate and a survey of Ixodes ricinus ticks in the National Park Sallandse Heuvelrug revealed that 2 out of 1460 ticks were positive for the TBEV . Subsequently, 2 human cases were reported in June 2016 from the Netherlands, both proven as autochthonous cases. One of these cases was linked to the geographic area where TBEV had been isolated in roe deer and ticks .
- Although seroprevalence studies previously had revealed the presence of TBEV in sentinel animals in Belgium, the very first 3 autochthonous clinical TBE cases were confirmed only in 2020 .
- The TBEV has recently been identified in ticks collected from roe deer in Norfolk in the east of the United Kingdom [31, 32]. A probable TBE case was reported in a traveler who got infected during a picnic in the Southampton region .
- The first known human case of TBE in France was identified near the German border in Alsace as early as 1968. Since then, over 200 human cases have been identified in France, which was previously considered a non-endemic country . However, since 2018, TBE cases were reported from 2 additional regions, Lorraine, and Rhône-Alpes . In 2020, a milk-borne outbreak was recorded from the Rhône-Alpes region affecting at least 33 patients (Food Safety News, June 26, 2020; https://www.foodsafetynews.com/2020/06/tick-borne-encephalitis-outbreak-linked-to-raw-milk-cheese-in-france).
- In Norway, TBE was first reported in 1997. Since then there have been annual notifications of TBE cases ranging from 0 to a peak of 45 cases in 2008 with huge fluctuations. TBEV positive I. ricinus ticks have recently been detected in north western and north eastern Norway as high as 66°N with seropositivity rates ranging from 3% up to 9% in nymphs and adult ticks, respectively [15, 36]. Seroprevalence studies indicate that the TBEV may circulate in Norway more widely and circulation may not be limited to the southern coast-line .
- In Japan, the first case of TBE was confirmed in 1993 on the northern island Hokkaido, followed by four additional cases from the same island between 2016 and 2018 . There is evidence now from serosurveillance in wild animals that the TBEV is endemic in many other regions of Japan . As no commercial ELISA test is available in the country, the real TBE case numbers in Japan remain elusive.
TBE has recently been reported from animal sero-surveys in Spain, Turkey, Greece, and Tunisia [21-25]. All these reports were based on ELISA testing only and positive results were not validated by neutralization test, by PCR detection, or by isolation of the TBEV. Given (1) the low specificity and in some cases even the lack of validation of the serological assays used and (2) the widespread circulation of
- other animal flaviviruses that may serologically cross-react with TBEV-antigens in ELISA tests (Louping ill virus and its subtypes in Greece, Turkey, Spain, West Nile virus, Usutu virus), these reports still need confirmation using more definite laboratory methods. To date, these regions are usually considered “TBEV-free”.
- Recent expansion of I. ricinus ticks to higher altitudes has been documented. In the Czech Republic, ticks have been collected at altitudes above 600 m a.s.l. (meters above mean sea level)  and acquisition of the TBEV by humans has been reported from 900 m a.s.l. in 1996 and 2001 in the upper part of the Sumava mountains in the Czech Republic . Occurrence of human TBE-infections at higher altitudes was also observed in Austria in recent years, where new infection sites were identified in Tyrol with individual infections sites at altitudes as high as around 1500 m a.s.l. .
3.2 Patterns on the epidemic curve
Besides emergence of TBE in new areas, increasing case numbers are a second concern. In Europe, 3 distinctive epidemiological patterns of TBE were identified (Figure 2, Figure 6): (1) Stable incidences around 5 per 100,000 population with substantial increases over the last years (Austria, Germany); (2) bell-shaped incidence patterns with huge peaks (>20/105) in the mid 1990s and with decreases to 5–10/105 ever since (Latvia; Estonia); (3) and continuous increases ever since the 1980s but incidences still at low levels (<4/105; Norway, Sweden, Finland).
|Figure 2.||TBE incidences 1979–2020 (as available) in Austria (The TBE Book, 2021), Germany (The TBE Book, 2021) (Baden Württemberg (RKI, SurvStat) and Bavaria (RKI, SurvStat), Latvia (The TBE Book, 2021) and Estonia (The TBE Book, 2021).|
A detailed analysis shows that in Austria as a whole, the reported peak TBE incidence was 8.68 per 100,000 population in 1979 reflecting 677 TBE cases (Figure 3). Vaccine uptake has increased slowly since then, reaching 88% in 2005, with a plateau of >80% since about the year 2000. The lowest overall TBE incidence (0.53/105) was observed in 1999. Recently, and despite a roughly similar vaccine uptake since 2000, incidences have started to increase again, particularly between 2016 and 2020, reaching a new peak in 2020. The relevant fluctuations are not well visible in Figure 2. Ever since the 1990s, TBE cases in Austria as a whole have been almost exclusively seen in unvaccinated subjects where the incidence fluctuates largely between 4–8/105 . However, there are relevant differences between regions and time periods. Highest TBE incidences in the unvaccinated population were reached in Styria in the early 1990s with incidences >30/105, similar to the peaks in Latvia and Estonia, whereas trends were decreasing during that time in other regions like Burgenland . For the first time since the late 1980s, peak case numbers in Austria were reached in 2020 with 216 cases (almost exclusively in unvaccinated cases), about 5 times higher than historically reported trough levels (compared to 41 in 1999) and with waves of varying length.
|Figure 3.||TBE epidemic curve in Austria (The TBE book, 2021) (with case numbers (red bars, right Y-axis) and vaccine uptake of the population (percent with >1 dose any time in life. Green line; right Y-axis).|
Thus, the overall epidemiology in Austria appears to be a summary effect resulting from opposite trends in different regions (Figure 4). In the state of Styria, the highest TBE incidence (7.7/105) was observed in 1994 but numbers decreased with the increasing vaccine uptake to below 2/105 in recent years. In contrast, Tyrol showed a sharp increase of annual TBE incidences starting from very low (0.48/105) in 1991 to reaching approximately 4/105 in 2017 and 2018. TBE incidence in Vienna was very low even in the 1990s and decreased even further over time. Overall, four out of nine Austrian states (Salzburg, Tyrol, Upper Austria, and Vorarlberg) showed an increasing trend of TBE over time while the other 5 had decreasing trends.
Neighboring Germany has no valid data for TBE vaccine uptake. Recent market research analysis indicates that overall about 44% of the population received >2 TBE vaccine doses in 2019; i.e. 37% in non-endemic and 58% in endemic regions (Pilz A. et.al. Vaccine Uptake in 20 countries in Europe 2020: Focus on Tick-Borne Encephalitis (TBE); manuscript in submission). In this context, TBE incidences in Germany fluctuated over time with 0.25/105 the lowest (2012) and 0.73/105 the highest (2018) (Figure 2). Increasing and highest disease incidences (2018, 2019, 2020) in Germany were reported from Bavaria (1.1, 1.5, 2.9/105) and Baden Württemberg (0.8, 1.6, 2.1/105) the two southern states with a combined total population of 24.3 million (total German population: ~85 million). Waxing and waning of case numbers is seen annually with peaks of varying and unpredictable height. Northern states such as Hesse, Saxony, and Thuringia had incidences below 0.6/105.
While the TBEV in fact is circulating in at least 14 of 16 German Federal States except Hamburg and Bremen , not all counties at a state level are considered “endemic” for TBE by the national public health authority (RKI), which requires a 5-year incidence significantly higher (p < 0.05) than the expected incidence of 1/105 . Over the past 19 years (2002 to 2021) a total of 89 counties were newly added to the list of “officially endemic” counties in Germany. Among these “newly endemic regions” in 2021, the county of Dessau-Roßberg was added to the list of “TBE endemic areas”, although no single autochthonous case had been reported from there between 2017 and 2020. However, the population size had decreased, and the lower denominator resulted in a higher TBE incidence . To date, no single county in Germany has officially been excluded from the list of TBE endemic areas as RKI experts believe that the waiting period for losing the “endemic” status should require a 20-year TBE-free period .
|Figure 4.||TBE incidence trend analysis of different states of Austria from 1991–2018 showing decreasing incidence in 5 states and increasing trends in 4 states with sharp increases in Tyrol and sharp decreases in Styria.|
Down to county levels in Bavaria and Baden-Württemberg, TBE incidences were compared between two 5-year time periods: 2014–2018 and 2001–2005. Bavaria showed incidence increases in its north-eastern, eastern, and southern Alpine regions bordering Austria and Switzerland (Figure 5). The increase was pronounced in Amberg-Sulzbach and Freyung-Grafenau counties with an incidence of 4–5/105 in 2014–2018. In contrast, the north-western region showed a decrease comparing 2014–2018 to 2001–2005. In the north-western region, cases even disappeared completely over the last 5 years in neighboring Schweinfurt and Kitzingen counties. This is noteworthy as the Schweinfurt area was the place in former West Germany where TBEV had first been detected as early as in 1970 . TBE cases, however, newly emerged mainly in the southern Alpine region where overall TBE incidences were increasing.
In Baden-Württemberg, newly emerging TBE cases were only reported from one county (Alb-Donau-Kreis County) located in the south-eastern region. Like in Bavaria, increasing TBE incidences were observed in the central and in the southern Alpine region. Counties with increasing TBE incidences showed in general higher average altitudes than those with decreasing incidences. Disappearance of TBE cases was only observed in one county (Main-Tauber-Kreis) situated in the north-eastern region bordering Bavaria, neighboring to the counties where TBE incidences were also decreasing or disappearing.
In contrast to most other countries discussed earlier, in Estonia, the epidemic curve is bell-shaped with a peak of 404 cases (1997) in a population of about 1.3 million (Figure 2). This was followed by an overall decreasing trend to lower levels, again with annual fluctuations reaching the lowest point to date with 83 cases in 2019 . TBE vaccine uptake in Estonia is <4%, and thus no relevant portion of the observed decrease of TBE cases can possibly result from any vaccine impact.
A similar bell-shaped epidemic curve with a huge peak in 1994 was observed in Latvia, another Baltic state (Figure 2) . The decrease in case numbers in the following years may at least in part result from an increasing vaccine uptake since 1995 reaching >50% in 2015.
While both Estonia and Latvia in the north show a bell-shaped epidemic curve for TBE, the southern-most of the Baltic states had low case numbers 1969–1992 followed
|Figure 5.||Differences in mean TBE incidences between 2014–2018 and 2001–2005 per 100,000 population in different counties of Baden-Württemberg (left) and Bavaria (right). Green regions: cases disappeared over a 5-year period; red: cases emerged over 5-year period.|
by annually fluctuating case numbers between 200 and 700 cases per year (1993–2019) (Mickiene, A. The TBE Book, 2021; data not shown).
The epidemic curve of TBE in Norway, Sweden and Finland (Figure 6) indicates, with a few outlier years, an overall increasing trend in the last 20 years. Another observation from Northern Europe is that case numbers appear to correlate with population density and with places around the coast lines and/or more densely populated areas, while there are few if any cases reported in less densely populated areas.
In this review, past and currently known areas of TBEV circulation are summarized in maps of Europe and Asia. Evidently, the TBEV substantially emerged over the past 2 decades and it is known today to circulate from the far west of Europe to far east Asia, only sparing the hotter Mediterranean regions in Europe and the equatorial regions in Asia. Still, comprehensive and consistent surveillance does not exist in many countries and case detection – except for Austria – is mostly “spontaneous and sporadic” at best. In Japan and South Korea, no ELISA test for TBE-serology is licensed and available, and in Poland and northern Germany, such tests are not regularly used in patients with CNS diseases as these regions are officially labelled as “non endemic”. Furthermore, no single country to date has ever investigated the completeness of serological testing for TBE in patients presenting with CNS diseases, e.g. by capture-recapture analysis. Thus, it is fair to state that even in known endemic countries in central Europe the “true disease burden” due to TBE is not known. With that in mind, reported cases may just represent the tip of the iceberg of the real case numbers.
For countries where the TBEV was “newly detected”, it remains unknown if this recent emergence is a result of first testing or of recent introduction of the TBEV, as there is a lack of valid historical data for comparison. What is clear though, is that the TBEV is now circulating at higher altitudes in central Europe as well as in colder regions in the Nordic countries. While this may be interpreted as a result of global warming, one would
|Figure 6.||TBE incidences in Norway, Sweden and Finland, 1979–2020.|
expect that climate change / global warming would also result in more cases in the Baltic states; however, case numbers in Latvia and Estonia dropped lately compared to the last decades in the 20th century. A previously accomplished simple and high-level analysis between temperature, precipitation and case numbers also showed no correlation between TBE cases and these climate factors in Germany, Austria and Estonia (Mahmood, S 2019, “The Changing Epidemiology of Tick-borne Encephalitis in Europe”, Master thesis, Université Claude Bernard Lyon 1). This is not unexpected as climate factors may change not only the number of ticks, but also TBEV-density in the tick population, in reservoir animals and the exposure rate in humans in different directions .
The analysis of the epidemic curves shown above identified 3 different patterns over the past decades: (1) increasing case numbers (Norway; Sweden; Finland); (2) huge annual fluctuations of varying lengths (Austria; Germany; and other countries not mentioned here in detail); (3) bell shaped epidemic curves with relevant peaks in the late 1990s with an overall decreasing trend ever since (Latvia; Estonia).
With a cautious interpretation of these diverse findings, the case increases in Norway, Sweden and Finland may perhaps be attributed to increasing TBE disease awareness among physicians and the public alike. Alternatively, the increase may be real (true increase of cases) and that could be explained with increasing leisure time and outdoor activity, with global warming or a combination of factors. The fact that case numbers in the adjacent Baltic states tend to decrease suggests that global warming is not the sole cause. Moreover, TBE in Northern Europe appears to concentrate in more densely populated areas (low population size wrongly indicates “no TBEV circulation”). As the TBEV seems to circulate in microfoci the size of a football field, low case numbers do not at all indicate low risk – outdoor activities within a microfocus would result in high risk, whereas living there may be a minimal risk only.
The huge annual fluctuations in reported TBE case numbers and incidences in central Europe with 4–5-fold differences within a few years time are more difficult to
interpret. These may result from the sensitive interplay between the TBEV, the number and density of its major reservoir animals (bank voles, yellow-necked mice), the availability of various smaller and larger mammals which ticks need for their blood meal, human influence on the landscape (e.g. deforesting, agricultural practices) and finally again on the quality and quantity of the time humans spend outdoor (farming, foresting, leisure activities). All these items are again influenced by climate and weather conditions, sometimes in opposite directions (Figure 7) .
Clearly, reported case numbers over time may represent diverse and sometimes even opposite trends in each region. Over a 5-year period, cases may newly emerge, or a region may even report no single TBE case at all. Even within a given county, incidences may show significant annual changes over a few years only. Taking these observations into consideration, and as case numbers cannot be predicted for the upcoming season, using incidences for estimating the risk for TBE-infections in a region is misleading. If incidences are mentioned at all, they should be calculated and reported for the unvaccinated population using a correction factor for the lack of diagnostic completeness.
The bell shaped TBE epidemic curve in Latvia and Estonia with huge peak case numbers observed in the late 1990s have not been sufficiently elucidated. It is speculated that these peaks might have resulted from poverty following the political changes after 1989, when mushroom-, berry- and wood-collecting were more commonplace to ensure plain survival . Alternatively, it was suggested, that in the Baltics “fever after a tick bite” had been (wrongly) reported as “TBE”. This appears to be unlikely as in a recent study in Latvia only about 20% of cases were “fever only cases” .
With all this in mind, the wish to inform the public in Europe and Asia or travelers from other continents about the size of the risk for TBEV-infection and on the need for disease prevention with valid data is an almost impossible task. As outlined, TBE-incidences are misleading for several reasons:
- They are usually reported without considering the impact of the local vaccine uptake;
- Huge annual incidence fluctuations are observed in the naïve population, and case numbers from the past do not allow precise and meaningful predictions for following years;
|Figure 7.||Factors known to influence annual TBE case numbers|
- TBE incidences depend on the size of a population (denominator) – and if population size is decreasing (see above: Germany), the incidence increases, even if no case was reported for some years;
- Likewise, as shown for northern Europe, areas with a low population density may have low case numbers while the TBE-risk for hiking travelers in such regions may in fact be very high;
- Predicting TBE incidences by using a range is also not helpful as the “real individual risk” in the end depends on behaviors as well as on the precise location of outdoor activities (presence of TBEV-microfoci);
- Finally, current incidences published for Europe and Asia consider neither the completeness of diagnostic efforts by country and county, nor the type and quality of reporting.
As a solution we propose here to use the risk-definition for arbovirus-infections by the European Centre for Disease Prevention and Control in general . These guidelines suggest calling an area “predisposed” if landscape, climate and wildlife would in principle allow the TBEV to circulate; it would be called “imperiled” if there was evidence for TBEV circulation (detection of the TBEV in ticks or serological evidence in sentinel animals); and it would be called “affected” if single human cases had been diagnosed; or “endemic” if human cases occurred annually.
Conception and design: S.M., H.-J.S, G.D.
Data collection and management: S.M., W.E.
Data analysis: S.M., Z.Y.
Interpretation of the results: All authors.
Drafting of the article: S.M., H.-J.S.
Critical revision of the article for important intellectual content: All authors.
Final approval of the article: All authors.
This study was sponsored by Pfizer, Inc.
Data Availability Statement:
Publicly available datasets were analyzed for TBE cases of Germany; climate parameters of Germany; and population data of Austria, Germany and Estonia in this study. These data can be found here: https://survstat.rki.de/Content/Query/Create.aspx, https://www.dwd.de/EN/climate_environment/cdc/cdc_node_en.html, https://www.statistik.at/web_en/statistics/PeopleSociety/population/population_censuses_register_based_census_register_based_labour_market_statistics/population_by_demographic_characteristics/index.html, and https://andmed.stat.ee/en/stat respectively. Restrictions apply to the availability of data regarding TBE cases of Austria and Estonia; and climate parameter of Austria and Estonia. Data were obtained from Center for Virology at the Medical University of Vienna, Kuulo Kutsar, Zentralanstalt für Meteorologie und Geodynamik (ZAMG) and Riigi Ilmateenistus respectively and are available with the permission of Center for Virology at the Medical University of Vienna, Kuulo Kutsar, Zentralanstalt für Meteorologie und Geodynamik (ZAMG) and Riigi Ilmateenistus respectively.
S.M., registered in the EMJMD LIVE (Erasmus+ Mundus Joint Master Degree Leading International Vaccinology Education), co-funded by the EACEA (Education, Audiovisual and Culture Executive Agency, award 2015-2323) of the European commission, received a scholarship from the EACEA. Editorial/medical writing support was provided by Qi Yan, PhD (Pfizer, Inc).
Conflicts of Interest:
S.M. received a stipend from Pfizer for his internship. GD is lecturer for Pfizer. W.E., Z.Y., and H.-J.S., are employees of Pfizer and may hold stock or stock options.
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