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Tick-Borne Encephalitis Virus: A General Overview

  • Dr. Oliver Donoso Mantke
Tick-Borne Encephalitis Virus:
A General Overview
Oliver Donoso-Mantke1, Luidmila S. Karan2 and Daniel Růžek3
1German Consultant Laboratory for Tick-borne Encephalitis,
Robert Koch Institute, Berlin,
2Laboratory of Epidemiology of Zoonoses, Central Research Institute of Epidemiology,
3Institute of Parasitology, Biology Centre of the Czech Academy of Sciences,
České Budějovice,
3Czech Republic
1. Introduction
Tick-borne encephalitis (TBE) virus is classified as one species with three subtypes, namely
the European subtype, the Siberian subtype and the Far Eastern subtype. TBE is distributed
in an endemic pattern of so-called natural foci over a wide geographical area from Western
Europe to the northern part of Japan. It is the most important flavivirus infection of the
central nervous system in Europe and Russia, with about 13,000 estimated human cases per
year. The epidemiology of TBE is closely related to the ecology and biology of ixodid ticks.
In nature, TBE virus is propagated in a cycle involving permanently infected ticks and wild
vertebrate hosts. Currently, the diagnosis of TBE is mainly based on the detection of specific
antibodies in serum and cerebrospinal fluid. No specific treatment for the disease is
available to date, but it can be prevented by active immunization.
2. Ecology of TBE virus
According to the concept of Pavlovskij, TBE virus is maintained in a cycle involving ticks
and wild vertebrate animals in forested natural foci under certain botanical, zoological,
climatical and geo-ecological conditions (Pavlovskij, 1939). The development of a TBE
natural focus depends on the coincidence of all these factors.
The principal carrier (vector) as well as the reservoir of the European TBE virus subtype is
the tick Ixodes ricinus (Rampas and Gallia, 1949), a dominant hard tick across Europe.
However, the virus has been isolated also from several other tick species (Grešíková and
Nosek, 1966; Křivanec et al., 1988; Grešíková and Kaluzová, 1997). I. ricinus ticks live
preferentially in the dense undergrowth of the forests where the relative humidity is high.
Oak, hornbeam as well as beech and fir woods with rich undergrowth of weeds, ferns, elder,
hazel, and bramble bushes provide an ideal habitat for these ticks (Süss, 2003).
Flavivirus Encephalitis
TBE virus strains from Far Eastern and Siberian subtypes are transmitted predominantly by
I. persulcatus. This tick, which aggressively attaches to humans, comprises 80–97% of all tick
species in the Ural, Siberia and the Far East region of Russia (Gritsun et al., 2003a). The
habitat of I. persulcatus is mainly distributed in different taiga forest types. Key factors
affecting I. persulcatus ticks are relatively warm and humid climate conditions. In the event
of high humidity the ticks are frequent in warm and drained spruce and small-leaved
forests. Under low humidity and warm conditions, the ticks are frequent in broad-leaved
coniferous forests and in shaded places. The natural (boreal) habitat of I. persulcatus ticks
spreads from the Baltic States to the Pacific. On the border of habitats (Baltic States, Finland,
Karelia, and several regions of the European part of Russia) sympatric habitations of I.
persulcatus and I. ricinus were observed (Votiakov et al., 2002).
The TBE natural foci do not expand beyond the natural habitats. However, TBE virus has
been isolated also from 18 other tick species in Russia (e.g. frequently from Dermacentor
marginatus in some steppe regions), but sporadically also from other parasitic invertebrates,
e.g. fly, flea and lice (Gritsun et al., 2003b).
The life cycle of ticks (Fig. 1) consists of three stages: the larva, nymph and adult. Each stage
feeds on a different individual vertebrate host, usually for a period of a few days. E.g., the
infection rate of fed adult ticks and their immediate progenies depends on the bigger
mammalian hosts: cattle and wild hares, foxes, boars and deer. Therefore, these hosts are of
primary importance for the existence and transmission of TBE virus.
Each stage of I. ricinus takes approximately one year to develop to the next stage. Thus, the
shortest life cycle takes 3 years on average to complete. However, it may vary from 2 to 6
years throughout the geographical range, depending on the availability of hosts and climatic
conditions (Süss, 2003). Following copulation, the female spends six to eleven days feeding
on blood and, during subsequent months, deposits 500 to 5,000 eggs. Several weeks later,
larvae measuring 0.6–1.0 mm hatch from the eggs. The molting occurs only twice. Six-legged
larva develops into an eightlegged nymph, which in turn molts to produce a similar but
larger adult (Süss, 2003). TBE virus can be transmitted to man or other hosts by all the tick
stages, i.e. larvae, nymphs, as well as adult ticks.
The virus infects ticks chronically for the duration of their life. Nevertheless, ticks
themselves do not develop the disease. The virus is transmitted from one developmental
stage of the tick to the next (transstadial transmission). In the period that precedes molting,
the virus multiplies in the tick and invades almost all the tick’s organs (Benda, 1958). TBE
virus can be also transmitted transovarially (from infected fertilized female to egg) (Benda,
1958) and during co-feeding of ticks on the same host (Labuda et al., 1993; 1997). Despite the
fact that the percentage of transovarial transmission of members of the European TBE virus
subtype in I. ricinus is much lower than of Siberian and Far Eastern strains in I. persulcatus, it
is sufficient under certain conditions to ensure the continuity of virus population. Co-
feeding of both infected and naïve ticks on the same host allows TBE virus transmission
even in the absence of systemic viremia. Results from laboratory experiments suggested that
in this case viremia could be a product, rather than a prerequisite, of TBE virus transmission
(Labuda et al., 1997). Frequently, it is observed that different stages of ticks belonging to
various generations feed on the same host. Therefore, the virus is transmitted efficiently
between generations of carriers for at least 5 consecutive years (Korenberg et al., 1991).
The prevalence of TBE virus infected I. ricinus ticks varies from 0.5% to 5%, whereas in I.
persulcatus in certain regions of Russia prevalence up to 40% was recorded (Charrel et al.,
Tick-Borne Encephalitis Virus: A General Overview
Fig. 1. Life cycle of ixodid tick and transmission cycle of TBE virus. Black lines show the
cycle of ticks with different developmental stages. At each stage, a blood meal is needed to
develop into the next stage. Therefore, each tick stage feeds on suitable hosts. Further, adult
female ticks need a blood meal for egg production. Grey lines show the possible
transmission of TBE virus. Thickness of grey arrows shows the most probable routes
Horizontal TBE virus transmission between ticks and their vertebrate reservoir hosts is
necessary for virus endemism (Fig. 1) (Nuttall and Labuda, 2003). The duration of viremia in
hosts is crucial for TBE virus transmission to ticks, because the virus is mostly ingested by
ticks just while engorging on a viremic host. Generally, the hosts are divided into three
groups: reservoir, indicator, and accidental hosts. Natural reservoir hosts of TBE virus, i.e.
animals that are sensitive to the virus, exhibiting viremia for long period of time without
becoming clinically ill and thus important for the transmission of the virus to ticks, include
rodents (Clethrionomys, Apodemus, Mus, Microtus, Micromys, Pitymys, Arvicola, Glis, Sciurus
and Citellus) (Kožuch et al., 1967), insectivores (Sorex, Talpa, Erinaceus) (Kožuch et al., 1967)
and carnivores (Vulpes, Mustela) (Süss, 2003; Karabatsos, 1985). Insectivores and rodents
harbor the virus also during the winter. The long-lasting viremia can be restored after the
awakening of the animals after the winter sleep (posthibernation viremia). Indicator hosts
have only brief viremia with low virus production and are not able to transmit the virus to
Humans are accidental hosts of TBE virus, i.e. they can develop a disease with viremia, but
they do not participate in virus circulation in nature and are, therefore, a dead end of the
natural TBE virus cycle.
Flavivirus Encephalitis
People can be infected (i) by a bite of an infected tick, (ii) by drinking infected unboiled milk,
or (iii) by inhaling infected aerosol or by needle-stick injury. In general, most frequently TBE
virus infection of humans occurs following the bite of an infected tick, which is unnoticed in
about a third of cases (Kaiser, 1999). The tick usually attaches itself to man while walking in
dense vegetation in forests. The virus is transmitted by saliva during first minutes of
feeding. On humans, ticks prefer to attach themselves to the hair-covered portion of the
head, to the arm and knee bends, hand, feet and ears as well as the gluteal and genital
regions. In children, 75% of ticks are situated on the head as children are closer to vegetation
than adults (Süss, 2003). The incidence of human TBE cases correlates with the activity of the
ticks. The seasonal activity of I. ricinus has two peaks: April–May and September–October.
Comparison of the tick population curves and the morbidity rate in humans shows that
there is approximately 14 days’ difference between the peaks of the two curves. The gap
between the peak of tick activity and the highest morbidity rate in humans corresponds to
the incubation period of the disease that is between 4 and 14 days. The activity of I.
persulcatus has only one peak and lasts from the end of April to the beginning of June.
During July only some sporadic cases can be seen. When the summer is very hot, sporadic
cases can be observed even in September, but not later (Grešíková and Kaluzová, 1997). The
duration of epidemic season in the Southern Far East is 6 to 7 months, since imago molt
from nymphs become active at once (Leonova et al., 1996).
Another natural route of human TBE virus infection is associated with the consumption of
nonpasteurized milk from viremic livestock (goats, sheep and cows). The virus can pass
from the blood of the livestock into the mammary gland. Experiments and epidemiological
studies have revealed that antibodies to TBE virus are readily eliminated, and one and the
same goat may be repeatedly infected and may excrete TBE virus with its milk (Korenberg,
1976). If a human drinks unboiled milk from infected animals, it can lead to the development
of a form of biphasic meningoencephalitis, called ‘biphasic milk fever’. The virus remains
stable for a relative long period also in various milk products such as yoghurt, cheese and
butter (Grešíková, 1959). Persistent infectivity in gastric juice is observed after ingestion of
such products for up to 2 h (Charrel et al., 2004). With the aim to decrease the risk of TBE
infection in humans by alimentary route, a candidate life attenuated TBE virus vaccine for
goats was developed (Mayer, 1966). However, recent molecular analysis of the vaccine strain
revealed that this vaccination strain is not an attenuated variant of TBE virus, but a strain of
virus Langat, possibly a result of laboratory contamination of cell cultures (Růžek et al., 2006).
Single cases of laboratory TBE virus infections from needle-stick injuries or associated with
aerosol infection of laboratory personnel were also described (Gallia et al., 1949; Molnár and
Fornosi, 1952; Hoffmann, 1973; Bodemann et al., 1977; Avšič-Županc et al., 1995).
3. Geographical distribution
TBE occurs in many parts of Central Europe and Scandinavia, particularly, in Austria, Czech
Republic, Estonia, Finland, Germany, Hungary, Latvia, Lithuania, Poland, Russia, Slovak
Republic, Slovenia, Sweden, Switzerland, and also Northern Asia (Fig. 2) (Donoso Mantke et
al., 2008; Süss, 2008; Lu et al., 2008). Recently, probable TBE cases were described in Turkey
(Ergünay et al., 2011). Further, new TBE foci are emerging and latent ones re-emerging in a
number of other European countries (Bröker and Gniel, 2003; Petri et al. 2010). In Russia, the
highest TBE incidence is reported in Western Siberia and Ural (Grešíková and Kaluzová,
1997). No TBE cases have been reported e.g. in Great Britain, Ireland, Iceland, Belgium, the
Tick-Borne Encephalitis Virus: A General Overview
Netherlands, Luxemburg, Spain and Portugal. Whereas Bulgaria, Croatia, Denmark, France,
Greece, Italy, Norway, Romania, Serbia, China and Japan are countries with only sporadic
TBE occurrence. Because of the increased mobility of people travelling to the risk areas, TBE
has become an international public health problem with relation to travel medicine. The risk
of an infection is especially high for people living in endemic areas or visiting them for
leisure activities in nature (Bröker and Gniel, 2003).
Although TBE virus is a growing concern in Europe, surveillance and notification schemes
are not uniform within the European countries. There is a lack of Europe-wide standard case
definition and the quality of national surveillance programs differs considerably. Therefore,
surveillance data from different countries are difficult to compare (Donoso Mantke et al.,
Generally, the distribution of TBE virus correlates with ixodid tick vectors. I. ricinus occurs
in most parts of Europe, and the distribution extends to the southeast (Turkey, Northern
Iran, and Caucasus). I. persulcatus is seen in the wide area extending from Eastern Europe to
China and Japan. Parallel occurrence of both tick species was reported in North-Eastern
Europe and the east of Estonia and Latvia as well as in several European regions of Russia
(Bormane et al., 2004; Golovljova et al., 2004).
Fig. 2. Geographical distribution of TBE.
U.gif; date of access April 11, 2011)
The increase of TBE virus incidence in most European countries during the last decades is
due to a complex interrelation of several factors that include ecological (effect of climate
change on the vectors), agricultural, social (changes in human leisure activities), as well as
technological factors (advanced diagnostics and increased medical awareness) (Donoso
Mantke et al., 2008). It has been reported that there is an increase (i) in the number of cases
in areas well known for TBE in humans; (ii) a reemergence of TBE in areas where it had
previously occurred but had not or only sporadically been observed since the 1970s, or (iii)
the emergence of TBE in areas where it had not been known to occur previously. Shift of the
Flavivirus Encephalitis
upper limit of the geographical habitats of ticks to higher altitudes was observed in Central
Europe and Sweden (Daniel et al., 2003). Previously, the limit of ticks’ occurrence was at
700–750 m above sea level and ticks were not able to finish their developmental cycle at
higher altitudes. However, recent studies have shown that ticks (including TBE virus
infected ones) shifted to the altitudes up to 1,000 m above sea level. This shift is in a clear
correlation with an increased average temperature since the numbers of game animals,
socio-economical factors or land-usage did not change in these areas (Danielová et al., 2008).
Since these mountain zones are often used for recreation and outdoor activities, the risk of
TBE virus infections in these areas increased considerably (Daniel et al., 2003).
4. Clinical picture
Serological surveys suggest that 70–95% of human TBE virus infections are either sub-
clinical or asymptomatic (Shapoval, 1976, 1977; Pogodina et al., 1979).
While courses and symptoms are quite similar in the early stage of disease, TBE caused by
viruses of the different subtypes may vary not only in the frequency of development of
certain disease forms (febrile, meningeal, meningoencephalitic, polyencephalitic,
poliomyelitic, polioradiculoneuritic, and chronic forms), but also in the severity of each
Siberian and Far Eastern TBE virus subtypes can be the cause of chronic disease (Pogodina
et al., 2004; Voronkova and Zakharycheva, 2007). For the Far Eastern TBE virus subtype, the
frequency of focal encephalitic symptoms is 31–64%, meningeal forms amount to nearly
26%, febrile forms 14–16% and biphasic forms 3–8%. Complete recovery occurs in 25% of all
cases (Votiakov et al., 2002). The current increase in the proportion of patients with a febrile
form is likely to be associated with the improved diagnostics. Case fatality rate is up to 35%
(Dumpis et al., 1999). Chronic disease develops in less than 0.5% of cases.
The Siberian subtype is associated with focal encephalitic forms in 5% incidents, meningeal
forms nearly 47%, febrile forms 40% and biphasic forms about 21%. Complete recovery
occurs in 80% of all cases. Case fatality rate is nearly 2% (Votiakov et al., 2002). Nevertheless,
infections with the Siberian subtype have a tendency for patients to develop chronic or
extremely prolonged infections accompanied by diverse neurological and/or
neuropsychiatric symptoms (Poponnikova, 2006).
However, due to differences in seroprevalence rates in Europe and in Russia, the higher
morbidity of Eastern TBE forms could, at least partly, be the result of selective notification of
mainly severe cases (Süss, 2003).
In contrast to the forms mentioned above, infections caused by European strains typically
take a biphasic course in 72–87% of patients (Kaiser, 1999; Günther et al., 1997; Holzmann,
2003): After a short incubation period (usually 7–14 days, with extremes of 4–28 days), the
first (viremic) phase presents as an uncharacteristic influenza-like illness lasting 2–4 days
(range 1–8 days) with fever, malaise, headache, myalgia, gastrointestinal symptoms,
leukocytopenia, thrombocytopenia and elevated liver enzymes as frequent symptoms. This
is often followed by a symptom-free interval of about one week (range 1–33 days) before the
second phase. Seroconversion without prominent morbidity is common.
The second phase of TBE occurs in 20–30% of infected patients (Gustaffson et al., 1992) and
is marked by four clinical features of different severity (meningitis, meningoencephalitis,
meningoencephalomyelitis or meningoencephaloradiculitis) and the appearance of specific
antibodies in the serum and cerebrospinal fluid (CSF). This is usually the time when patients
Tick-Borne Encephalitis Virus: A General Overview
with high fever and severe headache seek medical advice. Neurological symptoms at this
stage principally do not differ from other forms of acute viral meningoencephalitis
(Lindquist and Vapalathi, 2008).
The fatality rate in adult patients is less than 2%. However, severe courses of TBE infection
with higher mortality and long-lasting sequelae often affecting the patient’s quality of life
have been correlated with increased age (Lindquist and Vapalathi, 2008; Mickiene et al.,
2002). Further factors associated with severe forms are severity of illness in the viremic
phase and low neutralizing antibody titers at onset of disease (Kaiser and Holzmann,
5. Outbreaks history
Although the first hints of the existence of TBE date back to Scandinavian church records
from the 18th century (Åland islands, Finland), the first medical description of the disease
was given by the Austrian physician H. Schneider in 1931 (Schneider, 1931).
In 1937–39, the Russian Ministry of Health organized three successive expeditions to the Far
East with the purpose to elucidate the origin of severe infections of the central nervous
system (CNS), called ‘taiga encephalitis’ or ‘biphasic meningoencephalitis’, a disease that
had been observed there since 1914, but more frequently occurred since 1933. Initially, the
disease was misdiagnosed as a toxic form of influenza. The expeditions revealed viral origin
of the disease and the tick I. persulcatus as the main vector of the virus (Zilber, 1939). The
newly described disease was called ‘Russian spring-summer encephalitis’ (or Far East or
taiga encephalitis). The virus became known as Russian spring-summer encephalitis virus
and lately tick-borne encephalitis virus. After TBE virus strains were isolated, the clinical
picture and human pathology aspects were described, and in 1940 the first vaccine was
In the Ural, cases of Kozhevnikov’s epilepsy (epilepsia corticalis sive partialis continua; for
details see Vein and van Emde Boas, 2011), a supposed complication of TBE that develops
after acute meningoencephalitis, were described by V.P. Pervushin in 1901 and by M.G.
Polykovsky in 1917– 1920 (Votiakov et al., 2002). There, TBE virus was isolated for the first
time from the brain of a deceased patient in 1939 by M.P. Chumakov and N.A. Zeitlenok
(1940). The history of the discovery of TBE virus in the European part of Russia started with
the investigation of a TBE outbreak in the Volkhov Front’s armies in 1942–1943. In the same
period, the role of I. ricinus for virus transmission was demonstrated (Petrishcheva and
Levkovich, 1945), and TBE virus of the Siberian subtype was isolated from this tick
(Pogodina et al., 2004). In 1946, an expedition headed by L. Zilber isolated TBE virus from I.
ricinus ticks and from patients in Belarus. This virus was proved to be in close relationship
with the then known Louping ill virus rather than with the Far Eastern TBE virus strains.
Lately, the virus was named the ‘Western tick-borne encephalitis virus’.
In Central Europe, TBE virus was first isolated from human patients in Czechoslovakia after
the Second World War in 1948 (Gallia et al., 1949; Krejčí, 1949a) when the incidence of
clinical manifestations caused by the virus was so high that it was noticed by infectiologists
in affected regions (Krejčí, 1949b). Simultaneously, the virus was also isolated from I. ricinus
suggesting the role of the tick as a vector of the disease (Rampas and Gallia, 1949).
Retrospective analysis, however, revealed the presence of a clinically similar disease not
only in Czechoslovakia, but also in a number of other European countries for several
decades before the first isolation, because many clinical neurologists and physicians have
Flavivirus Encephalitis
observed and described the disease without knowing the etiology (reviewed by Izbický,
1954). In Czechoslovakia, this disease was previously known as ‘Encephalitis epidemica’. Since
1945, there was nearly a tenfold increase in the incidence of this disease (Izbický, 1954).
Shortly, after the description of TBE in Czechoslovakia, the virus was isolated in Hungary
(Fornosi and Molnár, 1952), Poland (Szajna, 1954), Bulgaria (Vaptsarov et al., 1954),
Yugoslavia (Bedjanič et al., 1955), Austria (Pattyn and Wyler, 1955), Romania (Draganescu,
1959), Germany (Sinnecker, 1960), but also in Finland (Oker-Blom, 1956) and Sweden
(Kaäriainen et al., 1961). Simultaneously, the virus was also revealed in Northern China and
Japan (Ando et al., 1952). Recently, a successful detection of TBE virus in South Korea was
reported (Kim et al., 2009; Ko et al., 2010).
The clinical course of the disease, its pathology and epidemiology, as well as the properties
of the virus, its ecology, and ecology of the vectors have been studied in detail. Most of the
studies were carried out in Russia, Czechoslovakia and Austria (Kunz and Heinz, 2003).
The incidence of TBE varies from year to year in different geographic regions. Across
Eurasia, more than 13,000 human cases are reported annually. Over the last two decades, the
most dramatic changes of all were the sudden increases (2- to 30-fold) in 1992–3 in Latvia,
Lithuania, Poland and Belarus, and with marked but lesser increases in Estonia, Germany,
Slovakia, and the Czech Republic. TBE cases have increased steadily since the mid-1970s in
Russia, and since the mid-1980s in Switzerland, Sweden, and Finland. In Austria, the only
country with extensive systematic vaccination coverage, TBE incidence has decreased
progressively since the early 1980s (Randolph, 2002).
Russia is the country with the largest geographical range of TBE virus and the highest TBE
incidence. In the early period of descriptive TBE studies in the 1930s-1940s, 200 cases were
reported annually in average (with some divergences in 1941 and 1942). The analysis of data
collected since 1948 demonstrates a registered shift in 1948 followed by a peak in 1956 (5,163
cases), and by a relative plateau thereafter (3,500 cases per year in average), with the next
peak in 1964 (5,204 cases). From 1964 to 1974, the incidence dropped to 1,119 cases per year.
The year 1975 brought a new shift that lasted till 1999 with peaks in 1993 (7,250 cases), 1996
(10,298 cases), and 1999 (9,955 cases). In some regions, the incidence rate reached 70 per
100,000 inhabitants. A negative trend in the incidence has been observed since 2000, with
2,796 cases reported in 2008. Since 2000, the average incidence showed a two-time decrease.
It should be noted that at the same time the registered trends are of opposite direction. In
the extreme north-west region of Russian TBE habitats, from 1997 to 2007 a continuous
positive trend was observed. In Karelia and Vologda regions, the incidence increased twice,
and in the neighboring Arkhangelsk region increased five times. But since most of the cases
in Russia are reported for Ural, Siberia and some Volga regions, the data for the north-west
region has not material impact on the incidence rate in the country as a whole. The data on
TBE incidences for Russia are based on the reports of the Federal Center of Hygiene and
Epidemiology in Moscow.
In Europe, the Czech Republic ranks among the countries with the highest incidence rate of
TBE. In this country, the incidence of the illness noticeably varied during the monitored
period, i.e. since 1950s. The high occurrence of the infection in 1960s gradually decreased
and in 1970s and 1980s reached values of 139–400 cases annually. Sporadically, there were
more than 400 cases per year in 1970, 1973, and 1979. A steep increase took place in 1990s
(according to data from EPIDAT, National Institute of Public Health in Prague –, when the annual incidence was more than two-fold higher in comparison
with the preceding period, 400–600 cases per year with a maximum of 745 cases in 1995 and
Tick-Borne Encephalitis Virus: A General Overview
706 in 2000 (Daniel et al., 2004). In the year 2006, the incidence (1,026 cases) of TBE in the Czech
Republic was almost twice as high than in the preceding years, the highest ever recorded,
indicating significantly increased epidemic activity of this important human pathogen (Daniel
et al., 2008). A similar increase in number of cases was observed also in other regions of
Europe ( This phenomenon is not definitely explained. One hypothesis
dealing with the increased incidence of the last years is based on impact of climatic changes on
the biology of the vector I. ricinus (Gray et al., 2009). Gradual raise of the temperature in the
last decades caused prolongation of the period of the tick development within a year and,
subsequently, acceleration of its development and increase of the density of its population
(Daniel et al., 2004). This allowed the intensification of the circulation of TBE virus, more
frequent contact of man with infected ticks, and caused dissemination of the ticks and TBE to
regions with no or rare previous records of their incidence (Daniel et al., 2003, 2006).
A particularly unusual outbreak was caused by infected goat milk in the Rožňava district of
Slovakia in 1951–52, when at least 660 people became infected (Blaškovič, 1954; Růžek et al.,
2010). Other milk-borne TBE virus outbreaks occurred in Petersburg and Moscow regions
(Drozdov, 1959) in Russia and in the Styrian region of Austria (Grešíková and Kaluzová,
1994). More recently, a relatively small outbreak of TBE by alimentary route was reported in
1999 in the Czech Republic. In this case, 22 people were infected by consumption of sheep
cheese. Some of the cases were severe (Daneš, 2000). In 2007, outbreak of alimentary TBE
after consumption of unpasteurized raw goat milk involving 25 patients of 154 exposed
persons occurred in Hungary in August 2007 (Balogh et al., 2010). Lastly, an outbreak of
TBE due to consumption of goat cheese from an alpine pasture of high altitude (1564 m
above sea level) was reported in 2008 from an area in Vorarlberg, Austria, in which 6
persons were infected. Four of them were hospitalized with typical TBE symptoms, 2 were
clinically asymptomatic (Holzmann et al., 2009).
6. Virology
TBE virus is the medically most important member of the tick-borne group of the genus
Flavivirus, family Flaviviridae (Thiel et al., 2005). Besides TBE virus, three other tick-borne
flaviviruses, i.e. Louping ill virus, Langat virus and Powassan virus, also cause encephalitis
in humans and/or animals, but these infections are infrequent and the viruses do not
produce significant outbreaks (Gritsun et al., 2003b).
TBE virus is subdivided into three subtypes: European (previously Central European
encephalitis), Far Eastern (previously Russian spring and summer encephalitis) and Siberian
(previously Western Siberian encephalitis) (Ecker et al., 1999).
Based on the antigenic similarity, the European TBE virus subtype is closely related rather to
Louping ill virus than to the Far Eastern and Siberian subtypes (Hubálek et al., 1995).
Moreover, on the basis of the comparison of genetic similarity of complete genomes,
inclusion of Louping ill virus, Turkish sheep tick-borne encephalitis virus, and Spanish
sheep encephalitis virus as different genotypes of TBE virus was proposed (Grard et al.,
2007), but this classification has not been generally accepted so far, mostly because of
important biological differences between these viruses.
Although TBE virus strains isolated from field collected ticks exhibit high heterogeneity
with respect to their biological properties (Růžek et al., 2008), sequence analyses of various
virus isolates have shown that the TBE virus is fairly homogeneous in endemic areas of
Europe and is not subject to significant antigenic variations. On the other hand, the diversity
Flavivirus Encephalitis
of TBE virus from Siberian and Far Eastern subtypes is much higher. Currently, at least two
groups in the Siberian genotype were identified (European and Asian groups, separated by
Ural mountains) (Pogodina et al., 2007). Nevertheless, the antigenic similarity is still high
enough to be sufficient for the cross-protection in the event of infection by TBE virus of the
different subtypes.
The virions of TBE virus are spherical particles, approximately 50–60 nm in diameter (Slávik
et al., 1967) with a nucleocapsid composed of a (+)ssRNA genome enclosed in a capsid (C)
protein and surrounded by a host cell-derived lipid bilayer. The genome is approximately
11 kb in length and contains one large open reading frame which is flanked by 5’ and 3’
untranslated regions, with 5’-cap but no 3’-poly(A) tail. The untranslated regions form
conserved secondary stem-loop structures that probably serve as cis-acting elements for
genome amplification, translation and packaging (Gritsun et al., 2003b). Translation yields a
3414 amino acids long polyprotein that is co- and post-translationally cleaved by cellular
and viral proteases into three structural proteins (C, prM, E) and seven non-structural
proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). The lipid envelope carries two
surface proteins, the large envelope protein (E) and a small membrane protein (M). M
protein is derived from its larger precursor, prM.
C protein binds viral DNA to form the virion nucleocapsid. The immature C protein contains a
CTHD (C-terminal hydrophobic domain), i.e. a 20 amino acid length polypeptide, which is
split off by serine protease to form a short CTHD polypeptide during polyprotein processing
(Yamshchikov and Compans, 1993). The proteolysis site modification in this region is likely to
predetermine the maturity rate of virions in the infected cells (Loktev et al., 2007).
The E protein is the major antigenic and virulence determinant of TBE virus and acts both as
the ligand to the cell receptor and as the fusion protein (Lindenbach and Rice, 2003).
The viral non-structural proteins have several functions, i.e. the NS1 protein soluble
homodimer is known as a complement-binding antigen; NS2A, NS4A and NS4B proteins
are involved in the function as a replicative complex (Loktev et al., 2007); the complex of
NS2B-NS3 proteins serves as viral serine protease; and NS5 is a RNA-dependent RNA
polymerase (Lindenbach and Rice, 2003).
The infection of the host cell begins with the binding of the virus to a cell receptor, which
has not been sufficiently identified till now (Kopecký et al., 1999). Apparently, just the
ability to use multiple receptors can be responsible for the very wide host range of
flaviviruses, which replicate in arthropods and in a broad range of vertebrates. After
binding to the receptor, the virus is internalized by endocytosis. Acidification of the interior
of the endosomal vesicle changes the conformation of the E protein and rearranges its
dimers to trimeric forms. These changes result in fusion of the viral envelope and the
membrane of the endosomal vesicle (Holzmann et al., 1995) and the release of the viral
nucleocapsid into the cytoplasm. After uncoating, translation of the positive-stranded genome
occurs, in parallel to synthesis of minus-strand RNA that serves as a template for RNA
replication. Processing of the polyprotein yields the individual viral proteins (Mandl, 2005).
In vertebrate cells, virus assembly takes place in endoplasmatic reticulum and leads to
formation of immature virions that contain the proteins C, prM and E. These immature
particles are transported through the cellular secretory pathway and, shortly before release,
prM is cleaved by furin or a similar enzyme in the acidic compartment of the trans-Golgi
network to yield mature and fully infectious virions (Mandl, 2005).
However, the TBE virus maturation process in tick cells is completely different than in the
cells from vertebrate hosts. In cell lines derived from the tick Rhipicephalus appendiculatus
Tick-Borne Encephalitis Virus: A General Overview
infected with TBE virus, nucleocapsids occur in cytoplasm and the envelope is acquired by
budding on cytoplasmic membrane or into cell vacuoles (Šenigl et al., 2006). The studies
focused on the adaptation of TBE virus to Hyalomma marginatum ticks and mammals
described the presence of respective adaptive mutations within the second domain of E
protein (Romanova et al., 2007).
Most of the studies on TBE pathogenesis have been done on laboratory mice that are
susceptible to TBE virus and develop lethal infection of CNS (Simon et al., 1966), analogous
to severe cases of TBE in humans (Mandl, 2005).
After the tick bite, the virus replicates in subcutaneous tissues (Fig. 3). Dendritic cells in the
skin are likely to serve as a vehicle for the transport of the virus to draining lymph nodes
(Labuda et al., 1996). The lymph nodes play an important part in the pathogenesis of TBE.
However, virus replication is not accompanied by any virus-specific histological changes
including any destruction of cells in the nodes (Málková and Filip, 1968). On the model of
Syrian hamsters inoculated intracerebrally with TBE virus strains differing in virulence,
specific involvement of the organs of the immune system (spleen, lymph nodes, and
thymus) was established and morphological features of the process described. The most
severe destructive changes of these organs (mass disintegration of lymphocytes, inhibition
of their migration, almost complete inhibition of regeneration processes up to the complete
elimination of germinal centers) were found in the hamsters inoculated with highly virulent
strains (Karmysheva and Pogodina, 1990). TBE virus can be isolated from blood leucocytes
during the first days after the tick bite indicating virus replication in immunocompetent
blood cells (Leonova and Maistrovskaya, 1996).
Fig. 3. Schematic drawing of the steps during TBE virus infection. (1) TBE virus transmission
from an infected tick, (2) TBE virus replication in regional lymph node, (3) primary viremia,
(4) replication of the virus in other organs and tissues, (5) secondary viremia, (6) TBE virus
crossing of the blood-brain barrier, and (7) virus infection of the brain
Flavivirus Encephalitis
Massive viral multiplication in the nodes leads to the spreading of virus into the blood
stream and induction of viremia (Málková et al., 1969). Temporary leukopenia in the white
blood picture is observed. A significant decrease is recorded in all cellular elements. In
regional lymph nodes, a significant decrease in lymphocytes appears (Málková et al., 1961).
Many extraneural tissues are infected during the viremic phase and, subsequently during
the secondary viremia, the virus invades the CNS by still unknown mechanism. Mice dying
due TBE exhibite severe systemic stress response, and increased levels of TNF-alpha
compared with recovering mice (Hayasaka et al., 2009). Characteristic, but not disease-
specific, are neuropathologic changes in CNS that include meningitis and
polioencephalomyelitis accentuated in spinal cord, brainstem and cerebellum associated
with inflammatory cell infiltration of infected animals (Gelpi et al., 2005). In mice, as well as
in human post-mortem cases, prominent inflammatory infiltrates and cytotoxic T-cells were
observed in close contact with morphologically intact neurons suggesting a key role for
cytotoxic T-cells in the development of encephalitis (Gelpi et al., 2006; Růžek et al., 2009).
Recent studies confirmed, that the host CD8+ T-lymphocytes infiltrating brain parenchyma
mediate immunopathology in TBE (Růžek et al., 2009). Thus, the host immune system
contributes significantly to the development and higher severity of the disease.
TBE virus infection, in addition to causing fatal encephalitis in mice, induces considerable
breakdown of the blood-brain barrier (BBB). The permeability of the BBB increases at later
stages of TBE infection when high virus load is present in the brain (i.e., BBB breakdown
was not necessary for TBE virus entry into the brain), and at the onset of the first severe
clinical symptoms of the disease. The increased BBB permeability is in association with
dramatic upregulation of proinflammatory cytokine/chemokine mRNA expression in the
brain. Breakdown of the BBB can be also observed in mice deficient in CD8+ T-cells,
indicating, that these cells are not necessary for the increase in BBB permeability that occurs
during TBE (Růžek et al., 2011).
7. Laboratory diagnosis
Since TBE shows clinical and laboratory findings similar to other CNS diseases which may
require special treatment, microbiological laboratories have to perform specific diagnostics
mainly for differential diagnosis (Donoso Mantke et al., 2007a).
This can be done (i) as direct detection of the virus or viral RNA in the first (viremic) phase
of infection, by virus isolation in mammalian cell culture or RT-PCR, or (ii) as indirect
detection of specific IgM and IgG antibodies with serological methods as enzyme im-
munoassay, immunofluorescence assay or neutralization test.
As the majority of patients come for medical attention when neurological symptoms are
manifest, it is the current experts’ opinion that virus isolation and RT-PCR at this time are of
minor importance for the diagnosis of TBE, because at the beginning of the second phase of
illness the virus itself is only rarely detectable in blood and CSF. Therefore, the diagnosis of
TBE is mainly done by serological methods, usually enzyme-linked immunosorbent assay
(ELISA) based on purified virions or recombinant virus-like particles, which have been
developed towards higher specificity and sensitivity in the last decade (Holzmann, 2003;
Sonnenberg et al., 2004; Günther and Haglund, 2005; Ludolfs et al., 2009).
However, detection by PCR methods could be valuable for an early differential diagnosis of
TBE (Saksida et al., 2005; Schultze et al., 2007). This is particularly true for patients living in
or coming from areas where more than one tick-transmitted disease is endemic. Detection of
Tick-Borne Encephalitis Virus: A General Overview
specific nucleic acid from blood and CSF depends on the sampling at the right time. The
highest yield of TBE virus specific RNA is obtained during the transient viremia in the first
week of the disease, much less in the second week after the appearance of antibodies and
only occasionally later on (Holzmann, 2003; Puchhammer-Stöckl et al., 1995).
The benefit of molecular detection methods depends on the attention that affected people
and clinicians pay to tick bites and symptoms. The earlier a correct diagnosis is obtained
(e.g. TBE or other etiology), the earlier an appropriate therapy can be introduced. This could
have dramatic influence upon survival and outcome of a suspected CNS disease.
RT-PCR can also be of great diagnostic help when the patient has not developed antibodies
at the beginning of the second phase, has a severe case of TBE or has died after a relatively
short course of infection (Gelpi et al., 2005; Schwaiger and Cassinotti, 2003).
Both serological and molecular detection methods for TBE are useful as single applications
or in combination for clinical diagnosis, immunity testing, epidemiological surveillance and
survey of virus prevalence in ticks and vertebrate hosts.
Although ELISA is currently the method of choice, due to its simple performance and ease
of automation, and new commercial serological assays have been developed with higher
sensitivity and specificity, certain restrictions have to be taken into consideration for the
application of serological methods (Table 1).
Method Serology RT-PCR
-Allows reliable detection of
IgM and IgG antibodies in
serum and CSF up from the
2nd week of disease
- Allows early diagnosis
by detection of TBE virus
specific RNA in the first
phase of infection, if
patient is hospitalized at
this time point
- High throughput of clinical
specimens is possible
- Provides opportunity to
discriminate between
TBE virus subtypes
- Commercial kits are
available - Provides opportunity to
quantify viral load
- Cross-reactions with
antibodies elicited by other
- Neutralization test has a
high specificity, but requires
higher containment
- Requires trained
laboratory personnel for
proper handling
Table 1. Advantages and disadvantages of serology and RT-PCR for the diagnosis of TBE
(modified from Donoso Mantke et al., 2007a)
An early diagnosis by detecting only IgM is questionable, since IgM antibodies can persist
for up to 10 months in vaccinees or individuals who acquired the infection naturally.
Therefore, confirmation by detection of specific IgG is recommended, but may turn out
negative in the first phase of infection. The necessary monitoring of an increase of IgG titers
Flavivirus Encephalitis
1–2 weeks later is rarely done. Moreover, a major problem when using ELISA and
immunofluorescence assays lays in the high cross-reactivity of the flaviviral antigenic
structure. Possible diagnostic difficulties may arise due to cross-reactions of antibodies
elicited by other flavivirus infections or vaccinations. This could happen in areas where
other flaviviruses co-circulate (e.g. West Nile virus in the southern parts of the TBE endemic
area), in patients recently returned from areas endemic for other flaviviruses (e.g. dengue
virus endemic areas) or in individuals being vaccinated against TBE virus, Japanese
encephalitis or yellow fever virus (Holzmann, 2003; Niedrig et al., 2001).
Thus, verification of positive results by neutralization test is advised which, due to the use
of infectious virus particles, requires the handling in higher containment laboratories which
makes this test time-consuming and expensive.
As mentioned, the molecular diagnostics for TBE are restricted to the first (viremic) phase of
infection. But, in combination with a higher awareness of the disease, this fact could be more
an advantage than an obstacle, leading to an early diagnosis of TBE (Table 1).
Also, the RT-PCR provides the opportunity to discriminate between all subtypes of TBE.
This could be an important aspect while facing co-circulation of the different subtypes in
some European regions (Růžek et al., 2007; Achazi et al., 2011). Unfortunately, a negative
PCR result in serum or CSF of a patient is not predictive for the absence of a TBE infection.
This may be caused either by the short viremia of the infection, by sampling at inap-
propriate times and/or by improper handling of diagnostic specimens. The lack of
commercial assays of standardized quality provides another reason why RT-PCR has not
been established so far in microbiological laboratories for TBE diagnosis (Donoso Mantke et
al., 2007a). The presence of many in-house assays especially for the molecular detection of TBE
requires quality control studies in order to avoid false positive and/or negative results and to
achieve the same diagnostic quality among the different assays (Donoso Mantke et al., 2007b).
8. Prevention and treatment
Besides general preventive measures, like wearing appropriate clothing or checking the skin
for attached ticks, TBE can be successfully prevented by active immunization (Kunz, 2003;
Heinz et al., 2007).
In Russia, several vaccines are produced by using Far Eastern TBE subtype viruses: e.g. the
vaccine of the Institute of Poliomyelitis and Viral Encephalitis (IPVE), in Moscow with strain
Sofjin, and EnceVir by Virion, in Tomsk with strain 205.
In Europe two vaccines are available which are based on European TBE virus strains: FSME-
IMMUN by Baxter Bioscience, Orth an der Donau, Austria with strain Neudoerfl, and
Encepur by Novartis Vaccines and Diagnostics, Marburg, Germany with strain K23.
The large envelope protein E induces the production of neutralizing antibodies important
for the protective immunity. Due to the highly conserved structure of this antigen broad
cross-protection by the vaccines could be shown against TBE viruses of all three subtypes
(Ecker et al., 1999; Leonova and Maistrovskaya, 1996; Klockmann et al., 1991; Holzmann et
al., 1992; Hayasaka et al., 2001).
Since their introduction both European vaccines have undergone several modifications and
are manufactured by the same steps during the production process (Rendi-Wagner, 2008).
Viral antigens are propagated in chick embryo cells, filtered and inactivated by
formaldehyde, and purified by ultracentrifugation. During the formulation the antigens are
adsorbed to aluminium hydroxide and stabilized with human albumin (FSME-IMMUN) or
Tick-Borne Encephalitis Virus: A General Overview
sucrose (Encepur). Thiomersal was removed from both vaccine formulations in the 1990s to
fulfill high safety and tolerability standards (Barrett et al., 2003).
The conventional immunization schedules for primary immunization are similar for both
vaccines, with three intramuscular doses given on 0, 21 days–3 months and 9–12 months.
Thus, both vaccines induce antibody concentrations that are believed to be protective in
over 90% of children and adults (Lindquist and Vapalathi, 2008). Due to the high homology
of the antigens and demonstrated cross-boostering in clinical studies, the two TBE vaccines
seem interchangeable after a complete primary immunization (Rendi-Wagner et al., 2004;
Bröker and Schöndorf, 2006). So far, the protective amount of antibodies is not clearly
defined and standardized for both vaccines. Also, occasional vaccine breakthroughs have
been reported (Bender et al., 2004; Kleiter et al., 2007; Andersson et al., 2010).
Besides vaccines for adults, both European vaccine manufacturers offer pediatric vaccine
formulations containing half the dose of viral antigen of the adult ones to improve
tolerability in children (Zent et al., 2003; Pavlova et al., 2003; Pöllabauer et al., 2010).
An age-dependent immune response after vaccination could be shown, with children having
an enhanced response in comparison to adults (Girgsdies et al., 1996), whereas especially
vaccinees aged over 60 years frequently have a poor antibody response (Hainz et al., 2005).
Data regarding the persistence of post-immunization antibodies led the manufacturers to
change their recommendations (Rendi-Wagner, 2008). Regular boosters are recommended
every 5 years for age-groups 49 years of age (except for the first booster after 3 years). In
age-groups > 49 years of age a 3-year-booster interval is recommended due to the
significantly gradual decline of post-immunization antibodies.
Rapid immunization schedules have been introduced by both vaccine producers for people
who require immunity at short notice, such as travelers travelling to TBE-endemic areas or
when the tick season has already started. However, since the experience with TBE vaccines
is mainly based on the conventional immunization schedules, these should be always ap-
plied wherever possible.
In Russia, IPVE vaccine is applied for adults and children of three years and over, the
vaccine is given in two doses over 5–7 months with the revaccination after 1 year, and then
every 3 years. EnceVir vaccine is administered to adults aged 18 years and more, the vaccine
is also given in two doses over 5–7 months, with the revaccination after 1 year and every 3
years thereafter. This vaccine is also available for the rapid immunization schedule: two
doses over 1–2 months.
Clinical therapy is only symptomatic with strict bed rest, usually in an intensive care unit,
until the fever and neurological symptoms have subsided. Maintenance of water and
electrolyte balances, sufficient caloric intake, and administration of analgesics, vitamins, and
antipyretics are the central pillars of clinical treatment of TBE patients.
Since there is no specific treatment for TBE available to date, and the administration of
hyperimmunoglobulin for a passive post-exposure prophylaxis is highly questionable
concerning the virtue and not recommended anymore due to concerns about antibody-
dependent enhancement of infection (Kaiser, 1999; Waldvogel et al., 1996; Jones et al., 2007),
active immunization should always be recommended for people living in or travelling to
TBE endemic areas.
9. Future trends
Since the first descriptions of TBE and its viral etiology in the 1930s/1940s the scientific
development in this research area has been tremendous. Today, we have knowledge about
Flavivirus Encephalitis
the structure and molecular biology of TBE virus and the biotic and non-biotic factors
underlying its natural cycle. Also, there are effective and safe purified inactivated vaccines
available on the market, which made vaccination an extremely successful measure for
preventing the disease.
However, there are several issues in the context of TBE which need to be deepened in the
future, like:
1. Further development of rapid differential diagnosis of TBE virus in combination with
other tick-borne pathogens by detecting both the nucleic acids and viral antigens.
2. Further efforts in identifying the genetic basis of TBE virulence.
3. Study of interaction of virus and immune cells for further prognosis of clinical course
and outcome of TBE and, if possible, for better treatment.
4. Establishment of international databases for TBE virus: epidemic risks, individual risks,
mapping and characterization of natural foci, circulating genotypes, circulation of other
tick-borne pathogens in TBE foci.
5. The taxonomic position of Louping ill virus (and subtypes Turkish sheep-, Spanish
sheep encephalitis virus) and Greek goat encephalitis virus is under consideration.
10. Acknowledgements
We acknowledge financial support by the Czech Science Foundation project No.
P302/10/P438 and No. P502/11/2116, and grants Z60220518 and LC06009 from the
Ministry of Education, Youth, and Sports of the Czech Republic.
11. References
Achazi, K., Nitsche, A., Patel, P., Radonić, A., Donoso Mantke, O., and Niedrig, M. 2011.
Detection and differentiation of tick-borne encephalitis virus subtypes by a reverse
transcription quantitative real-time PCR and pyrosequencing. J. Virol. Methods
Andersson CR, Vene S, Insulander M, Lindquist L, Lundkvist A, Günther G. Vaccine
failures after active immunisation against tick-borne encephalitis. Vaccine. 2010 Apr
Ando, K., Kuratsuka, K., Arima, S., Hironaka, N., Honda, Y., and Ishii, K. 1952. Studies on
the viruses isolated during epidemic of Japanese B encephalitis in 1948 in Tokyo
area. Kitasato. Arch. Exp. Med. 24: 49–61.
Avsic-Zupanc, T., Poljak, M., Maticic, M., Radsel-Medvescek, A., LeDuc, J.W., Stiasny, K.,
Kunz, C., and Heinz, F.X. 1995. Laboratory acquired tick-borne
meningoencephalitis: characterisation of virus strains. Clin. Diagn. Virol. 4: 51-9.
Balogh, Z., Ferenczi, E., Szeles, K., Stefanoff, P., Gut, W., Szomor, K.N., Takacs, M., and
Berencsi, G. 2010. Tick-borne encephalitis outbreak in Hungary due to
consumption of raw goat milk. J. Virol. Methods 163(2):481-5.
Barrett, P.N., Schober-Bendixen, S., and Ehrlich, H.J. 2003. History of TBE vaccines. Vaccine
21 (Suppl 1): S41-9.
Bedjanič, M., Rus, S., Kmet, J., Vesenjak-Zmijanac, J. 1955 Virus meningo-encephalitis in
Slovenia. Bull. World Health Organ. 12: 503-12.
Tick-Borne Encephalitis Virus: A General Overview
Benda, R. 1958. [The common tick “Ixodes ricinus” as a reservoir and vector of tick-borne
encephalitis. I. Survival of the virus (strain B3) during the development of ticks
under laboratory condition]. J. Hyg. Epidemiol. (Prague) 2: 314-30.
Bender, A., Jäger, G., Scheuerer, W., Feddersen, B., Kaiser, R., and Pfister, H.W. 2004. Two
severe cases of tickborne encephalitis despite complete active vaccination – the
significance of neutralizing antibodies. J. Neurol. 251: 353-4.
Blaškovič, D. 1954 [Outbreak of tick-borne encephalitis in Rožňava natural focus].
Bratislava: Vydavatelstvo SAV. [Book in Slovak]
Bodemann, H., Pausch, J., Schmitz, H., and Hoppe-Seyler, G. 1977. [Die Zeckenenzephalitis
(FSME) als Laborinfektion]. Med. Welt 28: 1779-81. [Article in German]
Bormane, A., Lucenko, I., Duks, A., Mavtchoutko, V., Ranka, R., Salmina, K., and Baumanis,
V. 2004. Vectors of tick-borne diseases and epidemiological situation in Latvia in
1993-2002. Int. J. Med. Microbiol. 293(Suppl 37): 36-47.
Bröker, M., and Gniel, D. 2003. New foci of tick-borne encephalitis virus in Europe:
consequences for travellers from abroad. Travel Med. Infect. Dis. 1: 181-4.
Bröker, M., and Schöndorf, I. 2006. Are tick-borne encephalitis vaccines interchangeable?
Expert Rev. Vaccines 5: 461-6.
Charrel, R.N., Attoui, H., Butenko, A.M., Clegg, J.C., Deubel, V., Frolova, T.V., Gould, E.A.,
Gritsun, T.S., Heinz, F.X., Labuda, M., Lashkevich, V.A., Loktev, V., Lundkvist, A.,
Lvov, D.V., Mandl, C.W., Niedrig, M., Papa, A., Petrov, V.S., Plyusnin, A.,
Randolph, S., Süss, J., Zlobin, V.I., and de Lamballerie X. 2004. Tick-borne virus
diseases of human interest in Europe. Clin. Microbiol. Infect. 10: 1040-55.
Chumakov, M.P., and Zeitlenok, N.A. 1940 [Tick-borne Spring-Summer encephalitis in the
Ural region. In: Neuroinfections in the Ural]. Sverdlovsk; pp. 23-30. [Chapter in
Daneš, L. 2000. [Human infections with tick-borne encephalitis virus]. Medicína 3: 16. [Arti-
cle in Czech]
Daniel, M., Danielová, V., Kříž, B., and Beneš, Č. 2006. In: Menne B, Ebi KL, Eds. Climate
change and adaptation strategies for human health. Steinkopff, Darmstadt,
Springer, pp. 189-205.
Daniel, M., Danielová, V., Kříž, B., and Kott, I. 2004. An attempt to elucidate the increased
incidence of tick–borne encephalitis and spread to higher altitudes in the Czech
Republic. Int. J. Med. Microbiol. 293(Suppl 37): 55–62.
Daniel, M., Danielová, V., Kříž, B., Jirsa, A., and Nožička, J. 2003. Shift of the tick Ixodes
ricinus and tick–borne encephalitis to higher altitudes in Central Europe. Eur. J.
Clin. Microbiol. Infect. Dis. 22: 327–8.
Daniel, M., Kříž, B., Danielová, V., and Beneš, C. 2008 Sudden increase in tick-borne
encephalitis cases in the Czech Republic, 2006. Int. J. Med. Microbiol. 298(Suppl. 1):
Danielová, V., Kliegrová, S., Daniel, M., and Beneš, Č. 2008. Influence of climate warming on
tick-borne encephalitis expansion to higher altitudes over the last decade (1997-
2006) in the Highland Region (Czech Republic). Cent. Eur. J. Public Health 16: 4-11.
Donoso Mantke, O., Aberle, S.W., Avsic-Zupanc, T., Labuda, M., and Niedrig, M. 2007b.
Quality control assessment for the PCR diagnosis of tick-borne encephalitis virus
infections. J. Clin. Virol. 38: 73-7.
Flavivirus Encephalitis
Donoso Mantke, O., Schädler, R., and Niedrig, M. 2008. A survey on cases of tick-borne
encephalitis in European countries. Euro Surveill. 13(17). pii: 18848.
Donoso-Mantke, O., Achazi, K., and Niedrig, M. 2007a. Serological versus PCR methods for
the detection of tick-borne encephalitis virus infections in humans. Future Virology
2: 565-72.
Draganescu, N. 1959. [Inframicrobial meningoencephalitis belonging to the group
transmitted by arthropods. Identification of the pathogenic agent and study of the
nerve lesions induced in white mice] Stud. Cercet. Inframicrobiol. 10: 363-9. [Article in
Drozdov, S.G. 1959. [Role of domestic animals in epidemiology of diphasic milk fever]. Zh.
Microbiol. Epidemiol. Immunobiol. 30: 102-8. [Article in Russian]
Dumpis, U., Crook, D., and Oksi, J. 1999. Tick-borne encephalitis. Clin. Infect. Dis. 28: 882-90.
Ecker, M., Allison, S.L., Meixner, T., and Heinz, F.X. 1999. Sequence analysis and genetic
classification of tick-borne encephalitis viruses from Europe and Asia. J. Gen. Virol.
80: 179-85.
Ergünay, K., Saygan, M.B., Aydoğan, S., Litzba, N., Sener, B., Lederer, S., Niedrig, M.,
Hasçelik, G., and Us, D. 2011. Confirmed exposure to tick-borne encephalitis virus
and probable human cases of tick-borne encephalitis in central/northern anatolia,
Turkey. Zoonoses Public Health 58(3):220-7.
Fornosi, F., and Molnár, E. 1952. [Meningoencephalitis in Hungary] Orv. Hetil. 93: 993-6.
[Article in Hungarian]
Gallia, F., Rampas, J., and Hollender, L. 1949. [Laboratory infection caused by tick-borne
encephaltis virus]. Čas. Lék. čes. 88: 224-9. [Article in Czech]
Gelpi, E., Preusser, M., Garzuly, F., Holzmann, H., Heinz, F.X., and Budka, H. 2005.
Visualization of Central European tick-borne encephalitis infection in fatal human
cases. J. Neuropathol. Exp. Neurol. 64: 506-12.
Gelpi, E., Preusser, M., Laggner, U., Garzuly, F., Holzmann, H., Heinz, F.X., and Budka, H.
2006. Inflammatory response in human tick-borne encephalitis: analysis of
postmortem brain tissue. J. NeuroVirol. 12: 322-7.
Girgsdies, O.E., and Rosenkranz, G. 1996. Tick-borne encephalitis: development of a
paediatric vaccine. A controlled, randomized, double-blind and multicentre study.
Vaccine 14: 1421-8.
Golovljova, I., Vene, S., Sjölander, K.B., Vasilenko, V., Plyusnin, A., and Lundkvist, A. 2004.
Characterization of tickborne encephalitis virus from Estonia. J. Med. Virol. 74: 580-
Grard, G., Moureau, G., Charrel, R.N., Lemasson, J.J., Gonzalez, J.P., Gallian, P., Gritsun,
T.S., Holmes, E.C., Gould, E.A., and de Lamballerie, X. 2007. Genetic
characterization of tick-borne flaviviruses: new insights into evolution,
pathogenetic determinants and taxonomy. Virology 361: 80-92.
Gray, J.S., Dautel, H., Estrada-Peña, A., Kahl, O., and Lindgren, E. 2009. Effects of climate
change on ticks and tick-borne diseases in Europe. Interdiscip. Perspect. Infect. Dis.
2009: 593232.
Grešíková, M. 1959. [Persistence of tick-borne encephalitis virus infection in milk and milk
products]. Čs. Epidem. Mikrobiol. Immunol. 8: 26-32. [Article in Czech]
Grešíková, M., and Kaluzová, M. 1997. Biology of tick-borne encephalitis virus. Acta Virol.
41: 115-24.
Tick-Borne Encephalitis Virus: A General Overview
Grešíková, M., and Nosek, J. 1966. Isolation of tick-borne encephalitis virus from
Haemaphysalis inermis ticks. Acta Virol. 10: 359-61.
Gritsun, T.S., Frolova, T.V., Zhankov, A.I., Armesto, M., Turner, S.L., Frolova, M.P.,
Pogodina, V.V., Lashkevich, V.A., and Gould, E.A.2003a. Characterization of a
Siberian virus isolated from a patient with progressive chronic tick-borne
encephalitis. J. Virol. 77: 25-36.
Gritsun, T.S., Lashkevich, V.A., and Gould, E.A. 2003b. Tick-borne encephalitis. Antiviral
Res. 57: 129-46.
Günther, G., and Haglund, M. 2005. Tick-borne encephalopathies: epidemiology, diagnosis,
treatment and prevention. CNS Drugs 19: 1009-32.
Günther, G., Haglund, M., Lindquist, L., Forsgren, M., and Sköldenberg, B. 1997. Tick-borne
encephalitis in Sweden in relation to aseptic meningoencephalitis of other etiology:
a prospective study of clinical course and outcome. J. Neurol. 244: 230-8.
Gustafson, R., Svenungsson, B., Forsgren, M., Gardulf, A., and Granstrom, M. 1992. Two-
year survey of the incidence of Lyme borreliosis and tick-borne encephalitis in a
high-risk population in Sweden. Eur. J. Clin. Microbiol. Infect. Dis. 11: 894-900.
Hainz, U., Jenewein, B., Asch, E., Pfeiffer, K.P., Berger, P., and Grubeck-Loebenstein, B. 2005.
Insufficient protection for healthy elderly adults by tetanus and TBE vaccines.
Vaccine 23: 3232-5.
Hayasaka, D., Goto, A., Yoshii, K., Mizutani, T., Kariwa, H., and Takashima, I. 2001.
Evaluation of European tick-borne encephalitis virus vaccine against recent
Siberian and far-eastern subtype strains. Vaccine 19: 4774-9.
Hayasaka, D., Nagata, N., Fujii, Y., Hasegawa, H., Sata, T., Suzuki, R., Gould, E.A.,
Takashima, I., and Koike, S. 2009. Mortality following peripheral infection with
tick-borne encephalitis virus results from a combination of central nervous system
pathology, systemic inflammatory and stress responses. Virology 390(1):139-50.
Heinz, F.X., Holzmann, H., Essl, A., Kundi, M. 2007. Field effectiveness of vaccination
against tick-borne encephalitis. Vaccine 25: 7559-67.
Hoffmann, H. 1973. [Die unspezifische Abwehr bei neurotropen Arbovirusinfektionen]. Zbl.
Bakt. Hyg. I. Abt. [Orig. A] 223: 143-63. [Article in German]
Holzmann, H. 2003. Diagnosis of tick-borne encephalitis. Vaccine 21(Suppl 1): S36-40.
Holzmann, H., Aberle, S.W., Stiasny, K., Werner, P., Mischak, A., Zainer, B., Netzer, M.,
Koppi, S., Bechter, E., and0 Heinz, F.X. 2009. Tick-borne encephalitis from eating
goat cheese in a mountain region of Austria. Emerg Infect. Dis. 15(10):1671-3.
Holzmann, H., Stiastny, K., York, H., Dorner, F., Kunz, C., and Heiz, F.X. 1995. Tick-borne
encephalitis virus envelope protein E-specific monoclonal antiobodies for the study
of low pH-induced conformational changes and immature virions. Arch. Virol. 140:
Holzmann, H., Vorobyova, M.S., Ladyzhenskaya, I.P., Ferenczi, E., Kundi, M., Kunz, C., and
Heinz, F.X. 1992. Molecular epidemiology of tick-borne encephalitis virus: cross-
protection between European and Far Eastern subtypes. Vaccine 10: 345-9.
Hubálek, Z., Pow, I., Reidl, H.W., and Hussain, M.H. 1995. Antigenic similarity of Central
European encephalitis and louping-ill viruses. Acta Virol. 39: 251-6.
Izbický, A. [Current situation in the research of epidemiology of Czechoslovak tick-borne
encephalitis]. Dissertation Thesis in Czech. Prague: Prof. Raška Institute of
Epidemiology and Microbiology 1954.
Flavivirus Encephalitis
Jones, N., Sperl, W., Koch, J., Holzmann, H., and Radauer, W. 2007. Tick-borne encephalitis
in a 17-dayold newborn resulting in severe neurologic impairment. Pediatr. Infect.
Dis. J. 26: 185-6.
Kaäriainen, L.E., Hirvonen, E., and Oker-Blom, N. 1961. Geographical distribution of
biphasis tick-borne encephalitis in Finland. Ann. Med. Exp. Fenn. 39: 316-28.
Kaiser, R. 1999. The clinical and epidemiological profile of tick-borne encephalitis in
southern Germany 1994-98: a prospective study of 656 patients. Brain 122( Pt 11):
Kaiser, R., and Holzmann, H. 2000. Laboratory findings in tick-borne encephalitis –
correlation with clinical outcome. Infection 28: 78-84.
Karabatsos, N. (Ed.) International Catalogue of Arboviruses. Including certain other viruses
of vertebrates. 3rd ed. San Antonio: American Society of Tropical Medicine and
Hygiene, 1985.
Karmysheva, V.Ia., and Pogodina, V.V. 1990. [Thymus involvement in the pathogenesis of
experimental tick-borne encephalitis]. Vopr. Virusol. 35: 144-6. [Article in Russian]
Kim, S.Y., Jeong, Y.E., Yun, S.M., Lee, I.Y., Han, M.G., and Ju, Y.R. 2009. Molecular evidence
for tick-borne encephalitis virus in ticks in South Korea. Med. Vet. Entomol. 23: 15-
Kleiter, I., Jilg, W., Bogdahn, U., and Steinbrecher, A. 2007. Delayed humoral immunity in a
patient with severe tick-borne encephalitis after complete active vaccination.
Infection 35: 26-9.
Klockmann, U., Křivanec, K., Stephenson, J.R., and Hilfenhaus, J. 1991. Protection against
European isolates of tick-borne encephalitis virus after vaccination with a new tick-
borne encephalitis vaccine. Vaccine 9: 210-2.
Ko, S., Kang, J.G., Kim, S.Y., Kim, H.C., Klein, T.A., Chong, S.T., Sames, W.J., Yun, S.M., Ju,
Y.R., and Chae, J.S. 2010. Prevalence of tick-borne encephalitis virus in ticks from
southern Korea. J. Vet. Sci. 11(3):197-203.
Kopecký, J., Grubhoffer, L., Kovář, V., Jindrák, L., and Vokurková, D. 1999. A putative host
cell receptor for tick-borne encephalitis virus identified by antiidiotypic antibodies
and virus affinoblotting. Intervirology 42: 9-16.
Korenberg, E.I. 1976. Some contemporary aspects of natural focality and epidemiology of
tick-borne encephalitis. Folia Parasitol. 23: 357-366.
Korenberg, E.I., Kuznetsova, R.I., Kovalevskiĭ, Iu.V., Vasilenko, Z.E., and Mebel’, B.D. 1991.
[The basic epidemiological traits of Lyme disease in the northwestern USSR]. Med.
Parazitol. (Mosk) 3: 14-7. [Article in Russian]
Kožuch, O., Grešíková, M., Nosek, J., Lichard, M., and Sekeyová, M. 1967. The role of small
rodents and hedgehogs in a natural focus of tick-borne encephalitis. Bull. World
Health Organ. 36(Suppl 1): 61-6.
Krejčí, J. 1949a. Isolement d’un virus noveau en course d’un epidémie de
meningoencephalite dans la region de Vyškov (Moraviae). Presse Méd. (Paris) 74:
1084. [Article in French]
Krejčí, J. 1949b. Epidemie virusových encefalitid na Vyškovsku [Outbreak of encephalitis
virus in the region of Vyškov]. Lék. Listy (Brno) 4: 73-5, 112-6, 132-4. [Articles in
Křivanec, K., Kopecký, J., Tomková, E., and Grubhoffer, L. 1988. Isolation of TBE virus from
the tick Ixodes hexagonus. Folia Parasit. 35: 273-6.
Tick-Borne Encephalitis Virus: A General Overview
Kunz, C. 2003. TBE vaccination and the Austrian experience. Vaccine 21 (Suppl 1): S50-5.
Kunz, C., and Heinz, F.X. 2003. Tick-borne encephalitis. Vaccine 21(Suppl 1): S1–2.
Labuda, M., Austyn, J.M., Žuffová, E., Kožuch, O., Fuchsberger, N., Lysý, J., and Nuttall,
P.A. 1996. Importance of localized skin infection in tick-borne encephalitis virus
transmission. Virology 219: 357-66.
Labuda, M., Jones, L.D., Williams, T., Danielová, V., and Nuttall, P.A. 1993. Efficient
transmission of tick-borne encephalitis virus between cofeeding ticks. J. Med.
Entomol. 30: 295-9.
Labuda, M., Kožuch, O., Žuffová, E., Elečková, E., Hails, R.S., and Nuttall, P.A. 1997. Tick-
borne encephalitis virus transmission between ticks cofeeding on specific immune
natural rodent hosts. Virology 235: 138-43.
Leonova, G.N., and Maistrovskaya, O.S. 1996b. [Viremia in patients with tick-borne
encephalitis and in patients with sucking ixodidae ticks]. Vopr. Virusol. 5: 224-8.
[Article in Russian]
Leonova, G.N., and Maistrovskaya, O.S., and Borisevich, V.B. 1996a. [Antigenemia in
subjects infected with tickborne encephalitis virus]. Vopr. Virusol. 6: 260-3. [Article
in Russian]
Lindenbach, B.D., and Rice, C.M. 2003. Molecular biology of flaviviruses. Adv. Virus. Res. 59:
Lindquist, L., and Vapalahti, O. 2008. Tick-borne encephalitis. Lancet 371: 1861-71.
Loktev, V.B., Ternovoĭ, V.A., and Netesov, S.V. 2007. [Molecular genetic characteristics of
tick-borne encephalitis virus]. Vopr. Virusol. 52: 10-6. [Article in Russian]
Lu, Z., Bröker, M., and Liang, G. 2008. Tick-borne encephalitis in mainland China. Vector
Borne Zoonotic Dis. 8: 713-20.
Ludolfs D, Reinholz M, Schmitz H. Highly specific detection of antibodies to tick-borne
encephalitis (TBE) virus in humans using a domain III antigen and a sensitive
immune complex (IC) ELISA. J Clin Virol. 2009 Jun; 45(2):125-8.
Málková, D., and Filip, O. 1968. Histological picture in the place of inoculation and in lymph
nodes of mice after subcutaneous infection with tick-borne encephalitis virus. Acta
Virol. 12: 355-60.
Málková, D., Mayer, V., and Vrubel, J. 1969. The significance of the regional lymphatic
system in penetration of an attenuated strain of tick-borne encephalitis virus into
blood of experimentally infected animals. Acta Virol. 13: 309-14.
Málková, D., Pala, F., and Šidák, Z. 1961. Cellular changes in the white cell count, regional
lymph node and spleen during infection with tick-borne encephalitis virus in mice.
Acta Virol. 5: 101-11.
Mandl, C.W. 2005. Steps of tick-borne encephalitis virus replication cycle that affect
neuropathogenesis. Virus Res. 111: 161-74.
Mayer, V. 1966. A mutant of tick-borne encephalitis (TE) virus with lost neurovirulence for
monkeys. Acta Virol. 10: 561.
Mickiene, A., Laiskonis, A., Günther, G., Vene, S., Lundkvist, A., and Lindquist, L. 2002.
Tickborne encephalitis in an area of high endemicity in Lithuania: disease severity
and long-term prognosis. Clin. Infect. Dis. 35: 650-8.
Molnár, E., and Fornosi, F. 1952. [Accidental laboratory infection with the Czechoslovakian
strain of tick encephalitis]. Orv. Hetil. 93: 1032-3. [Article in Hungarian]
Flavivirus Encephalitis
Niedrig, M., Vaisviliene, D., Teichmann, A., Klockmann, U., and Biel, S.S. 2001. Comparison
of six different commercial IgG-ELISA kits for the detection of TBEV-antibodies. J.
Clin. Virol. 20: 179-82.
Nuttall, P.A., and Labuda, M. 2003. Dynamics of infection in tick vectors and at the tick-host
interface. Adv. Virus Res. 60: 233-72.
Oker-Blom, N. 1956. Kumlinge disease; a meningoencephalitis occuring in the Aaland
Islands. Ann. Med. Exp. Biol. Fenn. 34: 309-18.
Pattyn, S.R., and Wyler, R. 1955. Viral meningoencephalitis in Austria. IV. Virus in blood in
experimental infection; attempted transmission by mosquitoes. Bull. World Health
Organ. 12: 581-9.
Pavlova, B.G., Loew-Baselli, A., Fritsch, S., Poellabauer, E.M., Vartian, N., Rinke, I., and
Ehrlich, H.J. 2003. Tolerability of modified tick-borne encephalitis vaccine FSME-
IMMUN "NEW" in children: results of post-marketing surveillance. Vaccine 21: 742-
Pavlovskij, E.N. 1939. [On natural focality of infectious and parasitic diseases]. Vestn. Akad.
Nauk SSSR 10: 98-108. [Article in Russian]
Petri E, Gniel D, Zent O. Tick-borne encephalitis (TBE) trends in epidemiology and current
and future management. Travel Med Infect Dis. 2010 Jul;8(4):233-45.
Petrishcheva, P.A., and Levkovich, E.N. 1945. [Spring-Summer encephalitis in Leningrad
region. Papers of Medical Officers of Volkhov Front]. Leningrad, Russia. [Book in
Pogodina, V.V., Bochkova, N.G., and Karan', L.S., Frolova, M.P., Trukhina, A.G., Malenko,
G.V., Levina, L.S., and Platonov, A.E. 2004. [Comparative analysis of virulence of
the Siberian and Far-East subtypes of the tick-born encephalitis virus]. Vopr.
Virusol. 49: 24-30. [Article in Russian]
Pogodina, V.V., Frolova, M.P., and Erman, B.A. 1979. [Chronic Tick-Borne Encephalitis].
Nauka, Moscow, Russia. [Book in Russian]
Pogodina, V.V., Karan', L.S., Koliasnikova, N.M., Levina, L.S., Malenko, G.V., Gamova, E.G.,
Lesnikova, M.V., Kiliachina, A.S., Esiunina, M.S., Bochkova, N.G., Shopenskaia,
T.A., Frolova, T.V., Andaev, E.I., and Trukhina, A.G. 2007. [Evolution of tick-borne
encephalitis and a problem of evolution of its causative agent]. Vopr. Virusol. 52: 16-
21. [Article in Russian]
Pöllabauer EM, Pavlova BG, Löw-Baselli A, Fritsch S, Prymula R, Angermayr R, Draxler W,
Firth C, Bosman J, Valenta B, Harmacek P, Maritsch F, Barrett PN, Ehrlich HJ.
Comparison of immunogenicity and safety between two paediatric TBE vaccines.
Vaccine. 2010 Jun 23;28(29):4680-5.
Poponnikova, T.V. 2006. Specific clinical and epidemiological features of tick-borne
encephalitis in Western Siberia. Int. J. Med. Microbiol. 296(Suppl 40): 59-62.
Puchhammer-Stöckl, E., Kunz, C., Mandl, C.W., and Heinz, F.X. 1995. Identification of tick-
borne encephalitis virus ribonucleic acid in tick suspensions and in clinical
specimens by a reverse transcriptionnested polymerase chain reaction assay. Clin.
Diagn. Virol. 4: 321-6.
Rampas, J., and Gallia, F. 1949. [Isolation of tick-borne encephalitis virus from ticks Ixodes
ricinus]. Čas. Lék. čes. 88: 1179-80. [Article in Czech]
Tick-Borne Encephalitis Virus: A General Overview
Randolph, S. 2002. The changing incidence of tick-borne encephalitis in Europe. Euro Surveill
6: pii=1953. Available online:
Rendi-Wagner, P. 2008. Advances in vaccination against tick-borne encephalitis. Expert Rev
Vaccines 7: 589-96.
Rendi-Wagner, P., Kundi, M., Zent, O., Banzhoff, A., Jaehnig, P., Stemberger, R., Dvorak, G.,
Grumbeck, E., Laaber, B., and Kollaritsch, H. 2004. Immunogenicity and safety of a
booster vaccination against tick-borne encephalitis more than 3 years following the
last immunisation. Vaccine 23: 427-34.
Romanova, L.Iu., Gmyl, A.P., Dzhivanian, T.I., Bakhmutov, D.V., Lukashev, A.N., Gmyl,
L.V., Rumyantsev, A.A., Burenkova, L.A., Lashkevich, V.A., and Karganova, G.G.
2007. Microevolution of tick-borne encephalitis virus in course of host alternation.
Virology 362: 75-84.
Růžek, D., Dobler, G., and Donoso Mantke, O. 2010. Tick-borne encephalitis: pathogenesis
and clinical implications. Travel Med. Infect. Dis. 8(4):223-32.
Růžek, D., Gritsun, T.S., Forrester, N.L., Gould, E.A., Kopecký, J., Golovchenko, M.,
Rudenko, N., and Grubhoffer, L. 2008. Mutations in the NS2B and NS3 genes affect
mouse neuroinvasiveness of a Western European field strain of tick-borne
encephalitis virus. Virology 374: 249-55.
Růžek, D., Salát, J., Palus, M., Gritsun, T.S., Gould, E.A., Dyková, I., Skallová, A., Jelínek, J.,
Kopecký, J., and Grubhoffer, L. 2009. CD8+ T-cells mediate immunopathology in
tick-borne encephalitis. Virology 384: 1-6.
Růžek, D., Salát, J., Singh, S.K., Kopecký, J. 2011. Breakdown of the Blood-Brain Barrier
During Tick-Borne Encephalitis in Mice Is Not Dependent on CD8+ T-cells. PLoS
One, 6(5):e20472.
Růžek, D., Šťastná, H., Kopecký, J., Golovljova, I., and Grubhoffer, L. 2007. Rapid subtyping
of tick-borne encephalitis virus isolates using multiplex RTPCR. J. Virol. Methods
144: 133-7.
Růžek, D., Štěrba, J., Kopecký, J., and Grubhoffer, L. 2006. The supposedly attenuated Hy-
HK variant of highly virulent Hypr strain of tick-borne encephalitis virus is
obviously a strain of Langat virus. Acta Virol. 50: 277-8.
Saksida, A., Duh, D., Lotric-Furlan, S., Strle, F., Petrovec, M., and Avsic-Zupanc, T. 2005. The
importance of tick-borne encephalitis virus RNA detection for early differential
diagnosis of tick-borne encephalitis. J. Clin. Virol. 33: 331-5.
Schneider, H. 1931. [Über epidemische akute „Meningitis serosa“]. Wien. Klin. Woch. 44: 350-
2. [Article in German]
Schultze D, Dollenmaier G, Rohner A, Guidi T, Cassinotti P. Benefit of detecting tick-borne
encephalitis viremia in the first phase of illness. J. Clin. Virol. 2007; 38: 172-5.
Schwaiger M, Cassinotti P. Development of a quantitative real-time RT-PCR assay with
internal control for the laboratory detection of tick borne encephalitis virus (TBEV)
RNA. J. Clin. Virol. 2003; 27: 136-45.
Šenigl, F., Grubhoffer, L., and Kopecký, J. 2006. Differences in maturation of tick-borne
encephalitis virus in mammalian and tick cell line. Intervirology 49: 236-48.
Shapoval, A.N. 1976. [Chronic Forms of Tick-Borne Encephalitis]. Medicina, Leningrad,
Russia. [Book in Russian]
Flavivirus Encephalitis
Shapoval, A.N. 1977. [Inapparent forms of tick-borne encephalitis]. Zh. Mikrobiol. Epidemiol.
Immunobiol. 5:11-7. [Article in Russian]
Simon, J., Slonim, D., and Zavadova, H. 1966. [Experimentelle Untersuchungen von
klinischen und subklinischen Formen der Zeckenencephalitis an unterschiedlich
empfänglichen Wirten: Mäusen, Hamstern und Affen. II. Hamster]. Acta
Neuropathol. 7: 89-100. [Article in German]
Sinnecker, H. 1960. [Zeckenencephalitis in Deutschland]. Zbl. Bakt. Orig. 180: 12-8. [Article in
Slávik, I., Mayer, V., and Mrena, E. 1967. Morphology of purified tick-borne encephalitis
virus. Acta Virol. 11: 66.
Sonnenberg, K., Niedrig, M., Steinhagen, K., Rohwäder, E., Meyer, W., Schlumberger, W.,
Müller-Kunert, E., and Stöcker, W. 2004. State-of-the-art serological techniques for
detection of antibodies against tick-borne encephalitis virus. Int. J. Med. Microbiol.
293(Suppl 37): 148-51.
Süss, J. 2003. Epidemiology and ecology of TBE relevant to the production of effective
vaccines. Vaccine 21(Suppl 1): S19–35.
Süss, J. 2008. Tick-borne encephalitis in Europe and beyond – the epidemiological situation
as of 2007. Euro Surveill 13(26). pii: 18916.
Szajna, M. 1954. [Tick-borne encephalitis in Poland]. Pol. Tyg. Lek. (Wars.) 9: 1625-7. [Article
in Polish]
Thiel, H.J., Collett, M.S., Gould, E.A., Heinz, F.X., Houghton, M., Meyers, G. et al. 2005. In:
Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, Eds. Virus Taxonomy:
Classification and Nomenclature, Eighth Report of the International Committee on
the Taxonomy of Viruses. Amsterdam, Boston, Heidelberg, London, New York,
Oxford, Elsevier Academic Press; pp. 981-98.
Vaptsarov, I., Turpomanov, A., Spasov, Z., Nikov, D., and Dragiev, M. 1954. [Recurrent viral
meningoencephalitis in southern Bulgaria]. Surv. Med. (Sofiia) 5: 86-103. [Article in
Vein, A.A., and van Emde Boas, W. 2011. Kozhevnikov epilepsy: the disease and its
eponym. Epilepsia 52(2):212-8.
Voronkova, G.M., and Zakharycheva, T.A. 2007. [The condition of tick-borne infections
problem in Khabarovsk region]. Bulletin SORAMN 4: 82-88. [Article in Russian]
Votiakov, V.I., Zlobin, V.I., and Mishayeva, N.P. 2002. [Tickborne encephalitis of Eurasia.
Ecology, molecular epidemiology, nosology, evolution]. Nauka, Novosibirsk,
Russia. [Book in Russian]
Waldvogel, K., Bossart, W., Huisman, T., Boltshauser, E., and Nadal, D. 1996. Severe tick-
borne encephalitis following passive immunization. Eur. J. Pediatr. 155: 775-9.
Yamshchikov, V.F., and Compans, R.W. 1993. Regulation of the late events in flavivirus
protein processing and maturation. Virology 192: 38-51.
Zent, O., Banzhoff, A., Hilbert, A.K., Meriste, S., Słuzewski, W., and Wittermann Ch. 2003.
Safety, immunogenicity and tolerability of a new pediatric tickborne encephalitis
(TBE) vaccine, free of proteinderived stabilizer. Vaccine 21: 3584-92.
Zilber, L.A. 1939. [Spring (spring–summer) epidemical tick-borne encephalitis]. Arch. biol.
Nauk 56: 9-37. [Article in Russian]
... The disease is endemic in wide areas of Europe and Northeastern Asia. Nowadays, TBE is one of the most important re-emerging zoonoses in Europe [2]. Human TBE infections mostly occur after the bite of infected Ixodes ticks; however, there are an increasing number of cases or case series of patients infected after consumption of raw milk from infected goats, sheep, or cows [3,4]. ...
... The first phase is characterized by fever and non-specific symptoms, while in the second phase neurological symptoms might occur due to the involvement of the central nervous system (CNS) and this is usually the time when the patients are hospitalized [5]. Since TBEV RNA only rarely can be detected in serum or cerebrospinal fluid (CSF) at the time of onset of the neurological phase, diagnosis of TBEV is most commonly confirmed by serology, usually enzymelinked immunosorbent assay (ELISA) [2]. In almost all patients, IgM and often IgG can be detected at the beginning of neurological symptoms [6]. ...
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Flaviviruses are a heterogeneous group of viruses that may induce broad antigenic cross-reactivity. We present a patient who was admitted to the infectious disease department with symptoms suggestive of aseptic meningitis. During the clinical workup, the patient reported a tick bite two weeks before the disease onset. High titers of IgM and IgG antibodies to tick-borne encephalitis virus (TBEV) were found in both serum and cerebrospinal fluid (CSF) samples, indicating acute TBEV infection. West Nile virus (WNV) and Usutu virus (USUV) IgM and/or IgG antibodies were also detected, and a virus neutralization test (VNT) was performed. A high titer of TBEV neutralizing (NT) antibodies (640) was detected, which confirmed acute TBE. However, NT antibodies to WNV and USUV were also detected (titer 80 for both viruses). After TBEV and WNV IgG avidity evaluation, previous flavivirus infection was highly suspected (avidity index 82% and 89%, respectively). Blood, CSF, and urine samples were negative for respective viruses’ RNA. The presented case highlights the challenges in flavivirus serodiagnosis. In the published literature, different degrees of cross-reactivity or cross-neutralization between TBEV and dengue, louping ill, Omsk hemorrhagic fever, Langat, and Powassan virus were also observed. Therefore, the serology results should be interpreted with caution, including the possibility of cross-reactivity. In areas where several flaviviruses co-circulate VNT is recommended for disease confirmation.
... [74][75][76][77][78][79][80][81][82] Humans are considered accidental hosts following a bite from an infected tick, which means that they can develop viraemia and disease, but are at a dead-end of the natural viral cycle. 72 Most TBE cases are usually reported in the warm months (April to November), which correlates with the highest tick questing and feeding activity. 7 ...
European and Asian countries. It is an emerging public health problem, with steadily increasing case numbers over recent decades. Tick-borne encephalitis virus affects between 10,000 and 15,000 patients annually. Infection occurs through the bite of an infected tick and, much less commonly, through infected milk consumption or aerosols. The TBEV genome comprises a positive-sense single-stranded RNA molecule of ∼11 kilobases. The open reading frame is > 10,000 bases long, flanked by untranslated regions (UTR), and encodes a polyprotein that is co- and post-transcriptionally processed into three structural and seven non-structural proteins. Tick-borne encephalitis virus infection results in encephalitis, often with a characteristic biphasic disease course. After a short incubation time, the viraemic phase is characterised by non-specific influenza-like symptoms. After an asymptomatic period of 2–7 days, more than half of patients show progression to a neurological phase, usually characterised by central and, rarely, peripheral nervous system symptoms. Mortality is low—around 1% of confirmed cases, depending on the viral subtype. After acute tick-borne encephalitis (TBE), a minority of patients experience long-term neurological deficits. Additionally, 40%–50% of patients develop a post-encephalitic syndrome, which significantly impairs daily activities and quality of life. Although TBEV has been described for several decades, no specific treatment exists. Much remains unknown regarding the objective assessment of long-lasting sequelae. Additional research is needed to better understand, prevent, and treat TBE. In this review, we aim to provide a comprehensive overview of the epidemiology, virology, and clinical picture of TBE.
... This method is highly sensitive and specific; however, several studies have reported low sensitivity of PCR for detection of TBEV RNA for routine diagnostic purposes, because of low concentration virus circulating in the bloodstream during acute infection. 17,18 Many patients with neurologic forms of TBE resolve their acute illness, but are left with chronic sequelae of infection. In contrast, some patients show evidence of a continuing disease, which is described as chronic (progressive) TBE. ...
Over the last decades, new knowledge has been accumulated on the worldwide spread of mixed tick-borne infections of different nature (viral, bacterial, protozoal), new pathogen species have been discovered, and it has been shown that individual ticks are infected with several pathogens simultaneously. This information has changed the ideas about the etiological landscape of diseases, which can develop by ixodid tick bites that led to the understanding that this practical problem requires comprehensive studies on the prevention, diagnosis, and treatment of these diseases. At present, there is an urgent need to develop unified approaches to the treatment of the mixed tick-borne infections of viral and bacterial nature. Simultaneous administration of specific drugs against both viral (tick-borne encephalitis virus) and bacterial pathogens (Borrelia spp., Rickettsia spp., Ehrlichia spp., Anaplasma phagocytophilum, and others) is required. This, however, is hampered by the scarcity of antivirals and the side effects of certain antibiotics, which can suppress the patient's immunity and possess a neurotoxic effect, aggravating the viral disease (in particular, tick-borne encephalitis). Thus, since the therapeutic approaches to tick-borne infections of viral and bacterial nature are fundamentally different, these coinfections present a major practical challenge for modern health care in affected regions. This chapter provides information on the spread of tick-borne encephalitis virus and the most significant bacterial pathogens in the world. It highlights Russian, European, and American recommendations for the treatment of tick-borne infections of viral and bacterial nature, as well as experimental studies on the effect of antibiotics on the acute and chronic course of tick-borne encephalitis.
... There is no specific therapy for TBE, and treatment is limited to supportive care. For those individuals who survive, long-term sequelae are common (Bogovič et al., 2018b;Caini et al., 2012;Cisak et al., 2010;Donoso-Mantke et al., 2011;Holzmann, 2003;Holzmann et al., 2009;Kaiser, 2008). ...
Full-text available
Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC 50 s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI-EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.
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Tick-borne encephalitis (TBE) is a viral arthropod infection, endemic to large parts of Europe and Asia, and is characterised by neurological involvement, which can range from mild to severe, and in 33–60% of cases, it leads to a post-encephalitis syndrome and long-term morbidity. While TBE virus, now identified as Orthoflavivirus encephalitidis, was originally isolated in 1937, the pathogenesis of TBE is not fully appreciated with the mode of transmission (blood, tick, alimentary), viral strain, host immune response, and age, likely helping to shape the disease phenotype that we explore in this review. Importantly, the incidence of TBE is increasing, and due to global warming, its epidemiology is evolving, with new foci of transmission reported across Europe and in the UK. As such, a better understanding of the symptomatology, diagnostics, treatment, and prevention of TBE is required to inform healthcare professionals going forward, which this review addresses in detail. To this end, the need for robust national surveillance data and randomised control trial data regarding the use of various antivirals (e.g., Galidesivir and 7-deaza-2′-CMA), monoclonal antibodies, and glucocorticoids is required to improve the management and outcomes of TBE.
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The book is a collection of articles devoted to the current viral infection for Russia and some countries of the world; – tick-borne encephalitis. The monograph deals with evolution; the current epidemiological situation and during the period of study of tickborne encephalitis in certain endemic territories. The accumulated data on the genetic heterogeneity of virus; the subtype change phenomenon; clinical manifestations of acute and chronic tick-borne encephalitis; pathomorphosis and pathogenesis of disease; deaths caused by the Siberian subtype virus; which dominates in the most of Russia; as well as the role of mixed tick-borne infections in the structure of infectious pathology are presented in detail. Great attention is paid to the effectiveness of vaccine prophylaxis of tick-borne encephalitis for the Siberian and Far Eastern subtypes of pathogen; analysing the causes of morbidity among the vaccinated; understanding the mechanism of the preservation of the virus in the immune organism; the features of laboratory diagnosis of acute and chronic tick-borne encephalitis in vaccinated individuals and to questions of specific and non-specific prevention. The book is intended for epidemiologists; virologists; infectious disease specialists; neurologists; as well as other specialists interested in the problem of tick-borne encephalitis. It can be used as a teaching aid in the training and advanced training of medical specialists; senior students of biological; medical faculties and graduate students.
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In a narrower sense, neuropsychology is a discipline that deals with the relationship between neuroscience and psychology. Here he mainly examines the connections between the central nervous system and the human psyche. This characteristic corresponds to the narrow interdisciplinary conception of this scientific field. However, in a deeper search of current professional published literature, one can find works that document the transcendence of this discipline into other medical and some social disciplines. In the form of a literary review, this work set itself the task of examining the professional literature published on this topic and selecting representative literary sources that document the interdisciplinary nature of this scientific discipline.
Conference Paper
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Po revolučnom roku 1989 zaznamenávame sociálno-ekonomickú transformáciu spoločnosti, ktorá interferovala životy mnohých rodín v súčasnosti. Príspevok objasňuje na základe kvalitatívnej analýzy dopady sociálno-ekonomických zmien v spoločnosti na život rodiny, s akcentom na vývin dieťaťa. Reštrukturalizácia hospodárskej sféry znásobila sociálne nerovnosti v rodinách, ktorých dôsledkom je chudoba, nezamestnanosť, zadlženosť. Rastúce požiadavky na trhu práce podmieňujú enormný záujem uplatniť sa v profesijnej oblasti, a tak na rodinu neostáva čas. Nedostatok emocionálneho prepojenia medzi členmi rodiny spôsobuje pocity osamelosti a disharmóniu rodinných vzťahov. Uspokojivé finančné zabezpečenie rodiny často determinuje nutnosť migrácie za pracovnými príležitosťami. Dlhotrvajúce odlúčenie rodičov od svojich detí ohrozuje fyzický vývin, psychickú pohodu a v konečnom dôsledku aj školskú úspešnosť dieťaťa.
In the last decades, the emergence of ticks and tick-borne diseases (TBD) has become a public health concern in Europe. In Piedmont region (Northwestern Italy) ticks were rare in the past, especially in mountain areas. However, in the recent years, we have been observing an increase in tick abundance in the environment but also in reported tick-bites and TBD cases in humans. Tick-borne diseases are characterized by complex transmission cycles; thus, an integrated approach is needed. The ‘One Health’ (OH) approach may effectively provide scientific evidence for TBD surveillance and prevention, and support decision makers. This PhD project investigates the presence and abundance of tick vectors and tick-borne pathogens in two natural areas of Piedmont region, recently invaded by ticks, to identify potential risk factors involved in their emergence, and to evaluate their impact on public health. Additionally, we aimed to identify ideal surveillance and control elements based on a OH approach. We recorded a further expansion of Ixodes ricinus in Europe, being maintained at altitudes up to around 1700 m a.s.l. The abundance of I. ricinus was significantly associated with altitude, habitat type and signs of roe deer presence and molecular analyses demonstrated its infection with several zoonotic agents: B. burgdorferi sensu lato, spotted fever group rickettsiae, Anaplasma phagocytophilum, Borrelia miyamotoi and Neoehrlichia mikurensis. Dermacentor spp. ticks were also collected, in particular D. marginatus and D. reticulatus. Rickettsia slovaca and Candidatus Rickettsia rioja, causative agents of SENLAT (Scalp Eschar Neck Lymphadenopathy) syndrome in humans, infected Dermacentor ticks and wild boar tissues, suggesting the greater contribution of wild boar in its eco-epidemiology and dispersion in the study area. We also confirmed that Piedmontese population is exposed to infected tick bites. However, a generalized low awareness was observed among the population; in fact, although most citizens perceive ticks as a health threat, they do not frequently adopt protective measures. This justified the longer duration of tick attachment generally observed in bitten patients (> 24 hours). A serosurvey in wild ungulates was additionally carried out in mountain areas to assess the circulation of tick-borne encephalitis virus. No serum sample yielded positive results, indicating the absence of this pathogen in our territory so far. Notwithstanding, this activity should be maintained in the long term for early pathogen detection and rapid response, since the virus is circulating in bordering areas of the Piedmont. Regarding tick ecology, this project integrated some investigations about tick symbionts, whose presence is key for tick development and survival. We detected the infection of Francisella-like endosymbionts in Dermacentor spp. which have been previously associated with positive effects in the tick fitness, by providing nutrimental support to ticks. Moreover, a large-scale study was carried out to investigate the infection of Rickettsiella symbionts in I. ricinus populations in Europe, identifying a great diversity within the Rickettsiella genus. Research on TBD requires the knowledge and skills from different disciplines. However, transdisciplinarity seems to work when structural support is provided by the system; instead, critical elements such as insufficient funding, system decentralization and monodisciplinary approaches threaten the response capacity of the systems. One Health operation and infrastructure aspects can strengthen surveillance systems and could be particularly important in areas of recent spread of ticks and TBD.
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Various types of viral diseases are emerging as the largest menace human beings have faced in the last few decades. Since the arrival of human immunodeficiency virus, the world has seen the emergence of deadly viruses like bird flu, Ebola, Nypah, Hanta, SARS, MERS, and currently the SARS-CoV-2. Other viral diseases like herpes, human papilloma virus, and hepatitis have become so common that despite their widespread infection rates, causes of liver and cervical cancer and consequent mortalities, they have not caught the attention of the general people in a way SARS-CoV-2 has done. Unlike small pox, polio, several types of hepatitis, and, to a certain extent, HPV, most other viral diseases have proved difficult to cure with vaccines or drugs. As with many other diseases, plants can form a possible source of therapeutics for HPV. There are around 250,000 species of flowering plants in the world; each species contain a range of phytochemicals with diverse pharmacological activities. For instance, over four dozen plants have been identified with antiviral activity against herpes virus, while a number of other plants and phytochemicals have shown promise against various viruses. Promising antiviral phytochemicals include coumarins, terpenoids, flavonoids, polyphenols, and alkaloids. This chapter will attempt to summarize the present state of knowledge regarding plants, formulations, and phytochemicals (against HPV) and discuss the potential of drug discovery from the promising phytochemicals.
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Twenty isolates of Central European encephalitis (CEE) virus were compared with 20 isolates of louping-ill (LI) virus in indirect immunofluorescence test (IIFT), using a panel of 17 monoclonal antibodies (MoAbs) prepared against the prototype LI virus. Three Asian members of the tick-borne encephalitis (TBE) complex were also included in the comparison: Turkish sheep encephalitis (TSE), Russian spring-summer encephalitis (RSSE) and Langat (LGT) viruses. Antigenic relationships of the viruses were evaluated by Dice similarity coefficient and cluster analysis. The results revealed antigenic heterogeneity of LI isolates, antigenic homogeneity of CEE isolates, and indicated that CEE and LI are related varieties of Eurasian TBE flavivirus that also includes TSE and RSSE strains.
The epidemiology of tick-borne encephalitis virus was investigated by comparative sequence analysis of virus strains isolated in endemic areas of Europe and Asia. Phylogenetic relationships were determined from the nucleotide and amino acid sequences of the major envelope (E) protein of 16 newly sequenced strains and nine previously published sequences. Three genetic lineages could be clearly distinguished, corresponding to a European, a Far Eastern and a Siberian subtype. Amino acids characteristic for each of the subtypes ('signature' amino acids) were identified and their location in the atomic structure of protein E was determined. The degree of variation between strains within subtypes was low and exhibited a maximum of only 2.2% at the amino acid level. A maximum difference of 5.6% was found between the three subtypes, which is in the range of variation reported for other flaviviruses.
An original modified method of tick-borne encephalitis (TBE) diagnosis was used to examine 1196 subjects. It is shown that tick bites frequently lead to TBE virus infection in all the age groups (24.9 ± 1.3%). Antigenemia in febrile TBE form occurred in 45.8 ± 6.0%, in severe form in 19.3 ± 4.2% of cases. Children with the highest viremia and antigenemia are considered as an indicator system of TBE virus infection rate in the population in different seasons. Population of TBE virus consists of 2 parts. The prevalent part is inapparent and does not induce manifest infection. The other part of the virus population with similar seasonal activity gives rise to severe clinical forms of TBE with lethal outcomes.
An original method of virus isolation developed by the authors made it possible to collect 64 strains of tick-borne encephalitis (TBE) virus isolated from the blood of TBE patients and subjects complaining of sucking Ixodidae ticks. It is demonstrated that only a small part of the tick natural population cause acute TBE. The majority of the strains (54 isolates) of TBE virus have been isolated from the blood of clinically healthy subjects. Half of the strains showed no immunogenic properties in human body. Season infectivity corresponds to monthly virusophority of the ticks.
The book represents the results of the cCASHh study that was carried out in Europe (2001-2004), co-ordinated by WHO and supported by EU Programmes. The flood events in 2002 and the heat wave of August 2003 in Europe had given evidence in a rather drastic way of our vulnerability and our non preparedness. The project has produced very important results that show that the concurrent work of different disciplines in addressing public health issues can produce innovative and useful results, providing an approach that can be followed on other public health issues. The project has shown that information on potential threats can be extremely useful in preparing the public for adverse events as well as facilitating the response when the events occur. This is a new dimension for public health which reverses the traditional thinking: from identifying and reducing specific risk factors, to taking action on the basis of prediction and early warning to prevent health consequences in large populations.
Der in der Tschechoslowakei isolierte Stamm JIR des ZE-Virus zeigte nach intracerebraler bzw. subcutaner Inoculation eine große Neurovirulenz gegenüber dem ZNS der Maus. Bei primärer (nach intracerebraler Inoculation) wie bei sekundärer (nach subcutaner Inoculation) Encephalitis wurde eine Reaktion vom Charakter des “Alles oder Nichts”-Typs beobachtet. Eine subklinische Form bildete sich nie aus.