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Tick-borne encephalitis (TBE) trends in
epidemiology and current and future management
Eckhardt Petri*, Dieter Gniel, Olaf Zent
Novartis Vaccines and Diagnostics GmbH, Marburg, Germany
Received 9 August 2010; accepted 9 August 2010
KEYWORDS
Tick-borne encephalitis;
Flavivirus;
Vaccine;
Travel;
Tourism;
Tick-borne disease
Summary Tick-borne encephalitis (TBE) is considered an international health issue, as the
number of risk areas and reported cases across Europe, Russia, and parts of Asia continues
to increase. The incidence of TBE has fluctuated considerably from year to year in many coun-
tries, but in the past decade the number of TBE cases has significantly increased in the Baltic
states, the Czech Republic, and Germany, in addition to occurring in countries previously
considered to be free from TBE, such as Denmark (specifically the main island of Zealand),
France, and Italy. A number of factors have been suggested to explain the increase in inci-
dence, including climate change, and increased travel and outdoor pursuits, placing people
in increased contact with infected ticks. There is no causal treatment available once infected,
but TBE can be effectively prevented by vaccination, for which several vaccines are widely
available. Three vaccination schedules are available for immunization against TBE, and the
recommendations for TBE vaccination vary considerably across the countries in which TBE foci
are found. However, plans are in place to raise awareness of TBE and to standardize the vacci-
nation programme across Europe, with the aim of reducing the number of future cases of TBE.
ª2010 Published by Elsevier Ltd.
Introduction
Tick-borne encephalitis (TBE) is a serious acute viral
infection that affects the central nervous system (CNS). In
those it infects, TBE can lead to severe neurological
syndromes, and can result in potentially long-lasting and
life-threatening complications, such as meningitis and
meningo-encephalitis. Tick-borne encephalitis was
previously confined to parts of Central and Eastern Europe
and Russia.
1
However, endemic regions have expanded over
the past 50 years to other parts of Europe and Asia, as well
as there being an increase in the number of reported cases
within endemic areas.
2,3
There has been speculation as to
the cause of the increased incidence of TBE and, in addition
to weather and climate changes, a number of factors are
thought to be responsible for the increase in the number of
reported cases of TBE, including increased human activity
in risk areas, as well as better surveillance, improved
recognition, and diagnosis.
4
Over the same period that has seen a rise in reported cases
of TBE, travel to endemic areas, including travellers from
* Corresponding author. Rudolf-Diesel-Ring 27, 83607 Holzkirchen,
Germany. Tel.: þ49 8024 908 5731; fax: þ49 8024 908 5799.
E-mail address: eckhardt.petri@novartis.com (E. Petri).
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/tmid
Travel Medicine and Infectious Disease (2010) 8, 233e245
1477-8939/$ - see front matter ª2010 Published by Elsevier Ltd.
doi:10.1016/j.tmaid.2010.08.001
overseas to European TBE-endemic areas, has also increased,
making TBE an international health issue.
1,5,6
The manage-
ment of traveller-related TBE infections is a key factor in
controlling TBE-infection rates, as currently there is a lack of
awareness of TBE among many travellers, particularly those
from non-endemic areas. In addition, the TBE vaccine is not
routinely recommended for travellers and TBE vaccines are
unavailable in some countries, such as the USA.
3,7,8
The increase in the reported incidence of TBE is due to
a complex combination of changes in ecology, climate, and
increased human activity in affected areas. These changes
are based on different socioeconomic factors, as well as an
increased recognition by health authorities.
3
In terms of
management of TBE, there are no causal treatments
available once an individual is infected. Post-exposure
treatment by (hyper)immunoglobulins (known as passive
immunization) is able to prevent various viral diseases or at
least to mitigate the severity of symptoms. The use of
immunoglobulins was a known treatment of TBE in the past.
However, later immunoglobulins were removed from daily
practice because of lack of formal proof of their effec-
tiveness and non-appropriate applications, and because of
cases of an aggravated course of illness post-treatment.
9e11
Specific immunoglobulin preparations were suspended by
manufacturers in the EU.
12
Today these preparations are
still available in Russia and some Commonwealth of Inde-
pendent States (CIS) countries. However, TBE is prevent-
able through prophylactic vaccination, for which a number
of established strategies exist.
13
Epidemiology and disease characteristics
The TBE virus belongs to the Flaviviridae family, a large
group of small envelope viruses, which also includes yellow
fever, dengue fever, Japanese encephalitis, and St. Louis
encephalitis viruses.
14
Of the Flavivirus viruses, TBE is the
most important in terms of human CNS infection in Europe
and Russia.
15
The TBE virus can be transmitted by different
species of ticks, depending on the geographical area;
however, two species have been identified as the chief
vectors that transmit the virus: Ixodes persulcatus and
Ixodes ricinus.
16
There are three subtypes of TBE virus; the European
subtype (carried by I. ricinus), and the Far-Eastern and
Siberian subtypes (both carried by I. persulcatus).
3
The
European subtype is endemic to areas in Central, Eastern,
and Northern Europe, whereas the Far-Eastern subtype is
found primarily in Russia, northeastern China, parts of
Japan, and as far west as the Baltic states. The Siberian
subtype was originally identified in Siberia, but has also been
found in Finland.
17
All three subtypes have been identified in
Estonia, Finland, and Latvia.
18,19
Overall, the TBE virus can
be found in a belt spanning from Western Europe, across
Russia, China, and Mongolia to Japan (Fig. 1). Virus trans-
mission over long distances is known to be caused by
migrating birds.
20
Anthropogenic factors are also known to be
responsible for the movement of the virus in Russia.
21
The
severity of human infection differs between the age of
individuals affected and virus subtypes, with infections from
the Far-Eastern subtype resulting in a more severe pheno-
type (with a case-fatality rate of 5e20%) than the European
subtype (with a case-fatality rate of around 0.5e2%).
22
Ticks require optimum climate conditions to start and
finish their lifecycle (from egg, larvae, nymphs, and adult
stages), including a humidity greater than 85%. In addition,
in order for ticks to find a host and to take a blood meal, an
ambient temperature greater than 7C is required.
23
As
a result, tick activity increases at times of the year when
climate conditions are optimal (i.e. spring and summer).
This coincides with increased human outdoor activities,
resulting in the period when most TBE cases occur.
The TBE virus is most commonly transmitted to humans
via the bite of an infected tick; however, the virus can also
be transmitted by the consumption of unpasteurized milk or
milk products from an infected animal.
24
The virus is trans-
mitted via the milk of goats to their offspring and, to a lesser
Figure 1 The tick-borne encephalitis virus belt.
2,36,37,56,61,98,99
(Dr Otgonbaatar 2009 (General Director, Center of Infectious
Diseases with Natural Foci, Personal communication)).
234 E. Petri et al.
extent, via the milk of cattle and sheep.
25
The transmission
of the virus from infected milk products, historically referred
to as ‘biphasic milk fever’, is a mode of infection that is
more common in Eastern Europe and the Baltic states, and is
becoming an increasing problem.
26
The nature of the
infection from consuming an infected milk product is that
a single, infected animal can result in a number of people
becoming infected. For example, in a case study by Holz-
mann et al., one single animal was shown to have infected
six individuals (of whom four were symptomatic).
25
In the
Czech Republic, from 1997 to 2008, there were 64 reported
cases of TBE resulting from the consumption of unpasteur-
ized goat and sheep milk and cheese.
27
Within Europe, TBE is endemic in regions of 27 coun-
tries.
24,28
The highest incidence (globally) can be found in
western Siberia, with between 40 and 80 cases per 100,000
people.
29
On average, global incidence of TBE ranges from
10,000 to 12,000 cases annually.
24
In total, Europe and
Russia reported 12,733 TBE cases in 1996, which was the
highest annual number between 1990 and 2007. The global
number of reported TBE cases dropped in 2007 to 5462;
however, some countries continued to observe an increase
in the number of cases.
30
All areas where TBE is currently endemic are highlighted
in Fig. 1.
Clinical characteristics
The median period from a bite from an infected tick to the
development of TBE infection is approximately 8 days
(range 4e28 days).
31
The European virus subtype follows
a biphasic course in the majority of cases,
26
where phase 1
consists of a non-specific influenza-like illness lasting 1e8
days, followed by a symptom-free phase (1e33 days,
median 8 days), and a febrile phase of the disease.
32
The
meningo-encephalitic phase presents in around 20e30% of
patients.
33
If confined to the meninges, the prognosis is
good; however, more severe symptoms can develop if the
virus spreads to the brain, upper spinal cord, or nerve roots.
Therefore, the long-term morbidity associated with TBE is
substantial, with approximately 26e50% of patients devel-
oping long-term neurological sequelae.
34
The clinical
characteristics of TBE infection are described more fully in
a study by Banzhoff et al. 2008.
35
TBE case definitions
Currently, there are differences in how European countries
define cases of TBE, in particular in the diagnostic assays
used for confirmation of cases assessed according to
different parameters and the methods used for mapping
risk areas, which differ widely across countries where TBE
is endemic.
15
Several methods can be used to investigate
the epidemiological situation of TBE, including the exami-
nation of ticks and animal reservoirs for the presence of
TBE virus or antibodies against it, a seroprevalance study of
people exposed to ticks, or a description of clinical cases
and geographic locations. In countries where TBE-endemic
areas are calculated based on the reported clinical cases it
is possible that areas declared non-endemic are not
necessarily free from the TBE virus, and may well contain
infected ticks.
8
High vaccination coverage rates may also
reduce the number of clinical cases of TBE, without
removing the presence of the TBE virus. Of the 22 countries
participating in a TBE survey carried out in 2008, TBE was
notifiable in 16 (73%) countries.
15
Clinical symptoms of TBE are similar to other CNS
infections and aseptic forms of meningitis and encepha-
litis
31,32
; therefore, definitive diagnosis requires laboratory
testing. However, there is considerable variation around
case definition, as well as the application of laboratory
tests for case confirmation across Europe.
15
For example, in
Austria, TBE cases are defined as serological, proven
hospitalized cases. The Czech Republic, Estonia, France,
Finland, Germany, Hungary, Poland, and Sweden also
require laboratory confirmation. Other countries do not
have a formal TBE case definition in place, including Latvia,
Lithuania, Switzerland, and Russia, despite Russia having
the highest reported rate of TBE.
15
In Russia, between 1998
and 2007, 54,526 TBE cases were registered; however, lack
of a formal definition may have led to under-reporting.
Therefore, the true incidence of TBE in Russia is speculated
to be much higher than the official number of cases that
have been reported.
4
Trends in incidence
Over the past 10 years, TBE incidence has increased in
virtually all European countries in which the disease is
endemic.
28
In addition to Europe and Russia, the incidence
of new TBE foci has also been reported in the north of
China,
36
as well as reports that TBE is endemic in Hokkaido,
in the northern island of Japan.
37
Globally, the incidence of
TBE dropped in 2007 to 5462; however, some countries
continue to observe an upward trend, with TBE continuing to
pose a significant threat.
30
In some European countries,
a variation in the incidence of TBE of more than 100%
between successive years is also a common phenomenon.
28
In the period between 1974 and 2003, an average increase
in the incidence of TBE of 400% could be registered in all TBE
countries across Europe, with the exception of Austria.
38
Scandinavia (Denmark, Finland, Norway, and Sweden)
Of the Scandinavian countries, Sweden has the highest
reported rate of TBE cases, with 211 cases reported in 2009
(Table 1). Annual case numbers of TBE were low in Sweden
from 1960 to 1983 (24 7), although there was a 3-fold
increase from 1983 to 1986, with a higher incidence
(65 20) reported from 1986 onwards.
39
From 2003 to
2007, on average, 150 annual cases were reported in
Sweden with the majority (62%) of cases occurring in the
counties of Stockholm.
4
Climate change has been impli-
cated in the spread of the TBE virus, with warmer winters
and the earlier arrival of spring allowing I. ricinus to expand
its distribution toward the north of the country and to
become more abundant in central Sweden from the 1980s
to the early 1990s.
40,41
Up to 1999, in Denmark (mainland and large islands), no
cases of TBE had been reported for 40 years,
2
and only the
island of Bornholm had been classified as a TBE risk-area
based on human cases reported in the past 20 years.
4
In
a study of 508 residents of Bornholm, 1.4% were TBE
TBE trends in epidemiology and management 235
positive, but among forest workers the figure was much
higher (30%).
2
However, there is now an indication of the
virus spreading; the TBE virus has also recently been
reported in another region of Denmark; Zealand.
42
In
addition, it is likely that there may also be regions of
microfoci in other parts of Denmark.
43
The northernmost occurrence of the TBE virus within
Scandinavia has been reported in Finland, which has
experienced an overall increase in the number of reported
cases from 2000 onwards. From 1999 to 2009 the number of
reported TBE cases in Finland ranged from 12 to 41 cases
annually, with the highest incidence of 41 cases occurring in
2000.
4,44
Norway is a relatively new TBE risk-area, with the
first case reported in 1997. In Norway, the TBE virus is
restricted to a region along the south coast, and from 1999
to 2009 the number of reported cases fluctuated between
0 and 12 cases annually.
44,45
The Baltic states (Estonia, Latvia, and Lithuania)
All three Baltic countries experienced a modest increase in
disease incidence during the 1970s and 1980s, followed by
a more significant rise from 1990 onwards. Relative to the
previous 10-year mean, an abrupt increase in TBE incidence
from 1992 to 1993 was observed for Estonia (64%; 2.6-fold
increase).
46
The highest reported incidence of TBE in
Estonia was observed in 1997 with 27.8 cases per 100,000
population.
47
From 1992 to 1993 the incidence of TBE in
Latvia also increased (175%; 4.5-fold increase).
46
In Lithuania, the number of reported cases during the
1980s was low (14 4 annually, below 5 in 100,000
cases).
39,46
However, from 1992 to 1993, there was an
abrupt increase of 1065%, equivalent to a 13.8-fold increase
relative to the previous 10-year mean.
46
From 1993 to 2004,
the incidence of TBE continued to rise in Lithuania with an
average of 365 157 cases reported annually, focused
within central regions of the country.
39,48
In Estonia, Latvia,
and Lithuania the increased number of cases was main-
tained from 1990 to 2005.
44,49
The number of reported cases of TBE in 2009 remained
high, with 179 cases in Estonia, 328 cases in Latvia, and 617
cases in Lithuania (Table 1). The abrupt increase in repor-
ted TBE incidence in the Baltic states has been attributed
to a combination of factors, including improved public
health practices, altered agricultural practices (resulting in
changes from agriculture and pasture land to woodland,
a perfect habitat for ticks), and increased human exposure
to woodland, based on changed socioeconomic and recre-
ational factors.
46
Alpine states (Austria, France, Germany, Italy, Slovenia,
and Switzerland)
Of the Alpine states, Austria used to be the most severely
affected TBE risk-area and, until 1999, eight of the nine
federal states of Austria were known to be endemic for
TBE.
2
However, following the successful introduction of
a vaccination programme, Austria has experienced
a decrease in the number of annually reported TBE cases
from 600 to 700 to currently 50 to 100, and it now has one of
the lowest number of reported cases among the European
TBE-endemic countries (Table 1). It is estimated that in
Table 1 Changes in TBE incidence in selected European countries and Russia, 1999e2009.
44
Reproduced by the kind
permission of Baxter AG, Vienna from the 12th ISW-TBE newsletter.
a
Region Country Number of TBE cases
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
b
Alpine countries Austria 41 60 54 60 82 54 100 84 45 86 79
France 5 0 0267066100
Germany 115 133 253 226 278 274 431 546 238 285 312
Italy 5 15 19 6 14 23 22 14 4 3 32
Slovenia 150 190 260 262 275 204 297 445 196 246 307
Switzerland 112 91 107 53 116 138 206 259 113 127 118
Baltic states Estonia 185 272 215 90 237 182 164 171 140 90 179
Latvia 350 544 303 153 365 251 142 170 171 181 328
Lithuania 171 419 298 168 763 425 242 462 234 204 617
Scandinavia Denmark 4 3 114840201
Finland 12 41 33 38 16 31 17 18 20 24 26
Sweden 53 133 128 105 105 160 130 163 190 224 211
Norway 1 2 12130512128
Visegra
´d states Czech Republic 490 719 411 647 606 500 652 1029 542 630 816
Hungary 51 45 76 80 114 59 90 115 170 53 55
Poland 101 170 205 126 339 262 174 316 233 193 335
Slovakia 57 92 76 62 74 70 28 91 46 77 66
Other Russia 9955 5931 6339 5150 4770 4235 4551 3510 3098 2798 3632
a
Number of reported TBE cases 2008 and 2009 from a personal communication of Professor Su
¨ss published in 12th ISW-TBE Newsletter
March 2010.
b
Preliminary data.
236 E. Petri et al.
Austria from 2000 to 2006, about 2800 TBE cases were
prevented by vaccination.
50
However, Austria remains
a high-risk area for unvaccinated tourists. The incidence in
unvaccinated individuals has increased, largely in people
over 60 years of age who have never been vaccinated
against TBE and residents in new endemic areas in the
western part of the country. The reasons for low vaccina-
tion coverage include people thinking they have acquired
TBE resistance as a result of receiving a large number of
tick bites in the past, or believing that avoiding areas where
ticks are abundant will provide sufficient protection.
Furthermore, there is sometimes also a belief that TBE
distribution is static; therefore, people may be unaware
that they are at risk.
51
Today, Germany has the highest reported TBE rate in the
region, and has experienced a large increase in cases over
the last 20 years. From 1993 to 2002, 185 cases of TBE were
reported each year, compared with 431 reported cases in
2005 and 546 cases in 2006. The number of identified risk-
areas in Germany has also increased, from 63 risk-areas in
1998 to 129 in 2007.
23
Of 440 German counties, 132 are
currently classified as TBE risk-areas,
4
mainly in the
southernmost states.
Switzerland and Slovenia both contain TBE-endemic
areas. The incidence of TBE in Switzerland has fluctuated
over the past decade, and from 2005 to 2006 there was an
81% increase in the reported incidence.
23
Slovenia has also
experienced a large increase in TBE cases from 1999 to
2009, with endemic foci spreading across the country. From
2001 to 2005, the 5-year average was 261 cases annually,
and in 2006, 445 cases were reported, fluctuating to 307
cases in 2009 (Table 1).
4,44
France has experienced a low incidence of TBE with no
reports of the disease prior to 1990. However, there has
been a trend of an increasing number of cases over the past
two decades from areas such as the Alsace region.
4
Sero-
prevalence rates in the areas affected (Alsace, Lothringen,
and Nancy regions) were found to be 1e2%.
24
There were no
reported cases of TBE in France in 2009 (Table 1). Italy is
another example of a country that used to be largely free of
TBE, with fewer than five annual cases reported before
1992. However, from 1992 onwards, rates have been
increasing in northern parts of Italy; 23 cases were reported
in 2004, 14 in 2006, and 32 in 2009 (Table 1).
4
Czech Republic, Hungary, Poland, and Slovakia
The Czech Republic has by far the highest-known TBE rate
in this region of Europe, and globally is second only to
Russia in the number of reported cases. The incidence is
higher in regions south of Prague, as well as in the western
part of the Czech Republic near the town of Pilsen.
4
From
the 1960s onwards there has been a high annual incidence
of 408 192 reported cases of TBE in the Czech Republic.
This decreased slightly in the 1980s (256 85) but approx-
imately doubled in 1993 (583 111).
39
In 2000, the inci-
dence of TBE in the Czech Republic was approximately 7.2
per 100,000 population.
52
From 2005 to 2006, TBE incidence
increased by 73%,
23
with a total of 7288 cases reported from
1997 to 2008. The average number of TBE cases reported
annually from 2003 to 2007 was 666, which increased to
1029 cases in 2006.
4
It is thought that unusually warm
weather during 2006 was responsible for the increase in the
reported incidence, as the increased temperature provided
optimum conditions for ticks, in addition to increasing
outdoor activities and, therefore, human exposure to
ticks.
19,52
In Hungary, from 1977 to 1996, there were, on average,
2.5 reported TBE cases per 100,000 inhabitants (range
1.3e3.8). The incidence dropped between 1997 and 2000
(to 0.5 per 100,000 inhabitants in 2000), but from 2000
onwards the number of reported cases increased and, from
2003 to 2007, an average of 106 cases were reported
annually. The reason for the observed reduction in TBE
incidence in 1997 may have been owing to changes in the
Hungarian public health service, resulting in under-report-
ing. In Hungary, financial constraints led to reduced diag-
nostic efforts, with diagnosis now only being requested in
situations of milk-borne outbreaks of TBE, or when prob-
lems with differential diagnosis occur.
4,53
In Poland, the number of TBE cases reported during the
1980s was low (13 7), and fewer than 50 cases were
consistently reported each year until the 1990s, when
a rapid increase was observed, with 607 cases reported
from 1999 to 2002
39,54
and 335 cases in 2009 alone. The
majority of cases were reported in the northeast of the
country, close to the Baltic area (Table 1). The reason for
the dramatic increase in the annual number of reported
TBE cases in Poland in 1993 is the result of the introduction
of appropriate serological tests and a countrywide educa-
tional campaign.
54
Recently, foci have been identified in
regions previously largely free from TBE in the north-
western provinces of Poland.
55
In Slovakia, the mean annual
number of reported TBE cases from 1998 to 2007 was 67
(range 46e92).
4
In 2009, the number of cases in Slovakia
was 66 (Table 1).
Russia
Over the past 20 years, the highest number of registered
TBE cases has been noted in Russia, where 58 million people
live in high-risk areas.
4
The highest numbers of TBE cases
were reported in 1996 (10,298 cases) and 1999 (9955
cases).
4
More recently, the number of cases in Russia
decreased to 3098 in 2007
4
and 3632 in 2009 (Table 1). The
northwestern part of European Russia, the Ural-area, the
whole area of Siberia, and the easternmost part of Russia
are all known to contain TBE foci.
56
In western Siberia, the
annual morbidity of TBE has been reported to vary by as
much as 10-fold.
57
Emerging factors
The exact reasons for the fluctuations in the number of TBE
cases are not yet fully understood. Several factors,
including the abundance of ticks, the prevalence of the
TBE virus among sub-adult ticks, and the yearly virulence
of the TBE virus, have all been suggested to influence the
variability in TBE morbidity. A recent analysis highlighted
the role of small mammals and suggested that the vari-
ability in TBE morbidity, at least in western Siberia, was
mainly affected by the intensity of the interaction between
small mammal hosts and immature arthropod vectors,
rather than the abundance of infected adult ticks.
57
In
addition to the status of the vectorehost relationship,
TBE trends in epidemiology and management 237
a number of other lifestyle and environmental factors are
implicated in the observed increased incidence and
epidemiology of TBE.
Climate change
The impact of climate change on TBE incidence continues
to be debated. One suggestion is that it may be as a result
of milder winters and warmer springs, which extends the
period of both human and tick activity in endemic areas
40
as ticks thrive in a humidity range above 85% and air
temperatures above 7C.
23
Climate change has also resul-
ted in increased precipitation and a shift in the infected
tick population to higher altitudes.
58
For example, Lukan
et al. analysed the distribution of TBE cases in Slovakia
from 1980 to 2003 and observed an increasing trend in the
prevalence of TBE at higher altitudes.
59
In addition, Zeman
and Bene
s demonstrated that global warming affected the
distribution of TBE cases in the Czech Republic by
increasing the TBE ceiling (by 5.4 m 1.7 m yearly) and
also indirectly by increasing the population of deer, which
act as tick hosts.
60
Similar data reported for the northwest
of European Russia indicate a shift of the TBE-endemic area
to the very north (the Archangel’sk area).
61
Travel
Climate change alone is not responsible for the increased
rates of TBE infection, only for an increased number of
ticks. The increased risk of human exposure to infected
ticks as a result of increased intercontinental travel to
highly TBE-endemic areas in Central and Eastern Europe
(such as Austria, Croatia, Czech Republic, Germany,
Hungary, and Switzerland) has been noted.
7,49
In addition,
the main travel period corresponds with the main tick-
activity period,
49
and regions with high TBE risk, such as the
Czech Republic, are becoming increasingly popular travel
destinations.
8
Europeans travelling within their own conti-
nent also do not consider themselves as travellers exposed
to travel-associated infections in the same way as when
they are travelling outside of Europe and, therefore, often
do not seek travel vaccine advice, highlighting a lack of
awareness of the risk of TBE within this group.
8
Americans
travelling to China, Europe, or Russia are also at risk, as
recognized in a routine survey analysing specimens from
patients with unexplained encephalitis travelling to TBE-
endemic countries. However, TBE is not a notifiable disease
in the USA.
6
Lifestyle
Greater human exposure to infected ticks may also be
brought about through altered socioeconomic circum-
stances, for example, increased leisure, outdoor activities,
and also in the changes made to the land cover and land
use, as a result of changes in farming.
19,49
In addition, there
has been an increase in human population, and in the
population density and migration of populations to
suburban areas, increasing the number of people exposed
to tick habitats.
58
Disease prevention
There are currently no specific post-exposure treatments
available. The only means to avoid infection is by taking
measures to avoid exposure to infected ticks, such as
avoiding forested areas and using insect repellent, and also
refraining from the consumption of unpasteurized milk
products in endemic areas. If going to an endemic area and
undergoing high-risk activities that will result in exposure
to ticks, the only form of protection is active prophylactic
immunization. Two vaccines are currently available for the
prevention of TBE in Europe; Encepur
(Novartis Vaccines
and Diagnostics GmbH, Marburg, Germany) and FSME-
Immun
(Baxter AG, Vienna, Austria), both of which have
been well characterized in different clinical studies.
35
No
widely published data are available for the Russian TBE
vaccines. Encepur is derived from the German isolate, K23,
whereas FSME-Immun is derived from an Austrian virus
strain (Neudo
¨rfl). Both vaccines provide effective protec-
tion against all three subtypes of the TBE virus.
62e64
Paediatric formulations for children 1e11 years of age
(Encepur
Children) or 1e15 years of age (FSME-Immun
Junior) have also been developed and are widely
available.
65,66
Both Encepur and FSME-Immun have undergone major
formulation modifications since their respective introduc-
tions.
67,68
Encepur was first approved in 1991 for use in
adults and children
68
; however, as a result of increased
reactogenicity when administering the full dose in children,
Encepur K(Novartis Vaccines and Diagnostics GmbH,
Marburg, Germany) was introduced in 1994 for children
under 12 years of age.
35
Further modifications were then
made as a result of reports of rare, immediate allergic
reactions to Encepur K, including generalized urticaria,
exanthema, itching, and swelling of the face or eyelids.
69
In
2001, new formulations of both Encepur and Encepur chil-
dren were brought to market, which were free of protein-
derived stabilizers.
67
FSME-Immun, containing the preservative thiomersal and
stabilizer human serum albumin (HSA), was approved in 1976;
however, in 1999 the mercury-containing thiomersal was
removed in line with European regulations.
65
In 2000,
a TicoVac
formulation of FSME-Immun was produced from
which the HSA stabilizer was removed. The TicoVac formula-
tion met the recommendations issued by the European
Medicines Agency (EMEA) regarding the safety of HSA, and the
importance of eliminating any risk of excipients that may
engender doubts in terms of viral or pathogenic safety.
70,71
However, it is likely that, as the antigen content of TicoVac
was not adjusted accordingly, the formulation resulted in
adverse events, which were primarily fever and febrile
convulsions in children, so the HSA was reintroduced in 2001 as
FSME-Immun
New (Baxter AG, Vienna, Austria).
72,73
Clinical data from two existing vaccines
Encepur
Following its introduction in 1991, paediatric and stabilizer-
free formulations of Encepur have been made available. In
2003, Zent et al. published pooled clinical trial data from
238 E. Petri et al.
trials conducted in the Czech Republic, Germany, and
Poland, comparing the safety and efficacy of the new
stabilizer-free formulation with the old formulation.
66
The
immunogenicity of the new formulation was non-inferior to
the old and was associated with fewer adverse events. It
was therefore concluded that removal of the polygeline
stabilizer improved tolerability without compromising
immunogenicity. Clinical trial and post-marketing data
have shown Encepur to have a favourable tolerability
profile and to elicit a long-term immune response against
TBE.
13
FSME-Immun
Clinical trials and post-marketing surveillance have shown
FSME-Immun to be well tolerated and effective, and to
provide long-term immunity against TBE. A large, placebo-
controlled clinical trial compared the formulation of FSME-
Immun New with the old formulation of the vaccine.
Immunogenicity of the new formulation was not inferior to
the older one, with a similar tolerability profile.
65
Interchangeability of TBE vaccines
Three vaccinations are required for TBE protection as part
of a primary vaccination schedule. The question of whether
the same product is required for all three vaccinations or
whether Encepur and FSME-Immun are interchangeable has
recently been addressed. Previously, data were limited
regarding the interchangeability of vaccines for the primary
vaccination schedule, so the same vaccine was recom-
mended for primary vaccination (except in special
circumstances, such as shortage of a specific vaccine). It
was recommended that switching vaccines should be avoi-
ded completely for the rapid schedule.
74
However, recent
clinical trial data have shown compatibility during the
primary vaccination using the conventional primary vacci-
nation schedule,
13
and TBE vaccines have also been shown
to be interchangeable for booster vaccination.
74
Recently, a study investigating the interchangeability of
paediatric vaccinations has demonstrated that a primary
vaccination schedule with FSME-Immun Junior can be
successfully completed with Encepur Children for conven-
tional and accelerated schedules, which are described
below.
75
Vaccination schedules
Primary vaccination schedules
There are three available schedules for TBE vaccination:
conventional (vaccinations given on Days 0, 28, and 300),
accelerated conventional (Days 0, 14, and 300), and rapid
(Days 0, 7, and 21) schedules (Table 2). The protection
conferred by conventional (Days 0, 28, and 300) versus
accelerated conventional (Days 0, 14, and 300) schedules was
compared in a trial by Wittermann et al.
75
Superior immu-
nogenicity was achieved with the conventional schedule
(as assessed using a neutralisation test [NT]) compared with
the accelerated conventional schedule.
75
Scho
¨ndorf et al.
also demonstrated improved immunogenicity with the
conventional schedule (second dose at Day 28) compared
with a modified conventional schedule (second dose at Day
21).
76
However, the latter is not licensed in the Summary of
Product Characteristics (SPC).
Scho
¨ndorf et al. completed a large comparative study of
primary vaccination schedules.
76
The study included 398
subjects and compared the rapid, conventional, modified
conventional and accelerated conventional schedules. The
study found that the conventional schedule provided the
highest titres on Day 42, with the rapid schedule able to
provide fast protection when required.
76
However, all
subjects developed adequate neutralizing TBE antibody levels
following the third dose (Day 300), regardless of schedule.
Encepur and FSME-Immun vaccines are both licensed for
a conventional schedule (Day 0, months 1e3, and 9e12 or
Day 0, months 1e3, and 5e12, respectively).
77
For faster
protection, Encepur is also licensed for a rapid schedule
(Days 0, 7, and 21) and both vaccines (Encepur and FSME-
Immun) for an accelerated conventional schedule (Days 0,
14, and months 9e12 or 5e12, respectively).
8,67
It should be noted that not all schedules are licensed in
all countries, and the appropriate local SPC should be
consulted.
Table 2 Tick-borne encephalitis vaccination schedules (according to manufacturer’s information). Reproduced by the kind
permission of Future Drugs Ltd. from Rendi-Wagner P.
8
Vaccination stage Age Vaccination schedules
Conventional Accelerated conventional/rapid
FSME-Immun
and Encepur
FSME-Immun
and Encepur
Encepur
Primary vaccination
(three doses)
1 year
(6 months)
a
0e1 to 3 months and
5e12/9e12 months
0e14 days to
5e12/9e12 months
0e7e21 days rapid
First booster 1 year
(6 months)
a
3 years 3 years 12e18 months
Second booster 49 years
b
5 years 5 years
c
5 years
>49 years
b
3 years 3 years 3 years
a
For high-risk groups only.
b
In Austria: 59 years.
c
In Germany for FSME-Immun
Junior every 3 years.
TBE trends in epidemiology and management 239
Table 3 Vaccination recommendations and coverage rates across Europe.
Country Official government programme
in place?
90
Vaccine recommendations Recommendation for travellers
90
Vaccination coverage rate
Alpine countries
Austria TBE national vaccination programme
introduced in 1981
15
Children over 1 year of age (6 months
of age in high-risk areas and if indicated)
Vaccination board of the Supreme Health
Counsel
82
Recommended for travellers going to
wooded areas, during springeautumn
86% (at least 1 dose) of
population in 2009
81
France No No Recommended for all people travelling
to rural or forested endemic areas in
Central, Eastern and Northern Europe
from spring to autumn
91
<1% [Personal communication
from Veronique Abitbol, 2010]
Germany Official vaccination recommendation
by the German Standing Vaccination
Committee (STIKO)
92
Recommended for people living in, and
travelling to, endemic counties within
Germany and those with occupational risk
92
Recommended for forested areas of
southern Germany
92
24% in 2007,
28
27% of population
in 2009
81
Italy No No MoH does not recommend directly any
prophylaxis for travellers through TBE-
endemic counties, but at the same
time refers to international WHO
recommendations
NA
Slovenia Official vaccination programme Only for occupationally exposed people
15
Vaccination and precautions against
bites advisable if going to forests
12% of population in 2009
81
Switzerland Official vaccination programme
(Swiss Commission for Vaccinations,
EKIF), MoH (BAG)
93
Recommended for all adults and children
(>6 years of age) living in, or travelling to,
endemic regions. Fully reimbursed
vaccination
93
Yes, for Swiss people travelling
internationally to endemic areas
17% in 2007,
28
17% of population
in 2009
81
Baltic states
Estonia Vaccination optional Vaccine available Sometimes recommended 14% up to 2006, 18% of population
in 2009
81
Latvia Official vaccination programme Free vaccinations for children (from 2007) Sometimes recommended 38% of the population in 2008,
39% of population in 2009
81
Lithuania Vaccination optional Vaccine available Vaccination strongly advisable 9% of population in 2009
81
Scandinavia
Denmark Recommended only for persons
with an association with Bornholm
94
Vaccine available, but not recommended
for children under 7 years of age
95
Yes, for people travelling to high-risk
areas in Central Europe and Sweden
96
Unknown
Finland Official vaccination programme Since 2006, Finland has offered free
vaccination for those over 7 years of age
in the A
˚land islands, which has the highest
incidence rate in the country
85
Take precautions against tick bites,
and consider immunization if visiting
A
˚land islands
Unknown
Sweden Vaccination recommended for
high-risk groups
Vaccine available No 12% in 2006/7,
28
11% of population
in 2009
81
Norway Vaccination optional, but not
officially recommended
Vaccine available No NA
240 E. Petri et al.
Booster vaccinations
The World Health Organization (WHO) recommends that
a booster should be given three years after the primary
vaccinations for the conventional schedule.
78
For the rapid
schedule, it is recommended that the first booster should
be given 12e18 months after primary vaccination.
79
Rendi-
Wagner studied 198 subjects 4 years post-booster vaccina-
tion; seroprotection rate was 95.7% for subjects under 50
years of age, 93% for those between 50 and 60 years of age,
and 91.7% for those over 60 years of age,
80
highlighting
successful protection from the booster vaccination after 5
years, but also the age-related differences in protection.
Long-term protection has also been demonstrated for
Encepur Children. In a study of 190 children 5 years after
their first booster of Encepur Children, a long-lasting
immune response was observed in 100% of subjects noted
by TBE antibody titres ([NT 10] and confirmed in 99% by
enzyme-linked immunosorbent assay [ELISA]).
75
The
authors concluded that a second booster could be sched-
uled at 5 years rather than 3 years, without losing
protection.
75
As a result of increasing evidence of pro-
longed immunity from the TBE vaccination, in 2004 the
Austrian Immunization Board altered its booster vaccina-
tion recommendation to every 5 years for those under 60
years of age, but maintained a recommendation of
boosters every 3 years for those over 60 years of age.
79
In coming years it would be helpful to have a harmoniza-
tion of TBE booster recommendations within the EU, as
currently there is regional variation in the vaccination
guidelines. Such harmonization could include administering
the first booster after 3 years, and giving subsequent vacci-
nations every 5 years for people under 50 years of age. For
those over 50 years of age, boosters should continue to be
given every 3 years, following repeated reports of TBE cases
in vaccinated individuals over 50 years of age.
8
Boosters are
only recommended by the WHO if there is continuing risk.
78
Vaccine recommendations
Trends of vaccination coverage in Europe
Vaccination coverage is highly variable among TBE-endemic
countries (Table 3). Austria has the highest vaccination rate
in Europe (86% of the population were vaccinated in 2009
with at least one dose) by virtue of its TBE vaccination
programme.
81
The TBE vaccination programme was intro-
duced in Austria in 1981, and has proven very successful in
reducing TBE incidence.
15
In Austria, vaccination is rec-
ommended for children over 1 year of age and in high-risk
areas from 6 months of age, and is considered to be
mandatory for school-age children. The vaccination pro-
gramme has had good results: before its introduction
(1971e1981), 19% of TBE cases were in children, whereas
between 1990 and 2000, only 2.3% of cases were in children
7e14 years of age.
82
However, the incidence still remains
above average for non-vaccinated adults. Heinz et al.
studied the field effectiveness of the TBE vaccination in
Austria from 2000 to 2006 (defined as cases of TBE infection
with neurological symptoms requiring hospitalization) and
found TBE vaccine effectiveness to be 99%.
50
Those with
irregular vaccination (who did not stick to the recom-
mended vaccination schedule) had a 3- to 8-fold increase in
Other
Czech
Republic
Vaccination optional, for residents
of endemic areas, no direct support
from the state in areas of high
epidemicity
Vaccine available. Recommendation
for children and therefore only partial
support for children and adolescents
No 16% of population in 2007,
28
16% of
population in 2009.
81
Currently
thought to vary from 7% in eastern
Bohemia to 32% in southern
Bohemia. Higher coverage rates in
young adults [Personal written
communication from Professor
Beran, Hradec Kra
´love
´,
Czech Republic]
Hungary For people in high-risk areas and at
occupational risk
Vaccine available Advised for campers and hikers 5% of population in 2008 (most in
low-risk areas)
15
Poland Recommended for high-risk groups Vaccine available Yes Unknown
Spain No No recommendation for locals MoH provides information for
travellers to endemic countries
NA
Russia Official vaccination programme in
TBE-endemic areas
Vaccinations are not funded (as
at 2008)
Sometimes recommended Unknown
UK Recommendation for occupational
health (lab workers) when indicated
97
No recommendation for locals
97
Department of Health recommends
for travellers to endemic countries
being exposed or at high risk
97
NA
MoH, Ministry of Health; TBE, tick-borne encephalitis; WHO, World Health Organization.
TBE trends in epidemiology and management 241
risk of acquiring TBE, highlighting the importance of
compliance to vaccination schedules.
50
Since 2004, Austria
has recommended a booster dose every 3 years for those
over 60 years of age, in contrast with to every 5 years for
those below 60 years of age, following investigations that
have shown the vaccine immune response to be lower in
those above 50 years of age.
83
With the exception of Austria, in other TBE-endemic
countries the vaccination rate is fairly low.
4
Only Austria,
Finland, Germany, Hungary, Latvia, Poland, Russia,
Slovenia, Switzerland, and the United Kingdom have
official government recommendations for TBE vaccination
15
(Table 3). In the remaining 14 European countries, the
option of vaccination is available but not widely reimbursed
by health insurance companies.
15
In Germany, health
insurance companies regularly cover the cost of TBE
vaccines only for those at risk of exposure within Germany.
The German vaccination coverage rate for people who have
received at least three vaccinations is approximately 24% of
the population in high-risk areas (not the whole pop-
ulation).
28
Health insurance companies also cover the cost
of TBE vaccines in Switzerland, for those at risk of expo-
sure. Switzerland implemented new recommendations for
vaccination in 2006 following the increase in TBE morbidity,
which proved successful. In 2005, 76,000 people received
160,000 doses whereas in 2006, 300,000 people received
630,000 doses.
38
In Switzerland, the vaccination rate was
17% in 2007, and remained the same in 2009
28,81
(Table 3).
Tick-borne encephalitis vaccinations are also available
in countries where an official vaccination programme is
absent, but where TBE is endemic. For example, in Estonia
the vaccination rate was 14% from 1997 to 2006, equating to
15,000 vaccinations annually, and increased to 18% in
2009.
81
In this period, Lithuania had a 6% vaccination
coverage rate, equating to approximately 7500 vaccinations
annually, which increased to 9% in 2009.
4,81,84
In Sweden,
the vaccination coverage rate was 12% in both 2006 and
2007, and decreased slightly to 11% in 2009.
4,81
Despite a high rate of TBE incidence in the Czech
Republic, there is no direct support from state institutions
for the vaccination of residents in high-risk areas, and only
partial support for children and adolescents, with reim-
bursement of a single dose of vaccine.
52
In 2007, the
vaccination coverage rate in the Czech Republic was esti-
mated to be 16%, with vaccination coverage varying from
7% in eastern Bohemia to 32% in southern Bohemia
28
(Prof.
Beran, Hradec Kra
´love´, Czech Republic, personal written
communication, 2010).
Since 2006, Finland has offered free vaccination for
those over 7 years of age living in the A
˚land islands, which
has the highest incidence rate in the country
85
(Table 3). In
Hungary and Slovenia, vaccination programmes are only
available for occupationally exposed people; however, the
vaccination rate in Hungary is very low with only 5% of the
population vaccinated, of which most live in low-risk areas,
making TBE a serious problem in rural areas.
15,86
In addi-
tion, a free vaccination programme for children was started
in Latvia in March 2007, although the average vaccination
rate in Latvia is 38%, with 30,000 people completing
a vaccination course each year.
4
In Russia, TBE vaccination
is widely recommended in endemic areas
15
and, depending
on the time of year, vaccination is funded by central or
regional government for children from 3 years of age and
adults, depending on the annual budgets.
The WHO recommends vaccination against TBE in
addition to precautions, such as wearing appropriate
clothing, e.g. long sleeves and trousers.
87
For travellers
from the USA to TBE-endemic areas in Europe, vaccination
is not possible as neither of the two European vaccines are
available in the USA.
7
Active vaccination
Active vaccination is considered to be the best way to
prevent TBE.
7
The rapid vaccination schedule offers a more
convenient option for travellers, and is aimed to improve
compliance; however, advance planning of 2e3 weeks is
still required.
38
Compliance is particularly poor among
travellers, with the first booster often given beyond the
recommended 12e18 month period.
35
Implications for travellers
The World Tourism Organization stated that nearly 900
million international tourist arrivals were recorded in 2007,
52 million more arrivals than 2006, of which Europe
accounted for 480.1 million (53.5%).
88
An unvaccinated
tourist spending 4 weeks in an endemic region of Austria has
a 1 per 10,000 man-months risk of contracting TBE. This is
an equivalent risk to acquiring Plasmodium vivax infection
during a trip to India, for which malaria prophylaxis is
routinely recommended.
7
Austria, Belgium, Estonia,
Finland, Germany, Greece, Latvia, Lithuania, Poland,
Slovakia, Slovenia, Spain, and Switzerland have recom-
mendations regarding TBE vaccinations for people travel-
ling to endemic areas.
15
However, the Centers for Disease
Control and Prevention (CDC) still does not explicitly
recommend TBE vaccination for Austria, nor for many other
countries that have TBE high-risk areas, including the Czech
Republic, Hungary, Latvia, Lithuania, Poland, and Russia,
despite recently published travellers’ TBE cases from these
areas (Table 3).
6
Although the CDC does not explicitly
recommend TBE vaccination, it does list TBE as a potential
risk in all of the above countries.
89
Conclusions
The number of TBE cases continues to increase in many
endemic regions, new foci have been identified in Europe
and evidence suggests expansion of current endemic areas.
The increase in TBE incidence is thought to be based on
a combination of biological and non-biological factors,
resulting in increased contact between humans and infec-
ted ticks as a result of increased travel and outdoor
activity. Lack of awareness of European travellers to the
risk of TBE in endemic areas has resulted in low vaccination
levels, despite the availability of vaccines.
35
Tick-borne encephalitis vaccination is recommended as
a basic vaccination for Europeans being frequently active
outdoors and travelling to areas of TBE risk. Improved aware-
ness among medical professionals, in addition to the general
public, is essential to ensure that travellers at risk are properly
vaccinated, as well as the local population. It is important
for medical professionals to recognize patients presenting
with TBE, in order to identify new TBE risk-areas. The best
242 E. Petri et al.
protection against TBE infection remains to be active,
prophylactic vaccination, and the availability of a rapid
schedule enables easier compliance, especially for travellers.
Acknowledgements
The authors would like to acknowledge Dr Eleanor Lowry of
Alpharmaxim Healthcare Communications for medical
writing support in the preparation of the manuscript.
Conflict of interest
The authors are employees of Novartis Vaccines and Diag-
nostics GmbH, Marburg, Germany.
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