Management

of Tick-borne Encephalitis
compendium of scientific literature

A service of
Vaccines

Content
1. Introduction
2. Etiology

....................................................... 5

................................................................ 7

2.1. The TBE virus ..................................................... 7

2.2. Virus transmission .............................................. 8
2.2.1. Transmission through ticks
2.2.2. Other routes of transmission
2.3. TBE natural foci .................................................. 9
2.4. The vector (Ixodes ricinus) ................................ 10
2.4.1. Developmental cycle
2.4.2. Seasonal tick activity
2.4.3. Mechanism of transmission
2.4.4. Mixed infection of ticks
2.5. Hosts ............................................................... 13
2.6. The biotope ...................................................... 15

3. Epidemiology

................................................... 17

3.1. The distribution of TBE natural foci

(TBEV in ticks and vertebrate hosts) .................. 17
3.2. TBE incidence in man ....................................... 19
3.2.1. Seroprevalence
3.2.2. TBE incidence in different age groups
3.2.3. Seasonal variations of TBE incidence
3.2.4. Risk of contracting TBE
3.2.5. Annual TBE morbidity
3.2.6. Mortality
3.2.7. Reported cases of TBE
3.2.8. Map: TBE in Europe

4 Clinical Description

..................................... 33

4.1. Clinical course and manifestations .................... 33

4.1.1. Stages of the disease
4.1.2. Pathogenesis
4.1.3. Immune response
4.2. Laboratory findings .......................................... 39
4.3. Prognosis ......................................................... 40
4.4. Pediatric clinical description .............................. 40
4.5. Mixed Infections .............................................. 41
4.6. Incidence and severity of TBE
in relation to other CNS viral diseases ............... 41

5. Therapy

.............................................................. 42

6. Diagnosis

.......................................................... 43

6.1. Laboratory diagnosis ........................................ 43

6.2. Differential diagnosis ........................................ 44

7. Prevention

........................................................ 46

7.1. General preventive measures ........................... 46

7.1.1. Control of tick populations
7.1.2. Protective clothing, repellents
7.1.3. Post-exposure prophylaxis
7.2. The Baxter TBE vaccine FSME-IMMUN ............ 47
7.2.1. FSME-IMMUN the vaccines
7.2.2. Immunization schedule
7.2.3. Route of administration
7.2.4. Contraindications and special
precautions for use
7.2.5. Immunogenicity
7.2.6. Clinical effectiveness
7.2.7. Safety
List of abbrevations .......................................................... 56
References ........................................................................ 57

introduction

Introduction
Even though TBE has already been described in 1931,

this dangerous form of encephalitis has been underestimated for a long time.
( C . K u n z , M D, c o - i n v e n t o r o f t h e f i r s t We s t e r n - E u r o p e a n T B E v a c c i n e , V i e n n a )

In several European countries, tick-borne

increasing mobility of people travelling to risk

Encephalitis (TBE) is one of the most impor-

areas. Today the risk of infection is especially

tant human infections of the central nervous

high for all people who pursue leisure activities

system. The disease agent, i.e. the TBE virus

in nature in endemic areas.

(TBEV), is transmitted via tick bites. The virus

persists in so-called natural foci, where it

TBE virus is rarely found in Bulgaria, Greece,

circulates among vertebrate hosts (mainly

Italy, Norway, Romania and Japan. Only spora-

rodents) and the arthropod host (tick).The

dic cases have been reported so far. In several

disease occurs in Western and Central Europe,

European countries no TBE cases have been

Scandinavia, countries that made up the

found as yet; among these are Great Britain,

former Soviet Union, and Asia, corresponding

Ireland, Iceland, Belgium, the Netherlands,

to the distribution of the ixodid tick reservoir.

Luxemburg, Spain, and Portugal.

Most natural foci are well described, but new

TBE areas could emerge or re-emerge. At least

Clinical symptoms: The typical clinical

10,000 cases of TBE are referred to hospitals

picture of TBE is characterized by a biphasic

each year. TBE has also become an interna-

course with non-specific influenza-like symp-

tional public health problem because of the

toms, followed by an asymptomatic interval

TBE virus is common in endemic foci in

Albania

Finland (SW Coast)

Russia

Austria

France

Serbia

Belarus

Germany

Slovenia

Croatia

Hungary

Slovakia

Czech Republic

Latvia

Sweden

Denmark (Bornholm Island)

Lithuania

Switzerland, Liechtenstein

Estonia

Poland

Ukraine

introduction

and a second stage of the disease with at least

Prevention: TBE is very easily prevented

four clinical manifestations of different seve-

by vaccination. The Austrian experience gives

rity: meningitis, meningoencephalitis, menin-

clear evidence that high vaccination coverage

goencephalomyelitis, meningoradiculoneuritis.

reduces national incidence of TBE effectively.

Patients may experience just one of the phases. Hospitalization varies between days and

Lyme borreliosis is another tick-borne disease

months. Up to 46 % of patients are left with

of similar epidemiologic dimensions in Central

permanent sequelae and need many years

Europe. It is caused by spirochetes and can be

of treatment and rehabilitation measures.

managed by the administration of antibiotics,

1)

whereas no effective therapy exists against

Diagnosis: TBE can only be diagnosed

TBE. This brochure will mainly deal with TBE.

accurately by means of laboratory techniques,

as the clinical symptoms are not specific for

The clinical picture of TBE was first described

the disease. The virus can be isolated from

in Austria in 1931 by H. Schneider.2) Shortly

the blood during the first phase of the disea-

afterwards, it was observed in the Far-East

se (PCR). Specific diagnosis usually depends

of the former USSR, and from 1939 onwards

on detection of specific IgM and IgG serum

also in its European part. In 1948, the virus

antibodies by ELISA.

was isolated for the first time outside the

former USSR.3) In subsequent years, TBE was

Case definition: A confirmed case of TBE

identified in other European countries. Syno-

is defined as a febrile patient with clinical

nyms for TBE are spring-summer meningo-

signs/symptoms of meningitis or meningoen-

encephalitis, Central European encephalitis,

cephalitis, mild to moderate elevation of cell

Far-East Russian encephalitis, Taiga encepha-

counts in CSF, and the presence of serum

litis, or Russian spring-summer encephalitis,

IgM and/or IgG antibodies against TBE virus.

biundulating meningoencephalitis, diphasic

milk fever, Kumlinge disease, Schneiders

Therapy: No causal therapy for TBE is

disease. The name tick-borne encephalitis

known so far.

refers to the tick, its main vector.

etiology

Etiology
The different subtypes of TBE virus in Europe and Asia are
antigenically very similar a prerequisite for the prevention of TBE
w i t h a s i n g l e v a c c i n e s t r a i n . ( F. X . H e i n z , P H D , V i e n n a )

2.1.

TBE virus

different structural proteins, i.e. the proteins

C (capsid), M (membrane) and E (envelope) 5, 6)

TBE virus (TBEV), like yellow fever, Japanese

(Figure 2). The protein C is the only protein

encephalitis, and dengue virus, is a member

component of the capsid, which encloses a

of the genus flavivirus belonging to the family

positive-stranded RNA approximately 11,000

Flaviviridae. Due to the specific route of

nucleotides in length.7) This RNA codes for

transmission by infected ticks (e. g., TBE virus,

the three structural proteins, as well as a set

Louping ill virus) or mosquitoes (e. g., yellow

of 7 non-structural proteins required for virus

fever virus, dengue viruses and Japanese

replication in the cell.5)

4)

encephalitis virus) many flaviviruses are socalled arboviruses (= arthropod-borne viruses).

The proteins E and M are incorporated in the

viral membrane. Glycoprotein E, the main

Flaviviruses are spherical, lipid-enveloped

component of the viral surface (Figure 2), is

RNA viruses with a diameter of approximately

responsible for the formation of neutralising

50 nm (Figure 1), which consist of only three

antibodies and the induction of protective

E
M

C
Figure 2: Schematic representation
of TBE virus (F.X. Heinz)
Figure 1: Electron micrograph of TBE virus

etiology

strain.10) Both subtypes of TBEV, the Western

and the Far-Eastern are transmitted mainly
by Ixodes ricinus and I. persulcatus. A third
subtype, the Siberian, has also been described. The high incidence of TBE in Western
Siberia is attributed to the active circulation of
these Siberian TBEV variants which showed
approximately 78% to 81% homology in proFigure 3: Diagram showing the three-dimensional structure of the protein E,
laterial view. (Courtesy of Nature)

immunity. By isolating a soluble, crystallizable

tein E genes with the Far-Eastern TBEV subtype.12) All subtypes are closely related both
antigenically and phylogenetically.

form of the TBE virus protein E, it was pos8)

sible to elucidate its three-dimensional structure using X-ray diffraction analysis.

2.2.

Virus transmission

9)

2.2.1. Transmission through ticks

Structural analysis (Figure 3) has shown that
protein E, unlike other lipid-enveloped viruses,

Ticks are the chief carriers (vectors) and reser-

does not form spike-like projections, but is

voir hosts of TBE virus in nature. The lack of

aligned parallel to the viral surface (Figure 2).

digestive enzymes in the tick gut favours the

survival of ingested microorganisms and may

Antigen analyses using monoclonal antibo-

explain why ticks transmit a greater variety

dies and comparisons of sequences of vari-

of pathogens than any other group of arthro-

ous virus isolates have shown that the TBE

pods.13) Their ability to feed on the blood of a

virus is quite homogeneous in all European

variety of host animals and to adapt to domes-

endemic areas (European subtype) and is not

tic animal species, as well as their long life

subjected to significant antigen variations

cycle make them ideal vectors for a variety of

under natural environmental conditions.

pathogens (rickettsiae, spirochetes, other bac-

10, 11)

teria, fungi, protozoans, nematodes, viruses),

TBE viruses isolated in the Asian part of Russia,

among them the TBE virus.

and in China (Far-Eastern subtype) are closely

related to the European subtype, having a

The TBE virus can be transmitted to man or

96 % identity in E-protein amino acid sequen-

other hosts by larvae, nymphs, or adult ticks

ces with the European Neudrfl prototype

(Figure 4).

Figure 4: Ixodes ricinus larva, nymph fasting and replete,

male replete and fasting, female fasting and replete. (A. Liebisch)

etiology

2.2.2. Other routes of transmission

Infection by the alimentary route as a result of

Factors governing the

formation of TBE foci

the ingestion of raw milk is also possible and

has been reported from Slovakia, Poland, and
other eastern countries. Recently the family
outbreaks of TBE in Lithuania have reappeared.
It is reported that in 2000 4 % of TBE patients
became infected via unboiled milk.14) Also, in
Slovakia, goats and sheep play an important

Population density and dynamics

of infected ticks and their hosts
Susceptibility of individual hosts
Proportion of immune hosts
Properties of the biotope
Temperature
Sociological changes 20)

role in alimentary TBE infections. Since 1974,

15)

more than 50 cases of TBE occurred in Slova-

Table 1

kia after the patients had eaten cheese made

from raw sheeps milk or drunk home produced

lopment of a TBE natural focus also depends

raw goat or sheep milk.

on the coincidence of other factors (Table 1).

Laboratory infections have likewise been

The circulation of TBE virus is also dependent

reported. Although it has not been obser-

on a certain population density of ticks and

ved, man-to-man transmission is a theoretical

their hosts. Virus prevalence in the tick popu-

possibility, e.g., when blood from a viremic

lation within TBE foci is determined by the

patient is transfused to a healthy person.

duration of viremia in hosts, because the virus

15)

16)

17)

is mostly ingested by ticks while engorging

2.3.

TBE natural foci

on a viremic host. Virus circulation in nature is

also influenced by the percentage of immune

A natural focus, as defined by Pawlowsky, is

hosts in a certain region.

a region of distinct geographic features and

ecological settings where by way of evolution

The properties of the biotope also play a role

a certain interrelationship between the species

in the development of TBE foci. In Austria,

has developed, i.e. by the pathogen (micro-

more than 90 % of all natural foci are within

organism) on the one hand and its carrier

the 7 C annual isotherm. Rare isolated natural

(vector) on the other. The latter transmits the

foci have been observed up to a height of

pathogen from a vertebrate host, acting as

1,300 meters above sea level.21)

the donor of infection, to another recipient

host under environmental conditions that are

The climate is one of the above mentioned

either conducive or adverse to further circu-

factors (Table 1), which influence tick-borne

lation of the agent in such biozoonoses.

disease dynamics. Even if the major discon-

18)

tinuities in the TBE incidence cannot be

The continental distribution of TBE in Europe is

explained satisfactorily by the recorded tem-

statistically associated with a specific pattern

perature increases, nevertheless a seasonal

of the seasonal dynamics of Ixodes ricinus,

shift in reported cases of TBE in Central and

and a particular characteristic of the seasonal

Northeast Europe suggest that TBE virus

land surface temperature profile. The deve-

transmission dynamics have changed some-

19)

etiology

what perhaps as a result of warmer tempe-

responsible for the spread of TBE virus (Wes-

ratures. Although the dependence of TBE on

tern subtype) in Europe. The Far-Eastern sub-

temperature is not a direct one and various

type of TBE virus is found mainly beyond the

factors could be involved, an impact of climate

Ural mountains;17) its vector is primarily Ixodes

warming on the vertical disease distribution in

persulcatus (Figure 10).

20)

Central Europe is evident.

22)

The scientific name Ixodes ricinus is derived

Apart from the temperature, tick activity is

from the replete ticks close resemblance to

dependent on soil humidity and relative humi-

a ricinus seed or castor bean. A fasting adult

dity. The critical water equilibrium for Ixodes

female is 34 mm in size, while male ticks

ricinus is at 92 % relative humidity. Without

are about 2.5 mm long.24) The body, which is

blood feeding, individual ticks can survive at

variously covered with hairs as well as warts

a higher relative humidity for several months,

and rings, is vastly extensible in the female

but they soon perish at levels below 92 %

and often takes on a light grey colour after

relative humidity.

blood feeding. The female can take in up to

23)

100200 times its own body weight in blood,

thus increasing its volume approximately
120 fold.25)
lxodes ricinus is equipped with piercing and
sucking mouthparts (chelicerae and hypopharynx) 26) (Figure 5). The saliva of blood-feeding
ticks contains numerous bioactive components with a broad spectrum of pharmacologic properties, among them anti-coagulants,
enzymes and inhibitors, local anesthetics and
anti-inflammatory compounds, toxins and
other secretions such as cement for anchoring
the mouth-parts in the hosts skin.27)
By use of sense organs the tick can react to
Figure 5: The mouthpart of Ixodes ricinus

thermic, chemical, and physical stimuli such

as vibrations or changes in temperature cau-

2.4.

The vector (Ixodes ricinus)

sed by a passing host. Probably also the CO2

and butyric acid discharged by the host play

Throughout the world 850 tick species have

a role in this process.28)

been described. Eight members of the family

of hard ticks have become notorious as car-

2.4.1. Developmental cycle

riers of disease agents in our climate. Ixodes

10

ricinus, the common castor-bean tick, is the

The common castor-bean tick (Ixodes ricinus)

most important and most common tick spe-

spends most of its life free-living on the ground

cies in Europe (Figure 4) and, thus, mainly

or among vegetation.

etiology

The ticks are characterized by a comparatively

roe deer

long life cycle, lasting several years, during

which the infecting virus may be maintained

moulting

replete female

from one developmental stage of the tick to

the next. Hence ticks act as highly efficient

eggs

nymph
imago

reservoirs of flaviviruses. Many tick-borne flaviviruses are transmitted vertically, from adult to

fox

offspring, although the frequency is too low to

maintain the viruses solely in the tick population. Instead, the survival of tick-borne flaviviru-

larva
mouse

ses is dependent on horizontal transmission,

moulting

both from an infected tick to a susceptible vertebrate host and from an infected vertebrate

hedgehog

nymph
nymph larva

mouse

to uninfected ticks feeding on the animal.29)

Figure 6: Developmental cycle of Ixodes ricinus

Copulation usually takes place on a host prior

to blood feeding. Following copulation, the

The average time in Central Europe is thought

female spends six to eleven days feeding on

to be two years (Figure 6), although in adverse

blood and during subsequent months deposits

environmental conditions each stage of deve-

500 to 5,000 eggs (Figure 7) in several oviposi-

lopment may take longer.

tions in the loose top layer of the soil. Seve30)

ral weeks later, larvae measuring 0.61.0 mm

2.4.2. Seasonal tick activity

hatch from the eggs. Unlike the subsequent

developmental stages (nymph and imago) lar-

All developmental stages of Ixodes ricinus

vae only have three pairs of legs, no stigmata,

hibernate under leaf litter in places where the

and no sexual openings.

temperature may be as low as 0 C (or, for

30)

short periods, even lower) and relative humidiIn each stage of development (larva, nymph,

ty amounts to at least 92%. Eggs and starved

and imago) ticks have to feed at least once

larvae perish at temperatures below 7 C. 34)

on a vertebrate host before they can develop

into the next stage. Male ticks do not feed on

Tick activity starts when the soil temperature

blood, but take only a small amount of tissue

rises to 57 C in March or April and ends late

fluid during a short feed. Larvae feed on

in the year 35) when the average air tempera-

a host for two to five days before they drop

ture has declined to about the same value in

off and moult into nymphs. These feed on a

October or November.

31)

vertebrate host again for two to seven days

and metamorphose into adults (imagoes).

The seasonal peaks of tick activity depend on

climatic factors. In Central Europe, a two-peak

The duration of the developmental cycle of

incidence curve has been observed for all

one tick generation from egg to oviposition by

developmental stages 36) with maximum acti-

a fertilized female, varies according to the lite-

vities in May/June and September/October

rature between six months and eight years.

(Figure 8). In Northern Europe, and mountain

32, 33)

11

etiology

Figure 7:
Some time after copulation the female, having
expanded to 200 times
of its former volume,
deposits up to 5,000 eggs
before dying. The second
picture shows a larva
crawling on eggs.

regions, these two peaks converge into a sin-

The activity of the larvae of Ixodes ricinus usu-

gle maximum in the summer months. ln the

ally starts one month later than that of nymphs

Mediterranean areas, maximum tick activity

and adults.38)

occurs between November and January.23)

2.4.3. Mechanism of transmission
Wet summers and mild winters tend to increase the tick population density. Warmer

Trans-stadial transmission (from one stage of

springs (March-May) might permit an earlier

development to the next) as well as trans ova-

onset of questing activity, while raised tempe-

rian transmission (from fertilized female to its

ratures throughout the spring-autumn period

egg) of TBE virus in Ixodes ricinus is possible

(March-September) would accelerate inter-

(Figure 9). Usually larvae and nymphs become

stadial development.

infected by feeding on viremic hosts and pass

20)

on the virus as nymphs or imagoes to other

Female ticks feeding in spring start to deposit

warm-blooded vertebrates; ticks themselves

eggs in early July. The larvae hatch in the

do not develop the disease.

same year, but mostly find their host in the

following spring. Larvae and nymphs feeding

The virus hibernates in ticks. Once a tick is

in spring or early summer undergo metamor-

infected, it carries the virus for life. In the

phosis and, in the same year, appear as the

period that precedes moulting, the virus mul-

next stage of development.

tiplies in the tick and invades nearly all its

organs.39)
Female ticks usually transmit the virus to a sing-

Number of ticks

1000

le host only. Male ticks feed more often and,

Larvae
Nymphs
Adults

800

in this way, may infect several vertebrates.40)

600
After attachment to the host, twelve hours may

400

pass until the tick starts feeding. On humans,

200
0

ticks prefer to attach themselves to the hairApril

Ma

Jun

July

Aug. Sept. Oct.

Figure 8: Seasonal dynamics of Ixodes ricinus in a TBE natural focus

12

Nov.
37)

covered portion of the head, behind the ears,

to the elbows and backs of knees, hands and
feet. Owing to the anesthetizing effect of the

etiology

ticks saliva, which contains analgesic, anti-

duals were multi-infected. Among these more

inflammatory and coagulation-inhibiting sub-

than 80 % were dually infected and 13 % con-

stances, the procedure causes no pain and

tained three species of pathogens simulta-

often passes unnoticed by the host.

neously. The prevalence of mixed infection

30)

by Borrelia and TBE virus in adult ticks varies

TBE virus is transferred to the host with the

depending on tick species and natural focus,

saliva of an infected tick; at the same time TBE

reaching 510% in some places.44) The presen-

virus contained in host tissue enters the ticks

ce of Borrelia in ticks has no apparent effect

intestine with blood feeding. A tick doesnt

on TBE virus, and vice versa, showing that

need to feed for a longer period of time to pass

these pathogens do not interfere with each

on the infection. A short feeding of tissue fluid

other within the tick.44)

by a male tick may suffice to transmit the

virus.41) The fact that tick bites are often not

2.5.

Hosts

even noticed may be the main reason why

persons with manifest TBE frequently cannot

The common castor-bean tick acts as a para-

remember having been bitten by a tick.

site on more than 100 different species of

mammals, reptiles, and birds. Table 2 gives a
selection of the most important hosts.

Imago
Infection of Ixodes ricinus with TBE virus by

Man

Nymph

Mammals
Reptiles
Birds

a host harbouring the virus is only possible

Eggs

during the viremic stage in the host, provided

the TBE virus titer in its blood is high enough
to infect the blood-feeding vector.

Raw milk (from cow,

sheep, goats)

Larva
For most hosts, TBE virus is apathogenic, i.e.

Figure 9: TBE Transmission cycle in a natural focus

showing man as a dead-end host

they hardly ever develop the disease.

An infected host develops specific antibodies

2.4.4. Mixed infection of ticks

to the TBE virus and then remains immune to

re-infection for life. Under these aspects, TBE

The spread of mixed infections with natural

virus circulation in nature would soon come to

focality transmitted by ixodid ticks is a well

an end; thus, virus persistence in a natural fo-

recognized phenomenon. Ixodes ricinus ticks

cus is dependent on the following conditions:

42)

coinfected by Borrelia burgdorferi, Babesia

microti, and Ehrlichia phagocytophila are common. Different combinations of pathogens,
which simultaneously infect the same Ixodes
tick, have been described mainly involving

a population of hosts with a sufficient

duration of viremia and a high virus titer,
a sufficient number of young animals
susceptible to infection,

TBE virus + Borrelia spp. and TBE virus +

different species of hosts,

Coxiella burnetii. A Russian survey found

large vertebrate hosts serving as feeding

43)

more than one-third of all infected tick indivi-

targets for numerous ticks.

13

etiology

Vertebrate hosts of Ixodes ricinus which may transmit the virus

Wild animals

Ticks can become airborne: they bite birds and bats.

Many ground-dwelling animals attract ticks: various species of mice and lizards.

Hosts below and above ground could be: mole, weasel, marten, badger, porcupine, squirrel.

Predators and prey alike attract ticks: insectivores like hedgehog or shrew, but also fox and hare.

Ticks also feed on larger mammals: wild boar, mouflon, roe deer and red deer.

Table 2a

14

etiology

Duration of viremia: A long viremic stage

virus. However, they often serve as hosts for

(two to eight days) along with a high virus titer

the immature stages of Ixodes ricinus and may

is likely to be observed in small mammals,

contribute to the spread of infected ticks.46)

such as the yellow-necked field mouse, the

red-backed vole, the common vole, the hazel

As a source of sustenance and infection man

mouse etc. Therefore, ticks are most likely

is only of tangential importance for ticks. He

to become infected by feeding on these hosts,

is a dead-end host in the chain of virus trans-

in which TBE virus can hibernate.

mission.

In large mammals (roe, goat) viraemia is short-

2.6.

39)

The biotope

lived and only low virus titers are reached.

However, recent findings suggest that, with

TBE focal areas normally exist in biotopes

several ticks feeding on large mammals, a

where Ixodes ricinus and its hosts find optimal

non-viremic transmission of the virus to ticks

living conditions. Infected ticks are frequently

may also play a role in the virus cycle.

found on forest fringes with adjacent grass-

During the viremic stage, milk from goats,

land, glades, riverside meadows and marsh-

cows, and sheep contains the virus and may

lands, forest plantations with brushwood and

be a source of infection for man.

shrubbery, on the transition between decidu-

45)

ous and coniferous forests or between timber

Birds only pass through a very short viremic

and coppic. Oak/hornbeam, as well as beech/

stage and play no role as reservoirs of TBE

fir woods with a rich undergrowth of weeds,

Vertebrate hosts of Ixodes ricinus which may transmit the virus

Domestic animals

Ticks suck blood from domestic animals: dog, horse, sheep, goat, cattle. And of course: humans.

Table 2b

15

etiology

Figure 10: Typical TBE biotope

ferns, elder, hazel, and bramble bushes, provi-

Contrary to a widespread belief, ticks do not sit

de an ideal habitat for ticks (Figure 10). Sites

on trees and jump down onto their hosts, but

of infestation are frequently situated on sunny

rather prefer vegetation that is closer to ground

slopes facing south and having a low plant

level. Larvae are usually found on grasses up to

cover of shrubs and hedges.

a level of 30 cm, nymphs on herbs and plants

47)

of less than 1 m, and imagoes on weeds or

Such rural landscapes, especially when ben-

shrubs up to 1.5 m high.39)

ches, cross-country tracks or barbecue pits

are provided, attract many people so that an

Keeping to the underside of foliage, ticks

increased risk of infection must be expected.

mostly sit at the ends of leaves or branches

It has been shown in various studies that TBE

next to footpaths and the trails of wild

natural foci are usually not eliminated by cul-

animals, from where they drop off onto their

tivation of the landscape. There is exposure

hosts or are brushed off by them.

48)

to ticks also in newly created gardens or ticks

are transported to homes by way of dogs,

In adult humans, ticks tend to attach them-

flowers, branches, or on clothing. Reducing

selves to the legs as well as the gluteal and

the habitats of small mammals to a few areas

genital regions. In children, 75 % of tick bites

not suitable for cultivation leads to an even

are observed on the head, in the remaining

increased circulation of TBE virus, because

cases legs and arms, trunk, gluteal and genital

the probability of virus transmission rises with

regions are affected.

26)

the population density of the hosts.

16

epidemiology

Epidemiology
TBE is endemic in regions of 26 European countries
a n d e v e r y y e a r w e d e t e c t n e w r i s k a r e a s . ( J. S s s , P H D, J e n a )

Knowledge about the distribution, persistence

mined by the factors listed in Table 1. The

and intensity of tick-borne diseases enables

number of infected ticks in known natural foci

us to characterize and predict transmission

may vary from year to year.

foci, and to recommend preventive measures.

To investigate the epidemiological situation

Widely differing figures are also given for TBE

of TBE several methods can be employed.

virus prevalence in the tick populations in

endemic areas of various European countries

Examination of ticks for TBEV presence

(by PCR)

(Table 3). Usually, questing ticks are collected

by flagging in special tick monitoring sites, and

Serological screening of tick-exposed persons

TBEV prevalence is investigated by examining

Describing of clinical cases and their geo-

individual ticks or by pooling ticks. When in-

graphical localisation

3.1.

vestigations are carried out on ticks removed

The distribution of TBE natural foci

(TBEV in ticks and vertebrate hosts)

The distribution of the TBE virus covers almost

TBE virus prevalence in the

tick population of endemic areas
in several European countries

the entire southern part of the nontropical

Country

Prevalence %

Source

Austria

>0.44 (max. 6.2)

54

eastern regions of China in the east (Figure 11).

Finland

0.072.56

55

The true extent of TBE infections has only

Italy

0.05

56

been revealed during the past few years. Little

Sweden

0.11

57

is known about the rate of infection in China.

Switzerland

0.101.36

46

Recently an isolated endemic area was identi-

Germany (high risk areas)

0,35.3

52

1.726.6 (I. ricinus)

037 (I. persulcatus)

51, 52

13.7

15

Eurasian forest belt, from Alsace-Lorraine in

the west to Vladivostok and the northern and

fied in Hokkaido/Japan.49)
Latvia
The development of new natural foci and the
stability of known endemic areas are deter-

Slovakia
Table 3

17

epidemiology

Western subtype

both subtype

Eastern subtype

Figure 11: Distribution map of Western and Eastern subtype of TBE virus 50)

from humans, the TBEV prevalence could be

As ticks are usually infected for life, it follows

up to ten times higher. The techniques of

that the degree of virus prevalence increases

investigating the TBEV prevalence in unfed

during their development from the egg to the

versus partially engorged ticks are not stan-

adult arthropod. Compared with nymphs,

dardised. Therefore, the prevalence values

three to five times more adult ticks are infec-

cant be compared across Europe.

ted with TBE virus.33)

51)

52, 53)

TBE virus prevalence is much higher in these

TBE virus or antibody prevalence among

vertebrate hosts in TBE endemic areas
Hosts

Prevalence

Source

Yellow-necked field mouse

47,9%

54

Red-backed vole

29,4%

54

Fox

18,0%

30

Deer

83,0%

58

Dog

2,05,6%

59

Goat

44%

56

Cattle

35,591,0%

60, 61

Table 4

18

hosts than in the tick populations (Table 4). On

account of their longer life span, large mammals can be repeatedly infested by infectious
ticks, and due to their size they often serve
as feeding targets for several ticks at a time,
either factor being conducive to the transmission of TBE virus.
The risk of contracting TBE in the most affected countries increased considerably between
1974 and 2003. In Lithuania, where incidence
increased by 1,033 %, and in Germany (with

epidemiology

an increase of 574 %), TBE came to be a serious problem. In addition to the already known

1100

risk areas, new risk areas formed in Norway,

1000

and possibly in the southern part of Sweden.

Lithuania

900

where national campaigns leading to consistent immunization reduced the number of new
infections from 600 to about 60.
The noted changes in the frequency of hospi-

TBE increase (%)

The only exception to this trend is Austria,

800

Finland

700

Poland

600

Germany
Estonia

500

talization are based on a multitude of factors.

400

Evidently, there are various parallel factors

300

working alongside, making interpretation of

Average
Sweden
Switzerland
Latvia
Czech Republic
Slovakia

200

strongly differing annual hospitalization and/or

100

virus prevalence patterns difficult. A possible

19741983 19841993 19942003

warming of the climate is discussed as one

of the reasons for an increased prevalence of

Figure 12: Increase (%) of the TBE incidence in Europe 83)

ticks. Table 5 contains ascertained influencing

factors.
3.2.

Some factors augmenting

the incidence, prevalence
and distribution of
vector-borne disease
1. The human population is increasing

TBE incidence in man

3.2.1. Seroprevalence
Data on TBE seroprevalence in the general
population and among the inhabitants of endemic areas are presented in Table 6a and 6b.

2. Increased population density (urbanization)

In endemic areas of Austria and Southern

3. Migration of populations to suburban areas

Germany, TBE prevalence has been found to

4. Changing of leisure habits

3.+ 4.: Greater exposure to vectors (ticks !)
Greater exposure to animal reservoirs
of infections

be 48 %. Only in the most severely affected

5. Displacement of human populations

(conflicts); (introduction of exotic diseases)

former USSR and former Czechoslovakia.

6. Changes in agricultural practices

A much higher percentage of TBE positive

7. Increased reforestation
increased density of deer population
increased deer tick population
increased incidence of Lyme disease
and Babesiosis
Table 5

83)

areas in the east and southeast of Austria

figures of up to 14 % may be reached. Prevalence is extremely high in some areas of the

individuals has been observed among risk

groups such as :
Individuals working in agriculture and forestry
Hikers, ramblers, people engaged in outdoor
sports
Collectors of mushrooms and berries.

19

epidemiology

Table 6b surveys the situation of risk groups

At present, mainly people who come to TBE

in areas endemic for TBE in some European

endemic areas in pursuit of their recreational

countries. These figures mainly refer to indi-

activities develop the disease. Recent increa-

viduals occupied in forestry. This risk group

ses of TBE cases in Central Europe and the

was most affected by outbreaks of the Eastern

Baltic states may have arisen largely from

subtype of TBE or Taiga encephalitis in Siberia

changes in human behavior that have brought

and, in Western Europe, also incurs the grea-

more people into contact with infected ticks.67)

test risk of infection.

On account of environmental concerns, the

rigorous treatment of TBE natural focus terri-

During the past two decades, however, the

tory in Russia was discontinued in the 1980s.

number of infections has substantially decli-

That may partly explain the increase of the

ned, particularly among individuals engaged

tick population and rate of infective ticks in

in agriculture and forestry who have partici-

this region.68)

pated in the vaccination programs.

Infection with TBE virus may happen at home,
when infected ticks are inadvertently carried

TBE virus or antibody prevalence

in the population
Country

Population in endemic areas (%)

in with bunches of wild flowers, Christmas

trees,28) clothes, or by dogs. Moreover, TBE
virus infections are more and more frequently
reported to have occurred in the patients own

Austria 50, 54)

48 (14)

Slovenia 88)

413

Finland 102)

0.35

3.2.2. TBE incidence

Poland

26, 63)

517

in different age groups

Norway (south) 99)

2.4

gardens, even in urban areas.

Sweden 57)

422

Every country reported TBE cases in child-

France

12

ren, the lowest incidence was found in small

Estonia 26)

314

children less than three years of age. With

Germany (Baden-Wrttemberg) 62)

043

26)

Lithuania 64)

increasing age, children showed higher incidences. The highest rate reported in children
was in the Khabarovsk region in Russia, where

Table 6a

26 % of TBE cases were in children aged

014 years.69) In Slovenia, children represented 23.5 % of all confirmed TBE cases in the

TBE virus or antibody prevalence of risk

groups in TBE endemic areas 46, 65, 66)
Country

Prevalence (%)

Austria

41

Switzerland

416

Czech Republic

1554

Table 6b

20

period of 1959 to 2000.70) In Austria, the 7- to

14-year-olds formerly were the age group with
the greatest annual incidence of TBE (19 %
of all cases). At present, however, due to the
Austrian vaccination program, and in particular
the vaccination campaign in schools, children
between 7 and 14 years are among the best
protected age groups (Figure 13). In Austria,

epidemiology

19711981 (n = 2378)

500

19902000 (n = 1056)

Number of cases

400

300

200

100

0
06

714

1520

2130

3140
4150
Age group

5160

6170

>71

Figure 13: Austria a comparison of the TBE cases before and after the start of the national school vaccination campaigns.

most cases of TBE now occur in older age

(Figure 14). In some countries including Poland,

groups. In Sweden about 10 % of the pati-

Baden-Wuerttemberg (Germany), Sweden, the

ents are younger than 15 years.

Czech Republic and recently also in Austria

71)

72)

just one peak of TBE incidence (July/August)

The youngest patient known thus far was

has been observed.76, 77)

three months old; the oldest patient was 83

and died showing signs and symptoms of
meningoencephalitis.

73, 74)

3.2.4. Risk of contracting TBE

As for TBE prevalen-

ce in the different age brackets, an increase

Exact calculations of the risk of infection and

with advancing age has been observed in TBE

the resulting morbidity rate are extremely

focal areas, although the prevalence in diffe-

difficult, as tick bites are often not noticed.

rent endemic areas may vary.

75)

Virus transmission may be estimated to occur

3.2.3. Seasonal variations

in one of about 3200 tick bites in areas ende-

of TBE incidence

mic for TBE, depending on the prevalence of

TBE virus in ticks (Table 3).

In many countries, two peaks of seasonal tick

activity in spring and fall are observed. The
incidence of clinical cases of TBE lags about
four weeks behind the seasonal tick activity

Figure 13a: Larvae and nymph are much

smaller than the adult female. Humans rarely
ever notice nymphs, but they are more
frequent than adult ticks.

21

epidemiology

TBE in several European countries. It is evident

2200

that, in the past, morbidity among forestry

workers in Austria was much greater than in

1800
8
6

Tick
activity

1400

TBE

1000
4

Number of ticks

10

4 weeks

4 weeks

Cases of clinical illness

Table 7 gives data on the annual morbidity of

2600

the population in general. Since regular vaccination campaigns have been organized by the
vocational organizations concerned, morbidity
of TBE in the most exposed groups has been

600

impressively reduced (see also 3.2.1.). Before

200

the annual vaccination campaign was introdu-

200

ced in 1981, the incidence of TBE in Austria

III

IV

VI

VII VIII

IX

XI

was in the range of 600 cases per year. As a

result of the vaccination campaign with the

Figure 14: Relationship between tick activity and incidence of CNS disease
in a TBE endemic area in Austria.78, 79)

Austrian TBE vaccine, the incidence has been

significantly declining and about 50 to 60 cases

In the different endemic areas of TBE, the risk

for infection of humans after a single tick bite
varies between 1: 200 and 1: 1000.26)
According to estimations by Roggendorf et al.,
the risk of infection in German endemic areas
is 1: 900.80) In a study of endemic areas in
Sweden, the annual incidence (new infections
within the studied population) was found to be
1.2 to 2.4 %, the risk of infection following a
tick bite was estimated to be about 1: 600.57)
3.2.5. Annual TBE morbidity
In the years 1997 to 2000, the average TBE
incidence in Germany with 82.2 million inhabitants and 533 clinical cases was 0.17 / 100,000
per year. In the German high-risk foci, the average incidence rates were 0.29 in Bavaria and
0.87 in Baden-Wuerttemberg. In Latvia, with
2.6 million inhabitants and 2,797 cases in the
last four years, the average TBE incidence was
26.9 / 100,000 per year. Latvia is in fact the
country with the highest TBE incidence in the
world.52)

22

Figure 15ac: A german TBE-patient

he too was in need of artificial respiration.

epidemiology

per year are now recorded.87) These figures

impressively demonstrate the effectiveness
in the field of FSME-IMMUN vaccine from

Annual morbidity from TBE

in various European countries

BAXTER.
Country
3.2.6. Mortality
In fatal cases, death occurs within the first
week after onset. It has been suggested that

Austria
unvaccinated
general population
forestry workers

Source

5.0
98100

81
65, 82

5.9

83, 84

Switzerland

0.47

85

Germany

0.25

52

areas where Far-Eastern TBEV subtype is pre-

Slovakia

0.21.6

15

valent has beeen reported to be significantly

Russia

16.5

86

the Far-Eastern TBEV subtype is more pathogenic for humans as compared to the European
TBEV subtype, because the mortality rate in

Czech Republic

Morbidity
(incidence per 100,000)

higher (520 %) than in Europe (03.9 %).50)

Table 7

However, the data of seroprevalence studies

against TBE, as is the case for Austria and

contradict these findings. The prevalence of

Bavaria, the number of reported cases of TBE

antibodies to TBEV in populations living in the

doesnt give enough information about the

endemic areas in Europe and Russia are in

actual risk of infection.

the range from 1% to 20 % and from 30 % to

TBE is a notifiable disease in many European

100 %, respectively.

countries, such as Austria, Czech Republic,

This raises the suspicion that a large propor-

Finland, Germany, Hungary, Latvia, Lithuania,

tion of mild diseases may not be diagnosed

Poland, Slovenia, Slovakia, Sweden and Swit-

or are underreported in some areas of Russia.

zerland. The maps shown on pages 30 and 31

The findings of different severity of TBE in

of this brochure give all regions in Europe and

different areas may either be the true diffe-

Asia where TBE infections have so far occurred.

rence in the clinical presentation or be a result

of different diagnostic criteria and patient

The TBE epidemiology is very complex. There

selection in the studies.

are low-risk areas, for example, in Finland,

89)

Sweden, Norway, and Switzerland with a grow3.2.7. Reported cases of TBE

ing trend towards spread and incidence. The

emergence of new foci in Sweden and Nor-

Table 8 lists the number of TBE infections

way has been reported, too. The example of

in those European countries, in which the di-

Denmark (Bornholm) shows that risk areas

sease poses a major problem to public health

can be forgotten and later rediscovered.53)

and/or such figures have been known for a

long time. In many of those countries, morbi-

Information on TBE in Europe is collected

dity has been continually increasing for years

by the International Scientific Working Group

(Table 8). In highly endemic areas in which

On Tick-Borne-Encephalitis (ISW-TBE) and can

the majority of the population is vaccinated

be found at http://www.tbe-info.com/.90)

23

epidemiology

Austria: In the pre-vaccination

new endemic areas have been described

era, Austria had the highest re-

around Mattsee, Wallersee and Thalgau, north

corded morbidity of TBE in Euro-

of the city of Salzburg.

pe with up to 700 hospitalized cases per year.

The increasing vaccination coverage (> 80 %)

For an unvaccinated tourist staying in a highly

led to a steady decline of TBE. In the period of

endemic province of southern Austria (e. g.

2000 to 2004 the 5 year average was 62 annual

Styria), the risk of acquiring TBE was describ-

cases, an incidence rate of 0.8 per 100,000.

ed to be 1/10,000 man-months of exposure.

The regions most affected by TBE are Styria,

Based on total numbers of tourist overnight

Carinthia, as well as Upper Austria, the south

stays in Austria during the summer season,

of Vienna, and parts of Burgenland. In 2003

about 60 travel-associated cases of clinical

91)

Number of reported cases of TBE from various European countries and Russia 91)
Country

1990

Albania

Austria

89

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

128

84

102

178

109

128

99

62

41

60

54

60

82

54

20

50

66

97

67

78

26

23

61

18

25

Belarus
Croatia
Czech R.

23

60

27

76

87

59

57

25

24

26

18

27

30

193

356

338

629

613

744

571

415

422

490

719

411

647

606

500

Denmark
Estonia

37

Finland

France

Germany
Hungary

222

68

163

166

177

175

177

404

387

185

272

215

90

237

182

14

25

16

23

10

19

17

12

41

33

38

16

31

44

142

118

306

226

114

211

148

115

133

253

226

278

274

288

206

329

258

234

224

99

84

51

45

76

80

114

11

15

19

14

23

791 1,366

1,341

716

874 1,029

350

544

303

153

365

251

426

309

645

548

171

419

298

168

763

425

209

101

170

205

126

339

Italy
Latvia
Lithuania

122

227

287

14

17

198

284

Norway
Poland
Russia

249

181

5,486 5,225 6,301 7,893 5,593

267

257

201

5,982 9,548 6,539 6,987 9,955 5,931 6,339 5,150 4,770 4,156

Slovak R.

14

24

16

51

60

89

101

76

54

57

92

76

62

74

Slovenia

235

245

210

194

492

260

406

274

136

150

190

260

262

275

204

Sweden

54

75

83

51

116

68

44

76

64

53

133

128

105

105

185

Switzerland

26

37

66

44

97

60

62

123

68

112

91

107

53

116

137

Ukraine
Table 8

24

12

epidemiology

TBE could be expected to occur among holi-

of Liechtenstein.94) A focus of TBE-virus-infec-

daymakers after their stay in Austria.92)

ted ticks is located on a much-used forest

path near Vaduz, the capital of the principality.95)

Germany: A map of TBE risk

The canton Zrich became the most dange-

areas is updated periodically by

rous region for TBE 85) in Switzerland, followed

the Robert Koch Institute. In Ger-

by Thurgau, St. Gallen, Aargau, and Bern.

many, 100 to 300 autochthonous clinical TBE

cases have been recorded annually. There are

France: There are some cases

high-risk areas in Bavaria and Baden-Wuerttem-

reported from the Alsace region

berg and ongoing low-risk areas in Hessen,

and single cases of infections are

Thuringia, and the Rhineland-Palatinate and

documented from the region Nancy/Lothringen.

single cases in Saxony. The TBE incidence

New cases were recently reported from

in Bavaria and Baden Wuerttemberg has been

Faverges and Grenoble.26)

53)

stable on a high level for years; outside these

areas increasing incidences were reported

Italy: A few clinical cases have

(Odenwald, Thuringia). In 2004, 274 cases

been recorded in Northern Italy

of TBE were notified in Germany (2002: 239;

in the area of Florence, Trento

53)

2001: 256). These occurred mainly in sou-

and Belluno. Antibodies for TBE virus were

thern Germany in the federal states of Baden-

found in about 1% of persons at potential risk

Wuerttemberg (42 %) and Bavaria (38%).

(foresters, hunters, woodcutters, gamekee-

93)

pers).96) Since the early 1990s 2 to 19 cases

Seventy nine of Germanys 440 counties are

have been reported annually.

currently classified as TBE risk areas and nine

as high risk areas. They are located in Baden-

Denmark: The island of

Wuerttemberg (30), Bavaria (47), Hessen (4),

Bornholm has long been known

Thuringia (3) and Rhineland-Palatinate (1). A

for TBE cases. In total, 14 cases

further five counties in Baden-Wuerttemberg

of TBE were found in the seven year period

are classified as endemic for TBE based on

1994 to 2000, giving an incidence of 3.81 per

seroprevalence studies. 3 cases have been

100,000 inhabitants.97) Four cases were noti-

reported from areas previously not defined as

fied in the year 2003. The minimum level of

risk areas: Brandenburg (2003), Mecklenburg-

prevalence of TBEV in ticks on Bornholm is

Vorpommern (2004), and Saxony Anhalt.

similar to what has been found in other Euro-

93)

pean countries where TBEV is endemic. The

Switzerland, Liechtenstein:

tick Ixodes ricinus was also found to carry the

In the period of 2000 to 2004 the

flavivirus Louping ill virus. The coexistence of

5 year average was 101 cases. In

TBEV and Louping ill virus in Denmark should

2004 138 cases were reported.

be taken into account.98)

There are mainly two high-risk

regions, one big one covering the

Sweden: Since the end of the

midland, with the exception of the far-western

1990s, around 100 cases have

part, a second smaller one being located in the

been reported annually. In the

upper Rhine valley, including the principality

period of 2000 to 2004 the five year average

25

epidemiology

was 127 annual cases. In the year 2004 the

incidence rate (763 cases, 22 per 100,000

high number of 183 cases was reported. Most

population) was double the average incidence

of the infections were acquired in the counties

over the last ten years, and was the highest

of Stockholm (62%), Sdermanland (13%) and

annual rate recorded since notification began

Uppsala (8%). In the county of Vstra Gtaland

at the end of the 1960s. This rate was also

(to the south of Lake Vnern), five to ten cases

the highest of all the Baltic countries in 2003.

are notified annually. Sporadic cases occur in

Four lethal cases of TBE were notified in 2003.

the rest of Sweden every year.

TBE is normally transmitted by a tick bite but,

in 2003, 22 cases of TBE (four clusters) were

Norway: In 1997 TBE was re-

acquired by consuming unpasteurised goats

ported in the coastal area of Sout-

milk a well-recognized transmission route.

hern Norway for the first time.

The highest incidences of TBE, about 80 % of

All cases were acquired within a limited area on

all notified cases, are recorded every year in

the southern coast, and four were diagnosed

the northern and central part of the country

in the municipality of Tromy, three of them in

mainly in three counties: Kaunas, Panevezys

tourists. A study done among regular patients

and Siauliai. In 2003, the incidence rate in

attending a health center in Tromy: showed

these areas was the same, but incidence rates

a seroprevalence of 2.4 % with TBEV antibodi-

were much higher in many other counties.

es. In previous studies, IgG antibodies to TBE

Eight districts out of 44 reported a two to five

virus were found in 0.3 to 0.4% of persons from

times higher incidence rate than the average

different parts of Agder counties, a region

incidence in Lithuania. The highest incidence

where TBE has previously not been seen.

rate was in Panevezys, at about 100 per

99)

99)

100)

100,000 population.104)
Finland: In the period of 2000
to 2004 an average of 32 annual

Latvia: Latvia is considered

cases was reported with a record

the TBE endemic country with

number of 41 cases in 2000.

101)

the highest incidence rates in

The known en-

demic areas are situated mainly in land (66 %

the world. Even in and around the city park of

of 125 cases 1987 to 1997, 80 / 100,000 / year

Riga TBE cases have been reported. In 1993,

in 2000), Archipelago of Turku (10 %), Kokkola

annual incidence quadrupled from the mean

region (6 %) and Lappeenranta region (5 %).

level of the previous two decades (nearly eight

According to antibody analyses, approximately

cases per 100,000 population), reaching the

every one in five landers is infected during

highest levels in 1994 and 1995 at 53 cases per

his or her lifetime. Recently, nine cases have

100,000. Since 1999 the incidence has been

been identified altogether from an island close

significantly lower, down to 6.5 cases in 2002,

to the city of Helsinki.

but back up to 15.7 per 100,000 in 2003.105)

90)

102, 103)

Food-borne outbreaks (caused by dairy pro-

26

Lithuania: TBE is present in all

ducts, mainly goat milk) amounted up to 5%

districts of Lithuania. In 2004 a

of total annual cases. Two different tick spe-

total number of 425 hospitalized

cies transmit TBE: Ixodes ricinus in the western

cases was reported. In 2003, the epidemiolo-

part of the country and Ixodes persulcatus in

gy of TBE in Lithuania was very unusual. The

the east.

epidemiology

Estonia: TBE morbidity in

Slovakia: The number of re-

Estonia has been 199 annual

ported cases at country level has

cases (15/100,000).

ranged from 54 to 101 cases per

106)

The high-

est TBE distribution rate is in West Estonia

year in the last ten years. In 2002 the number

(Prnumaa, Lnemaa), East Estonia (Ida-

of reported cases was 62 (incidence 1.15 per

Virumaa), Saaremaa (island in west) and

100,000), and in 2003 the number of reported

Southeast Estonia (Polvamaa, Tartumaa).

107)

cases was 74 (incidence 1.38 per 100,000).

Some of the reported cases were caused

Poland: Since 1993, the num-

by drinking raw goat and sheep milk (home

ber of reported cases at country

production). New foci have been identified in

level ranged from 100 to 350 ca-

areas of eastern Slovakia traditionally thought

ses per year. In 2003 the number of reported

to be free of the virus.15)

cases was 339 (incidence 0.89 per 100,000).

In Poland, the north-east of the country (around

Czech Republic: TBE exists

Bialystok) is the main area of endemicity.

in all parts of the country. In the

80 % of cases occurred in two northeastern

period 2000 to 2004 an average

76)

provinces adjacent to Lithuania and Belarus.

of 576 cases of TBE occurred annualy. In 2003,

Another important focus of the disease is in

the approximate incidence of TBE was 5.9 per

the southwestern part of Poland, in districts

100,000 population. The incidence is higher in

adjacent to the Czech Republic.

regions south of Prague near the city of Ceske

90)

Budejovice. There has been constantly high

Ukraine: The foci of TBE were

incidence near the town of Pilsen in the wes-

found throughout the whole of

tern part of the Czech Republic. Recently, TBE

the mountain forest zone of the

foci have been identified in the northern part

Crimea and coincided with the habitat area of

of the province of Bohemia. In the east of the

lxodes ricinus, the main vector of TBE.

country there has been a high incidence near

108)

About

a hundred patients with TBE were recorded

Olomouc. Clinical cases of TBE are notified

over the decade 1980 to 1990 in the Crimea,

from April until November every year with one

where co-infections with TBE and Crimean-

peak in July.111)

Congo hemorrhagic fever can be found.109)

Hungary: The average yearly
Moldavia: Although reliable

incidence between 1977 and

data is missing it is assumed

1996 was 2.5 per 100,000 population (range 1.3 to 3.8), with the highest inci-

that TBE is present.

dences between 1981 and 1990. From 1997

Romania: Risk of tick-borne

to 2000, a significant decrease in the number

encephalitis is reported for the

of registered/diagnosed TBE cases was ob-

Tulcea district and in Transyl-

served, with an incidence of 0.5 per 100,000

vania at the base of the Carpathian Mountains

in 2000. Since 2001, the incidence has been

and Transylvanian Alps, but the information

increasing again. In the period of 2000 to 2003

was never published, neither were details

an average of 79 cases was reported annu-

about annual numbers of TBE cases.

ally. Extended areas of high-risk are in western

110)

27

epidemiology

Hungary and along the danube region: the

Belarus: About 20 to 80 cases

counties of Zala, Somogy, Vas (western Hun-

of TBE occur annually in Bela-

gary), Ngrd (northern Hungary), and around

the lake Balaton.

rus with a peak of 97 cases in

1996. There is not enough information avail91)

able about clinical cases in Belarus, which is

Slovenia: Endemic foci of TBE

believed to be a country with high risk areas

are spred all over the country.

and a high prevalence of TBEV in ticks. In

In the period of 2001 to 2003

2003, 25 clinical cases were reported in the

the 3 year average was 265 cases. The highest

area of Minsk.112)

number of TBE cases was reported in the

Kazakhstan: Cases of TBE are

year 1994 with 530 cases.

supposed to have occurred but

Croatia: Only one natural

there is not enough information

focus in the northern part of the

available.

country is described, between

the rivers Sava and Drava. During the past ten

Russia: TBE is endemic from

years, the number of annual cases ranged

Kaliningrad to Wladiwostok. The

from 23 to 87.

TBE morbidity rate in Russia

26)

recently increased dramatically from 6,000 to

Bosnia: In the northern parts of

10,000 persons per year. The highest morbidity

the country there may be some

rate is registered in the Ural, Perm, Sverdlovsk

cases. There is not enough infor-

regions: 13.4 /100,000 of population; Udmurt

mation available about the number of cases.

26)

Republic: 53.5 /100,000; West Siberia, Tomsk

region: 72.5/100,000; East Siberia, Krasno-

Serbia: A few cases have

yarsky Krai: 37.0 /100,000.113) The most dange-

been reported in the area near

rous foci of TBE were found to be located in

Belgrade, including food-borne

the southern Okhotsk region, were dark coni-

outbreaks near the coastal regions of the Adria,

ferous forests grow 114) and in the Sikhote-Alin

but there is not enough information available.

Mountain range (near Vladivostok).115) In the

Primorye region (far-eastern part of Russia,

Albania: Natural foci are found

on the coast of the Sea of Japan) 126 people

in the whole of Albania. Older

were hospitalized between January and August

publications show a prevalence

2004 with a diagnosis of TBE, 17 of whom

of TBE virus in the Albanian population of 22%.

were children.

Alimentary cases of TBE have been reported.

Before 1990, 25 new cases were registered

A total of 8 people among those contracting

annually. No further data are available after

TBE have died.116) The total number of TBE

that time.26)

patients in the Lake Baikal region between

1996 and 1999 ranged from 460 to 780 cases

28

Greece: Single cases were

per year and shows a tendency to increase.

reported in the north of the

The relative index per 100,000 population

country ( Thessaloniki).

varied between 2.6 and 18.1.117)

epidemiology

The Sverdlovsk Region has long been known

China: Data on TBE morbidity

as the natural nidus of tick-borne encephalitis.

is scarce. Natural foci are the

The majority of people are attacked in Yekate-

Hunchun area, Jilin province and

rinburg and in 2003 the number of tick attak-

in the subtropical region of western Yunnan

ks has increased, as compared to 2002. Other

near the Burmese border.26)

foci are in Nizhni Tagil, Kamensk-Uralsky, in

Verkhnyaya Pyshma, Nizhnyaya Tura, Nevyansk,

Japan: TBE virus is endemic in

and Sukhoy Lo.

Japan, where TBE virus was iso-

118)

lated from the blood samples of

Ixodes persulcatus is the main vector of TBEV

sentinel dogs, tick pools, and rodent spleens

in the asian and European parts of Russia.

since 1995. In 1993, a case of TBE was repor-

Lethal TBE outcomes were registered in Siberia

ted in the southern part of Hokkaido. A sero-

(Irkutsk region and Krasnoyarsk territory) and

epidemiological survey was performed among

in Russias European part (Yaroslavl region).

humans and animals, and it was concluded

119)

that the TBE virus may be endemic in Japan,

Mongolia: In 2004 some

at least on the island of Hokkaido.120) The main

endemic areas were described

principal vector on Hokkaido was identified as

next to the Russian border in

I. ovatus and genomic sequence and phylo-

the north of the country (provinces of Selenga

genetic analyses of a virus isolate revealed a

and Bulgan) and around the capital city Ulan-

close relationship with the Far-Eastern sub-

Bataar.

type of the TBE virus.

29

epidemiology

TBE/FSME in Europe
30

60

50

2500 m
1500 m
1000 m
500 m
200 m
200 m
0m
Depr.
200 m
2000 m
4000 m

30

40

40

10

10

epidemiology

Tick-borne Encephalitis /FrhSommerMeningoEncephalitis

0

30

40

50

60

70
60

60

40

Basemap Ed. Hlzel, Vienna

A service of

Vaccines
31

epidemiology

References TBE/FSME in Europe, Epidemiological map 2005

Albania: Information based on Sss, J.: Epidemiologisches

Bulletin Nr. 7/2003, Robert-Koch-Institut; endemic areas based
on studies of TBE virus prevalence in healthy population and
documented cases
Austria: Information based on Heinz, F. X. et al.: Institut fr Virologie Wien, Hygieneinstitut der Universitt Innsbruck, Hygieneinstitut der Universitt Graz 2004, TBE map: www.univie.ac.at/
virologie/seiten/epidem/zeck.htm; (official publication in Jan
2005); endemic areas are based on documented cases
Belarus: Information based on Sss, J.: Epidemiologisches
Bulletin Nr. 7/2003, Robert-Koch-Institut; endemic areas based
on studies of TBE virus prevalence in healthy population and
documented cases
Croatia: Information based on Sss, J.: Epidemiologisches
Bulletin Nr. 7/2003, Robert-Koch-Institut; endemic areas are
based on documented cases
Czech Republic: Information based on Benes, C.: Epidat 2003,
National Institute of Public Health (official communication); endemic areas are districts with a TBE incidence of 1>13/100,000
Denmark: Information based on Kristiansen, K.: TBE in
Denmark in particular on Bornholm, Int J Med Microbiol. 2002
Jun; 91 Suppl 33:62; and official publication from the SSI
Statens Serum Institut, Denmark, 2004, www.ssi.dk; endemic
areas are based on documented cases
Estonia: Information based on reported cases of the Health
Protection Inspectorate Estonia, Nov 2004; endemic areas are
based on districts with a TBE incidence of 1>12/100,000
documented cases during 19932003
Finland: Information based on reported cases of the KTL
National Public Health Institute, Finland, Nov 2004; www.ktl.fi;
endemic areas are based on documented cases
France: Information based on Sss, J.: Epidemiologisches
Bulletin Nr. 7/2003, Robert-Koch-Institut; and Garin, D.:
Defenses Medical Research Center Emile Pard/La Tranche
cedex, (personal communication 2004); endemic areas are
based on documented cases
Germany: Information based on Sss, J.: Robert-Koch-Institut
2004: www.rki.de/INFEKT/EPIBULL/2004/21_04.PDF and Sss,
J.:Federal Research Institute for Animal Health, Jena/Germany
personal communication Oct 2004;TBE endemic areas are
based on defined risk areas (5 autochthonous TBE cases in
a region during a 5 year period or min. 2 cases in one year),
high risk areas (min. 25 TBE cases in a region during
a 5 year period) and endemic areas (regions with TBE antibody prevalence in a wood worker population)

32

Kazachstan: Information based on official data from the MOH

Centre of Medicinal products of the Republic of Kazachstan,
Dec 2004: www.dari.kz, and information from Albedo company http://kz.narod.ru/partner/albedo.html; endemic areas are
based on screening for TBE antibodies in healthy population
and on documented cases
Latvia: Information based on documented cases reported by
the State Agency "Public Health Agency", Latvia, official communication in Nov 2004, www.sva.lv; endemic areas are based
on districts with a TBE incidence of 1>53/100,000 documented cases during 19932003
Lithuania: Information based on reported cases of the Centre
of Promotion and Control of Infectious Diseases of Lithuania,
official communication in Nov 2004; endemic areas are based
on districts with a TBE incidence of 1>22/100,000 documented cases during 19932003
Norway: Information based on reported cases of the National
Institute of Public Health (Norge), Norway, official communication in Nov 2004, www.folkehelsa.no; endemic localities are
based on documented cases
Poland: Information based on Stefanoff, P.: National Institute
for Hygiene Warszawa, official communication in 2004; endemic areas are based on documented cases, screening for TBE
antibodies in healthy population and screening for viruses in
ticks and hosts
Ukraine: Information based on Vorobyeva, M.S.: State
Research Institute for Standardization and Control of Medical
Biological Preparations L.A. Tarasevich, Russia, personal
communication in Dec 2004
Russia: Information based on Prochorow, B.B.: Practical
science web atlas 1998 environment and health of the
population of Russia http://sci.aha.ru/ATL/ra55a.htm; endemic
areas are based on morbidity data /100,000 inhabitants
>1.2 (1.252.0) per region updated 1995/96 and personal
communication in Dec 2004 with Vorobyeva, M.S.: State
Research Institute for Standardization and Control of Medical
Biological Preparations L.A. Tarasevich, Russia
Slovakia: Information based on Maderova, E.: Public Health
Authority of Slovakia, official communication in Oct 2004; endemic areas comprise districts with natural foci based on TBE
virus prevalence in ticks and reservoir animals between 196497
Slovenia: Information based on Kraigher, A.: Centre for
Communicable Diseases, Institute of Public Health, Lubljiana,
Slovenia, official communication in 2004 and Sss, J.:
Epidemiologisches Bulletin Nr. 7/2003, Robert-Koch-Institut;
endemic areas are based on documented cases

Hungary: Information based on published data of Emke, F.:

Department of Virology of the National Institute of Epidemiology, Hungary, 2004, www.antsz.hu and Sss, J.: Epidemiologisches Bulletin Nr. 7/2003, Robert-Koch-Institut; endemic
areas are based on documented cases

Sweden: Information based on official publication from the

Swedish Institute for Infectious Disease Control (SMI), 2004:
www.smittskyddsintitutet.se; endemic areas are based on
documented cases

Italy: Information based on official publication of the Instituto

Superiore di Sanita, Italy 2004 and Sss, J.: Epidemiologisches
Bulletin Nr. 7/2003, Robert-Koch-Institut; endemic areas are
based on documented cases

Switzerland: Bundesamt fr Gesundheit, Bern/Switzerland:

Nov 2004 (official publication); endemic areas show defined
high risk areas which are based on documented cases.
www.bag.admin.ch/infekt/publ/wissenschaft/d/fsme_karte.pdf

clinic

Clinical
Description
With increasing age severe courses of disease accumulate,
n e u r o - p s y c h i a t r i c s e q u e l a e f r e q u e n t l y p e r s i s t . ( R . K a i s e r, M D , P f o r z h e i m )

TBE (Table 9), but then the symptoms subside

Clinical course
and manifestations

4.1.

without developing into the second stage.

The typical course of TBE is diphasic in at

About one third of those symptomatic with

least two-thirds of patients,

TBE proceed into the second stage of the

121)

and can be de-

scribed as follows. The incubation period may

disease after the virus has spread to the CNS.

last between 2 and 28 days, but on average

5077% of these patients run through the

7 days. The first stage, which may last for 2

typical biphasic course of the infection. In the

to 8 days, corresponds to the viremic phase.

remaining 2350% the infection is in-apparent

It is associated with non-specific systemic

during the first stage, and the onset of clinical

signs and symptoms such as fatigue, heada-

illness coincides with the beginning of the

che, aching back and limbs, nausea, and

second phase of the disease.

general malaise; in most cases the temperature is rising to 38 C or higher. Sometimes

exceptionally high initial temperature may
incubation stage 1 interval stage 2

occur, rising above 40C (Figure 16) An afebrile

41

interval follows the first stage of TBE, and lasts

40

Not all individuals infected with TBE go

38
37
36

discharge

beginning of the second stage (Figure 16).

admission

rise of temperature to high values marks the

39

infection

usually free of symptoms. Another sudden

Temperature (C)

1 to 20 days. During this time patients are

through the entire course of the disease. In

approximately two thirds of infected individuals the infection remains either silent, though
viremia can be demonstrated, or the patients
show the clinical picture of the initial stage of

22. 24. 26. 28. 30. 1. 3. 5. 7. 9. 11. 13. 15. 17. 19. 21. 23.

October

November

Dec.

Figure 16: Typical temperature curve in a case of TBE

after laboratory infection with the virus 122)

33

clinic

The course of disease

Siberian subtype with respect to the course of

with the Far-Eastern variety

disease in humans. However, animal studies

clinically differs from the

have demonstrated that the limited number of

European form. The onset

Siberian subtype strains studied have higher

of illness is more often

virulence in mice than Far-Eastern strains.124)

gradual than acute with a

prodromal phase including,

4.1.1. Stages of the disease

fever, headache, anorexia,

nausea, vomiting and

Incubation period: The incubation period,

photophobia. These symp-

in most cases, is between 7 and 14 days prior

toms are followed by a

to the onset of the first stage but may last

stiff neck, sensorial changes, visual disturban-

from 2 to 28 days.

ces, and variable neurological dysfunctions,

including paresis, paralysis, sensory loss and

First stage: On average the first stage lasts

convulsions. In fatal cases, death occurs with-

2 to 4 days (durations of 1 to 8 days have

in the first week after onset. The case-fatality

rarely been observed), and corresponds with

rate is approximately 20 % compared to 12 %

the viremic phase. It is associated with un-

for the European form,

characteristic flu-like symptoms (Table 9), with

22, 123)

but these figures

may be biased by the different standards of

temperature rising to 38 C in most cases.

medical treatment available in Western Europe

Sometimes an exceptionally high initial tem-

and eastern regions. It is supposed that, in

peratures may occur.

contrast to the European form the disease

caused by the Far-Eastern variety is more

Asymptomatic interval: An asymptomatic

severe in children than in adults. Neurological

interval lasting about 8 days (extreme values

sequelae occur in 30 80% of survivors, espe-

between 1 and 20 days have been observed)

cially residual flaccid paralyses of the shoul-

follows the first stage of TBE. During this pe-

der girdle and arms. Little information is avail-

riod, patients are usually without symptoms.

able on the virulence of the recently described

Second stage: About 2 to 4 weeks following infection, one third of patients passes into

Flu-like symptoms during

the first stage of TBE

the second stage of the disease, which is characterized by CNS involvement.125) The clinical
picture is that of meningitis, encephalitis,

Fever >38.0C
Fatigue
Headache
Aching back and limbs
Catarrhal symptoms of the upper airways
Gastrointestinal symptoms
Anorexia
Nausea
Table 9

34

meningoencephalomyelitis or meningoencephaloradiculitis (Table 10). The mortality rate

in adult patients in Europe is about 1% and
increasses to about 3 % in patients with a
severe course of TBE including meningoencephalitis, meningoencephalomyelitis, and dysfunction of the autonomic nervous system.126)
The patients have temperatures that are often
higher than temperatures associated with

clinic

Course of TBE, according to publications involving large number of patients

Reference

Meningitis

Meningoencephalitis

Meningoencephalomyelitis

128

286

161 (56.3 %)

98 (34.3 %)

27 (9.4 %)

129

117

72 (61 %)

28 (24 %)

17 (15 %)

130

805

398 (49 %)

354 (43 %)

23 (3 %)

131

549

393 (71.6 %)

111 (20.2 %)

45 (8.2 %)

132

38

20 (52.6 %)

12 (31.6 %)

6 (15.8 %)

133

100

60 (60 %)

32 (32 %)

3 (3 %)

134

120

70 (58 %)

39 (33 %)

11 (9 %)

76

152

51 (34%)

89 (59 %)

12 (8 %)

121

850

400 (47 %)

356 (42 %)

93 (11 %)

Total

3017

1625 (53.9 %)

1119 (37 %)

272 (9 %)

Meningoencephaloradiculitis

30 (4 %)

5 (5 %)

Table 10: Different courses of severity of TBE

other forms of viral meningitis or meningo-

symptoms prevail, and the patient is sent to a

encephalitis.

psychiatric ward.

127)

The age related distribution of

the clinical manifestations of the disease is

shown in Figure 17.

Symptoms of polyradiculitis may occur five

to ten days after the remission of fever;

The main symptoms of meningitis are a seve-

they are usually accompanied by a paresis of

re headache, nausea and retching, nuchal rigi-

the shoulder girdle.135) Paralysis may progress

dity, and high fever (Table 11). Special atten-

up to two weeks, followed by a moderate

tion should be paid to the lack of meningeal

tendency of improvement.

symptoms in 10% of patients diagnosed with

TBE.76) Lack of meningeal signs in the course
of TBE does not exclude serious neurological
complications.
Encephalitis is characterized by disturbances
of consciousness ranging from somnolence to
sopor and, in rare cases, coma. Other symptoms include restlessness, hyperkinesia of mus-

Meningitis

Encephalitis/Myelitis

100
80
34 %

36 %
46 %

60

59 %

40

67 %

cles of limbs and face, lingual tremor, convulsions, vertigo, and speech disorders (Table 11).

0
When cranial nerves are involved, mainly
ocular, facial, and pharyngeal muscles are
affected. In some cases, neuropsychiatric

86 %

20

115

1630

3145 4660
Age

6175

7690

Figure 17: Age & Clinical manifestation of TBE 136)

35

clinic

Systemic manifestations
in the second stage of TBE
Symptoms
Meningomyelitis

Meningitis

Meningoencephalitis

Fever

Meningeal symptoms

Meningeal symptoms

Headache

Lack of drive

Facial paresis

Nausea

Increased inclination to sleep

Paresis of the upper

Vomiting

Disturbed sleep

Retching

Somnolence/ unconsciousness

Vertigo

Nystagmus

Photophobia

Tremor capitis

Phrenic nerve paresis

Nuchial rigidity

Lingual tremor

Lesions of the medulla

Slight pharyngeal catarrh

Speech disorders

oblongata and the central

Presence of Kernigs sign

Hyperesthesia

portions of the brain stem

and/or lower limbs

Atonic paresis in the region
of the shoulder girdle

Passive and intention tremor

Bulbar paralysis

Gait ataxia

Toxic damage of the

Hyperkinesia of the muscles

of limbs and face
Transient Babinskis sign
Abnormal reflexes
Cranial nerve paralysis
Hemiplegia
Cerebropsychotic episodes
Pain in arms and/or legs
Cystoplegia
Facial pareses
Opthalmoplegia
Disorders of the autonomic
nervous system
Hallucinations
Mental disorders with severe psychosis

36

Meningoencephalomyelitis

liver parenchyma
Severe myocarditis
Life-threatening conditions

clinic

TBE is a serious case

of acute central
nervous system disease,
which may result in death
or long-term neurological
sequelae in 3558%
of patients.
(WHO, State of the Art of New Vaccines:
Research & Development 2003)

Prognosis
Meningitis

Meningoencephalitis

Meningomyelitis
Meningoencephalomyelitis

Usually full recovery.

In some patients sequelae have been

The following sequelae

In individual cases

reported to persist for several years, e. g.,

have been observed:

sequelae may persist

Headache

Spinal paralysis

for several months, e.g.,

Lack of concentration

Facial paresis

Headache

Decreased vitality

Cerebellar insufficiency

Lack of concentration

Auton. nerv. system disorders

Atrophic paresis, particularly in

Disorders of the auto-

Mood disorders

the region of the shoulder girdle

Psychic handicaps

In about 2 % of patients

Ophthalmoplegia

the disease is lethal.

nomic nervous system.

19% of patients reported
some cognitive dysfunc-

Facial paresis

tion affecting quality of

Hearing impairment

life after one year.

Lethal courses

141)

have been observed.

Table 11

37

clinic

The greatest extent of neurological abnorma-

Post-encephalitic syndrome: A post-menin-

lities of TBE is found in the meningoencepha-

goencepahlitic syndrome may occur after TBE.

lomyelitic manifestation of the disease, wich

It impairs the quality of life, causes high costs

is primarily characterized by flaccid paresis of

for the health care system with long periods

the extremities. Since TBE viruses have a par-

of hospitalization, inability to work, as well as

ticular predilection for anterior horn cells of

long-lasting neurological symptoms and social

the cervical spinal cord, paresis usually affects

distress of the patients.137) Although severe

upper limbs, shoulder girdle and/or head leva-

manifestations usually subside after 1 to

tor muscles. Mono-, para- and tetra paresis

3 weeks, TBE may cause long-lasting, mainly

may develop including paresis of the respira-

cognitive CNS dysfunction and the convales-

tory muscles. This clinical form of TBE closely

cence period may be very long.138)

resembles polio virus infection, however, compared with poliomyelitis. Paresis in TBE tends

According to a literature review by M. Haglund

to have a proximal distribution, and more

and G. Gnther in 2003, the incidence of se-

often affects the upper than the lower extre-

quelae following TBE varies between 35 and

mities. If the lesion spreads to the lower por-

58 %.139, 97) In Austria, 1020% of patients with

tion of the brain stem, and particularly to the

a severe course of TBE have been reported

medulla oblongata, bulbar syndrome may

to develop long-term or permanent neuro-psy-

develop with the risk of sudden death due to

chiatric sequelae such as a severe heada-

respiratory failure or circulation disturbances.

che, dizziness, lack of concentration, depres-

However, bulbar syndrome can be observed

sion, disorders of the autonomous nervous

in the meningoencephalitic form of TBE, without association of myelitis. On all occasions

this is the sign of an adverse prognosis.124)
Apart from myelitis, a meningoencephaloradiculitic form of TBE may also occur. Polyradiculitic symptoms usually develop some days
after the remission of fever. Severe back-pain,
pain of the extremities, combined with sensitivity disturbances and weakened reflexes are
typical for this form of TBE. In more severe
cases paresis may also develop.
These cases have a better prognosis compared to those with paresis due to myelitis. The
latter only have a slight tendency to regression, and are generally followed by pronounced muscle atrophy. In a german study 1 out
of 9 TBE patients with radiculitis and paresis
and all of 15 patients with myelitis were left
with residual paresis.124)
38

Figure 18: Atrophic shoulder following TBE (R. Kaiser)

clinic

system, hearing impairment and mood disor-

lium into the brain tissue. TBE virus may also

ders. Next in frequency are residual pareses

spread along nerve fibers. This route may be

and atrophies in 311%. The pareses usually

relevant, especially in laboratory infections by

tend to remit, but in rare cases muscular atro-

aerosols. After infecting the neuroepithelial

phies may persist. In some patients a spas-

cells of the nasal mucous membrane, the virus

mophilic tendency has been observed for as

directly enters the brain via the fila olfactoria.

long as four years following TBE infection.

Considering the short incubation period and

140)

the often extremely severe course of such

The post-encephalitic syndrome causes major

infections, this route of entry seems likely.41)

expenses both to the health care system and

However, in arthropod-borne infections neural

society as long-term working disability ensues.

spread of the virus is of little importance.

Moreover, the long-lasting sequelae have a substantial impact on the patientsquality of life.

Histopathological studies from lethal human

cases revealed neuronal and glial destruction,

TBE with hemorrhagic syndrome: 8 fatal

spongiform focal necrosis, inflammation and

cases of tick-borne encephalitis with an

perivascular infiltration, cellular nodule forma-

unusual hemorrhagic syndrome were identified

tion and edema. Residual pathological lesions

in 1999 in the Novosibirsk Region. Hemorrha-

are characterized by neuronal loss and micro-

gic fever was associated with the Far-Eastern

glial scarring.143) Detection of viral RNA during

TBEV subtype.12)

the encephalitic stage of disease in cerebrospinal fluid (CSF) is difficult, which indicates

4.1.2. Pathogenesis

that the main pathogenic mechanism may be

due to inflammatory mediators, even if TBEV

The picture of manifest TBE depends on

may be concealed in the neurons without lea-

the virulence of the virus, and the individual

king into the CSF.

resistance of the patient. After the bite of an

infected tick, the virus usually replicates in the

4.1.3. Immune response

dermal cells at the site of the tick bite. The

virus spreads via the lymphatic system and

A TBEV infection confers life-long protection

the bloodstream, and it invades other suscep-

and there is no known human case of symp-

tible organs or tissues especially the reticulo-

tomatic re-infection.

endothelial system. Massive virus replication

takes place there, and only after this stage

4.2.

Laboratory findings

it is possible for the virus to reach the central

nervous system. High production of the virus

Blood count: The typical changes in blood

in the primarily affected organs is a prerequi-

count in TBE are as follows: With the onset of

site for the virus to cross the blood-brain bar-

the meningoencephalitic stage, leukopaenia

rier since the capillary endothelium is not

which is observed during the first stage of

easily infected. Once it has invaded these

the disease and the asymptomatic interval

endothelial cells from the lumen, the virus

disappears. It is followed by transient leuko-

replicates and enters the central nervous sys-

cytosis with leukocyte counts that are consi-

tem by seeding through the capillary endothe-

derably higher than in other forms of viral

39

clinic

meningitis (6,60014,600/mm3). Usually, leuko-

severe course, leading to paralysis and some-

cytosis changes into leukopaenia before nor-

times ending in death.32) The results of labora-

malisation of the blood count is observed after

tory examinations seem to have little predic-

some time. The blood sedimentation rate may

tive value for the severity of the course of the

be as high as 100 mm/h. The frequency and

disease, excluding CSF cell counts, which may

the extent of abnormal values do not corre-

indicate the intensity of CNS infection, and

late with the diagnosis or prognosis of TBE.

correlate with the severity of the disease.76)

Elevated C-reactive protein is detected in more

Similarily, TBE antibody concentration as

than 80 % of the patients.

detected by ELISA does not correlate with the

1)

121)

121)

outcome of the infection, whereas the neutra Cerebrospinal fluid: Pleocytosis (mainly

lizing antibody titer together with the CNS

lymphocytes) is observed in the cerebrospinal

cell count seems to be more predictive for

fluid, reaching maximum values of 5,000/mm

the clinical outcome. At onset of disease, the

cells. Frequently, cell counts of several hund-

presence of a low concentration of neutralizing

red mm , as well as protein values between

antibodies in serum, and a high cell count in

50200 mg/dl are observed. Usually it takes

the CSF might indicate an unfavourable course

four to six weeks for the CSF lab parameter

of TBE.144)

values to normalize, but in individual cases elevated values may persist for several months.1)

4.3.

4.4.

Prognosis

Pediatric clinical description

TBE in children can run a severe course and

may lead to permanent sequelae. In children

Hospitalization is usually required for about

and juveniles, meningitis is the predominant

three weeks; however, in severe cases it may

form of the disease; this is why the infection

last much longer, sometimes even several

usually takes a milder course with better pro-

years. With rising age of the patient, especially

gnosis than in adults. Retrospective studies

in persons above 60, TBE increasingly takes a

have shown TBE infection occur as young as

3 months.168) A higher incidence of TBE was
reported in boys (ratio 7: 3), who show signs
of focal encephalitis more often.138) There is a
clear tendency for a more severe course of
TBE above the age of 7 years.145) Severe cases
have been reported even in young children146)
with permanent neurologic sequelae, mild or
severe, e. g. headache, behavioral disorder,
seizures, pareses.69) The most common symptoms and signs of acute TBE in children are
raised body temperature (38C), headache and
Figure 19: MRT of a 5 year old girl with TBE.
T2 sequence shows significant changes within both
thalami and the right nucleus lentiformis without
enhancement by contrast medium. (W. Zenz, 2003)

40

clinic

to a more severe course of TBE.126, 148) Similar

Hospitalized children in
Slovenia aged 015 years 1, 138)

findings of mixed infections are described in

children, most commonly TBE and Lyme borreliosis.145) Double infections occur more fre-

48.5 % had aseptic meningitis

quently in areas where I. persulcatus ticks are

48.5 % had meningoencephalitis

abundant.149) A study from the Czech Republic

3.0 % had meningoencephalomyelitis

5.2 % were admitted to the intensive care unit

demonstrated that TBE/HGE (human granulocytic ehrlichiosis) co-infections can also be

Table 12

encountered in Central Europe.150)

meningeal signs, fatigue and vomiting.70, 145)

4.6.

Cizman also reports an unusually high rate of

Incidence and severity of TBE in

relation to other CNS viral diseases

children aged 015 years, which were hospitalized (n=133) due to severe TBE virus infec-

According to a study conducted in 1958, the

tion in Slovenia between 1993 and 1998.

proportion of TBE in the total number of CNS

Symptoms of sequelae in children heada-

viral diseases in Austria was 56% (Figure 20).151)

ches, sleep/concentration disturbances, verti-

Thus, before the start of the vaccination pro-

go, fatigue and epileptic disorder.

gram, it was the most important and most fre-

138)

1)

quent disease of this type in adults with seve4.5.

Mixed Infections

ral hundred cases being reported each year.

Co-infections involving various combinations

In Switzerland, in 1981 TBE ranked fourth

of pathogens are frequently described, and

among viral infections of the central and peri-

some tend to be particularly severe. Diseases

pheral nervous system, only picorna, mumps

caused by mixed TBE virus-Borrelia infections

and Varicella zoster infections were more fre-

have already been revealed in several countries

quent. In some cantons, however, it was the

of Central Europe. Co-infection with Borrelia

most frequent cause of CNS diseases.152) In

burgdorferi is reported in about 15 % of pati-

Germany, TBE accounts for up to 50% of all

ents on the basis of seropositive results in

viral diseases,153) and Lithuania TBE accounts

serum and/or CSF. 76) In the majority of patients

for more than half (53 %) of all CNS infections.

42)

with concomitant infection the clinical features at presentation were characteristic of, or
consistent with, TBE.147) It is suggested that in
confirmed cases of tick-encephalitis in patients
with acute lymphocytic meningitis or meningoencephalitis, originating in TBE and Lyme
borreliosis endemic regions, an additional infection with Borrelia should be considered,147)
since if present the latter can be successfully treated with antibiotics. There is some
information in the literature that co-infection
with B. burgdorferi sensu lato might contribute

56 %
Figure 20: In Austria a significant number
of viral encephalitis can now be avoided.

41

therapy

Therapy
T h e b a d n e w s : Yo u c a n n o t a b s t a i n f r o m T B E
a n d t h e r a p e u t i c p o s s i b i l i t i e s a r e p o o r. B u t t h e r e i s g o o d n e w s
r e g a r d i n g p r e v e n t i o n . ( M . K u n z e , M D, V i e n n a )

No specific therapy for TBE is known so far.

Maintenance of the water and electrolyte

Since there is no specific treatment targeting

balances, sufficient caloric intake, and the

the virus itself, symptomatic treatment of pati-

administration of analgesics, vitamins, and

ents with TBE is required. Strict bed rest for at

antipyretics constitutes the most important

least ten days is imperative. In many Austrian

lines in the clinical management of patients.

hospitals, encephalitis patients are referred to

Physiotherapy of paralysed limbs is essential

intensive care units for continuous surveillance

to prevent muscular atrophy.

as a precaution. Only when their temperature

is down to normal, and neurological symptoms

Man is the dead-end host in the natural trans-

have subsided, the patient may start to leave

mission cycle of TBE. As man-to-man trans-

bed briefly for washing and using the toilet.

mission of the virus has never been observed,

For another 1 to 2 weeks predominant bed

there is no need to isolate TBE patients.

rest is recommended to avoid complications.

42

therapy

diagnosis

Diagnosis

It will only be possible to clearly identify

the endemic TBE areas in Europe, when every case of meningitis
i s t e s t e d f o r a p a t h o g e n . ( A . M i c k i e n e , M D, K a u n a s )

The diagnosis of TBE is based on 143)

results have no influence on the therapy of TBE,

Epidemiological information: stay in an area

and mainly serve to differentiate a TBE virus

of risk of TBE, facultative history of a tick bite

Clinical data: uncharacteristic and usually

infection from other causes of meningoencephalitis, which may require special treatment.

not sufficient for diagnosis

Demonstration of TBE-specific IgM and IgG

The method of choice is the demonstration of

antibodies in serum (adequate evidence of

specific IgM and IgG serum antibodies by en-

infection) and CSF

zyme-linked immuno-sorbent assay (ELISA).155)

As the symptoms affecting the CNS are not

6.1.

Laboratory Diagnosis

usually observed until two to four weeks after

the tick bite, the antibody test is nearly inva-

The actual diagnosis of TBE must be establis-

riably positive at the time of admission to hos-

hed in the laboratory because of the non-spe-

pital. Soon after infection IgM antibodies are

cific clinical features it presents. The laboratory

more specific, while later, IgG antibodies are

Diagnosis: VIS, PCR serological tests

viremia
neurological symptoms
IgM antibodies in CSF
lgM ab

lgG ab

fever
>

>

infection

25 d.
414 d. phase 1 23 d.
intervall
incubation period

~ 3 weeks
phase 2

weeks post infection

Figure 21:
Biphasic course
of a TBE virus infection.
(F.X. Heinz, 2005)

43

diagnosis

more reactive (Figure 21). A recent infection

low seroconversion after active immunization

can be established by the qualitative deter-

and control of humoral immune status.

mination of IgM. Specific IgG antibodies and

rheumatoid factors do not interfere with the

In the past, antibody identification relied on

test. However, in cases of other flavivirus con-

four tests: hemagglutination inhibition, com-

tacts (e. g. vaccinations against yellow fever

plement fixation, plaque reduction neutraliza-

or Japanese encephalitis; dengue virus infec-

tion test, and the indirect fluorescent antibody

tions) the performance of a neutralization as-

(IFA) test. Positive identification using these

say (e. g. RFFIT, rapid fluorescent focus inhibi-

IgM and IgG based assays requires a four-

tion test) is necessary for assessing immunity

fold increase in titer between acute and con-

due to the interference of flavivirus cross-reac-

valescent serum samples. The sensitivity and

tive antibodies in ELISA and hemagglutination

specificity of new assays, e. g. IIFT (indirect

inhibition test.

immunofluoerescence test), ELISA, and

154)

immunoblot test systems are considerably

The high cross-reactivity rate of yellow fever

higher than that of tests used in the past, and

and TBE antibody-positive sera in dengue virus

cross-reactivity with related flaviviruses is

antibody assays should be taken into account

significantly reduced.156)

in the interpretation of laboratory tests for the

diagnosis of flavivirus infections, and when

In the viremic phase of the initial stage of

undertaking seroepidemiological surveys.

the disease before seroconversion, TBE virus

Neutralization tests like RFFIT require

can also be identified by reverse-transcriptase

handling infectious virus, which makes the

polymerase chain reaction (RT-PCR), by elec-

test cumbersome, costly and only available in

tron-microscopy, or by cultivation. In fatal

highly specialized virus laboratories. IgG anti-

cases, the virus can be isolated or detected

bodies are detected by qualitative methods,

by RT-PCR from the brain and other organs.154)

e. g. to establish the prevalence of TBE in the

Electron-microscopy and cultivation are not

population or in a group of patients, or to fol-

suitable as a routine diagnostic tool. In con-

155)

trast to many other flaviviruses, the PCR

method is not very useful for the laboratory
diagnosis of TBE in clinical practice.154)
The overall prevalence of TBE can be established serologically, since the infection leads
to immunity for life and the presence of antibodies to the TBE virus in the patients blood.

6.2.

Differential Diagnosis

Fever, headache and meningism associated

with signs of inflammation in serum (leukocytosis, elevation of the sedimentation rate
Figure 22: Analysis of vaccine preparations on microtiter plates

44

and of C-reactive protein), and predominance

diagnosis

of neutrophilic cells over lymphocytes in the

CSF are main findings in patients with TBE,

Differential diagnosis of TBE

but are also highly indicative of bacterial

meningitis. Consequently, most patients are

Clinical Picture

treated with antibiotics at least until the TBE

Lyme disease

serology is found to be positive.

Acute human granulocytic ehrlichiosis

154)

Poliomyelitis
Thus, many viral and bacterial infections have
to be considered in the differential diagnosis
of TBE (Table 13).

Coxsackie virus infection

ECHO virus infection
Parotitis
Measles

Lyme disease (lyme borreliosis) has been

Herpes virus infection

recognized as the most frequent vector borne

Lymphocytic choriomeningitis

disease in mild climate areas, and has to be

Japanese B encephalitis

included in the differential diagnosis of TBE.

St. Louis encephalitis

Its causative agent, Borrelia burgdorferi sensu

Eastern and Western equine encephalitis

lato complex (B. burgdorferi sensu stricto, B.

Adenovirus infection

garinii and B. afzelii), is transmitted by ticks and

West Nile Fever

other arthropods. In our part of the world, its

Louping Ill virus infection

incidence is higher than that of TBE. Contrary

Tuberculous meningitis

to TBE, the various stages and the manifestations of lyme borreliosis occur facultatively;
transitions may be indistinct. High-dose administration of penicillin, cephalosporin, macrolide or doxycycline is the therapy of choice.157)

Leptospiral meningitis
Tularaemia
Q-fever
Tick typhus
Tick paralysis caused by salivary toxin of ticks
Bacterial meningitis caused by common
pathogens

Acute human granulocytic ehrlichiosis (HGE)

is an emerging tick-borne disease, which

Table 13. Differential diagnosis of TBE

should now be included in the differential diagnosis of febrile illnesses occurring after a

the duration of fever in the initial phase of TBE

tick bite in Europe. HGE is caused by Ehrlichia

is shorter (median 4 days vs. 7 days in patients

phagocytophila (Anaplasma), gramnegative

with acute HGE). Clinical signs including chills,

intracellular bacteria that infect white blood

myalgia and arthralgia, and laboratory findings

cells. Comparing the clinical signs and labo-

e. g. elevated values for lactate dehydroge-

ratory findings in adult patients with proven

nase and C-reactive protein direct towards a

acute HGE with that of patients in the initial

diagnosis of acute HGE rather than the initial

phase of tick-borne encephalitis shows that

phase of TBE.158)

45

prevention

Prevention
Va c c i n a t i o n i s r e c o m m e n d e d f o r e v e r y o n e , c h i l d r e n a n d a d u l t s a l i k e ,
r e s i d i n g i n o r t r a v e l l i n g t o e n d e m i c a r e a s . ( I . M u t z , M D, L e o b e n )

Elimination of the disease by controlling all

skin and permethrin to clothing. But, do not

vectors is not possible, and no effective or

apply it to clothing while it is being worn,

practicable tools are available for interrupting

and allow the clothing to thoroughly dry

the virus cycle in nature.

before wearing.
Performing daily checks of skin for ticks.

7.1.

General preventive measures

Check children two to three times a day.

Check under waist bands, sock tops, under

Avoiding tick-infested areas when possible

Wearing light-coloured clothing that show

arms, and any other moist areas.

Removing ticks by using fine-tipped twee-

ticks easily and covers arms and legs. Wear

zers (Figure 23). Grasp the tick firmly and as

long-sleeved shirts, tight at the wrists, long

closely to the skin as possible. Using a stea-

pants tight at the ankles and tucked into

dy motion, pull the ticks body away from

socks, and shoes covering the whole foot.

the skin without rotation. If parts of the tick

Applying diethyltoluamide (e.g., DEET) to

remain stuck in the skin, they should be

removed as soon as possible. Suffocating
the tick with oil, cream etc. may induce
injection of more infectious material into the
body so do not use petroleum jelly, burning matches or cigarette ends, nail polish or
other products.
7.1.1. Control of tick populations
Ticks being the chief vector of TBE virus, past
efforts to fight TBE concentrated on the control of tick populations in TBE endemic areas.
In former Czechoslovakia and USSR, largescale control measures using Tetrachlorvin-

Figure 23: Removing of a tick

46

phos, DDT, or Hexachlor did not produce the

prevention

desired effect. As the virus persists not only

benefit-risk ratio may be negative and there-

in ticks, but also in wild animals, such mea-

fore, TBE immunoglobulin must not be used

sures are of no use in the elimination or even

for post-exposure prophylaxis in children and

control of the disease.

adolescents up to the age of 14 years.

7.1.2. Protective clothes, repellents

7.2.

As ticks attach to any spot on the host, and

Currently no causal treatment is known for

from there try to reach an uncovered part of

TBE. However TBE can be successfully pre-

the skin, adequate clothing may help to make

vented by active immunization. Prevention

access to the skin more difficult for ticks. Pro-

by special clothing and/or tick repellents has

tective clothes must be completely closed to

proven not reliable enough and the registra-

be really effective, but this may be found into-

tion of TBE-specific hyperimmunoglobulin for

lerable by people spending their leisure time or

post exposure prophylaxis has been suspended

holidays in endemic areas in the warm season.

due to concerns about antibody dependent

Active immunization

enhancement of infection.161)
In former Czechoslovakia, forestry workers
were given protective clothes impregnated

Baxter offers the leading TBE vaccine in Europe,

with DDT and were regularly disinfested after

FSME-IMMUN 0.5 ml for adults from 16 years

work.

But these preparations afford protec-

of age and FSME-IMMUN 0.25 ml Junior for

tion for a few hours only. Moreover, there have

children and adolescents 115 years. FSME-

been reports from the former USSR of ticks

IMMUN has been registered in Austria since

becoming resistant to repellents.

1979 and has been widely used for many years

159)

34)

in more than 20 European countries. 80 million

All these preventive measures directed at ticks

doses have been administered since then.

have offered only limited protection. It was

realized quite early that a vaccine was required
for protection from the causative agent itself,
the TBE virus.

Vaccination coverage
in Austria 2004*
Age

Vaccination coverage (%)

112

81

1319

95

2029

93

3039

90

4049

87

5059

87

6069

83

defence at that time160) and is limited to admi-

7079

79

nistration for up to 48 hours after the tick bite.

80+

68

7.1.3. Post-exposure prophylaxis

In nearly all patients, IgM and IgG antibodies
can be detected at the time of presentation
for medical care; the antibody titer may reach
its maximum level by the first blood test. Thus,
the administration of IgG concentrates is unlikely to be of benefit to the patients immune

Therefore, IgG is not available any more in

European countries. Especially in children the

*) Fessel-GfK Austria 2005

Table 14

47

prevention

Residents of and travellers to TBE endemic

creased to a very low rate of 2.3% of the total

areas, who are at risk of tick bites, are advised

recorded cases (Figure 13).87)

to receive TBE vaccination.83, 81)

The increased vaccination coverage has resulThe Austrian example shows that contain-

ted in a marked decline of the morbidity of

ment of TBE is feasible by mass vaccination.

TBE in Austria. This s not seen in other Euro-

In the pre-vaccination era, Austria had a very

pean countries with low vaccination coverage.

high recorded morbidity of TBE probably at

The incidence of TBE can only be influenced

that time the highest in Europe. In high risk

by a high vaccination coverage and is not achie-

areas, the average annual incidence in the

ved until general vaccination is undertaken.87)

population exposed to ticks in their working

environment was 0.9/1000.162) A mass vacci-

7.2.1. FSME-IMMUN vaccines

nation campaign was started in 1982 and continues annually since then. The vaccination

BAXTERs FSME-IMMUN vaccines are inactiva-

coverage of the total Austrian population is

ted whole virus vaccines containing a suspen-

high and reached 86% in 2001; in the highest

sion of purified tick-borne encephalitis virus

risk areas even 95% (Table 13). 66 % of the

(strain Neudrfl), propagated in chick-embryo

total population abide to the recommended

fibroblast cells of specific pathogen free eggs

vaccination schedule, including regular booster

and subsequently subjected to inactivation.

vaccinations.

A number of modifications have been made

to the manufacturing process and formulation

48

In particular, the vaccination program for

of FSME-IMMUN since the first tissue culture

school children has proven to be highly effec-

derived vaccine in the early 1970s.163) The pro-

tive. TBE infection in this age group has de-

duct is highly purified by the use of continuous-

prevention

Pharmaceutical composition of FSME-IMMUN vaccines

FSME-IMMUN 0.5 ml

FSME IMMUN 25 ml Junior

2.4 g (target)
22.75 g (range)

1.2 g (target)
11.375 g (range)

1 mg

0.5 mg

0.5 mg

0.25 mg

3.45 mg
0.22 mg
0.045 mg

1.725 mg
0.11 mg
0.0225 mg

Max. 15 mg

Max. 7.5 mg

Max. 5 g

Max. 2.5 g

Protamine sulfate

Trace

Trace

Neomycin and gentamicin

Trace

Trace

Add 0.5 ml

Add 0.25 ml

Active substance: formaldehyde-inactivated,

sucrose gradient purified, TBE virus antigen
Adjuvant: aluminum hydroxide
Stabilizer: human serum albumin
Buffer system
Sodium chloride
Na2HPO4.2H2O
KH2PO4
Sucrose
Formaldehyde

Water for injection

Table 15

flow zonal ultracentrifugation and is thiomer-

an elected date followed by a second dose

sal free. Each batch is extensively tested for

between 1 and 3 months later. The third dose

efficacy and safety in cell cultures and test

should be given between 5 and 12 months

animals.

after the second vaccination (Figure 24).

The licensed vaccines, FSME-IMMUN 0.5 ml

Rapid immunization schedule: First and

(for adults from 16 years of age) and FSME

second dose should be given two weeks apart,

IMMUN 0.25 ml Junior (for children and ado-

in order to ensure rapid protection if primary

lescents aged 115 years) contain 2.4 g and

immunization is started during spring or sum-

1.2 g TBE virus antigen, respectively, adsorbed

mer. A third dose should be given 512 months

on aluminium hydroxide (Table 15). The vaccine

after the second vaccination (Figure 25).

134)

may be stored at 2 C to 8 C for 24 months.

7.2.2. Immunization schedule
The optimal time to start vaccination against
TBE is during winter in order to ensure protection prior to the start of the tick season in
spring.
Conventional primary immunization
regimen: The first dose should be given on

49

prevention

Booster doses: The first booster dose

age, or dependent on a childs development

should be given 3 years after the primary im-

and nutrition status, the vaccine is adminis-

munization series. Sequential booster doses

tered into the thigh muscle (vastus lateralis

should be given at 35 year intervals in accor-

muscle). Care must be taken to avoid acci-

dance with national recommandations. In per-

dental intravascular administration.

sons with an impaired immune system

165)

it

is recommended to determine antibody con-

7.2.4. Contraindications

centrations in order to assess the need for

and special precautions for use

sequential doses. In general, effective protection can only be ensured if the recommended

TBE vaccination should be postponed if the

dosages and intervals are followed. Extending

person is suffering from an acute febrile infec-

the interval between immunizations may leave

tion. Allergies to components of the vaccines

persons with inadequate protection against

or severe reactions to egg ingestion constitute

infection in the interim period.

contraindications. Non-severe allergy to egg

protein does not usually constitute a contra-

7.2.3. Method and

indication to TBE vaccination. However, such

route of administration

individuals should only be vaccinated under

appropriate supervision. As for all injectable

The vaccine is administered by intramuscular

vaccines facilities for emergency management

injection, preferably into the upper arm (del-

of hypersensitivity reactions should be avai-

toid muscle). In children up to 18 months of

lable. In the case of a known or suspected

Basic vaccination schedule

day 0

13 months

512 months
after 2nd vaccination

3 years
after 3rd vaccination

every
35 years

Figure 24: The first two injections should be given prior to the tick season in spring.

Rapid vaccination schedule

day 0

day 14

512 months
after 2nd vaccination

Figure 25: Fast protection for late-comers and travellers

50

3 years
after 3rd vaccination

every
35 years

prevention

dose with respect to safety and immunogenicity in adults from 16 years of age.166) In this
study, the second vaccination was administered 21 to 35 days after the first. A seroconversion rate of 97 %, as determined by ELISA
and neutralisation test, was observed 21 to
35 days after the second vaccination with the
2.4 g dose. The high seroconversion rate
after the second vaccination was paralleled
by a geometric mean concentration (GMC)
of 631.3 VIE U/ml,166) as determined by ELISA.
After the third vaccination, the seroconversion
rate was 100% and the GMC increased to
1503.0 VIE U/ml. The excellent immunogenicity of FSME-IMMUN 0.5 ml was confirmed
autoimmune disease, an unfavorable influence

by another clinical study that showed similar

of the vaccination on the autoimmune disea-

results after the third vaccination.167)

se must be weighed against the risk of a TBE

virus infection. A protective immune response

The rapid immunization schedule, with the

may not be elicited in individuals undergoing

second dose being given within 2 weeks after

immunosuppressive therapy or individuals with

the first vaccination, has been applied in most

an impaired immune system. In such cases

European countries for many years. The cour-

TBE antibodies should be determined in order

se of the immune response was investigated

to assess the immune response and the need

in an open-label, phase IV study in healthy

for sequential doses. Caution is required when

adults in order to establish the earliest time

considering the need for vaccination in persons with pre-existing cerebral disorders. The
safety of TBE vaccines for use during pregnancy and lactation has not been investigated
in controlled clinical trials, and therefore FSMEIMMUN should only be administered after

Seropositivity after the

second vaccination using the
rapid immunization schedule 169)
Days after 2nd vaccination
(day 12+/ 2)

Seropositivity
rate* (%) ELISA

Seropositivity
rate** (%) NT

21.4

89.3

28.6

96.4

Immunogenicity of FSME-IMMUN 0.5 ml

14

92.9

98.2

in adults: Several clinical studies with FSME-

21

96.4

100

IMMUN 0.5 ml were conducted to assess the

42

98.2

100

individual consideration of potential risks and

benefits.50)
7.2.5. Immunogenicity

immunogenicity of the vaccine. In a dose find-

*) as determined by ELISA (>126 VIE U/ml)

ing study, the 2.4 g target dose of the FSME-

**) as determined by NT (titer 10)

IMMUN vaccine was found to be the optimal

Table 16

51

prevention

point at which vaccinees show seropositive

The immunogenicity of the pediatric formula-

antibody levels after two vaccinations.

tion was further tested in an open label phase

169)

By

day 14 after the second vaccination, more

III clinical study in healthy children and ado-

than 92% of subjects showed seropositive

lescents (115 years), using the conventional

antibody levels as determined by ELISA

immunization schedule. In this study, high

(Table 16). The GMC of TBE virus antibodies

overall seroconversion rates (96.0% and 99.7%)

as determined by ELISA reached a peak of

as determined by ELISA were observed

593.2 VIEU/ml at day 21 after the second vac-

2135 days after the second and third vacci-

cination, similar to the GMC observed with the

nation, respectively.171) No age dependency

conventional schedule. Seropositivity rates

was detected regarding seroconversion rates.

determined by NT showed a more rapid rise

The high seroconversion rates after the 2nd

with 89.3% of the subjects being seropositive

and 3rd vaccinations were paralleled by GMCs

on day 3 after the second vaccination. Geo-

of 1,473 VIEU/ml and 5,720 VIEU/ml, respec-

metric mean titers (GMTs) determined by NT

tively, confirming that FSME-IMMUN 0.25 ml

also reached their peak (142.2) on day 21 after

Junior is highly immunogenic for vaccination

the second vaccination. These results confirm

of children and adolescents.

that the recommended time point for the administration of the second dose is appropriate.

Published data for an accelerated schedule,

where the 2nd dose was given 2 weeks after
the 1st dose, is available for children.
In 1981 in a prospective controlled
study, 37 asthmatic children received a previous generation
vaccine on day 0 and day 10.
92% of these children seroconverted 2 weeks after the
2nd dose as demonstrated
by the haemagglutination
inhibition test (95 % when
retested using ELISA) as
compared to 94% seroconversion
of 17 children, vaccinated according to the

Immunogenicity of FSME-IMMUN 0.25 ml

conventional scheme, and tested with the

in children: For the immunization of children

HI test only.172)

a pediatric formulation of FSME-IMMUN was

52

developed: FSME-IMMUN 0.25 ml Junior

Antibody persistence of FSME-IMMUN:

(Table 15). In dose-finding studies in children

A study investigating antibody persistence in

and adolescents aged 115 years, half the

adults, who had received at least a complete

adult dose (containing 1.2 g TBE-virus) was

primary immunization (3 vaccinations) with

shown to be the optimal dose with respect to

FSME-IMMUN, showed that all 430 subjects

safety and immunogenicity for the pediatric

had neutralizing TBE antibodies for at least

population.

3 years (median 11 years) after their last

170)

prevention

Effectiveness of vaccination with FSME-IMMUN in the field 87)

Year

No. of cases

Population at risk (x 10 3)

Protection rate (%)

Unvaccinated

2 doses

> 3 doses

2 doses

> 3 doses

1994

172

2340/165

390/1

5070/6

96.4

98.3

1995

109

2110/104

460/1

5230/4

95.6

98.4

1996

125

2051/114

328/0

5421/11

100.0

96.0

1997

99

2161/93

390/0

5249/6

100.0

97.5

2000

60

1250/58

2001

54

1120/50

6550*/2
160/0

99.3

6720/4

100.0

98.7

*) No. of doses unknown

Table 17

primary or booster immunization. The analysis

7.2.6. Vaccine effectiveness

also showed that subjects with low and/or

negative to borderline ELISA concentrations

FSME-IMMUN has been shown to be highly

were older and more often had only received

immunogenic in clinical studies and effective

a primary vaccination. The authors concluded

in the field. While no formal efficacy study has

that after one or more booster vaccinations

been conducted, the decrease in the annual

(at least 4 vaccinations), a longer than anti-

number of TBE cases reported in relation to

cipated immunity against TBE is provided.

the vaccination rate in Austria an endemic

173)

These data were considered indicative that

the first booster with FSME-IMMUN should
be given 3 years after completion of primary
700

immunization. Following publication of these

Austria

data sequential boosters have been recom-

Czech Rep.

600

up to 60 years of age. For individuals older

than 60 years of age 3 year booster intervals
should be observed.

Number of cases

mended at 3 to 5 year intervals for persons

500
400
300

In case of prolonged booster intervals, a

single booster administration was shown to
be sufficient to re-establish protection.173) If

200
100

the last booster has been given longer than

8 years ago, it is recommended to assess the
booster response by serological investigation.

0
1979

1983

1987

1991 1995
Years

1999

2003

Figure 26: TBE in Austria and Czech Republic 19792004

53

prevention

TBE in children in Austria 19942003:

Estimate of cases prevented by vaccination with FSME-IMMUN

69)
69)

no. cases
age group (years)

no. cases
in unvaccinated

no. cases
in vaccinated

expected in vaccinated

protection rate

014

36

136

98,5 %

1519

103

100 %

Table 18

country where mass TBE vaccination was ini-

Herd immunity: TBE vaccination cannot

tiated in 1982 shows the effectiveness of TBE

induce herd immunity because the virus is not

vaccination. The data of the Austrian surveillan-

transmitted by person-to-person contact.

ce program demonstrates that the protection

rate of FSME-IMMUN exceeds 96% (Table 17).

Breakthrough: Breakthrough disease is rare

The calculated rate of protection is based on

and tends to occur, for the most part, in hig-

the assumption that the whole Austrian popu-

her age groups. Vaccination failures are seen

lation (7.8 million) is equally at risk (Table 17).

approximately four times more frequently in

individuals who received only two doses than

FSME-IMMUN is also used in highly endemic

in fully vaccinated persons (> 3 doses).87)

areas in Russia and Asia; cross-protection

potency studies in mice showed that the TBE

7.2.7. Safety profile

virus vaccines are effective not only against

European strains but also against Russian and

Safety profile of FSME-IMMUN 0.5 ml

Asian strains of the virus.

in adults: The high safety profile of FSME-

11, 164)

IMMUN 0.5 ml has been demonstrated in

Effectiveness in children: Similarly to the

several clinical studies involving more than

protection rate in adults, a protection rate

4,000 subjects. As expected with intramuscularly administered vaccines, local reactions

exceeding 98 % in children and adolescents

was calculated for FSME-IMMUN (Table 18).

69)

54

such as local pain and tenderness, reddening

prevention

and swelling at the injection site were observed. General reactions such as headache,
muscle pain, malaise and fatigue were transient and mainly mild in nature (Table 19).
Safety profile of FSME-IMMUN 0.25 ml
Junior in children: In an open label study
FSME-IMMUN 0.25 ml Junior was demonstrated to have a high safety profile in 2,400 children and adolescents aged 115 years. The

Most frequently reported symptoms after

the first vaccination with FSME-IMMUN
0.5 ml in adults in a clinical study 167)*
Headache

5.7 %

Malaise

4.5 %

Muscle pain

4.8 %

Fatigue

6.2 %

Joint pain

1.3 %

Fever

0.8 %

*) n=2977

Table 19

majority of observed local and systemic reactions were mild. Local pain and tenderness

usage. Most of the reactions were reported

were the most common reactions. The most

after the first vaccination, with 65% occurring

frequently reported systemic symptoms were

in the 12 years olds. Fever was mostly mild:

fever and restlessness in young children, as

transient severe fever (> 40.0 C) occurred in

well as headache in all children.

0.01%. No fever convulsions, nor cases of

171)

Fever was

mainly mild (between 38.0 and 38.5C), of very

neurologic syndroms were observed. The

short duration (<24 hours), and occurred most

authors conclude that the currently available

frequently in children aged 12 years (Figu-

TBE vaccines are safe. Therefore the vacci-

re 27a, 27b).

nations should be offered to all persons living

174)

Fever rates reported after the

second and third vaccination were generally

or travelling to TBE endemic areas.142) None

lower than after the first vaccination.

of the clinical studies in adults and children

reported any causal relationship to clinically

In order to assess the safety of TBE vaccines

serious adverse experiences.

in the field, a large scale sentinel study was

performed during 2002 by the Austrian Green

Pharmacovigilance of FSME-IMMUN:

Cross for Preventive Medicine in Austria. A

Vaccine pharmacovigilance is the continual

total of 25,905 doses of TBE vaccines were

evaluation and monitoring of a vaccines safety

applied and adverse reactions were reported

after it has received marketing authorization.

at a rate of 0.41%. This confirms the excellent

Recent pharmacovigilance data confirm the

tolerability of TBE vaccinations in broadscale

excellent safety profile of both the pediatric

Adverse reactions reported from Dec. 1, 2001 to Feb. 28, 2005

for FSME-IMMUN 0.5 ml and FSME-IMMUN 0.25 ml Junior 174)
TBE vaccine

doses distributed

adverse drug reactions

(reporting rate/100,000 doses distributed)
non-serious

serious

total

FSME-IMMUN 0.5 ml

12,526,043

337 (2.69)

104 (0.83)

441 (3.52)

FSME-IMMUN 0.25 ml Junior

2,658,818

91 (3.42)

25 (0.94)

116 (4.36)

Table 20

55

prevention

and the adult presentation of FSME-IMMUN

(Table 20). From December 2001 until February
Classification of fever after the 1st vaccination
25 %

2005, the reported rate of adverse drug reactions was 3.52 and 4.36 per 100,000 doses
distributed in adults and children, respectively

20 %
12 years n=183
36 years n=183
715 years n=183

15 %

(Table 20), confirming the excellent tolerability

demonstrated in clinical studies.

10 %

FSME-IMMUN vaccines are produced in Orth

5%

on the Danube, near Vienna, Austria, where

some 500 employees research and further

0%

38,0
38,5 C

38,6
39,0 C

39,1
39,5 C

39,6
40,0 C

> 3 days

develop vaccines. Several decades of experience and a state-of-the-art technology ensure

Figure 27a: No severe cases of fever were observed. Fever reactions reported
were mostly in the 12 year age group.

the ensure the high quality of FSME-IMMUN

vaccines.
Both Baxter and the health authorities test
every batch of TBE vaccine. Of all batches

Duration of mild fever after the 1st vaccination

25 %

produced during the last 30 years not a single

one has been rejected.

20 %
12 years n=183
36 years n=183
715 years n=183

15 %
10 %
5%
0%

< 24

1 day

2 days

3 days

> 3 days

Figure 27b: Fever was almost always of short duration.

List of abbreviations

56

CNS

Central nervous system

IgG

Immunoglobulin G

DDT

Dichlorodiphenyltrichloroethane

PCR

Polymerase chain reaction

(organochlorine insecticide)

RNA

Ribonucleic acid

ELISA

Enzyme-linked immunosorbent assay

TBE

Tick-borne encephalitis

FSME

Frh-Sommer-Meningo-Encephalitis

TBEV

Tick-borne encephalitis virus

German term for TBE

VIE U/ml

Vienna units/ml TBE ELISA titer unit

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Baxter Vaccine AG
Industriestrasse 67
A-1221 Vienna, Austria
Product information:
Sissy Alphart
Global Marketing Manager TBE Vaccines
T: +43 1 20 100 2899
F: +43 1 20 100 5073
Sissy_alphart@baxter.com
Medical Director:
Dr. Eva Maria Pllabauer
T: +43 201002345
Eva_maria_poellabauer@baxter.com
For product information please see the national package insert on FSME-IMMUN
specific for your country. FSME IMMUN has received marketing authorization under
the trade name of TICOVAC in Italy, France, Denmark, Norway and Finland. BAXTER,
FSME-IMMUN and TICOVAC are trademarks of Baxter International Inc.,
its subsidiaries of affiliates.
Sources: pictures of ticks, patients and production: Baxter archive; animals:
museum of Natural Hisory Vienna, Landesmuseum Niedersterreich (F. Gauermann);
art, illustrations: MedNews archive; printed in Groebersdorf, May 2005

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