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R
Seroprevalence of tick-borne encephalitis virus and
vaccination coverage of tick-borne encephalitis, Sweden,
2018 to 2019
Bo Albinsson1, 2,* , Tove Homan1,* , Linda Kolstad¹ , Tomas Bergström , Gordana Bogdanovic , Anna Heydecke , Mirja Hägg ,
Torbjörn Kjerstadius , Ylva Lindroth , Annika Petersson , Marie Stenberg10 , Sirkka Vene¹ , Patrik Ellström2,3 , Bengt Rönnberg1,2
, Åke Lundkvist¹
1. Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
2. Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala, Sweden
3. Zoonosis Science Centre, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
4. Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
5. Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
6. Centre for Research and Development, Uppsala University, Region Gävleborg, Gävle, Sweden
7. Laboratory Medicine, Clinical Microbiology, Central Hospital, Karlstad, Sweden
8. Department of Laboratory Medicine, Medical Microbiology, Lund University, Skåne Laboratory Medicine, Lund, Sweden
9. Department of Clinical Chemistry and Transfusion Medicine, Växjö Central Hospital, Växjö, Sweden
10. Laboratory Medical Center Gotland, Visby hospital, Visby, Sweden
* These authors contributed equally to the work and share the first authorship.
Correspondence: Bo Albinsson (bo.albinsson@akademiska.se)
Citation style for this article:
Albinss on Bo, Homan Tove , Kolstad Linda, Bergström Tomas, Bogdanovic Gordana, Heyde cke Anna, Hägg Mir ja, Kjerstadius Torbjörn , Lindroth Ylv a, Petersson
Annika , Stenberg Marie, Vene Sirkka , Ellström Patrik, Rönnberg Beng t, Lundkvis t Åke. Seroprev alence of tick-bor ne encephalitis virus and vaccination coverage of
tick-bor ne encephalitis , Sweden, 2018 to 2019. Euro Surv eill. 2024;29(2):pii=2300221. https://doi.org/10.2807/1560-7917.ES. 2024.29.2.23 00221
Article submit ted on 14 Apr 2023 / accep ted on 07 Nov 2023 / published on 11 Jan 2024
Background: In Sweden, information on seropreva-
lence of tick-borne encephalitis virus (TBEV) in the
population, including vaccination coverage and infec-
tion, is scattered. This is largely due to the absence
of a national tick-borne encephalitis (TBE) vaccina-
tion registry, scarcity of previous serological studies
and use of serological methods not distinguishing
between antibodies induced by vaccination and
infection. Furthermore, the number of notified TBE
cases in Sweden has continued to increase in recent
years despite increased vaccination. Aim: The aim
was to estimate the TBEV seroprevalence in Sweden.
Methods: In 2018 and 2019, 2,700 serum samples from
blood donors in nine Swedish regions were analysed
using a serological method that can distinguish anti-
bodies induced by vaccination from antibodies elicited
by infection. The regions were chosen to reflect differ-
ences in notified TBE incidence. Results: The overall
seroprevalence varied from 9.7% (95% confidence
interval (CI): 6.6–13.6%) to 64.0% (95% CI: 58.3–
69.4%) between regions. The proportion of vaccinated
individuals ranged from 8.7% (95% CI: 5.8–12.6) to
57.0% (95% CI: 51.2–62.6) and of infected from 1.0%
(95% CI: 0.2–3.0) to 7.0% (95% CI: 4.5–10.7). Thus,
more than 160,000 and 1,600,000 individuals could
have been infected by TBEV and vaccinated against
TBE, respectively. The mean manifestation index was
3.1%. Conclusion: A difference was observed between
low- and high-incidence TBE regions, on the over-
all TBEV seroprevalence and when separated into
vaccinated and infected individuals. The estimated
incidence and manifestation index argue that a large
proportion of TBEV infections are not diagnosed.
Introduction
Tick-borne encephalitis virus (TBEV) is a member of
the Flavivirus genus of theFlaviviridae family [1]. The
virus is a health risk for humans and is prevalent in
large areas of forested parts of Europe and in parts of
Asia [2]. Three main TBEV subtypes have been identi-
fied: the European (TBEV-Eur), the Siberian (TBEV-Sib)
and the Far Eastern (TBEV-FE) [1]. Two other subtypes,
the Baikalian (TBEV-Bkl) and the Himalayan subtype
(TBEV-Him), have also been described [3]. The geo-
graphical distribution of the TBEV subtypes mimics
the geographical distribution of the main vectors, the
sheep tickIxodes ricinus for the TBEV-Eur subtype and
the taiga tick I. persulcatus for the TBEV-Sib and the
TBEV-FE subtypes, but mixing of subtypes in the two
vector species occurs [4]. Although TBEV is mainly
transmitted to humans via tick bites, consumption of
unpasteurised milk and milk products has also been
reported as a source of infection [5-7]. The reservoir
hosts of the virus are the ticks themselves and small
mammals (e.g. voles and mice), while larger wild mam-
mals (e.g. roe deer (Capreolus capreolus)) act as main-
tenance hosts for ticks [8]. The 11 kilobases long TBEV
genome encodes a single polyprotein representing
three structural proteins, capsid (C), membrane (M),
envelope (E) and seven non-structural (NS) proteins
(NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [9].
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The virus affects the central nervous system and tick-
borne encephalitis (TBE) can vary from mild to severe
illness. The disease typically presents as a two-phase
illness. In the initial phase, individuals may experience
symptoms, such as fever, fatigue, headache, muscle
aches and nausea. The second phase involves the
neurological system and includes symptoms of menin-
gitis and/or encephalitis [10]. The case fatality rate in
Europe is estimated to 1–2% [1,10]. Long-lasting seque-
lae may occur after an infection [1,10,11]. The frequency
of subclinical infections is largely unknown, but they
are considered to be quite common [1,12]. No specific
treatment is available in Europe, although post-expo-
sure immunoglobulins are available in Russia [1,3,12].
Effective vaccines exist and give good protection, but
booster doses are needed, and vaccine breakthroughs
or failures occur [13-15].
Tick-borne encephalitis is an important and growing
public health problem in Europe [16-18]. There is a com-
mon European case definition which is used in various
versions [10]. In 2020, the European Centre for Disease
Prevention and Control (ECDC) received information of
3,817 notified cases from 24 European Union/European
Economic Area (EU/EEA) countries [19]. Notification is
compulsory in 19 countries and the notification rate
was highest in Lithuania (24.3 cases per 100,000
inhabitants), followed by Slovenia and Czechia (8.9
cases per 100,000 inhabitants). The numbers of noti-
fied cases are increasing, and a spread to new regions
and countries has been observed, which highlights the
need for improved surveillance and updated vaccina-
tion recommendations [6,13,19-21].
Since 2004, notification of TBE cases has been man-
datory in Sweden. As in the other parts of Europe, the
number of notified cases in Sweden has increased
despite increased vaccination, judged by increased
number of vaccine doses sold along with a spread of
TBE cases to new geographical regions [18,22]. The
annual notified incidences of TBE vary largely between
Swedish regions, from 0 in the north to > 10 cases per
100,000 inhabitants in the southern parts of the coun-
try. Currently, TBE is endemic in the southern part of
Sweden with almost all cases reported from the south-
ern third of the country. Vaccination against TBE is
not included in the national vaccination programme
in Sweden and there is no national vaccination regis-
try for TBE, but it can be assumed that the proportion
of vaccinated individuals increases over time, as the
number of doses sold per year has increased, based
on sales statistics from vaccine companies. However,
there is a lack of information on TBEV seroprevalence
and vaccination coverage of TBE in the Swedish popu-
lation [23-26].
In this study, we used a serological method, a TBEV
suspension multiplex immunoassay (TBEV SMIA),
that can distinguish antibodies induced by vaccina-
tion from antibodies elicited by infection by simul-
taneously detecting antibodies directed against the
whole virus (WV) and NS1 antigens [27,28]. The TBEV
NS1 antigen is absent, or possibly present in minute
amounts, in the TBE vaccines available in the EU/EEA
area ‒ FSME-Immune (Pfizer) and Encepur (Bavarian
Nordic) [29-33]. Hence, TBE-vaccinated individuals only
develop detectable levels of antibodies against the WV
antigen whereas individuals exposed to TBEV develop
What did you want to address in this study?
Tick-borne encephalitis (TBE) is a vaccine-preventable viral disease af fecting the central ner vous system.
Infections occur in Sweden, but little is known on how many people had a TBE virus infection or are protected
from disease by antibodies af ter vaccination. We analysed serum samples from blood donors with a method
that can distinguish between antibodies produced by vaccination and infection and compared the results
with the number of notified TBE cases.
What have we learnt from this study?
We found that 1–7% of the Swedish blood donors had previously been infected by the virus and that there
was a difference between regions with a low and high known frequency of the disease. We estimated that
more than 160,000 individuals could have undergone the infection and more than 1,600,000 individuals
had antibodies from vaccination against the disease. The results indicate that more individuals have had
TBE virus infection than was previously estimated.
What are the implications of your findings for public health?
The findings may lead to an improved understanding of TBE in Sweden, both in regions with a few TBE
cases and in those with many cases. The finding that more people have had TBE virus infection than was
previously known can probably be generalised to other countries where TBE regularly occurs and guide
public health authorities and the general public.
KEY PUBLIC HEALTH MESSAGE
3www.eurosurveillance.org
antibodies against both WV and NS1. The TBEV SMIA
is currently employed as a national reference method
for TBE diagnostics at the Laboratory of Clinical
Microbiology, Uppsala University Hospital, Sweden.
The aim of the study was to estimate the TBEV sero-
prevalence in Sweden, including infection and vac-
cination coverage, using blood donor sera collected
2018–2019 from nine different regions in Sweden.
Methods
Serum samples
In 2018 and 2019, 2,700 blood donor sera were
collected from nine regions of Sweden (Gotland,
Gävleborg, Kronoberg, Skåne, Stockholm, Uppsala,
Värmland, Västerbotten, Västra Götaland), 300 sam-
ples per region. In 2018, sera were collected from all
regions except for Kronoberg where samples were
collected in the beginning of 2019. The anonymised
serum samples were routinely tested for blood-borne
infections and collected without being selected by the
medical doctor in charge of the clinical microbiological
laboratory of the region. The exact donation site was
unknown in regions with more than one blood donation
site. Information on gender and age as well as donor
residency was not available.
Grouping of geographical regions
The regions included were grouped into three TBE inci-
dence levels based on the mean number of notified TBE
cases per 100,000 inhabitants 2004–2018: (i) absent–
low (0–1 case), (ii) low–medium (1–4 cases) and (iii)
high (> 4 cases). Incidence data were retrieved from the
Public Health Agency of Sweden [22].
Tick-borne encephalitis virus suspension
multiplex immunoassay
A previously developed, evaluated and published
Luminex-based TBEV SMIA for detection of antibodies
against TBEV WV and NS1 antigens was used for the
analyses [27,28]. Briefly, TBEV WV and NS1 antigens
were coupled to differentially colour-marked magnetic
microspheres. Serum samples diluted 1:50 were added
to 96-well microtitre plates. After re-suspension of the
microspheres, a vortexed and sonicated microsphere
mixture was added to each well, giving a final serum
dilution of 1:100. After 60 min incubation at room tem-
perature (RT) and a washing step, biotinylated pro-
tein G was added, followed by a 30 min incubation
at RT followed by a washing step and re-suspension.
Streptavidin–phycoerythrin at a concentration of 2 μg/
mL was then added and incubated for 15 min at RT.
Finally, the mixture was washed once prior to re-sus-
pension. The analysis was performed using a Luminex
200 instrument (Luminex Corporation, Austin, the
United States) and the output data were reported as
median fluorescence intensity (MFI). The assay cut-off
values were 200 and 250 MFI for NS1 and WV, respec-
tively. Samples were classified into three subgroups
depending on the TBEV SMIA results: i) vaccinated (WV
positive and NS1 negative), ii) infected (WV positive
and NS1 positive) and iii) negative (WV negative and
NS1 negative).
Due to the absence of methods capable of detecting
antibodies against TBEV NS1 on the commercial mar-
ket, a classical determination of the analytical perfor-
mance of the TBEV SMIA is lacking. Clinical sensitivity
has been calculated to 86–100%, depending on the
antibody isotype and antigen, using patient samples
T 1
Annual notified incidence of tick-borne encephalitis and seroprevalence of tick-borne encephalitis virus in blood donorsa,
per region, Sweden, 2004–2019 (n = 2,700)
Region TBE incidenceb
Sera
TBEV seroprevalence
VaccinateddInfectedeTotal
Rate Levelcn % 95% CI n % 95% CI n % 95% CI
Gotland 2.4 Low–medium 300 39 13.0 9.5–17.5 31.0 0.2–3.0 42 14.0 1 0.3 –18.4
Gävleborg 0.7 Absent–low 300 54 18.0 13.9–22.9 31.0 0.2–3.0 57 19.0 14.7–23.9
Kronoberg 0.7 Absent–low 300 26 8.7 5.8–12.6 31.0 0.2–3.0 29 9.7 6.6–13.6
Skåne 0.6 Absent-low 300 53 17.7 13.6–22.6 41.3 0.4–3.6 57 19.0 14.7–23.9
Stockholm 4.8 High 300 171 57.0 51.2–62.6 21 7.0 4.5–10.7 192 64.0 58.3–69.4
Uppsala 9.1 High 300 84 28.0 23.1–33.5 93.0 1.2–5.4 93 31.0 25.8–36.6
Värmland 1.5 Low–medium 300 97 32.3 27.1–38.0 93.0 1.5–5.8 106 35.3 29.9–41.0
Västerbotten 0.1 Absent–low 300 34 11.3 8.1–15.6 31.0 0.2–3.0 37 12.3 8.8–16.6
Västra Götaland 1.6 Low–medium 300 120 40.0 34.5–45.8 93.0 1.5–5.8 129 43.0 37.3 –4 8.8
Total 2,700 678 25.1 23.5–26.8 64 2.4 1.8–3.0 742 27.5 25.8–29.2
CI: confidence interval; NS1: non-structural protein 1; TBE: tick-borne encephalitis; TBEV: tick-borne encephalitis virus; W V: whole virus.
aSerum samples from blood donors in Gotland, Gävleborg, Skåne, Uppsala, Värmland, Västerbotten and Västra Götaland were taken 2018
and those from Kronoberg in 2019.
bAnnual notifications per 100,000 inhabitants 2004–2018. Data source: Public Health Agency of Sweden.
cAbsent–low: 0–1 case/100,000 inhabitants; low–medium: 1–4 cases/100,000 inhabitants; high: > 4 cases/100,000 inhabitants.
dIndividuals were defined as vaccinated if antibodies were detected against TBEV W V but not against NS1.
eIndividuals were defined as infected if antibodies were detected against TBEV W V and NS1.
4www.eurosurveillance.org
from defined TBE cases. Clinical specificity has been
calculated to 94–100%, depending on antibody iso-
type and antigen, using samples from a vaccine trial
[27]. See Supplementary material for more detailed
information.
Calculations and statistics
Calculations of TBEV seroprevalence, including confi-
dence intervals, were performed with R version 4.1.1 (R
Core Team, 2021), using the Exact method in the pack-
age binom[34]. The estimated number of vaccinated
and infected individuals was calculated by multiplying
the population number with the percentage of vacci-
nated and infected in the region. To rule out children
and a part of the elderly population and hereby reflect
the blood donor as a group, we included the age group
15–64 years in the calculations (Data source: Statistics
Sweden, www.scb.se). The manifestation index (MI),
which is a ratio between notified cases of TBE and the
number with the antibody pattern indicative of TBEV
infection, was calculated as reported by Euringer et al.
[35].
Results
Level of incidence of tick-borne encephalitis
The calculated and determined level of TBE incidence
was absent–low in Gävleborg, Kronoberg, Skåne and
Västerbotten; low–medium in Gotland, Värmland and
Västra Götaland; and high in Stockholm and Uppsala,
the latter with the highest mean number of notified TBE
cases per 100,000 inhabitants 2004–2018 (Table 1).
Seroprevalence of tick-borne encephalitis virus
The overall seroprevalence among all blood donors
was 27.5% and varied from 9.7 to 64.0% between the
regions and the proportions of vaccinated and infected
individuals from 8.7 to 57.0% and 1.0 to 7.0%, respec-
tively (Table 1). Blood donors in Stockholm, Västra
Götaland, Värmland and Uppsala region had the high-
est overall seroprevalence (64.0%, 43.0%, 35.3% and
31.0%), vaccination coverage (57.0%, 40.0%, 32.3%
and 28.0%) and proportion of infected individuals
(7.0%, 3.0%, 3.0% and 3.0%). The proportions of TBE
vaccinated, infected and seronegative (unvaccinated/
uninfected) blood donors per region and the geograph-
ical location of the regions included are presented in
the Figure. Seven serum samples (0.3%) tested posi-
tive for only NS1 (WV negative and NS1 positive) in two
separate runs.
Estimated total number of individuals
vaccinated against tick-borne encephalitis and
infected by tick-borne encephalitis virus
In 2018 and 2019, an estimated 1,644,100 individu-
als aged 15–64 years were vaccinated against TBE and
168,000 had been infected by TBEV in the studied
regions when recalculated from the blood donor sero-
prevalence data (Table 2). The regions with the highest
population sizes (Stockholm, Västra Götaland, Skåne
and Uppsala) had the highest estimated numbers of
vaccinated and infected individuals, as well as the
highest numbers of notified TBE cases 2004–2018.
Calculated manifestation index
The calculated manifestation index (MI) ranged from
0.4 to 8.7% between the studied regions (Table 3).
Uppsala had the highest MI and Västerbotten the low-
est. The mean MI was 3.1%.
Discussion
We investigated the TBEV seroprevalence among blood
donors indicative of previous infection and vaccination
in nine Swedish regions. The overall TBEV seropreva-
lence during the study period was 27.5%, ranging from
9.7% to 64.0% between the regions. Previous studies
in Sweden have included fewer regions, which compli-
cates comparisons with other studies [23-26].
F
Estimated proportion of tick-borne encephalitis
vaccinated, tick-borne encephalitis virus infected and
seronegative blood donors, per region, Sweden, 2018–2019
(n = 2,700)
18%
1%
81%
Gävleborg
28%
3%
69%
Uppsala
57%
7%
36%
Stockholm
13%
1%
86%
Gotland
9%
1%
90%
Kronoberg
11%
1%
88%
Västerbotten
32%
3%
65%
Värmland
40%
3%
57%
Västra Götala nd
18%
1%
81%
Skåne
Proportions of blood donors vaccinated depicted in orange,
infected in yellow and seronegative (unvaccinated or uninfected)
in green per investigated region in blue. In total, 300 blood
donor sera collected in 2018 (Gotland, Gävleborg, Skåne,
Uppsala, Värmland, Västerbotten and Västra Götaland) or 2019
(Kronoberg) were analysed per region.
The map was created with mapchart.net.
5www.eurosurveillance.org
We used the mean number of notified TBE cases per
100,000 inhabitants from 2004 to 2018 to categorise
the incidence levels. Since the number of notified TBE
cases has increased over time and cases are noti-
fied in new areas, our calculations do not accurately
reflect the most recent situation. For instance, in 2004,
Värmland and Västra Götaland had a TBE incidence of
< 1 case per 100,000 inhabitants. In 2018, the TBE inci-
dence had increased to 4.3 cases per 100,000 inhabit-
ants in Värmland and to 3.5 per 100,000 inhabitants in
Västra Götaland.
According to the World Health Organization (WHO),
the TBE incidence in an area is high if more than 5
cases per 100,000 inhabitants are annually notified
and moderate or low if fewer than 5 cases per 100,000
inhabitants are notified [36]. We used a three-point
TBE incidence scale (absent–low, low–medium and
high) to compare our results on TBEV seroprevalence
with notified TBE incidence. A difference was seen in
the seroprevalence when regions of low TBE incidence
were compared with those of high incidence, both con-
cerning the overall seroprevalence and when divided
into subgroups of vaccination and infection. Gotland
and Uppsala were the two exceptions in the study. For
several years, Uppsala and Stockholm regions have
had a high TBE incidence, and Uppsala for several con-
secutive years [22]. In our study, Uppsala region had
a lower seroprevalence compared with Stockholm, but
similar to Värmland and Västra Götaland regions with a
low–medium incidence. This finding was unexpected,
since Uppsala has been a high incidence region for
many years and usually with a higher incidence than
Stockholm. This high incidence in Uppsala region
is likely due to hot spot areas of TBEV, a high abun-
dance of ticks in the vicinity of lakes, watercourses
and other tick habitats and many inhabitants living
in the countryside. The lower TBEV seroprevalence in
the Uppsala region in our study could be explained by
some serum samples originating from individuals resid-
ing in an urban area in the Gävleborg region, which has
an absent–low TBE incidence. We were not aware of
this during sample collection and serological analyses.
Gotland is an island and has a small population, which
leads to relatively high variation in incidence between
years, as isolated cases can greatly impact the inci-
dence rate. For the other regions, including Stockholm,
the TBEV seroprevalences of this study were congruent
with notified incidences.
By measuring antibodies against NS1 we estimated
that 2.4% of the blood donors had a past TBEV infec-
tion. The NS1 IgG seroprevalence ranged from 1.0 to
7.0% and was highest in the Stockholm region with a
high TBE incidence. The latter infection seroprevalence
is in line with a study by Euringer et al., a TBEV NS1 IgG
seroprevalence of 5.6% in blood donors from a highly
endemic district in south-western Germany measured
in 2021 [35]. Information about the persistence of TBEV
NS1 specific IgG is limited. In one patient, anti-TBEV
NS1 IgG could be detected 28 years after confirmed
TBE [33], indicating long-term immunity. We estimated
the total number of infected and vaccinated individuals
per region by extrapolating the seroprevalence results
to the population in the studied regions. According to
our estimations, more than 160,000 individuals could
have been infected by TBEV and 1,600,000 individu-
als could be TBE vaccinated, in the study regions and
in the age group 15–64 years. Assuming anti-TBEV
NS1 IgG (and anti-TBEV WV IgG) can be detected for
approximately 20 years after infection, it is probable
that this seroprevalence has been accumulated during
the last two decades. Although a larger sample size
would provide more accurate estimates, we consider
T 2
Estimated number of individuals aged 15–64 years infected by tick-borne encephalitis virus, vaccinated against tick-borne
encephalitis and notified number of tick-borne encephalitis cases, per region, Sweden, 2004–2019
Region PopulationaEstimated TBE vaccinatedbEstimated TBEV infectedbTBE notif ications 2004–2018c
n95% CI n95% CI nIncidence
Gotland 35,046 4,600 3,300–6,100 400 100–1,100 21 2.5
Gävleborg 170,671 30,700 23,700–39,100 1,700 500–5,300 28 0.7
Kronoberg 121,274 10,600 7,000–15,300 1,200 400–3,800 21 0.7
Skåne 848,053 150,100 115,300–191,700 11,000 3,400–30,500 107 0.6
Stockholm 1,534,225 874,500 785,500–960,400 107, 40 0 69,000–164,200 1,521 4.8
Uppsala 239,927 67,000 55,300–80,200 7,200 2,900–12,900 469 9.1
Värmland 168,738 54,500 45,700–64,100 5,100 2,500–9,800 61 1.5
Västerbotten 167,76 5 21,800 13,600–26,200 1,700 500–5,200 50.2
Västra Götaland 1,075,801 430,300 371,200–492,700 32,300 16,100–62,400 394 1.6
Total 4,360,870 1,644,100 168,000 2,627
CI: confidence interval; TBE: tick-borne encephalitis; TBEV: tick-borne encephalitis virus.
aAge group 15–64 years. Source: Statistics Sweden (www.scb.se), 31 December 2018.
bSerum samples from blood donors in Gotland, Gävleborg, Skåne, Uppsala, Värmland, Västerbotten and Västra Götaland were taken in 2018
and those from Kronoberg in 2019.
cAll age groups. Source: Public Health Agency of Sweden.
6www.eurosurveillance.org
that these results give an important indication of the
true prevalence, given the scarce knowledge on TBEV
infections in Sweden. A notable par t of TBEV infections
is assumed mild or subclinical, however, our results
indicate that a large proportion of TBEV infections are
not diagnosed and therefore not notified. Reasons for
this may be subclinical infections, mild and rapidly
transient symptoms or delay of diagnosis, i.e. TBEV
infection is not considered so TBEV testing is not per-
formed. Information on the estimated number of vac-
cinated individuals is of value although our data do not
contain detailed information on vaccination, such as
the number of given vaccine doses or the immunity of
the blood donors.
We included nine Swedish regions with notified TBE
incidences ranging from absent and low to high. The
mean MI was 3.1%, which is in line with the MI from a
highly TBE endemic district in Germany (2%) [35]. Thus,
most TBEV infections (96.9%) are not diagnosed and
thereby not notified in Sweden. For future comparisons
of European TBE manifestation indices of different
countries, a harmonisation of the TBE case definition
in the EU is needed [10]. Comparing the MI in a region
over time could be a way to detect a potential shift to
another subtype of TBEV. For example, a more patho-
genic subtype or variant could result in a higher MI as
a greater proportion of the infected individuals would
be likely to seek medical care and be diagnosed. This
would require more continuous monitoring of sero-
prevalence. In Sweden, the notified TBE incidence has
increased since the disease became notifiable in 2004,
with some fluctuation between the years [22], even
though there are good vaccines available on the mar-
ket in Sweden since the 1980s and vaccination cam-
paigns are common in high-risk areas. A top record of
TBE cases in Sweden was noted in 2021 – one year into
the coronavirus disease 2019 (COVID-19) pandemic,
with a doubling of cases from the year before. The
number of reported cases will be even higher in the
year 2023 [22]. The increasing TBE incidence and the
high number of notified TBE cases in 2021 are likely a
result of several factors, such as an increasing tick and
rodent abundance, climatic conditions favouring virus
replication and tick phenology (the timing of host-seek-
ing activity), increased awareness by doctors leading
to increased diagnosis, a decrease in given vaccine
doses during 2021 [37] and changes in human behav-
iour leading to increased contact between humans and
infected ticks, i.e. more individuals spending more
time in the same habitat as ticks (e.g. increased out-
door activities during the COVID-19 pandemic due to
contact and travel restrictions) [22,38]. We would likely
have seen more TBE cases without vaccination, which
stresses the importance of immunising individuals liv-
ing, visiting and working in TBE risk areas, as well as
the need for a national vaccination registry in Sweden.
A national registr y would not only help individuals to
follow the vaccination recommendations but also to
vaccinate in time, i.e. before the star t of the tick sea-
son. Unfortunately, it cannot be ruled out that the cost
of vaccination could have a negative influence on the
willingness to vaccinate against TBE in Sweden as there
is no government subsidy. However, some Swedish
regions (Södermanland, Uppsala and Östergötland)
have introduced free vaccinations for children aged
3–18 years and more regions seem to follow.
The geographical distribution and seasonality of TBE
cases correspond to the geographical distribution and
seasonality of ticks. In the northern hemisphere, tick
habitats are connected to water. Most TBE cases in
Sweden have thus been repor ted from areas around
Lake Mälaren and the Stockholm archipelago, but
a northern and western spread has been observed,
including areas around Lake Vänern and north of
Gothenburg [22]. The ability of Ixodes ticks to spread
to new areas is highly influenced by the presence of
hosts, temperature and precipitation or humidity
[38,39]. Additionally, the phenology of ticks is tem-
perature-dependent [39]. Most TBE cases are reported
during the tick season: in Sweden between July and
T 3
Calculated manifestation indices of tick-borne encephalitis, per region, Sweden, 2004–2019
Region Notified TBE case incidenceaTBEV infection incidencebTBE MI (%)
Gotland 4.0 50.0 8.0
Gävleborg 1.1 50.0 2.2
Kronoberg 1.2 50.0 2.3
Skåne 0.8 66.7 1 .3
Stockholm 6.6 350.0 1.9
Uppsala 13.1 150.0 8.7
Värmland 2.4 150.0 1.6
Västerbotten 0.2 50.0 0.4
Västra Götaland 2.4 150.0 1.6
Mean 3.5 118.5 3.1
MI: manifestation index; NS1: non-structural protein 1; TBE: tick-borne encephalitis; TBEV: tick-borne encephalitis virus; WV: whole virus.
aAnnual notifications per 100,000 inhabitants 2004–2018. Data source: Public Health Agency of Sweden.
bInfected (WV positive and NS1 positive) per 100,000 inhabitants and year; estimated duration of TBEV NS1 IgG: 20 years.
7www.eurosurveillance.org
September, but cases are repor ted also in January and
December [22]. Climate change has rapidly changed
the distribution ofIxodesticks and the pathogens they
transmit. In Sweden, this has resulted in an expanding
geographical range and longer host-seeking periods
for I. ricinus[38,40], explaining why TBE cases are
reported from new regions but also during the winter
season. Since the epidemiology of TBE is changing and
ticks are expanding their geographical range in Sweden
[41], sentinel monitoring using serological examination
of TBEV in wildlife and bulk tank milk [42], the latter
allowing easier sampling, should be performed nation-
ally. All regions that report detection of TBEV in wild-
life and bulk milk should be classified as a potential
risk area for TBE and recommend TBE vaccination to
everyone at risk of getting a tick bite in the region. At
present, it is up to each region to issue vaccination rec-
ommendations based on their local situation.
Sera from blood donors were used in this study, so a
generalisation of the results to the entire population
should be made with caution. Blood donors are prob-
ably healthier and have a more active lifestyle than
others, including outdoor activities where exposure to
TBEV can be expected [43]. Blood donors are adults,
aged 18–65 years, so children and elderly individu-
als are not included. Blood donors may have a more
positive attitude to vaccinations, including TBE vacci-
nation. Furthermore, TBE is more commonly diagnosed
among men in Sweden [22] and Swedish men are
slightly over-represented among blood donors in the
age group 25–64 years [44]. Information on age and
gender as well as residency was not available for the
blood donors, which is a limitation of this study. Some
regions have more than one blood donation site. The
serum samples in our study could originate from differ-
ent sites of the region, making it impossible to differen-
tiate the results beyond the region level. Flaviviruses
can cross-react, especially for IgG. False positive IgG-
reactivity against, for example, dengue or yellow fever
may occur, but we assess the risk as low and limited
to those who may have been exposed during travel
or vaccination, as no other flaviviruses than TBEV are
endemic in Sweden. There is an ongoing discussion
about the possible presence of NS1 protein in the TBE
vaccines used in Europe [29-32]. As most studies have
either not detected the NS1 protein or detected minute
amounts in the vaccine preparations, we assume that
any potential NS1 antibodies in samples from individu-
als vaccinated would be present in amounts below
the detection limit of the method used. Of the serum
samples included in this study, 0.3% tested positive
for only anti-TBEV NS1 antibodies. We regarded these
samples as unspecific.
Conclusion
In conclusion, we present seroprevalence results of
TBEV in samples from blood donors from nine Swedish
regions. In general, there was a difference in the sero-
prevalence when regions of low TBE incidence were
compared with those of high incidence, both concerning
the overall seroprevalence and when divided into sub-
groups of vaccination and infection. The results also
indicate that a large proportion of TBEV infections in
Sweden are not diagnosed and therefore not notified
as cases, possibly because of mild symptoms or sub-
clinical disease.
Ethical statement
Ethical approval was not required for this study according to
the Swedish Ethical Review Authority 2022-07228-01.
Funding statement
The study was funded by Region Uppsala, the Swedish
Research Council (VR: 2018-02569), the European Union
Horizon 2020 Research innovation programme (Grant num-
ber 874735 (VEO)) and the SciLifeLab Pandemic Laboratory
Preparedness projects LPP1-007 and REPLP1:005.
Acknowledgements
The authors acknowledge the statistical work in this study
performed by Johan Bring at Statisticon Statistics and
Research Ltd, Uppsala, Sweden. We also acknowledge Bert
Blomqvist at the Department of Clinical Microbiology, Region
Västerbotten, Sweden, for contributing with samples to this
study.
Conflict of interest
None declared.
Authors’ contributions
BA: Planning, laboratory analyses, data analyses, interpre-
tation and writing. TH: Funding, data analyses, interpreta-
tion and writing. LK: Laboratory analyses, data analyses,
interpretation and writing. TB, GB, AH, MH, TK, YL, AP, MS:
Sample contribution, interpretation and writing. SV and
PE: Planning, supervision, interpretation and writing. BR:
Planning, major part of laboratory analyses, data analyses,
interpretation and writing. ÅL: Funding, planning, supervi-
sion, data analyses, interpretation and writing. All authors
have read and approved the final version of the manuscript.
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