Review

Seroprevalence and susceptibility to hepatitis A in the

European Union and European Economic Area: a systematic
review
Paloma Carrillo-Santisteve*, Lara Tavoschi*, Ettore Severi, Sandro Bonfigli, Michael Edelstein, Emma Byström, Pierluigi Lopalco, and the ECDC
HAV Expert Panel†

Most of the European Union (EU) and European Economic Area (EEA) is considered a region of very low hepatitis A Lancet Infect Dis 2017;
virus (HAV) endemicity; however, geographical differences exist. We did a systematic review with the aim of describing 17: e306–19

seroprevalence and susceptibility in the general population or special groups in the EU and EEA. We searched Published Online
June 20, 2017
databases and public health national institutes websites for HAV seroprevalence records published between
http://dx.doi.org/10.1016/
Jan 1, 1975, and June 30, 2014, with no language restrictions. An updated search was done on Aug 10, 2016. We S1473-3099(17)30392-4
defined seroprevalence profiles (very low, low, and intermediate) as the proportion of the population with age-specific *Joint first authors
anti-HAV antibodies at age 15 and 30 years, and susceptibility profiles (low, moderate, high, and very high) as the †Members listed at end of report
proportion of susceptible individuals at age 30 and 50 years. We included 228 studies from 28 of 31 EU and EEA
European Centre for Disease
countries. For the period 2000–14, 24 countries had a very low seroprevalence profile, compared with five in 1975–89. Prevention and Control, Solna,
The susceptibility among adults ranged between low and very high and had a geographical gradient, with Sweden
three countries in the low susceptibility category. Since 1975, EU and EEA countries have shown decreasing (P Carrillo-Santisteve MD,
L Tavoschi PhD, E Severi MSc,
seropositivity; however, considerable regional variability exists. The main limitations of this study are that the studies S Bonfigli MSc,
retrieved for analysis might not be representative of all EU and EEA publications about HAV and might have poor M Edelstein MBChB,
national representativeness. A large proportion of EU and EEA residents are now susceptible to HAV infection. Our Prof P Lopalco MD); Karolinska
Review supports the need to reconsider specific prevention and control measures, to further decrease HAV circulation Institutet, Stockholm, Sweden
(E Severi); Ministry of Health,
while providing protection against the infection in the EU and EEA, and could be used to inform susceptible travellers Rome, Italy (S Bonfigli); Public
visiting EU and EEA countries with different HAV endemicity levels. Health Agency of Sweden,
Stockholm, Sweden
Introduction for Disease Prevention and Control (ECDC) Annual (M Edelstein, E Byström MSc);
and Department of
Hepatitis A virus (HAV) is primarily transmitted via the Epidemiological Report,6 13  038 confirmed cases of Translational Research and
faecal–oral route, either by person-to-person contact hepatitis A were reported in 2012 by 29 EU and EEA New Technologies in Medicine
or by consumption of contaminated food or water. countries, corresponding to a notification rate of and Surgery, University of Pisa,
Additionally, sexual transmission, particularly among 2·60 cases per 100 000 individuals. The notification rate Pisa, Italy (Prof P Lopalco)

men who have sex with men, and parenteral transmission of hepatitis A varied greatly across the region with the Correspondence to:
Dr Paloma Carrillo-Santisteve,
through infected syringes or blood components have highest rates observed in eastern EU countries. In 2012, European Centre for Disease
been documented.1 HAV circulation in a population is the notification rate ranged from 66·8 and 17·9 cases per Prevention and Control,
strongly associated with socioeconomic development,2 100 000 individuals in Bulgaria and Romania, respectively, 171 65 Solna, Sweden
and transmission has been reduced by improving to 0·0 in Malta and 0·1 in Portugal.6 However, particular p.carrillosantisteve@gmail.com

sanitation, promoting hygiene in the food production
chain, and vaccination against HAV.
Up to 90% of HAV infections in children younger than
6 years are asymptomatic. Disease severity increases with
age, and in adults symptoms can last for several weeks.
About 15% of patients have persistent or recurring
symptoms over a 6–9 month period.3 Acute liver failure
and death occur in similar proportions (around 1 in
1000 symptomatic cases), more frequently in individuals
older than 50 years or with underlying chronic liver
disease.4 No specific treatment for HAV infection is
available.2
HAV endemicity is defined by the prevalence of HAV
antibodies in a community or region (appendix).
Geographical areas can be characterised by high,
intermediate, low, or very low levels of endemicity
patterns of HAV infection, and European Union (EU)
and European Economic Area (EEA) countries have
previously been classified as areas of low and very low
levels of endemicity.5 According to the European Centre
aspects inherent to surveillance systems, such as
completeness of reporting, should be considered when
interpreting these data because the level of under­
estimation of number of cases might be different among
countries.
A safe and effective vaccine for HAV has been available
in Europe since 1991, and in the USA since 1996.7 WHO
recommends universal vaccination for intermediate
endemicity countries, and vaccination of only risk groups
in low and very low endemicity countries.7 However,
some low and very low endemicity countries recommend
universal HAV childhood vaccination—eg, two doses of
the vaccine have been administered to infants aged
1–2 years in the USA since 20068 and in Israel since See Online for appendix
1999.9 In the EU and EEA, an HAV universal childhood
vaccination programme, which provides the vaccine free
of charge to specific age groups, was introduced in
Greece in 2008 (infants aged 1 year)10 and the regions of
Puglia (Italy) in 1997 (infants aged 1 year),11 and Catalonia
(Spain) in 1998 (children aged 12 years).12 The rationale

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 Review

for the introduction of vaccination was based on the
recognition of the small effect and low coverage of
selective vaccination strategies on the reduction of
disease incidence, and of the high risk for large
outbreaks, as seen in Puglia between 1996 and 1997.11,13
Seroprevalence studies are based on the detection of
anti-HAV IgG antibodies. Age-stratified seroprevalence
allows indirect measurement of age-specific incidence
rates of HAV infection and is considered the best way to
evaluate the hepatitis A situation in a country.7 However,
seroprevalence in children younger than 1 year should be
A Low susceptibility profile B Moderate susceptibility profile
100
75
Seroprevalence (%)
interpreted cautiously because anti-HAV antibodies can
be passively transferred as maternal antibodies, which
decay rapidly and offer protection only for the initial
6–12 months of life.14 Given the nature of the infection,
alongside seroprevalence, susceptibility to HAV infection
is a useful indicator of population risk that accounts for
changing exposure patterns, such as those resulting
from globalised food markets—eg, the amount of food
produced or processed in HAV endemic areas that is
imported to low endemicity areas.15–17 Also, travellers and
people visiting friends and relatives returning from
HAV-endemic countries can pose a risk for susceptible
populations in low endemicity areas and can spark
community outbreaks.18–20
Most of the EU and EEA is considered a very low HAV
endemicity area.5,6 However, large differences between and
within member states have been reported, including
epidemiological changes in the past 40 years, and require
a more thorough epidemiological assessment. In particular,
epidemiological transitions to lower endemicity levels are

Age threshold
accompanied by a reduced force of infection and shift in
50 15 years age of infection to later adulthood. These transitions
30 years subsequently result in increased relative incidence of acute
Time period symptomatic hepatitis A. Understanding the mechanisms
1975–89
1990–99
and the timing of epidemiological transitions in the EU
25 and EEA region might help to improve the assessment of
2000–14
Quality score not only the size of the population currently at risk and the
0
1
demand for adequate preventive measures, but also the
2 need for tailored control programmes to accelerate such
0
transitions. Therefore, the objective of this systematic
review is to retrospectively describe HAV seroprevalence
C High susceptibility profile D Very high susceptibility profile and susceptibility in the general population of individuals
100 older than 1 year in each EU and EEA country by collecting,
assessing, and synthesising available evidence from
published studies and the grey literature reporting
seroprevalence data.
75

Methods
Seroprevalence (%)

Search strategy and selection criteria

We systematically searched PubMed, Embase, Cochrane
50
Library, SCOPUS databases, Google Scholar, and EU and
EEA public health national institutes websites for HAV
seroprevalence records in all languages, published
25
between Jan 1, 1975, and June 30, 2014. An update of
the search was done on Aug 10, 2016, and new studies
highlighted in the Discussion section. The search
strategies combined the concepts of HAV and sero­
0 prevalence using controlled vocabulary (ie, MeSH and
0 25 50 75 100 0 25 50 75 100 Emtree terms) and natural vocabulary (ie, keywords) and
Age (years) Age (years) are available in the appendix. No geographical or
Figure 1: Hepatitis A virus seroprevalence in countries of the European Union and European Economic Area by
language restrictions were made. We transferred the
susceptibility profile and curve of best fit results to an EndNote X6 library and de-duplicated them
Age-specific hepatitis A virus seroprevalence in countries with low (A), moderate (B), high (C), and very high (D) using built-in features followed by a manual check.
susceptibility profiles. The curve of best fit is a synthetic representation of the seroprevalence profiles. Horizontal Additionally, the list of retrieved references was shared
segments correspond to age-specific seroprevalence estimates and are slightly more transparent. The thickness of
the horizontal segments represent the study quality score. Age intervals (ie, horizontal segments) from the same
with the ECDC national focal points for foodborne and
study are connected by a thin semi-transparent line. Two vertical dotted lines mark the two age thresholds at 15 and waterborne diseases from 31 EU and EEA member states
30 years as per WHO criteria for endemicity classification.7 and with the ECDC HAV expert panel (members listed at

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 Review

the end of the report) for further suggestions on relevant
publications and grey literature.
We divided the records retrieved into two subsets to
be screened by title or abstract independently by
two reviewers (PL and LT, subset 1; PC-S and ES, subset 2)
applying predefined inclusion and exclusion criteria. We
included original research articles, review papers, or
abstracts, in all EU and EEA languages, that reported
data on HAV seroprevalence in the general population or
special groups in one or more EU and EEA countries or
any of their regions or districts (excluding European
outermost regions and overseas territories). Special
population groups included were military recruits
not deployed to the field, and blood donors, with no
distinction between first-time donors and returning
blood donors, or voluntary or paid donations. We
included review articles and included original articles
included within these reviews if additional information
was deemed necessary. Studies were excluded if they did
not report primary HAV seroprevalence data in any EU
or EEA country (or European outermost regions and
overseas territories), and if the study population
was selected on the basis of specific risk factors for
HAV infection, such as patients with acute or chronic
liver disease or haemophilia, health-care workers, and
institutionalised patients. Additional details are provided
in the appendix. We included studies on non-general
populations if they contained and reported data on
control groups (only data on control groups were
extracted). We retrieved the full-text versions of selected
records and screened them according to the same set of
criteria. Six reviewers (PL, LT, ES, PC-S, ME, and EB)
contributed to full-text review according to their language
skills. Translation was done with the help of colleagues
proficient in the language in question. Disagreements
were resolved by consulting at least one other reviewer.
groups, we allowed only age bands with a maximum
width of 10 years for individuals younger than 25 years,
20 years for individuals older than 25 years, and 15 years
for intervals including 25 years of age (eg, age 18–30 years
was included). The age bands without a lower or upper
limit were excluded (eg, >60 years age group). We did not
include seroprevalence estimates for infants younger
than 1 year because of the potential presence of maternal
antibodies.
Data exploration and graphics
We used age-specific assessment of the seroprevalence
level by country to generate two indicators: seroprevalence
or endemicity (at 15 and 30 years of age), categorised as
very low, low, intermediate, and high (appendix) on the
basis of WHO endemicity criteria;7 and susceptibility or
seronegativity to HAV antibodies (based on the inverse of
the seroprevalence at age 30 and 50 years), categorised
as low, moderate, high, and very high (appendix). We
divided seroprevalence data into three time periods:
4465 records identified through 81 additional records identified
database searching through other sources
4276 records after duplicates
removed
4276 titles or abstracts screened
3844 records excluded
2482 non-EU or EEA
359 non-HAV
483 non-prevalance
356 non-general population
163 not found or other

Quality assessment
We assessed the quality of each included study by 432 full-text articles assessed
for eligiblity
developing an ad-hoc framework. Two major possible
sources of selection bias were identified: sample size and
sampling approach. Each domain was attributed a score 110 full-text articles excluded
3 non-HAV
(0 or 1) depending on the relative risk of bias (sample 78 non-prevalence
size, 1 point for samples of 500 or more; sampling 19 non-general population
approach, 1 point if random sampling). Included 10 not found or other

studies could score 0 (low quality), 1 (medium quality), or

2 (high quality) points. This information was displayed
322 eligible studies for data
graphically (with thicker lines indicating a higher study extraction
quality) and is presented in the appendix.
94 not abstractable data
Data extraction and management
We extracted seroprevalence data from the articles
including information on country, study timeframe, 228 included in systematic
and age-group-specific seroprevalence estimates. The review
complete list of extracted variables can be found in
the appendix. Age-stratified seroprevalence data were Figure 2: Selection of studies
included. To avoid excessive heterogeneity in the age EEA=European Economic Area. EU=European Union. HAV=hepatitis A virus.

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 Review

1975–89, 1990–99, and 2000–14. The susceptibility

A
assessment was provided for the period 2000–14. For
countries without seroprevalence estimates between
these time periods, extrapolations were made on the
basis of previous seroprevalence estimates and on the
assumption of an overall infection-induced decreasing
seroprevalence. Countries with discordant assessments
at 30 years and 50 years of age were classified according
to the lower level of susceptibility to HAV infection.
HAV seroprevalence profile 1975–89
We created a synthetic representation of the
Very low seroprevalence profiles by drawing a curve of best fit on
Low the scatter plots (figure 1). A generalised logistic
Intermediate
No data regression function was used to generate the best fit
EU or EEA members curve for the mean point estimates of the seroprevalence
Yes for each age group (figure 1). The statistical packages and
No
software used to generate the best fit curves are listed in
Luxembourg the appendix.
Age seroprevalence graphs and curves can be used as a
Malta
proxy for virus circulation and incidence in a population
(figure 1). Thus, a concave curve (C-shaped) is suggestive
B of a high number of cases in younger age groups, and
high levels of virus circulation and low susceptibility in
older age groups. Sigmoid curves (S-shaped) suggest a
lower number of cases in younger age groups (and lower
virus circulation than that of the C-shaped curve) and a
low susceptibility in older age groups. Convex curves
(J-shaped) suggest a low number of cases both in
younger and older age groups, low virus circulation, and
HAV seroprevalence profile 1990–99
high susceptibility in adults.
Very low
Low
Intermediate Results
No data
We identified 4276 unique articles, screened 432 full-text
EU or EEA members
Yes
articles, and included 228 publications (figure 2). These
No 228 publications included 279 studies, defined as reports
of HAV prevalence data for a defined population group,
Luxembourg
in a specific country over a specific time period, which
Malta were used for data extraction. From the included studies,
we extracted 1315 age-specific seroprevalence data points
C (median of four estimates per study; range 1–32). A
search update done on Aug 10, 2016, retrieved 342 articles
of which two met our inclusion criteria (one undertaken
in Italy21 and one in Spain22), which are described in the
Discussion section. Therefore, a total of 228 publications
were included. No eligible publications were found for
Hungary, Latvia, and Lichtenstein. The median number
of studies per country was four (range 1–70). Date of
HAV seroprevalence profile 2000–14 sampling ranged from 1975 to 2013. 100 studies were
Very low classified as high quality, 127 as intermediate, and 52 as
Low
Intermediate
low (appendix). Most studies were done in Italy (n=70),
No data Spain (n=64), France (n=20), Germany (n=20), UK
EU or EEA members
Yes
No Figure 3: Geographical distribution of the HAV seroprevalence profiles of EU
and EEA countries between 1975 and 2014
Luxembourg HAV seroprevalence profiles between 1975 and 1989 (A), 1990 and 1999 (B),
and 2000 and 2014 (C). EU and EEA membership is shown for countries with no
Malta data. EEA=European Economic Area. EU=European Union. HAV=hepatitis A
virus. Maps produced using EMMa software and templates from EuroGraphics
and UN-FAO.

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 Review

(n=16), and Greece (n=13; appendix). The sample size of

Population of Population of low Population of very Population of
the studies differed considerably (appendix). intermediate seroprevalence low seroprevalence unknown
seroprevalence countries countries seroprevalence
Seroprevalence countries countries
Data were available from 23,23–114 24,27,34,49,50,53,54,77,95,98,104,106,112,115–203 1980 133 738 138 (28·7%) 284 082 424 (61·0%) 22 502 299 (4·8%) 25 629 685 (5·5%)
and 2898,106,126,140,149,172,204–244 countries for the three time 1990 33 207 390 (6·9%) 155 954 230 (32·5%) 266 159 399 (55·5%) 24 326 663 (5·1%)
periods of 1975–89, 1990–99, and 2000–14, respectively. 2000 22 455 485 (4·6%) 60 215 275 (12·3%) 394 754 781 (80·6%) 12 603 359 (2·6%)
Figure 3 illustrates country-specific seroprevalence by
Data are n (%).
time period.
Five countries had a very low seroprevalence profile in Table: Seroprevalence profiles of the general population of European Union and European Economic Area
the earliest period (1975–89; figure 3A), 15 in 1990–99 countries in 1980, 1990, and 2000
(figure 3B), and 24 between 2000 and 2014 (figure 3C).245
Six countries were classified at the intermediate level
between 1975 and 1989, two between 1990 and 1999,
and one between 2000 and 2014. We estimated that
approximately 5% of the EU and EEA population lived in
areas of very low endemicity in 1980 compared with
about 80% in 2000 (table).

Susceptibility
Of the 28 countries98,106,126,140,149,172,204–244 for which HAV
seroprevalence data in adults were available for 2000–14,
three were classified as having low susceptibility in adults
(Portugal, Bulgaria, and Romania), ten as moderate
(Cyprus, France, Greece, Italy, Lithuania, Malta, Poland,
Slovakia, Slovenia, and Spain), ten as high (Austria,
Belgium, Croatia, Czech Republic, Estonia, Germany,
Ireland, Luxembourg, the Netherlands, and UK), and
five as very high (Denmark, Finland, Iceland, Norway,
and Sweden; figure 4).
Epidemiological transition over time
Countries were grouped according to their susceptibility
profile (low, moderate, high, and very high). A similar
pattern of decreasing seroprevalence over time was
observed in each of the four groups. This decrease is
illustrated by the shifting of the seroprevalence curve,
obtained by plotting all datapoints available for each
susceptibility profile group and time interval.
Distinct curves of best fit synthetically represent each
susceptibility profile over the study periods (figure 1).
The shape of the interpolation curves changed over time
and across groups of countries. C-shaped curves are
visible in figure 1A, corresponding to a low susceptibility
profile. S-shaped curves are visible in figure 1B and
figure 1C, corresponding to moderate and high
susceptibility profiles at different time intervals. J-shape
curves are shown in figure 1D, corresponding to a very
high susceptibility profile.
Countries with low susceptibility in adults, such as some
eastern EU countries, show that the shape of the curve for
2000–14 was different to that for 1975–89 and 1990–90,
with about 60% of the population seropositive at age
30 years. In countries with moderate susceptibility in
adults, (eg, most eastern and southern EU countries) the
proportion of the general population who were seropositive
at age 30 years decreased from 75% in 1975–89 to 30% in
HAV susceptibility
profiles 2000–14
Low
Moderate
High
Very high
No data
EU or EEA members
Yes
No
Luxembourg
Malta
Figure 4: Geographical distribution of the HAV susceptibility profiles of EU and EEA countries between 2000
and 2014
EU and EEA membership is shown for countries with no data. Maps produced using EMMa software and templates
from EuroGraphics and UN-FAO. EEA=European Economic Area. EU=European Union. HAV=hepatitis A virus.
2000–14. The shape of the seroprevalence curve in this
group changed in 2000–14, progressively moving towards
a J-shaped and a low or very low endemicity profile.
Countries with high susceptibility in adults, mainly central
and western EU countries, had little endemic circulation
of the virus between 1975 and 1989; the shape of the
seroprevalence curve changed from S-shaped in 1975–89
to J-shaped in 2000–14 showing increasing susceptibility
among adults. Those countries with very high susceptibility
in adults (ie, Nordic countries) show little local virus
circulation for the whole study period (1975–2014) with the
proportion of general population who were seropositive at
age 30 years remaining below 15%. The few studies
included from 1990 to 2014 for these countries indicated
high susceptibility in children and adults.
Discussion
This Review provides a comprehensive assessment of
HAV seroprevalence in each EU and EEA country over

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 Review
several decades, describing the HAV epidemiological
transition within the region. Overall, the results indicate
a decreasing trend of seropositivity over the past four
decades together with a wide range of both spatial and
temporal variability. Decreases in seropositivity might be
attributable to improvements in hygiene, sanitation, and
socioeconomic conditions, implementation of food-safety
measures, and the introduction of vaccination
programmes for high-risk groups.2
According to the WHO criteria to assess HAV
endemicity on the basis of seroprevalence, most of the
EU and EEA countries (24 of 28 countries) have a very
low profile. Seroprevalence characterisation based on
two age points (15 and 30 years) might provide an
accurate tool to assess HAV endemicity in areas of high
or intermediate seroprevalence, where virus circulation
is high (ie, infection predominantly occurs early in
life), as proven by previously published studies.5,246
Nevertheless, this indicator might not be sufficiently
sensitive to detect meaningful differences in the
epidemiological situation of EU and EEA countries.
On this basis, we generated a second epidemiological
indicator, based on the inverse measure of the level of
seroprevalence among adults (aged 30 and 50 years),
termed susceptibility (panel). The susceptibility indicator
shows a specific epidemiological pattern, with Nordic
countries showing the highest susceptibility level, and
with a gradient towards lower susceptibility levels in
southern and eastern Europe (figure 4). Our analyses
clearly show that countries with the same susceptibility
profile had similar patterns of transition both over time
and also while progressing from low to high and very
high susceptibility profiles (figure 1). Although other
alternative indicators have been proposed,18 on the basis
of our findings, we hypothesise susceptibility to HAV
infection in adults to be a more specific indicator of the
Panel: Policy and research implications
• Susceptibility profiles provide a better defined picture to
estimate the level of risk of hepatitis A in different
population age groups in Europe
• Identification of susceptible age groups helps to better
discriminate the size of the population at risk for planning
targeted interventions
• Country-specific profiles might offer an opportunity to
define effective policy options at national levels (eg,
universal vaccination, vaccination of at-risk groups,
traveller vaccination)
• Despite the fact that overall circulation of hepatitis A virus
has been decreasing since the 1970s, hepatitis A is still
endemic in some European countries, thus calling for
urgent action
• Better data both on disease surveillance and vaccination
coverage are needed to enable the correct interpretation
of the susceptibility profiles and their policy implications
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hepatitis A endemicity level in the EU and EEA region
than seroprevalence because it captures the outcome of
epidemiological transitions occurring at different time-
points throughout the region. In fact, susceptibility
reflects the level of seroprevalence in the adult population
that, in turn, is very much influenced by the time during
which the overall level of endemicity in a particular
country shifted from high to low.
According to these findings, a substantial part of the
EU and EEA population could now be considered
susceptible to HAV infection. Additionally, since the risk
of disease and complications increases with age,2
susceptibility among adults might be a better indicator
than seroprevalence to quantify the population at risk and
to predict the burden of disease. Of the 12 696 confirmed
cases of hepatitis A reported in 2012 from the countries
included in this study,6 8509 (67·1%) were reported in
the three countries with a low susceptibility profile,
2175 (17·1%) in the ten countries with a moderate
susceptibility profile, 1820 (14·3%) in the nine countries
with a high susceptibility profile (Croatia joined the EU
in 2014 and only started reporting then), and 192 (1·5%)
in the five countries with a very high susceptibility
profile.
The two studies21,22 identified in the search update
were published in 2016, with samples collected between
January and June, 2008, and October and December,
200922 and between September, 2013, and January, 2015.21
The studies were done in countries assessed as having a
moderate risk of HAV infection in adults and supported
the epidemiological picture previously described: young
adult and adult populations had a moderate to high
susceptibility to HAV. In the Italian study,21 lower HAV
seroprevalence was found in nursing students aged
19–38 years compared with patients of the same age
attending hospital in the same area in 2008. In the
Spanish study, a statistically significant increase in HAV
seroprevalence was found in the 2–5 year age group
sampled in 2008 compared with previous surveys. This
increase could be explained by migration trends from
endemic countries or the effect of vaccination.
We have retrieved and included data from almost all
EU and EEA countries. Nevertheless, the heterogeneity
of included primary studies was substantial in terms of
number of studies per country, sampling time variation,
geographical coverage, study design approach, and age
band definitions. As a result, we have not done any
meta-analysis or data pooling, and preferred instead to
present each data element separately while providing a
category-based assessment of the seroprevalence and
susceptibility level in the EU and EEA (appendix). Using
this approach, we show a sustained decreasing trend of
HAV endemicity in the EU and EEA between 1975 and
2014, which was supported by the two studies21,22 retrieved
through the search update. Using the susceptibility
indicator we were able to group EU and EEA countries
according to the evolution of hepatitis A epidemics and to

illustrate the transition to a lower level of infection in the
younger populations (children and young adults) and a low
level of virus circulation (figure 1). For example, Nordic
countries, which have a very high susceptibility profile
(figure 1D), are at the extreme end of the range because
they have had consistently low incidence rates for a long
period of time,6 leaving most of the population, including
adults, susceptible unless vaccinated.
Considering the limitations that result from differential
data quality and availability (by country and time period),
our analysis allows for comparison between different
patterns of the temporal evolution of HAV infection
epidemiology and for assumptions over possible future
trends. As shown in figure 1, the current profile for low
susceptibility countries is similar to that of moderate
susceptibility countries in the 1980s, the current profile
for moderate susceptibility countries is similar to that of
the high susceptibility countries in the 1980s, and the
current profile for high susceptibility countries is similar
to that of very high susceptibility countries in the 1980s.
These similarities would suggest that without any further
prevention measures, within two or three decades low
susceptibility countries such as Bulgaria, Portugal, or
Romania could have similar HAV seroprevalence
patterns as the moderate or high susceptibility countries,
including Belgium, France, or Germany.
The Panel describes research and policy implications
of these findings. 80% of the surveyed EU and EEA
population reside in countries with low HAV sero­
prevalence, meaning virtually no local circulation of HAV,
subsequently increasing levels of susceptibility. Routinely
collected hepatitis A data on hospital admissions and
notification could be useful to monitor the effect of HAV
infection in communities with high levels of susceptibility
in adult and elderly populations, who are at increased risk
of severe outcomes. Areas of high susceptibility to HAV
infection are at risk of outbreaks following virus circulation
or importation. Evidence of local virus circulation within
the EU and EEA has been provided by HAV outbreaks,
some of which were associated with the re-introduction of
HAV through food products16,17 or travellers and people
visiting friends and relatives returning from endemic
countries.19,20 A review of the cost of 13 hepatitis A
outbreaks in developed countries showed wide variation
in the costs attributed to an outbreak—eg, in 2007, the
costs per case in an outbreak situation ranged from
US$3824 to $200  480.247 The costs of an outbreak,
particularly those of foodborne origin, should be
appropriately accounted for in economic evaluations of
vaccination programmes in low-incidence countries,
including not only costs related to human health, but
also those borne by the food sector. Universal or
selective vaccination has been considered on the basis
of cost-effectiveness studies in several low-endemicity
settings.248–250 Because economic evaluation is expected to
be extremely dependent on local situations, our data could
be useful to guide policy decisions. Moreover, our data
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Review
might help identify areas at higher risk of virus circulation,
and therefore could be used to inform susceptible
travellers visiting EU and EEA countries with different
HAV endemicity levels and promote vaccination before
travel.18
Regarding vaccination of high-risk groups, most low or
very low seroprevalence countries in the EU and EEA
follow WHO recommendations.7 However, a high level
of heterogeneity exists regarding the country-specific
definition of what a risk group is, as well as in financial
coverage provided for HAV vaccination. Universal HAV
vaccination, which WHO recommends to intermediate
endemicity countries,7 is only recommended or provided
by a few countries or regions in the EU and EEA at low or
very low levels of seroprevalence.11,12 Regarding outbreak
control, evidence exists that both HAV and normal
human immunoglobulin decrease the risk of developing
hepatitis A following contact with a patient with
hepatitis.251 Most EU and EEA countries advise the use
of either, or both, following contact with a patient
with hepatitis A, alongside general hygiene advice.
Mass vaccination has been implemented to interrupt
transmission in community-wide outbreaks.252,253
The EU and EEA is a region with free movement of
people and trade. For this reason, when assessing
prevention and control measures to further decrease HAV
circulation in the EU and EEA, the region can be addressed
as one entity and should aim for similar outcomes and
similar implementation approaches. However, differences
in population susceptibility might justify more tailored
approaches. Additionally, immunisation against HAV
might not be of high priority in some countries because of
economic reasons or because most HAV infections occur
in children, in whom the disease is usually asymptomatic
or less severe than in adults.
Limitations
Our systematic review has a number of limitations. First,
the publications retrieved and selected for inclusion in
the Review might not be fully representative of the
epidemiological situation in particular EU and EEA
countries, because we did not search alternative databases
such as Global Health (CABI), POPLINE, and Web of
Knowledge (Web of Science), or because of publication
bias. Historical factors might have also affected the
search, and in particular retrieval of information from
former Soviet Union countries such as the Baltic states
might result in a potential geographical bias. Additionally,
not all EU and EEA countries sent feedback on additional
grey literature.
Second, national representativeness of the data might
be suboptimal because many published studies were
done at the local level (eg, focusing on major cities,
districts, or regions within a country) or they focused only
on particular time periods. Regional variations in HAV
seroprevalence levels within countries are known, and
published studies might over-represent areas at higher or
 Review
lower endemicity depending on local research interests.
Third, at least 15% of the studies included blood donors
among the sampled participants, which might not fully
represent the general adult population; however, these
participants might be close to our inclusion criteria
because particular groups are excluded from blood
donation. Conversely, blood donors’ seroprevalence of
HAV could be underestimated in volunteer donors and
overestimated in reimbursed donors.
Fourth, the studies included in this Review were
graded qualitatively according to sample size and
study design (random or non-random sampling). Never­
theless, a sample size cutoff was not applied.
Information on sample collection and laboratory testing
strategy were not extracted or analysed. Different
sample collection methods (eg, serum, plasma, or blood
spot) could lead to different sensitivity and specificity of
the estimates. Similarly, different diagnostic methods
can affect comparability of the results, even more so
if we consider the developments in laboratory HAV
diagnosis since 1975.254
We used WHO’s framework for the assessment
of country seroprevalence7 to ensure reasonable
comparability and coherence with already published
evidence. By contrast, we developed the susceptibility
profile assessment framework ad hoc on the basis of
available evidence, because to our knowledge no similar
approaches have been published in the literature.
Finally, we did not take into account the information
regarding the effect of vaccination coverage on population
seroprevalence, because this information is not easily
available. After the licensure of the vaccine, very few
or no studies designed to capture vaccine-induced
protection were done in some countries. This was the
case for Sweden, a country for which no seroprevalence
data are available since 1997, but with high hepatitis A
vaccination coverage reported among travellers (79% of
travellers were immunised against hepatitis A in 2007).20
Generally, a shortage of robust and widespread data on
hepatitis A vaccine coverage at the national and EU levels
hampers the accurate assessment of seroprevalence in
the EU and EEA population.
Conclusions
This Review provides a comprehensive description of
the HAV infection epidemiology across the EU and EEA
during the past 40 years. The Review shows that HAV
circulation has been decreasing steadily over time in the
EU and EEA as a whole, although important differences
exist at national and subnational levels, and that a
progressively growing part of the EU and EEA population
has become susceptible to HAV infection. We show that
susceptibility among adults can serve as a more accurate
indicator of the epidemiological situation in the EU and
EEA than HAV seroprevalence in the population.
The analysis of epidemiological transition patterns has
revealed important similarities between countries with
e313 www.thelancet.com/infection Vol 17 October 2017
similar susceptibility profiles and can be used to predict
future developments and to identify what preventive
measures are needed to accelerate the progression of
countries towards lower endemicity levels. At the same
time, the lower rates of infection in the region and the
high level of susceptibility of the population is a cause for
concern. The increasing susceptibility among the adult
population (at risk of more severe disease) poses the risk
of increasing incidence of acute symptomatic HAV
infection and occurrence of outbreaks due to local
circulation of HAV in the EU and EEA area through
common-source food exposures or travellers returning
from endemic countries.
In conclusion, our review supports the need to
reconsider specific prevention and control measures,
such as vaccination strategies, to further decrease HAV
circulation while providing protection against the
infection in the EU and EEA, a heterogeneous region
with free movement of people and trade.
Contributors
PC-S, LT, ES, and PL contributed to the conception of the work and the
development of the study protocol, did the literature search, and
reviewed the abstracts. PC-S, LT, ES, PL, ME, and EB contributed to the
full-text review and data extraction. ES and SB contributed to the data
analysis. SB created the graphs. PC-S, LT, ES, and PL contributed to the
first draft of the manuscript. All authors critically revised all drafts of the
manuscripts and approved the final version.
ECDC HAV Expert Panel
Valeria Alfonsi (Istituto Superiore di Sanità, Rome, Italy), Roman Chilbek
(Faculty of Military Health Sciences, University of Defence, Czech
Republic), Angela Dominguez (Barcelona University; CIBER
Epidemiología y Salud Pública, Spain), Emmanouil Galanakis (University
of Crete, Greece), Denisa Janta (National Institute of Public Health,
Bucharest, Romania), Mira Kojouharova (National Centre of Infectious
and Parasitic Diseases, Sofia, Bulgaria), Jördis J Ott (Helmholtz Centre
for Infection Research, Germany), Noele Nelson (Division of Viral
Hepatitis/NCHHSTP, Centers for Disease Control and Prevention,
Atlanta, GA, United States), Vassiliki Papaevangelou (University General
Hospital ATTIKON, Paediatrics Department, Greece), Daniel Shouval
(Hadassah University Hospital, Liver Unit, Israel), Ingrid Uhnoo (Public
Health Agency of Sweden, Sweden), Vytautas Usonis (Vilnius University
Faculty of Medicine, Clinic of Children Diseases, Lithuania).
Declaration of interests
We declare no competing interests.
Acknowledgments
We thank Johana Takkinen, Ana-Belen Escriva, Irene Muñoz,
Irina Dinca, Dragoslav Domanovic, Diamantis Plachoura,
Alexandra Salekeen, and all the other European Centre for Disease
Prevention and Control colleagues who helped with translation of
papers. This Review was funded by the European Centre for Disease
Prevention and Control, an Agency of the European Union.
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