Vaccine xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Review

A review of recommendations for rotavirus vaccination in Europe:

Arguments for change
Dirk Poelaert, Priya Pereira, Robert Gardner, Baudouin Standaert, Bernd Benninghoff ⇑
GSK, Avenue Fleming, 20, Wavre B1300, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Background: More than 10 years after the authorisation of two rotavirus vaccines of demonstrated effi-
Received 9 August 2017 cacy and with a strongly positive benefit-risk profile, uptake in Europe remains low. Only 13 countries
Received in revised form 15 February 2018 in Europe provide a fully-funded rotavirus universal mass vaccination (UMV) programme, three provide
Accepted 19 February 2018
a partially-funded programme, and one provides full funding for a reduced programme targeting at-risk
Available online xxxx
infants. Around 40% of countries in Europe currently have no existing recommendations for rotavirus vac-
cine use in children from the national government.
Keywords:
Methods: We provide an overview of the status of rotavirus vaccine recommendations across Europe and
Rotavirus
Vaccine
the factors impeding uptake. We consider the evidence for the benefits and risks of vaccination, and argue
National immunization program that cost-effectiveness and cost-saving benefits justify greater access to rotavirus vaccines for infants liv-
ing in Europe.
Results: Lack of awareness of the direct and indirect burden caused by rotavirus disease, potential cost-
saving from rotavirus vaccination including considerable benefits to children, families and society, and
government/insurer cost constraints all contribute to complacency at different levels of health policy
in individual countries.
Conclusions: More than 10 years after their introduction, available data confirm the benefits and accept-
able safety profile of infant rotavirus UMV programmes. Europe serves to gain considerably from rota-
virus UMV in terms of reductions in healthcare resource utilization and related costs in both
vaccinated subjects and their unvaccinated siblings through herd protection.
Ó 2018 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd. This is an open access article under the
CC BY license (http://creativecommons.org/licenses/by/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Rotavirus vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Rotavirus vaccine recommendations in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. The benefits of rotavirus vaccination in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. The safety of rotavirus vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Why isn’t uptake of rotavirus vaccines higher in Europe? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Perceptions about value versus cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Incomplete awareness of the burden of disease and its associated costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. Incomplete awareness of the benefits of UMV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.4. Low priority and cost constraints. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Moving forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Focus on the patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abbreviations: AGE, acute gastroenteritis; GSK, GlaxoSmithKline; HRV, human rotavirus vaccine; HBRV, human-bovine reassortant rotavirus vaccine; RRV-TV, tetravalent
rhesus-human rotavirus vaccine; RVGE, rotavirus gastroenteritis; UMV, universal mass vaccination; WHO, World Health Organization.
⇑ Corresponding author.
E-mail addresses: Dirk.X.Poelaert@gsk.com (D. Poelaert), Priya.P.Pereira@gsk.com (P. Pereira), Robert.C.Gardner@gsk.com (R. Gardner), Baudouin.A.Standaert@gsk.com (B.
Standaert), Bernd.X.Benninghoff@gsk.com (B. Benninghoff).

https://doi.org/10.1016/j.vaccine.2018.02.080
0264-410X/Ó 2018 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
2 D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx

The problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
The evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Focus on the parent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Trademarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Contributorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction 6 weeks of age with an interval of at least 4 weeks between doses,

The incidence of rotavirus infection has decreased in countries
where rotavirus vaccine universal mass vaccination (UMV) pro-
grammes are in place. Nevertheless, global coverage of rotavirus
vaccines is estimated to be 25% and rotavirus remains one of the
most common causes of severe diarrhoeal illness in children <5
years of age world-wide [1,2]. Before vaccination, 3.6 million epi-
sodes of rotavirus diarrhoea were estimated to occur annually in
<5 year olds in Europe, resulting in >87,000 hospitalisations,
approximately 700,000 outpatient visits and 231 deaths [1,3].
Prospective surveillance of acute gastroenteritis (AGE) during the
REVEAL study in seven European countries found evidence of rota-
virus in 40.6% of children with AGE, with an annual incidence of
2.07–4.96 cases/100 children <5 years of age [4]. Children with
rotavirus gastroenteritis (RVGE) were more likely to have severe
clinical disease including dehydration than children with non-
rotavirus AGE, and up to 36.0% of children with rotavirus were hos-
pitalised [5]. As well as contributing to healthcare burden, rota-
virus infections in children have a substantial negative impact
upon families. Up to 91% of parents of children with RVGE in the
REVEAL study lost 2.3–7.5 work days during their child’s illness
[6]. Parents report concerns extending beyond clinical symptoms
of severity, to weight loss, peri-anal inflammation, and pain [6–
8]. Among United Kingdom (UK) families with a child with rota-
virus, another family member developed secondary gastroenteritis
in 52% of cases [8].
As well as causing community-acquired gastroenteritis, rota-
virus is also an important cause of nosocomial infections. A review
of the literature from Europe found that among children aged <5
years, RVGE accounted for between 47% and 69% of all hospital-
acquired AGE and prolonged hospital stays by 4–12 days [9]. In a
Belgian study, up to 12% of all inpatient bed-days were due to
RVGE prior to UMV [10].
Two orally administered rotavirus vaccines were licensed in the
European Union in 2006. In 2009 the World Health Organization
(WHO) recommended that rotavirus vaccine be included in all
national vaccination programmes [11]. However, more than 10
years after the authorisation of rotavirus vaccines of demonstrated
effectiveness and safety, uptake in Europe remains low. Here we
review the current status of recommendations for rotavirus vacci-
nation across Europe and the perceptions that underlie its incom-
plete implementation. We consider the evidence around the
benefits and risks of vaccination, arguing for greater access to rota-
virus vaccines for infants living in Europe.
A summary contextualizing the content of this review and its
clinical relevance is displayed in the Focus on Patient section, for
the benefit of health care professionals.
2. Rotavirus vaccines
The two rotavirus vaccines currently available in Europe are
both administered orally: Rotarix (human rotavirus vaccine or
HRV: GSK), is administered as two doses to infants beginning at
and completion preferably by age 16 weeks and no later than 24
weeks; RotaTeq (human-bovine reassortant rotavirus vaccine or
HBRV: Merck and Co), is administered as three doses beginning
at 6 weeks of age with completion preferably by age 20–22 weeks
and no later than 32 weeks.
HRV and HBRV showed similar efficacy in clinical trials, pre-
venting 70–73% of all RVGE in the first year of life, 77–80% of sev-
ere cases and 80% of cases requiring hospitalisation [12]. Both
vaccines show similar safety profiles, and both have addressed
specific challenges since licensure including quantifying the risk
of intussusception.
3. Rotavirus vaccine recommendations in Europe
In 2008 the European Society for Paediatric Infectious Diseases
and the European Society for Paediatric Gastroenterology, Hepatol-
ogy and Nutrition recommended that rotavirus vaccination be
offered to all healthy infants in Europe [13]. An update in 2014
re-stated the recommendation, adding that rotavirus vaccination
be offered equally for breast-fed and formula-fed infants without
interruption of breast-feeding [14].
Where available, we checked rotavirus vaccination and reim-
bursement policies from recommending bodies or national health
agencies in each country, and then verified these findings with
local GSK medical directors across Europe. The results of these
requests are summarised in Table 1. Currently 14 countries in Eur-
ope have no existing national government recommendation for
rotavirus vaccine use in children (Fig. 1). Thirteen countries in Eur-
ope provide a fully-funded (UMV) programme, and another five
countries provide a partially-funded programme which is either
fully funded for certain risk-groups (Croatia) or in specific regions
(Sweden), or requires a parent co-payment (Belgium, Greece and
Slovakia).
4. The benefits of rotavirus vaccination in Europe
Five countries in Europe with recommendations for rotavirus
UMV have data evaluating vaccine impact (Table 2). The majority
of these studies compare the rate of RVGE hospitalisations and/or
other outcomes such as the number of rotavirus-positive samples,
or outpatient/emergency department visits, over a defined post-
implementation period compared to historical data prior to imple-
mentation of the UMV recommendation.
Belgium was the first country to recommend universal vaccina-
tion of infants, introduced in 2006. Vaccine coverage of the com-
plete series [2 doses (HRV) or 3 doses (HBRV)] stands at around
85%. In the first two years after vaccine introduction, hospitalisa-
tions for community-acquired rotavirus infection decreased in
children aged 5 years by 78%, and nosocomial RVGE decreased
by 76% [15]. Impact studies have demonstrated sustained declines
in RVGE hospitalisations in excess of 70% in children <5 years of
age, including those too old to be vaccinated [15–17]. Compared

Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
 Table 1
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine

Recommendations for rotavirus vaccination across Europe as from Dec 2017.

Country Recommendation by national authority Reimbursement status Recommending government body Medical/scientific societies that took the
position to recommend
Albania All infants (UMV) 100%  Ministry of Health, Public Health  University Hospital Centre ‘‘Mother Teresa”
Institute Pediatrics Department
Austria All infants (UMV) 100%  Bundesministerium für Gesundheit  Austrian Society of Paediatrics & Adoles-
cent Medicine
Belgium All infants (UMV) Partial  Conseil supérieur de la Santé/Hoge  Belgian Society of Pediatrics
Gezondheidsraad
Bosnia and None None  Agency for Medicines and Medical  Pediatrics Association of Republic of Srpska
Herzegovina Materials. (Bosnia and Herzegovina entity)
 Institute of Public Health of the
Federation of BiH
Bulgaria All infants (UMV) 100% (limited annual budget, re-  Expert Committee, Ministry of  Advisory Committee for surveillance of
assessed yearly based on Health Communicable Diseases
vaccination coverage)
Croatia At-risk groups 100% for at-risk children  Croatian Institute for Public Health,  National Committee for the Promotion and
Department of Epidemiology Prevention of Rotavirus Infection in
Children
Cyprus Included in the private sector vaccination schedule which differs None  Ministry of Health  Scientific committee of Cyprus Paediatric
from the public sector schedule Society for the private sector’s vaccination

D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx

calendar
Czech Republic All infants (UMV) 100% (if budget is made available)  Národní imunizační komise  Česká vakcinologická společnost (Czech
(National Immunization Commit- Vaccination Society)
tee, NIKO)
Denmark None None  Sundhedsstyrelsen (National Board  Dansk Pædiatrisk Selskab, (Danish Paedi-
Health Technology Assessment) atric Society)
Estonia All infants (UMV) 100%  Ministry of Social Affairs, Health  University of Tartu, Department of Public
Department Health
 State Agency of Medicines
Finland All infants (UMV) 100%  THL, National Institute for Health  Finnish Medical Society Duodecimi
and Welfare  Rokotetutkimuskeskus. Tampere Univer-
 KRAR, National Advisory Commit- sity Vaccine Research Centre
tee for Vaccination  Finnish Pediatric Association
France All infants (UMV) from 2014, suspended in 2015 None  Haut Conseil de la Santé Publique  Association Française de Pédiatrie Ambula-
at the date of the recommendation toire & Groupe de Pathologie Infectieuse
(Haute Autorité de Santé since Pédiatrique (paediatric societies) (2012)
March 2017)  Groupe Francophone d’Hépatologie, Gas-
troenterology et Nutrition Pédiatriques
(2007)
Germany All infants (UMV) 100%  Ständige Impfkommission (STIKO)  Deutsche Akademie für Kinder- und
Jugendmedizin e. V.
 Gesellschaft für Neonatologie und Pädia-
trische Intensivmedizin e. V.
Greece All infants <6 months (UMV) 75%  Ministry of Health  National Immunisation Committee
 Hellenic Paediatric Association
Hungary All infants (UMV) None  Országos Epidemiológiai Központ  Hungarian Pediatric Association
(National Centre of Epidemiology)  Association of Hungarian Primary Care
Paediatricians
Iceland None None  Embætti landlæknis  Icelandic Pediatric Association
Ireland All infants (UMV) 100%  Department of Health  Royal College of Physicians of Ireland
 National Immunisation Advisory
Committee

(continued on next page)

3
 4
Table 1 (continued)
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine

Country Recommendation by national authority Reimbursement status Recommending government body Medical/scientific societies that took the
position to recommend
Italy All infants from 2018 (UMV) 100%  Ministero della Salute  Pediatrician and Preventive medicine sci-
entific societies
 Centro Nazionale di Epidemiologia, Sorveg-
lianza e Promozione della Salute
 Società Italiana di Pediatria
 Federazione Italiana Medici Pediatri
Kosovo None None  Ministry of Health Kosovo  National Institute of Public Health
Latvia All infants (UMV) 100%  Centre for Disease Prevention and  Slimıbu profilakses un kontroles centrs
Control (Centre of Immunology and prophylactics)
 Latvia Paediatric Association
Liechtenstein Pending None  Fürstentum Liechtenstein Amt für  Eidgenössische Kommission für Impffragen
Gesundheit
Lithuania None None  Ministry of Health  Centre for Communicable Diseases Preven-
tion and Control
Luxembourg All infants (UMV) 100%  Ministère de la Santé  Société Luxembourgeoise de Péd.
 Conseil Supérieur des Maladies
Infectieuses
Macedonia None None  Ministry of Health and Committee  Pediatric Society of Macedonia
for Immunisation

D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx

Malta None None  Ministry of Health  Advisory committee on immunisation
Montenegro None None  Institute of Public Health of  Institute of Public Health of Montenegro
Montenegro
Netherlands Dutch Health council advised the MoH to implement rotavirus None  Ministry of Health  Gezondheidsraad (Health Council)
vaccination within the Dutch NIP only if the cost benefit  Zorginstituut Nederland (national health
assumption is positive, otherwise to consider a risk benefit care institute) (provides advice about reim-
approach (Dec 2017) bursement for indicated groups only)
Norway All infants (UMV) 100%  Norwegian Institute of Public  Norwegian Child Medical Association
Health/Norsk Folkehelseinstitutt
Poland All infants (UMV) None  Ministry of Health  The Pediatric Experts Group on National
Immunization; Polish Society of Vaccinol-
ogy Program
Portugal None None  Comissão Técnica de Vacinação  Sociedade Portuguesa de Pediatria – Socie-
dade Portuguesa de Infecciologia pediátrica
e Secção de Gastroenterologia e Nutrição
Pediátrica
Romania None None  The Romanian Ministry of Health  The Romanian Pediatric Society
Serbia None None  Ministry of Health  Batut Institute
Slovakia All infants (UMV) Partial (20%)  Regional Public Health Agency  Neonatal Section of Pediatric Society
Slovenia All infants (UMV) None  Nacionalni inštitut za zdravje  Slovenia Paediatric Society
(National Institute for Public
Health)
Spain None None  Ministry of Health, Social Services  Spanish Association of Pediatrics
and Equality.
Sweden All infants (before Sept 2017: all infants in 8/21 counties; 100% in Jönköping, Stockholm,  Ministry of Health  Public Health Agency Sweden
Jönköping, Stockholm, Västra Götaland, Örebro, Uppsala, Västra Götaland, Örebro, Uppsala,
Gävleborg, Dalarna och Västmanland) Gävleborg, Dalarna och
Västmanland
Switzerland Pending None  The Federal Office of Public Health  Swiss Society of Paediatrics Eidgenössische
Kommission für Impffragen
United Kingdom All infants (UMV) 100%  Public Health England  Joint Committee on Vaccination and
Immunisation)

UMV – universal mass immunisation.

 D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx
Fully-reimbursed rotavirus UMV implemented
Recommended but not funded/parally funded
At-risk groups only
Naonal opinion pending
No UMV implemented
Smaller countries not included on the map:
No UMV implemented in Cyprus, Kosovo, Malta or
Montenegro
For Liechtenstein, naonal recommendaon pending
Fig. 1. Overview of recommendations for rotavirus vaccination across Europe as from December 2017.
with the pre-vaccination period, hospitalisations due to RVGE also
decreased by 63% among individuals aged 10 years or older [16].
Austria recommended vaccination of all infants with rotavirus
vaccines the following year (2007). Vaccine coverage of the full
schedule was estimated to be 84% in 2011 [18]. Hospital-based
surveillance has shown a 73% decrease in RVGE hospitalisations
in children <5 years compared to the pre-vaccination period [18].
Finland introduced UMV for rotavirus in 2009 and reached cov-
erage rates of >95%. Compared to the pre-vaccination period, hos-
pitalisations of children <1 year of age due to rotavirus decreased
by 80.3%, and hospital outpatient attendances for RVGE decreased
by 78.8% [19]. In a prospective hospital-based surveillance study,
RVGE discharges decreased by 79% in children <16 years of age
[20]. Inpatient bed days due to rotavirus infection were reduced
by 83–93% among 0–2 year-olds and by 79–86% in 0–16 year-
olds in the years after vaccine introduction [21]. Extrapolation of
these data to the national setting estimated 1880 bed days were
prevented among 0–16 year olds for RVGE annually. A total of
6219 bed days were prevented due to all-cause AGE.
Rotavirus vaccines became available in Germany in 2008 but
were not recommended nationally until 2013. In the interim some
regions elected to recommend and fund vaccination, allowing a
unique comparison between regions with lower (26–28%) versus
moderately high (56–65%) rotavirus vaccine coverage (Table 2)
[22,23]. These studies show a clear link between coverage and vac-
cine impact in Germany, with greater reductions in the number of
rotavirus-positive samples and in RVGE hospitalisations in regions
where coverage was higher. These data highlight that the benefits
of rotavirus vaccination are proportional to coverage and suggest
that high coverage is necessary to gain the most benefit from
vaccination.
The UK introduced rotavirus UMV in 2013 and rapidly achieved
86% coverage of 2-doses within several months. Hospital-based
discharge and national notification data confirm large reductions
in the number of rotavirus-positive samples, RVGE hospitalisations
Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
5
and medically attended visits during the first rotavirus season after
the commencement of UMV. In the target age group for vaccination
aged <1 year, hospitalisations for RVGE decreased by 69%-80% and
medically attended visits by 94% [24,25]. Large reductions in RVGE
hospitalisations were also observed in cohorts too old to be vacci-
nated, including a 69% reduction in RVGE hospitalisations in 2–4
year olds [26]. Before vaccination of one full birth cohort, the
UMV programme saved an estimated 10.5 million Euro during its
first year [24].
Remarkably, herd effects have been observed in four countries
with UMV, with marked reductions in RVGE hospitalisations and
in rotavirus-positive infections in cohorts too old to be vaccinated,
especially among children aged 0–5 years. In the first year after the
commencement of UMV in the UK, decreases were observed in
rotavirus-confirmed infections and in hospitalisations for all-
cause AGE in all age groups, with more than 50,000 hospitalisa-
tions for AGE prevented [29,30]. In Austria, RVGE hospitalisations
decreased by 22% in 32–60 month-old children within 2 years of
the commencement of UMV [27]. One study in Austria recorded
a 50% decrease in community-acquired RVGE hospitalisations in
6–18 year olds, and importantly, reduced community-acquired
and nosocomial RVGE hospitalisations in neonates aged 42 days
[28]. Similarly, a 50% reduction in confirmed rotavirus infection
was observed in individuals 10 years of age and older in Belgium
[16].
Vaccine impact has confirmed or exceeded estimates of vaccine
efficacy from clinical trials. In a prospective case-control study in
Belgium, vaccine effectiveness of 2 doses of HRV against RVGE hos-
pitalisation was 90% (95% confidence interval [CI] 79–96) [31]. Vac-
cine impact against RVGE hospitalisation ranged between 79% and
97% in Finland, Austria and Germany [18–20,32], and was 88% for
HRV and HBRV in Germany after 5 years of follow-up of the vacci-
nated child [23].
Together, real-world evidence gathered to date have confirmed
the expectations of rotavirus vaccines in Europe. The data
 6
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine

Table 2
Impact of rotavirus vaccines in European countries with existing universal mass immunisation (UMV) programmes.

Author, ref Coverage Study years Setting Design Age % decrease post versus pre-vaccination periods
(years)
Positive Hospitalisations Medical
tests visits
Belgium: UMV since 2006 (HRV and HBRV)
Standaert et al. [17] >85% after 1 year 2005–06 v. 2007–13 11 hospitals Retrospective hospital database <6 76.6% – –
analysis
Sabbe et al. [16] 85.8% in 2012 1999–06 v. 2008–14 National sentinel surveillance Retrospective database analysis All ages 76.9% 73.3% –
(various)
Raes et al. [15] 90% in 2008 2004–06 v. 2007–09 12 hospitals Retrospective hospital database 5 80% 78% (CA) –
analysis 76% (NO)
Austria: UMV since 2007 (HBRV then HRV)
Prelog et al. [28] 2002–07 v. 2007–12 Hospital sentinel surveillance (11 hospitals) Retrospective database analysis 42 days – 56.2% (CA) –
72.5% (NO)
Paulke-Korinek et al. 81% in 2011 2001–05 v. 2010–11 Hospital sentinel surveillance (11 hospitals) Retrospective database analysis <5 – 73% –

D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx

[18]
Finland: UMV since 2009 (HBRV)
Hartwig et al. [21] 96% 2000–01 v. 2011–12 2 hospitals Retrospective database analysis 0–16 – 2303 prevented –
annually
Leino et al. [19] – 1999–2005 v. 2010 National Hospital Discharge register Retrospective database analysis <1 – 80.3% 78.8%
Hemming-Harlow >95% 2001–06 v. 2009–13 2 hospitals Prospective surveillance Age- – 94.4% –
et al. [20] eligible
<16 – 79% –
Germany: UMV since 2013, varying regional coverage from 2008 (HRV and HBRV)
Uhlig et al. [23] 65% in high coverage 2006–12 Statistisches Retrospective database analysis 0–1 74% 60% –
area, 2012 Bundesamt
26% in low coverage area, 49% 19% –
2012
Dudareva-Vizule et al. 56% in Eastern states, 2004–06 v. 2008–11 Notification data Retrospective database analysis <2 – 36% –
[22] 2010
28% Western states, 2010 25%
United Kingdom: UMV from 2013 (HRV)
Marlow et al. [24] 86%, 2014 2012–13 v. 2013–14 Bristol Hospital ED Retrospective database analysis <1 94% 69% (children) 94%
1–4 65% 67–70%
<18 – 54% (all cause) 52% (all
cause)
Inns et al. [30] 90–92% 2014–15 2004–13 v. 2014–15 Anglia, Essex, PHE notification data Retrospective database analysis <5 80.6– – –
82.9%
Atchison et al. [29] 87.5 2000–14 v. 2013–14 England, PHE notification data Retrospective database analysis <5 67% – –
Atchison et al. [25] 93% 2000–13 v. 2013–14 Laboratory notifications and Hospital Retrospective database analysis <1 77% 80% –
Episode Statistics 5 50% – –
Hungerford et al. [26] – 2002–13 v. 2013–15 Liverpool 1 hospital Retrospective database analysis <2 – 84% –
2–4 – 69% –
0–15 – 83% CA and NO –

CA = community acquired, ED = emergency department, HBRV = human-bovine reassortant rotavirus vaccine, HRV = human rotavirus vaccine, NO = nosocomial, v. = versus PHE = Public Health England.
 D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx 7

demonstrate that rotavirus vaccines induce herd effects in age
groups too old and too young to be vaccinated, but require cover-
age rates of 65% and above to do so.
5. The safety of rotavirus vaccines
Rotavirus vaccines are administered orally and are generally
very well tolerated, with rates of fever, diarrhoea and vomiting
after vaccination that are similar to recipients of placebo [12].
The key safety concerns have centred around the risk of
intussusception.
5.1. Intussusception
Intussusception is a rare condition that usually occurs in infants
between 4 and 10 months of age. A literature review of worldwide
intussusception incidence rates found an overall incidence of 74
cases per 100,000 children <1 year of age, ranging between 9 and
328 per 100,000 across different countries, and peaking between
4 and 6 months of age [33]. Because of the temporal association
previously observed between vaccination with the first oral rota-
virus vaccine (tetravalent rhesus-human reassortant vaccine, Rota-
shield, RRV-TV) which was licensed in 1998 and the development
of intussusception, the safety profile of HRV and HBRV has
undergone substantial scrutiny. No increased risk of intussuscep-
tion compared to placebo was observed during pre-licensure Phase
III studies of HRV and HBRV that enrolled at least 60,000 infants
[34,35]. However, monitoring data in even larger populations has
identified a small but quantifiable risk which is lower than that
of RRV-TV. A meta-analysis determined an increased risk of intus-
susception within 7 days of vaccination with HRV and HBRV,
equating to up to 6 additional cases per 100,000 infants vaccinated
in countries with a background incidence of 25–101 per 100,000
infants per year [36–38]. There is limited evidence of a smaller
increased risk following the second dose.
Evaluation studies of HRV and HBRV conducted in England, Fin-
land and Spain after the meta-analysis show similar results
(Table 3) [39–41]. In England and Finland, the number of excess
intussusception cases per 100,000 vaccine doses was estimated
to be 4.53 and 1.04, respectively [39,40]. In England, this equates
to 21 additional intussusception cases annually, which need to
be considered in the context of potentially 50,000 AGE hospitalisa-
tions prevented seasonally through direct and herd effects [25].
Similarly, in Finland rotavirus vaccination is thought to lead to
1.04 excess intussusception cases per 100,000 first doses adminis-
tered [40], but to prevent 80–90% of rotavirus disease and hospital-
isation (Table 2). In Spain, the risk estimates for intussusception
were not statistically significant, possibly due to the low number
of cases and low coverage (<50%) achieved during the study period
[41]. In all three studies, the risk of intussusception after vaccina-
tion with rotavirus vaccines was highest after the first dose. An
increased risk after the second dose was only observed in England
in a modified assessment.
Recommendations for universal rotavirus vaccination were
made by the French High Council of Public Health in November
2013, but vaccination was not publically reimbursed. However,
on the basis of safety concerns arising from pharmacovigilance
data between 2006 and 2014, the recommendation was suspended
in 2015 [42]. At that time the French Medicines Agency noted that
two infants had died from intussusception after receiving rotavirus
vaccines, and that the incidence of adverse events after vaccination
was worrying. A statement from WHO indicated that one infant
died without having received medical care seven days after vacci-
nation; and that the other infant death followed the third dose of
vaccine. So far, in published studies the third vaccine dose has
not been associated with an increased risk of intussusception
[36–38]. As the third dose is usually administered at an age of
highest incidence of intussusception, making this case more likely
to be a coincidental event [43]. However, due to the concern about
intussusception, no routine implementation of rotavirus vaccina-
tion is currently proposed in France, with the safety council requir-
ing reassurance that appropriate strategies are in place to ensure
physicians recognize the signs and symptoms of intussusception.
The European Society for Paediatric Infectious Diseases consensus
recommendations indicate that the risk of intussusception in the
first 7 days after rotavirus vaccine can be minimised by vaccinating
at a young age [14].
The risk of intussusception during the first 7 days post-
vaccination is very low. The benefit-risk profile of rotavirus

Table 3
Intussusception (Brighton Diagnostic level 1) following rotavirus vaccination in European countries: post-dose 1 data.

Author Vaccine, Design Data source Case Follow- Risk period (comparison N Outcome (95% CI)
Country schedule identification up period) cases
period
Stowe et al., HRV, 2, 3 Retrospective Hospital Episode ICD-10 2013– 1–7 days (with age effect 15 RI 13.81 (6.44–28.32)
England months SCCS Statistics database 2014 adjustment using historical
[39] data)
8–21 days (with age effect 5 RI 1.59 (0.34–3.75)
adjustment using historical
data)
1–21 days (with age effect 20 RI 4.53 (2.34–8.58) 1
adjustment using historical additional case per 52,350
data) doses
Leino et al., HBRV, 2, Retrospective National Hospital ICD-10 K56.1 1999– 1–21 days (22–42 days) 5 IRR 2.0 (0.5–8.4). 1
Finland 3, 5 SCCS Discharge Register 2013 additional case per 96,000
[40] months first doses
1–15 days (22–42 days) 5 IRR 2.8 (0.5–14.5). 1
additional case per 74,600
first doses
Perez-Vilar HRV and Retrospective, Spanish Hospital ICD-9 560.0 2007– 1–7 days (22–42 days) 3 IRR (age-adjusted) 4.7
et al., HBRV SCCS (Valencia Discharge Database 2011 (0.3–74.1)
Spain [41] Region) (CMBD)
8–21 days (22–42 days) 1 IRR (age-adjusted) 0.8
(0.1–13.9)

ICD = International classification of diseases, HBRV = human-bovine reassortant rotavirus vaccine, HRV = human rotavirus vaccine, IRR = incidence rate ratio, N = number of
diagnostic level 1 cases, RI = relative incidence, SCCS = self-controlled case series, 95% CI = 95% confidence interval.

Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
8 D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx
Public percepon of benefit → vaccinaon
Most influence
Government
recommendaon
Recommendaon from
naonal scienfic
agencies
Least influence
European Union/WHO
recommendaon
Fig. 2. Necessary events to achieve high coverage of vaccines.
vaccines remains favourable. However, vaccination should be
accompanied by parental advice for the close monitoring of infants
and the signs and symptoms of intussusception, with instructions
to seek medical advice early. To this end, healthcare professionals
need to be educated and encouraged to systematically inform par-
ents about the risk of intussusception and the benefits of early
medical attention.
6. Why isn’t uptake of rotavirus vaccines higher in Europe?
In a 2014 review of the drivers and barriers to rotavirus vaccina-
tion in Europe, Parez et al. [44] noted that vaccine coverage rates in
individual countries were generally related to the strength of the
recommendation in that country (Fig. 2). In countries lacking a
national recommendation, moderately high vaccine coverage rates
can be achieved if the medical community is committed to vaccina-
tion, as observed in Portugal and Spain [44–46]. In 2017, barriers to
rotavirus vaccination remain centred around incomplete awareness
of cost-effectiveness; the low priority ascribed to RVGE prevention,
and less frequently, safety concerns as currently observed in France.
6.1. Perceptions about value versus cost
Uncertainty remains about whether rotavirus vaccine in UMV is
cost-effective as compared with no vaccination. This is partly a
function of the disease itself, which is seasonal, limited to young
children, self-limiting and which rarely causes death in developed
countries [47], and partly because of the baseline assumptions
used in models that measure the cost-effectiveness results. There
is little doubt that rotavirus UMV is very cost-effective in middle
to low income countries because the disease burden expressed in
Quality Adjusted Life Years (QALYs) or Disability Adjusted Life
Years is very high, reflecting the high mortality rate. Given the
same evaluation criteria in high income countries, the level of
cost-effectiveness is less because mortality is much lower [48].
Economic analyses usually focus on medical encounters and ignore
effects outside the healthcare setting. Furthermore, for a disease
such as RVGE which peaks during winter at the same time as other
Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
Goal
High coverage
Healthcare Fully funded
professionals offering
vaccinaon and
counselling parents
Parally funded
Vaccine available on Not funded
the market
common infectious diseases (such as influenza), disease prevention
through vaccination reduces the burden on emergency depart-
ments and hospital wards during the busy winter period.
Static models have been shown to underestimate the value of
rotavirus vaccination [49]. This is because they do not include
herd effects which are proving to be substantial for rotavirus vac-
cines, and they assume that immunity and protection wane
rapidly, whereas evidence from Belgium and Germany show high
levels of protection persisting for 4 and 5 years, respectively
[23,49]. The impact on quality of life of infants and on families
as expressed through reduced QALYs is difficult to measure;
infants are unable to articulate suffering, and questionnaires for
parents and carers are not usually designed to collect accurate
data on levels of symptoms such as anxiety or fatigue. The latter
is often left out of economic evaluation models [47], and wider
impacts of RVGE such as secondary cases among family members
and transmission to other children, particularly while in hospital,
may not be fully accounted for. Moreover, a study in Belgium
showed that bed-day occupancy, bed-day turnover and
unplanned readmissions for AGE were all reduced in the period
after the introduction of rotavirus vaccine [50]. By reducing the
winter peak in RVGE-related hospitalisations, pressure on hospital
resources was reduced.
In an UK study, the quality of life of children with RVGE and
their families was evaluated using questionnaires, rotavirus infec-
tion incurred a higher burden (3.1–3.5 QALYs per 1000 cases in
children and 2.7–3.4 QALYs per 1000 primary carers) than esti-
mates used in cost-effectiveness studies (QALY loss of 2.2 and
1.8, respectively) [8]. A study from Belgium showed that for
women with a first born child, vaccination reduced days absent
from work by 2.24 days every three years [51]. The accumulated
net cost gain resulting from vaccination was estimated to be of
€187 per working mother.
The availability of real-world data from UMV programmes
underway in Belgium, Austria, Finland and the UK will inform on
the accuracy of cost-effectiveness estimates, perhaps triggering
re-analysis of the cost-effectiveness of rotavirus UMV in some
countries.
 D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx
6.2. Incomplete awareness of the burden of disease and its associated
costs
Compared to developing countries, relatively few children (an
estimated 231 annually) die from RVGE disease in European coun-
tries [3], potentially contributing to a perception amongst health-
care professionals that RVGE is a mild disease; yet 40% of
childhood hospitalisations for AGE in Europe are due to rotavirus
infection [4]. RVGE causes an important economic burden in terms
of direct healthcare costs associated with medical practitioner vis-
its, hospitalisations, and strain on the healthcare system during
winter months when other seasonal infections also occur. Less
apparent to the healthcare professional is the burden to families
which manifests as parental stress and worry, secondary infec-
tions, lost income due to days off work, and societal costs due to
reduced productivity. Understanding the burden of disease and
the collateral consequences is critical to motivating healthcare pro-
fessionals to vaccinate when vaccine is available but unfunded
(Fig. 2), and in convincing policymakers of the full benefits of rota-
virus UMV.
6.3. Incomplete awareness of the benefits of UMV
In many countries the cost-benefits of vaccination continue to
be expressed in terms of the payers perspective, whereas it is
increasingly appreciated that true benefits of vaccination are far-
reaching, impacting individuals, households, communities and
society [52]. Prevention of RVGE through vaccination has had
important impacts in countries where UMV recommendations
are in place (Table 2). These impacts include a 70–90% reduction
in RVGE hospitalisations in the target age group and substantial
reductions in hospitalisations for RVGE and all-cause gastroenteri-
tis among age groups too old or too young to be vaccinated. The
impact on families and society has yet to be fully quantified.
6.4. Low priority and cost constraints
Prevention of RVGE has low priority in some countries – either
because the disease burden is under-appreciated – or because cost
constraints direct healthcare funding into other areas perceived to
have a greater need [44]. Priority may be given to expensive treat-
ments for diseases such as cancer and diabetes due to pressure
from European league tables, such as the Euro Health Consumer
Index [53], for the treatment of key diseases. At the public inter-
face, healthcare professionals may feel unable to spend time coun-
selling families about non-mandatory vaccinations unless they
perceive a compelling need.
7. Moving forward
There has been little progress in achieving European-wide pro-
tection against rotavirus since a previous review published in 2014
[44]. This is despite solid evidence quantifying the burden of RVGE
and the benefits of vaccination including herd effects, and long-
standing recommendations at a European and global level. Grow-
ing evidence from countries such as the UK, Austria, Finland and
Belgium confirm that the benefit-risk ratio of rotavirus vaccination
is favourable, and that Europe serves to gain considerably from
rotavirus UMV in terms of reductions in healthcare resource uti-
lization, improved productivity and related costs. While some
countries are currently in the process of considering UMV strate-
gies, further work is needed to convince policymakers of the ben-
efits of rotavirus UMV programmes in their individual country. In
all countries, but particularly those in which the key drivers for
rotavirus vaccination (a government recommendation and full re-
Please cite this article in press as: Poelaert D et al. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine
(2018), https://doi.org/10.1016/j.vaccine.2018.02.080
9
imbursement) are lacking, it is commitment to vaccination by
the healthcare professional that will have the greatest impact on
rotavirus prevention. Healthcare professionals equipped with
information on the disease burden in their country and with evi-
dence about the wide-ranging benefits of vaccination from a
healthcare, economic and societal perspective, are best positioned
to be the advocates for rotavirus vaccination.
Focus on the patient
The problem
 40% of childhood hospitalisations for acute gastroenteritis in
Europe are due to rotavirus.
 Rotavirus gastroenteritis causes a substantial economic burden
in terms of direct healthcare costs associated with medical
practitioner visits and hospitalisations. Less apparent is the bur-
den to families – parental stress and worry, impact of secondary
cases within the family, and lost income due to days off work.
 Effective rotavirus vaccines have been available for over 10
years. Although the World Health Organization recommends
that rotavirus vaccines be included in vaccination schedules
worldwide, only 13 countries in Europe currently have recom-
mendations and full funding for rotavirus prevention.
The evidence
 Countries with recommendations and funding for infant rota-
virus vaccination have recorded a 70–90% reduction in RVGE
hospitalisations in the target age group, as well as substantial
disease reductions in age groups too old and too young to be
vaccinated (herd effects).
Focus on the parent
 The benefit-risk ratio for rotavirus vaccines is positive. In accor-
dance with WHO guidelines, rotavirus vaccination should be
offered to all children. The risk of intussusception during the
7 days post-vaccination is low, and pre-vaccination counselling
helps to reduce the clinical consequences of such an event.
 Healthcare professionals equipped with information on the dis-
ease burden and evidence about the wide-ranging benefits of
vaccination are best positioned to be the advocates for rotavirus
vaccination to their patients.
Trademarks
Rotarix is a trademark of the GSK groups of companies. RotaTeq
is a trademark of Merck & Co. Rotashield was a trademark of Pfizer.
Acknowledgements
Writing support services were provided by Joanne Wolter (inde-
pendent medical writer on behalf of GSK); editing and publication
coordinating services were provided by Emmanuelle Ghys (XPE
Pharma & Science on behalf of GSK). All costs related to the devel-
opment of this manuscript were met by GlaxoSmithKline Biologi-
cals SA.
Funding
GlaxoSmithKline Biologicals SA funded all costs associated with
the development and the publishing of the present manuscript.
10 D. Poelaert et al. / Vaccine xxx (2018) xxx–xxx

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