Rotavirus-Vaccination-Expert Opinion-September-2017

SCIENTIFIC ADVICE
Expert opinion on rotavirus

vaccination in infancy
September 2017
www.ecdc.europa.eu
ECDC SCIENTIFIC ADVICE
Expert opinion on rotavirus vaccination in

infancy
This report of the European Centre for Disease Prevention and Control (ECDC) was coordinated by Kari Johansen.
The production of this expert opinion was supported by an external ad hoc scientific panel of experts and ECDC
internal experts.
Acknowledgements
The scientific panel included the following external experts (in alphabetical order):
Gualtiero Grilli, MD, PhD, former Coordinator, Infectious Diseases Control and Vaccinations; Public Health
Department; Marche Region, Italy.
Daniel Levy-Bruhl, MD, PhD, Medical Epidemiologist, Head of the Vaccine Preventable Diseases Surveillance Unit
at the Institut de Veille Sanitaire, Paris, France.
Aurora Limia, MD, PhD, Public Health Officer, National Vaccination Program Coordination Area, Directorate General
of Public Health, Ministry of Health, Social Services and Equality, Madrid, Spain.
Paul McKeown, MD, MPH FFPHM(I), Consultant in Public Health Medicine, Head of Gastro-zoonotic Unit, Health
Protection Surveillance Centre, Dublin, Ireland
Miriam Wiese-Posselt, MD, MPH, Medical Epidemiologist, Department for Infectious Disease Epidemiology,
Immunisation Unit, Robert Koch Institute, Berlin, Germany.
The following internal disease experts from ECDC contributed to the literature reviews and assessment of articles:
Tek-Ang Lim, Benedetto Simone and Pier Luigi Lopalco.
The literature searches were conducted by Irene Munoz, ECDC Library.
ECDC wishes to thank the EuroRotaNet strain surveillance network for supplying genotyping results of circulating
rotavirus strains in the EU/EEA for the time period 2006 to 2016 and the Eudravigilance team at the European
Medicines Agency for providing information on spontaneously reported intussusception cases retrieved from the
Eudravigilance database.
Suggested citation: European Centre for Disease Prevention and Control. ECDC Expert opinion on rotavirus
vaccination in infancy. Stockholm: ECDC; 2017
Stockholm, September 2017
ISBN 978-92-9498-084-7
doi 10.2900/362947
TQ-02-17-947-EN-N
© European Centre for Disease Prevention and Control, 2017

Reproduction is authorised, provided the source is acknowledged.
ii
SCIENTIFIC ADVICE Expert opinion on rotavirus vaccination in infancy
Contents
Abbreviations ................................................................................................................................................ v
Executive summary ....................................................................................................................................... 1
Aim ......................................................................................................................................................... 1
Methods................................................................................................................................................... 1
Results .................................................................................................................................................... 1
Conclusions and possible implications for public health practice and research ................................................. 3
1. Background .............................................................................................................................................. 4
Rotavirus disease ...................................................................................................................................... 5
Rotavirus vaccines available in EU/EEA countries ......................................................................................... 8
Rotavirus vaccines authorised in non-EU/EEA countries and vaccine candidates ............................................ 12
Overview of human rotaviruses ................................................................................................................ 14
Post-authorisation monitoring of circulating rotavirus strains in EU/EEA countries ......................................... 15
Rotavirus immunisation programmes in EU/EEA countries .......................................................................... 18
2. Methods .................................................................................................................................................. 22
Methodology used for evaluating burden of severe rotavirus disease in EU/EEA ............................................ 22
Methodology used for evaluating rotavirus vaccine efficacy......................................................................... 22
Methodology used for evaluating rotavirus vaccine effectiveness ................................................................. 22
Methodology used for evaluating rotavirus vaccine-induced herd protection ................................................. 23
Methodology used for evaluating rotavirus vaccine safety ........................................................................... 23
Methodology used for evaluating rotavirus vaccine cost-effectiveness in the EU/EEA ..................................... 24
Methodology used for evaluating attitudes to rotavirus vaccination .............................................................. 24
Expert panel opinion ............................................................................................................................... 24
Updated expert opinion following ECDC Advisory Forum review and public consultation ................................ 24
3. Results .................................................................................................................................................... 25
Burden of rotavirus disease in EU/EEA countries ........................................................................................ 25
Rotavirus vaccine efficacy ........................................................................................................................ 29
Rotavirus vaccine effectiveness ................................................................................................................ 31
Herd protection provided by infant rotavirus vaccination ............................................................................. 33
Rotavirus vaccine safety .......................................................................................................................... 34
Rotavirus vaccine cost-effectiveness in EU/EEA countries ........................................................................... 45
Attitudes to rotavirus vaccination among parents and healthcare workers .................................................... 50
4. Options for monitoring and evaluating impact of rotavirus vaccination .......................................................... 51
Preparing for rotavirus vaccine introduction............................................................................................... 51
Monitoring impact of rotavirus vaccine programmes ................................................................................... 51
5. Conclusions and possible implications for public health practice and research ................................................ 53
6. Strengths of methodology used in this expert opinion .................................................................................. 54
7. Limitations of methodology used in this expert opinion ................................................................................ 54
8. Next steps ............................................................................................................................................... 54
9. Expert opinion update .............................................................................................................................. 54
10. Annexes ................................................................................................................................................ 55
11. References ............................................................................................................................................ 64
Figures
Figure 1. Number of rotavirus samples per age group submitted to16 EU/EEA countries’ rotavirus reference
laboratories for genotyping 2006-2016............................................................................................................ 5
Figure 2. Rotavirus particle .......................................................................................................................... 14
Figure 3. Schematic overview of the rotavirus reassortment process when two sero/genotypes infect one enterocyte
simultaneously ............................................................................................................................................ 15
Figure 4. Temporal distribution of rotavirus positive samples submitted to the EuroRotanet strain surveillance
network database in consecutive seasons, 2006-2016 .................................................................................... 16
Figure 5. Overall distribution of rotavirus genotypes by EU/EEA country reported to the strain surveillance network,
2006-2016 ................................................................................................................................................. 17
Figure 6a. Rotavirus vaccine efficacy compared with placebo over a follow-up period of 2 years in randomised
control trials reported as risk ratio – RVGE leading to hospitalisation, first and second year ............................... 30
Figure 6b. Rotavirus vaccine efficacy compared with placebo over a follow-up period of 2 years in randomised
control trials reported as risk ratio – RVGE any severity, first and second year .................................................. 30
Figure 7. Forest plot of pooled odds ratios for occurrence of hospitalisation due to RV disease in fully RV-vaccinated
children, case-control studies published between 2010 and 2013 .................................................................... 31
Figure 8. Forest plot of pooled risk ratios for occurrence of hospitalisation due to RV disease in fully RV-vaccinated
children, cohort studies, published between 2007 and 2011 ........................................................................... 32
iii
Expert opinion on rotavirus vaccination in infancy SCIENTIFIC ADVICE
Figure 9. Schematic overview of the most common form of intussusception and its treatments with enema ........ 35
Figure 10. Global annual incidence of intussusception by month of life during first year of life ............................ 37
Figure 11a. Cases reported to EMA Eudravigilance database until 1 July 2014, known interval between dose 1 RV1
and development of intusussception ............................................................................................................. 39
Figure 11b. Cases reported to EMA Eudravigilance database until1 July 2014, known interval between dose 1 RV5
and development of intussusception ............................................................................................................. 44
Tables
Table 1. Rotavirus vaccine contents, indications, contraindications, route of administration, dose regimens and
frequency of reported undesirable effects according to EU/EEA Summary of Product Characteristics ...................... 9
Table 2. Percentage of RV1-vaccinated subjects developing serum rotavirus-specific IgA antibody titers >20 U/mL
post-immunisation, using different EU immunisation schedules ............................................................................. 11
Table 3. Percentage of RV5-vaccinated subjects developing at least a threefold rise in serum rotavirus-specific IgA
antibodies from baseline 42 days post immunisation using different EU immunisation schedules ............................ 11
Table 4. Current status of rotavirus immunisation programmes in EU/EEA countries as of May 2017 ................... 20
Table 5. Overview of EU/EEA studies evaluating percentage of children < 5 years hospitalised due to acute
gastroenteritis in whom rotavirus excretion was identified ............................................................................... 27
Table 6. Background intussusception incidence in eight European countries before rotavirus vaccination ............. 36
Table 7. Incidence of intussusception by month during first year of life, assessed in two EU/EEA countries .......... 36
Table 8. Risk estimates for intussusception and RV1 ....................................................................................... 41
Table 9. Risk estimates for intussusception and RV5 ....................................................................................... 42
Table 10. Main assumptions/parameter values of cost-effectiveness studies in the EU/EEA on infant RV vaccination .......... 48
Table 11. Main results of cost-effectiveness studies in the EU/EEA on infant rotavirus vaccination....................................... 49
iv
Abbreviations
ADR adverse drug reaction
AGE acute gastroenteritis
Australian TGA Australian Therapeutic Goods Administration
CI confidence interval
DNA deoxyribonucleic acid
EC European Commission
ECDC European Centre for Disease Prevention and Control
ED emergency department
EEA European Economic Area
ELISA enzyme-linked immuno-sorbent assay
EMA European Medicines Agency
EMA CHMP European Medicines Agency Committee for Medicinal Products for Human Use
EMA EV European Medicines Agency Eudravigilance database
EU European Union
GMT geometric mean titers
GSK GlaxoSmithKline
IgA immunoglobulin A
IgG immunoglobulin G
IS intussusception
MSD Merck Sharp Dome Vaccins
NICU neonatal intensive care unit
NITAG national immunisation technical advisory group
OR odds ratio
PCV porcine circovirus
QALY quality-adjusted life year
RCT randomised placebo-controlled clinical trial
RR relative risk
RV rotavirus
RV1 monovalent rotavirus vaccine (Rotarix™)
RV5 pentavalent rotavirus vaccine (RotaTeq™)
RVGE group A rotavirus-induced gastroenteritis
SCID severe combined immunodeficiency
SMR standardised morbidity ratio
SPC Summary of Product Characteristics
German STIKO German Standing Committee on Vaccination
UK JCVI United Kingdom Joint Committee on Vaccines and Immunization
US ACIP United States Advisory Committee on Immunization Practices, Centers for Disease Control and
Prevention
US CDC United States Centers for Disease Control and Prevention
US FDA United States Food and Drug Administration
US NIAID United States National Institute of Allergy and Infectious Diseases
US VAERS United States Vaccine Adverse Event Reporting System
VLP virus-like particle
VP viral protein
WHO World Health Organization
WHO SAGE World Health Organization Strategic Advisory Group of Experts on immunization
v
Executive summary
Aim
Since 2006, two oral live vaccines (RV1 and RV5) have been available in the European Union/European Economic
Area (EU/EEA) for prevention of rotavirus-induced gastroenteritis (RVGE). The main objective of rotavirus
vaccination in organised national immunisation programmes is to provide protection against moderate-to-severe
disease and thereby prevent hospitalisation and death. To exclude possible strain replacement induced by
immunological pressure following vaccination, strain monitoring was requested in the EMA Risk Management Plan.
The aim of this expert opinion is to provide EU/EEA Member States with relevant scientific information and expert
opinion to support the decision-making process on the possible introduction and monitoring of routine vaccination
of infants against RVGE.
Methods
The evidence presented in this document are based on reviews of the literature published in scientific journals,
grey literature and a search in the European Medicines Agency Eudravigilance database (EMA EV) for reported
cases of intussusception following rotavirus vaccination. The information collected summarises:
burden of RVGE in the EU/EEA in children under five years of age
rotavirus vaccine efficacy in countries with low mortality due to RVGE (hereafter referred to as ‘low-mortality
rotavirus countries’)
rotavirus vaccine effectiveness in low-mortality rotavirus countries
herd protection provided by infant rotavirus vaccination in low-mortality rotavirus countries
rotavirus vaccine safety in low-mortality rotavirus countries
cost-effectiveness of using rotavirus vaccines in EU/EEA immunisation programmes
attitudes to rotavirus vaccination among parents and healthcare workers
The expert opinion provided in this document, is based on available evidence evaluated by a group of independent
EU/EEA public health experts. The opinion highlights issues to be considered before and after introduction of
rotavirus vaccines. It also identifies knowledge gaps and areas in need of further research.
Results
Burden of rotavirus disease in the EU/EEA
A literature review identified 46 studies conducted in eighteen EU/EEA Member States assessing severe disease
leading to hospitalisation, suggesting that approximately 300−600 children per 100 000 under the age of five years
are hospitalised due to RVGE annually. However, significant variation occurs over time and between countries.
Extrapolating these data to the whole EU/EEA with a birth cohort of approximately five million infants suggests that
~75 000−150 000 hospitalisations in children under five years occur on an annual basis. In addition, an estimated
2-4 times more children seek medical evaluation in emergency rooms or other out-patient facilities. Mortality rates
reported in two studies were low (one study found death rates of less than 0.1/100 000 and the other less than
0.2/100 000 children under five years of age). A few risk factors for development of severe RVGE were identified,
but severe disease may develop in any child. The risk factors identified were low-birth-weight (<2 500 g) (OR 2.8;
95% CI 1.6−5.0), day-care attendance (OR 3.0; 95% CI 1.8−5.3) and having another child aged under 24 months
in the same household (OR 1.6; 95% CI 1.1−2.3).
Children seeking medical attention in emergency departments/out-patient clinics or those hospitalised with RVGE
have the potential to be sources of nosocomial infection in other children attending medical services. In a recent
meta-analysis of studies of nosocomial RVGE, an adjusted year-round incidence of 0.7 (95% CI 0.0−1.8) per 100
hospitalisations was estimated for children under five years.
The vast majority of human cases with RVGE within EU/EEA are caused by six genotypes within serogroup A
rotaviruses, namely G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and G12P[8]. New emerging genotypes for EU/EEA
were identified at lower incidence but no novel emerging strain causing larger outbreaks had been detected until
2016, although the time period surveyed is short for virus evolution. However, there is no evidence to date that
rotavirus vaccination programmes are driving the emergence of vaccine escape strains.
Vaccine efficacy
A Cochrane review published in 2012 evaluated vaccine efficacy of RV1 and RV5 in 41 randomised controlled trials
with 186 263 participants. The trials compared one of the rotavirus vaccines with placebo, no intervention or
another vaccine. The RV1 vaccine was evaluated in 29 trials involving 101 671 participants and the RV5 vaccine in
12 trials involving 84 592 participants. The large trials were conducted in low- and high-mortality settings
1
throughout the world. The Cochrane analysis showed that in the first two years of life, RV1 and RV5 prevent more than
80% of severe cases of RVGE in low-mortality developed country settings. Furthermore, a German systematic review and
meta-analysis of randomised placebo-controlled clinical trials (RCTs) assessing RV1 and RV5, conducted in Europe, Australia,
Canada, USA, Latin America and Asia and published in 2013 suggests a vaccine efficacy against rotavirus-induced
hospitalisation during the first two years following vaccination of 92% (95% CI 82−96%).
Vaccine effectiveness
Rotavirus vaccine effectiveness was assessed in observational studies using either case-control or cohort study
designs in the following rotavirus low-mortality and developed countries: Australia (RV1 and RV5), Austria (RV1 and
RV5), Belgium (RV1 and RV5), Finland (RV5), France (RV5), Germany (RV1 and RV5), Spain (RV5), and the US (RV1
and RV5). After at least two doses of rotavirus vaccine, pooled vaccine effectiveness in preventing severe RVGE
leading to hospitalisation was estimated at 84% (95%CI 75−89%) in case-control studies (based on 15 studies) and
at 91% (95%CI 88−94%) in cohort studies (based on four studies).
Herd protection
A meta-analysis of studies conducted to estimate herd protection in children less than one year of age in low-mortality
rotavirus countries (n=5) reporting on RVGE outcomes suggest a median herd effect on RVGE morbidity of 22%
(19−25%) across 12 study years.
Vaccine safety
An earlier first generation, US-licensed oral live rotavirus vaccine RRV-TV (Rotashield, authorised 1998) was withdrawn
from the market because of an associated estimated excess of one additional case of intussusception (IS) per 4 670
to 9 474 infants vaccinated (beyond the natural background incidence of IS).
In pre-authorisation trials, which served as the basis for authorisation of the new second generation of rotavirus
vaccines in the EU/EEA, no increased risk of IS was observed in recipients of either rotavirus vaccine (RV1 or RV5),
compared to the placebo groups. This was also the conclusion of the 2012 Cochrane systematic review assessing
vaccine safety in randomised placebo-controlled clinical trials. However, a risk of IS lower than one additional case in
10 000 vaccinated infants could not be excluded in the conducted trials. Formal pharmaco-epidemiological studies in
Australia, Brazil, Mexico and the US assessing the second generation of rotavirus vaccines used in routine vaccination
programmes indicate that rotavirus vaccines carry an increased risk of intussusception during the first seven days
following dose 1, ranging between 1 per 20 000 to 1 per 69 000 for RV1 vaccinated infants and 1 per 14 000 to 1 per
67 000 for RV5 vaccinated infants in the different studies. Contrary to this, in the studies conducted by Belongia et al,
Shui et al and Haber et al, using the US VAERS or US VSD data, no increased risk of intussusception following RV5
was observed, possibly due to small sample size. Following a formal review of available data by the EMA, the EU
Summaries of Product Characteristics (SPCs) for both rotavirus vaccines were updated in May 2014:
‘Data from observational safety studies performed in several countries indicate that rotavirus vaccines carry an
increased risk of intussusception, mostly within 7 days of vaccination. Up to 6 additional cases per 100,000
infants have been observed in the US and Australia against a background incidence of 33 to 101 per 100,000
infants (less than one year of age) per year, respectively. There is limited evidence of a smaller increased risk
following the second dose. It remains unclear whether rotavirus vaccines affect the overall incidence of
intussusception based on longer periods of follow up’.
Risk minimisation strategies to reduce incidence of intussusception following rotavirus vaccination have been
recommended by a few European public health agencies/NITAGs in three countries (Germany, Norway and two
regions in Sweden) recommending initiation of vaccination early within the first 6-8 or 12 weeks of life. The impact of
these strategies needs to be carefully studied but a recent meta-analysis indicates that if vaccination with the first
dose is provided at under 12 weeks of age, rather than later than 12 weeks, the risk of intussusception following
vaccination is reduced from approximately 1 in 20 000 to approximately 1 in 50 000.
Other identified adverse events include severe gastroenteritis and long-term excretion of rotaviruses by severely
immunocompromised vaccinated infants (SCID), for whom RV vaccines now are contraindicated. Furthermore, any
vaccinated infant may transmit vaccine virus to severely immunocompromised contacts of any age and therefore
contact between a newly vaccinated child and such individuals should be avoided.
Cost-effectiveness in EU/EEA Member States

Identified studies on cost-effectiveness of universal rotavirus vaccination in the EU/EEA provide discrepant results. The
inclusion of societal costs and/or positive indirect benefits of the vaccines such as herd immunity, significantly affects
the cost-effectiveness ratios. A recent survey in EU/EEA Member States conducted by the VENICE III network found
that eight out of eleven countries having undertaken economic assessments have introduced rotavirus vaccines into
their programmes.
2
Rotavirus immunisation programmes in EU/EEA

As of May 2017, thirteen EU/EEA Member States were recommending vaccination against RVGE in their national
paediatric immunisation programmes and had initiated or were about to initiate the programme and one further
Member State have implemented vaccination in some regions of the country.
Attitudes to rotavirus vaccination among parents and healthcare

workers
One study is available from the EU/EEA on attitudes to rotavirus vaccination among parents and healthcare
workers. This study from the Netherlands concluded that when deciding about vaccination against rotavirus,
parents are driven by the out-of-pocket costs, vaccine effectiveness, duration of protection, and frequency of
severe side effects. Further, the highest vaccination coverage is expected for a vaccine with high effectiveness and
long protection duration implemented within the national immunisation programme context. In countries that
report vaccination coverage for rotavirus vaccines used in national immunisation programmes, the coverage ranges
between 61 and 93%, suggesting good acceptance among parents, care providers and healthcare workers.
Conclusions and possible implications for public health

practice and research
Burden of disease studies assessing RVGE overall and severe disease leading to hospitalisation conducted in
eighteen EU/EEA countries suggest that ~75 000−150 000 hospitalisations occur annually in children aged under
five years, while mortality is low. In addition, an estimated 2-4 times more children seek medical evaluation in
emergency rooms or other out-patient facilities. Two rotavirus vaccines (RV1 and RV5) for use in routine
immunisation programmes have been authorised for prevention of RVGE and shown, in a series of studies, to be
effective in preventing severe RVGE leading to hospitalisation as well as mild to moderate disease in need of
medical attention. Vaccine effectiveness against RVGE-related hospitalisation ranges from 85−90 % in countries
with low mortality due to rotavirus disease (all EU/EEA countries categorised as low-mortality countries).
Furthermore, herd protection contributes to the overall impact of vaccination programmes. A risk of up to six
additional intussusception cases per 100 000 infants within 7 days of vaccination has been identified for both
rotavirus vaccines, as specified in respective EU/EEA SPC. Benefit-risk has been assessed by many regulatory
agencies throughout the world including Australian TGA, EU EMA, US FDA and found to be positive, given the
severity of rotavirus disease and availability of treatment for cases of intussusception. However, in accordance with
the recommendations of several public health agencies, options for risk minimisation with the current vaccines
should be explored and vigilance among parents, care-providers and healthcare workers is essential to ensure that
affected infants are promptly treated.
The expert scientific panel suggests the following set of data collection and monitoring to be considered at the EU-
level and in EU/EEA Member States before and after introduction of rotavirus vaccines into a routine immunisation
programme:
case-based routine or sentinel surveillance of severe RVGE leading to hospitalisation and/or death
virological surveillance in a statistically sound and geographically representative sample of circulating strains
investigation and reporting of hospitalised breakthrough rotavirus disease in vaccinated individuals (including
genotyping and detection of other possible pathogens, i.e. adenovirus, norovirus, sapovirus, etc.)
estimation of country-specific background rates of intussusception (by month of age during first year of life)
collection of data on individual vaccine exposure (including age and batch number) in manual or electronic
registries and overall vaccine coverage
Furthermore, EU/EEA countries could consider measuring the impact of rotavirus vaccines in formal epidemiological
studies for clinically relevant disease endpoints that may include surveillance of reduction in hospitalisation of
children due to RVGE, reduction in emergency room visits due to RVGE and reduction in the number of stool
samples referred to laboratories for rotavirus diagnostics. Three generic study protocols for vaccine effectiveness
and impact studies using different methodologies are available for use on the ECDC website. Further studies
assessing the frequency, extent of complications (e.g. need for surgical resection of intestine) and possible
underlying medical conditions predisposing to development of IS are needed in the European setting. In addition,
EU/EEA countries that have implemented risk reduction strategies with early vaccination should consider
conducting pharmaco-epidemiological studies to inform others of the potential impact of such interventions.
Finally, sharing available health economic models assessing cost-effectiveness of rotavirus vaccination should be
encouraged so they could be used in various settings by those EU/EEA countries interested.
3
1. Background
In 2006, two live rotavirus vaccines for oral use in infants were authorised by the European Commission for
prevention of group A rotavirus-induced gastroenteritis (RVGE); Rotarix™ (RV1), and RotaTeq™ (RV5) (1, 2).
Uptake of rotavirus vaccines into EU/EEA routine immunisation programmes has been limited. As of May 2017
thirteen EU/EEA Member States were recommending vaccination against RVGE in their national paediatric
immunisation programmes and had initiated or were about to initiate the programme and one further Member
State have implemented regional programmes.
Rotaviruses are classified serologically into serogroups (A-G) (see Figure 2 in the Section ‘Overview of human
rotaviruses’). Rotaviruses in group A are the most common cause of gastroenteritis in young children worldwide
and the new rotavirus vaccines offer protection against these infections.
Estimates suggest that by the age of five years, every child in the world will have been infected with group A
rotaviruses at least once. While infected, many of these children will suffer severe disease and be in need of
medical attention due to extensive fluid loss (3). Furthermore, group A rotaviruses are a frequent cause of
diarrhoea-associated deaths estimated at approximately 528 000 (range, 465 000-591 000) worldwide annually in
year 2000 (4, 5), occurring mainly in developing countries while in developed countries mortality is low, thanks to
medical supportive healthcare being readily available (6).
Already in 2007 WHO SAGE recommended the inclusion of rotavirus vaccines into national immunisation
programmes in regions where efficacy data from randomised clinical trials suggested that rotavirus vaccines would
provide significant protection against severe disease, mainly in the Americas and Europe (7).
In 2009, after clinical trials had been performed in more deprived settings, the recommendation was extended to
include all infants throughout the world, with the vaccination being provided any time between six and fifteen
months of age (8). Furthermore, in 2013, although still favouring early immunisation, starting as soon as possible
after six weeks of age along with DTP vaccination, WHO SAGE recommended the removal of the upper age
restriction of 15 months for the first dose, to also enable children whose immunisation was delayed to be fully
vaccinated (9). By recommending that the age restriction be removed, it was hoped that it would be possible to
help protect vulnerable children in settings where DTP doses are given late. However, because of the typical age
distribution of rotavirus infections, rotavirus vaccination of children > 24 months of age was not recommended.
The aim of this expert opinion on rotavirus vaccination in infancy is to provide EU/EEA countries with relevant
scientific information to support the decision-making process on the possible introduction and monitoring of routine
vaccination to prevent RVGE.
4
Rotavirus disease
Symptoms
The clinical spectrum of RVGE is wide in young children, ranging from transient mild diarrhoea to severe
gastroenteritis with concomitant fever. Primary infections frequently result in a symptomatic episode of acute
gastroenteritis (AGE), while reinfections are often asymptomatic or mild and only rarely lead to hospitalisation (10,
11). Symptoms such as diarrhoea, vomiting and fever may all contribute to the significant dehydration observed in
some children (12).
The vast majority of RVGE episodes are mild or moderate, however, severe rotavirus disease leading to
hospitalisation is often observed in the age group 0–36 months (see Figure 1), an age group when children are
particularly vulnerable to dehydration. This is also the age when most children acquire their first rotavirus infection
(13, 14).
The incubation period for RVGE is 1–2 days. Symptoms are commonly relieved within three to eight days, but may
last up to two or occasionally even three weeks in healthy, well-nourished children.
Figure 1. Number of rotavirus samples per age group (years) submitted to 16 EU/EEA countries’
rotavirus reference laboratories for genotyping 2006–2016 and reported to EuroRotaNet*, showing
that the major burden of disease is in the 0–3 year age group but disease is reported in all age
groups
14000
12000
10000
Number
8000
6000
4000
2000
0
2.5-3
0.5-1
1.5-2
3.5-4
4.5-5
>90
1-1.5
2-2.5
4-4.5
5-6
6-7
7-8
8-9
9-10
10-20
20-30
30-40
40-50
50-60
60-70
70-80
80-90
<0.5
3.3.5
Age in years
*Further information available at www.eurorota.net
Complications
In some children extensive nausea and vomiting results in difficulties in providing oral rehydration in home settings,
and may lead to severe fluid loss with or without accompanying electrolyte disturbances (hypo-, iso- or hypertonic
dehydration that may require prolonged rehydration treatment). Further complications may include seizures due to
high fever or electrolyte disturbances, encephalitis/meningitis, shock and possibly death. Long-term, some children
develop chronic diarrhoea and in more deprived settings malnutrition. In an observational retrospective cohort
study conducted in Sweden (n=987), complications requiring additional medical attention, other than general
dehydration, were observed in >15% of hospitalised children with RVGE (15). Younger children (<12 months) were
particularly prone to more severe dehydration (>10% of body weight).
Extraintestinal spread of rotaviruses to blood, cerebrospinal fluid, heart and liver has been reported and is
suggestive of rotaviruses causing an invasive viral infection, rather than one confined to the intestinal mucosa (16-
21). In previously healthy well-nourished children, treated for rehydration before development of shock, no residual
sequelae develop following an acute rotavirus infection. However, access to good clinical supportive care is crucial.
Natural rotavirus disease has only rarely been identified as a cause of intussusception (22).
5
Infections in immunocompromised children

In general, rotaviruses do not cause more severe clinical symptoms in moderately immunocompromised patients,
however, prolonged shedding of rotaviruses may occur in these individuals (23, 24). Severe, prolonged and even
fatal rotavirus disease may develop in those with severe immunodeficiency conditions such as severe congenital
immunodeficiency, solid organ or bone marrow transplantation (25).The severity of rotavirus disease among
children infected with HIV may be similar to that of non-HIV infected children (24), however whether the incidence
rate of severe rotavirus disease among HIV-infected children is similar to or greater than that among non-HIV
infected children is unknown.
Nosocomial infections
Children seeking medical attention in emergency departments/out-patient clinics or hospitalised with rotavirus
disease have the potential to become sources of nosocomially-acquired infections (26-29).
Infections in family and household members

Household transmission of rotavirus disease is common. Adults and older siblings in contact with young children
experiencing their primary rotavirus disease are at particularly high risk of developing a rotavirus disease. In a
Canadian study it was shown that in 47% of hospitalised rotavirus cases at least one other family member
experienced AGE in association with an index case infection (30). Among these household contacts experiencing
diarrhoea, most were below five years of age but 16% were adults. Only occasionally did household members
need medical attention, but symptoms prevented some from attending school or work.
Asymptomatic infections
Asymptomatic rotavirus infections are common among neonates (31-33), older children and adults (34, 35),
including healthcare workers (36). All these groups are likely to be protected against symptomatic disease due to
an immune response acquired during one or more previous rotavirus infections earlier in life or, in the case of
neonates, through maternal antibodies providing protection during the first 3–4 months of life (37, 38). Viral load in
stool samples from individuals with symptomatic infection is significantly higher than in individuals with
asymptomatic infection (39). Nonetheless, asymptomatic carriers are likely to play a role in sustained transmission
of rotaviruses in the human population as well as boosting the initial acquired primary immune response.
Risk factors for severe disease

Severe rotavirus disease may develop in any child, however a limited number of risk factors for development of severe
disease were identified in three studies (40-42). In these studies low-birth-weight infants (<2 500 g) were shown to
be at increased risk of hospitalisation even beyond the first few months of life (OR 2.8; 95% CI 1.6–5.0) and children
in day-care were more likely to be hospitalised than those cared for at home (OR 3.0; 95% CI 1.8–5.3). In addition,
another child <24 months of age in the household was also shown to be a risk factor (OR 1.6; 95% CI 1.1–2.3). In
contrast, breast-feeding was shown to protect against hospitalisation for rotavirus disease, with an increased risk for
infants <6 months of age if not breastfed in the month before hospitalisation (OR 5.1; 95% CI 1.2–13.2).
Pathogenesis
Rotaviruses, first discovered in 1973 (43, 44), primarily infect mature intestinal epithelial cells on the tips of the
small intestinal villi. Destruction of infected cells and subsequent development of villous atrophy reduces digestion
and absorption of fluid and nutrients, resulting in secretory diarrhoea with loss of fluids and electrolytes into the
intestinal lumen. In addition, one of the viral non-structural proteins, NSP4, which can be detected early during a
rotavirus infection has been reported to function as a viral enterotoxin, and is thought to play a role in the
development of symptoms (45). Further, spread of rotaviruses systemically may be more common than previously
understood, since antigenemia/viraemia and subsequently elevated transaminases (S-AST and S-ALT) have been
reported (17-21, 46, 47).
Mode of transmission
Rotaviruses are mainly transmitted from person-to-person through the faecal-oral route, but transmission may also occur
through contaminated objects (e.g. door-handles, water-taps, toilet-seats and toys), airborne droplets or contaminated
water or food (48, 49). Rotaviruses may persist on dry surfaces for up to two months (48). Animal rotaviruses from
infected animals are also occasionally transmitted to humans and may result in co-infections with human rotaviruses and
development of new emerging serotypes/genotypes through the reassortment mechanism (50).
6
Infectious dose and virus shedding

The infectious dose is small, an inoculum of as few as 10–100 particles is sufficient to produce illness in susceptible
individuals. The typical excreted virus load is between 108–1010 particles per mL faecal sample in children with their
first rotavirus infection. Virus shedding has been described for up to three weeks or even longer in healthy
immunocompetent individuals (51). Moreover, cases of chronic rotavirus shedding have been reported among
severely immunodeficient children (23).
Routine diagnostics
As mentioned earlier, there are several serogroups of rotaviruses that may infect humans, including A, B and C.
Serogroup A is the most common and therefore most laboratory assays only detect serogroup A rotaviruses.
Excretion of rotaviruses may be confirmed by using antigen-detecting assays (enzyme immunoassays,
immunochromatographic rapid tests), genome-detecting assays (PCR) or electron microscopy.
Clinical management
Clinical management is directed towards early replacement of fluid losses using oral rehydration at home. However,
with more extensive fluid losses there may be a need for nasogastric or intravenous rehydration, alone or in
combination, provided in hospital settings. Earlier no other treatment apart from fluid replacement was available
and no other therapy is required in previously healthy individuals since the condition is self-limiting. In some clinical
settings probiotics (e.g. Lactobacillus GG) have been used to reduce duration of gastroenteritis (52). However, with
the authorisation of racecadotril (Lincoln Medical Limited, UK), an additional treatment option is available that will
reduce the number of days with diarrhoea (53). Racecadotril, an enkephalinase inhibitor with potent antisecretory
activity but only limited effect on gut motility, is intended for children older than three months and is administered
via the oral route together with oral rehydration solution. Treatment should be continued until two normal stools
are recorded and should not exceed seven days. No antiviral drugs are available. In the rare instances that
immunodeficient children develop chronic excretion of rotaviruses, treatment with intravenous or oral
immunoglobulin may be indicated, however, oral immunoglobulin administered for prevention of rotavirus disease,
although safe, did not provide protection against rotavirus disease in hospitalised low birth-weight infants (birth-
weight <2500 g) according to a 2011 Cochrane review (54).
Protective efficacy induced by natural disease against subsequent

clinical infections
The protective efficacy of an episode of natural infection in a young child against subsequent symptomatic re-
infections is estimated to be 58–75% (10, 11, 55). However, it is important to distinguish between symptomatic
and asymptomatic infections. Re-infections occur throughout life. In a prospective cohort study performed in
Mexico, a single rotavirus infection early in life was shown to provide protection against a subsequent laboratory-
confirmed infection with rotavirus in 38% of all children, while 77% were protected against a subsequent
symptomatic laboratory-confirmed rotavirus infection and 87% against a subsequent severe symptomatic
laboratory-confirmed rotavirus-induced gastroenteritis (10). In a large observational retrospective study in a
northern European setting (n=987) spanning 11 years, it was shown that children are rarely hospitalised more than
once (<0.2% of hospitalised children with rotavirus disease) for an acute rotavirus infection (15).
Serological correlates for protection including cross-immunity

Serological correlates of protection against rotavirus infections are poorly understood, but are likely to involve
neutralising antibodies to the rotavirus outer surface viral proteins (VP4 and VP7). Rotavirus-specific IgA and IgG
antibodies, neutralising antibodies directed to VP4 and VP7 (see Figure 2 ‘Human rotavirus particle’) and cell-
mediated immunity all develop after a primary rotavirus disease infection (56). In addition, a humoral immune
response is known to develop to other internal viral proteins such as VP6 and the non-structural protein 4 (NSP4)
known to have toxic effects (57, 58).
Immune response after a primary infection with group A rotaviruses is thought to be mostly against the infecting
serotype/genotype but heterotypic cross-protection is also observed (59). A broader heterotypic response is elicited
following further re-infections (symptomatic or asymptomatic), possibly explaining why immunity is cumulative.
Since natural rotavirus infections do not provide sterilising immunity, it is not expected that the vaccines will
provide sterilising immunity in vaccinated individuals. Reinfections are also expected in vaccinated individuals,
which will likely induce and maintain heterotypic protection.
7
Rotavirus vaccines available in EU/EEA countries

Two live vaccines for oral use providing prevention against rotavirus disease were authorised in EU/EEA in 2006;
Rotarix, a monovalent vaccine (RV1) developed from a human rotavirus strain attenuated through serial passage in
cell culture (GlaxoSmithKline Biologicals, Rixensart, Belgium) and RotaTeq, a human-bovine rotavirus reassortant
pentavalent vaccine (RV5) derived from several cell-culture-adapted human rotavirus strains and a bovine rotavirus
strain (MSD, Lyon, France) (1, 2). The indication for these vaccines is active immunisation of infants for prevention
of gastroenteritis due to rotavirus (see Table 1).
EU dose recommendations
The dose recommendations, as mentioned in respective EU/EEA SPC, vary for the two rotavirus vaccines:
RV1 should be administered in two doses any time from the age of six weeks, with an interval of at least four weeks
between the doses. The full vaccination course of two doses should preferably be given before 16 weeks of age, but
must be completed by the age of 24 weeks. RV1 should not be used in infants >24 weeks of age (see Table 1).
RV5 should be administered in three doses any time from the age of six weeks, with an interval of at least four weeks
between each of the three doses. The first dose should be provided at no later than 12 weeks of age, and it is preferable
that all three doses should be administered before the age of 20–22 weeks. If necessary, the third dose may be given up
to the age of 32 weeks (see Table 1).
The reason for the narrow age window for dose 1 in particular, but also for completion of the whole series, is to ensure
protection before observed peak of rotavirus infection and the experience with an earlier first generation oral live
rotavirus vaccine, Rotashield® (RRV-TV), licensed in 1998 in the US. Following the introduction of this rotavirus vaccine
into the US national immunisation programme it was found to be effective in providing protection against hospitalisation
due to RVGE (60), but an adverse event was reported – development of intussusception (IS). IS was later found to be
epidemiologically associated with this vaccine and the vaccine was therefore withdrawn from the US market (61, 62). An
estimated risk of one additional case of intussusception per 4 670 to 9 474 infants vaccinated was identified. Infants with
intussusception who had received the first or second dose of RRV-TV fourteen or fewer days before the onset of this
condition were younger than other infants with naturally occurring intussusception (mean age at the time of
hospitalisation, 4.1 vs. 6.4 months, P<0.001; range, 2.0 to 7.0 vs. 1.0 to 11.0 months) (61). In further follow-up studies
of this vaccine it was also shown that infants vaccinated before day 60 of life had no increased risk (>70 000 doses
administered) and infants vaccinated day 61–90 of life were significantly less prone to develop intussusception than
children vaccinated after day 90. (63).
EU/EEA countries may recommend immunisation schedules within the span of the EU/EEA SPC recommendations (see
Table 4 for choices made by countries that have introduced rotavirus vaccines.)
Breastfeeding and rotavirus vaccination

Breastfeeding should be continued ad lib around the time of rotavirus vaccination and withholding breastfeeding at
that time is unlikely to improve the vaccine immunogenicity (41, 64).
Concomitant administration of other paediatric vaccines

Both rotavirus vaccines can be administered concomitantly with other monovalent and/or combination infant
vaccines containing one or more of the following antigens: D, T, aP, Hib, IPV or OPV, HBV, PCV, Men B and MenC.
Non-concomitant administration of the two live viral vaccines RV and OPV is an alternative (65).
Vaccination of premature infants

The recommendations for vaccination of premature children differ between the two vaccines. RV1 may be given to
preterm infants born after at least 27 complete weeks of gestational age (66). RV5 may be given to infants born
prematurely provided that the period of gestation was at least 25 weeks (67). Apnoea has been reported in
premature infants following administration of RV1 and RV5.
Due to excretion of vaccine virus in stool from vaccinated infants that may cause symptoms in the youngest and
most vulnerable premature infants, most neonatal intensive care units (NICUs) do not offer vaccination until the
infants are discharged from hospital. This results in a number of unvaccinated premature children vulnerable to
severe rotavirus disease undergoing prolonged treatment period in NICUs. A retrospective cohort study using
electronic records and assessing clinical symptoms in RV5 vaccinated (n=96, born at gestational age 32.6 weeks
±5.0) and unvaccinated patients (n=801, born at gestational age 34.8 weeks ±5.0) treated in a neonatal intensive
care unit was conducted to evaluate safety. Results suggest that RV5 vaccination was well tolerated, with no
indication of symptomatic transmission to neighbouring unvaccinated infants, but diarrhoea was observed in 18/96
(19%) vaccinated infants compared to 1/801 control infants (68). Authors conclude that a larger prospective study
is needed to assess severity of observed diarrhoea, virus shedding and transmissibility.
8
Table 1. Rotavirus vaccine contents, indications, contraindications, route of administration, dose

regimens and frequency of reported undesirable effects according to EU/EEA Summaries of Product
Characteristics (1, 2)
RV1 RV5
Rotavirus genotypes Human rotavirus strain P1A[8]G1 Five reassortant strains with a bovine rotavirus
included in vaccine strain WC3, P7 [5] G6 expressing viral surface
proteins corresponding to the human rotavirus
genotypes G1, G2, G3 and G4, and P [8]
Formulations Live attenuated Live
Vaccine production Vero cells Vero cells
Excipients Lyophilised Rotarix: 9 mg sucrose per dose, 1080 mg sucrose per dose
13.5 mg sorbitol per dose
Liquid Rotarix: 1073 mg sucrose per dose
Indications Prevention of GE due to rotavirus disease Prevention of GE due to rotavirus disease
Contraindications  Hypersensitivity to the active substance or to  Hypersensitivity to the active substance or
any of the excipients. to any of the excipients.
 Hypersensitivity after previous  Hypersensitivity after previous
administration of rotavirus vaccines administration of rotavirus vaccines
 Previous history of intussusception.  Previous history of intussusception.
 Subjects with uncorrected congenital  Subjects with uncorrected congenital
malformation of the gastrointestinal tract malformation of the gastrointestinal tract
that would predispose for intussusception. that would predispose for intussusception.
 Diarrhoea and vomiting.  Known or suspected immunodeficiency
 Febrile illness. including HIV.
 Severe combined immunodeficiency (SCID)  Diarrhoea and vomiting
 Febrile illness.
 Severe combined immunodeficiency (SCID)
Route of
Oral Oral
administration
Dose regimensǂ  Two doses from the age of 6 weeks.  Three doses from the age of 6 weeks.
Interval of at least four weeks between Interval of at least four weeks between
doses. doses.
 The vaccination course should preferably be  The first dose should not be given later
given before 16 weeks of age, but all doses than the age of 12 weeks.
must be completed by the age of 24 weeks.  It is preferable that all three doses should
 RV1 should NOT be used in the paediatric be administered before age of 20–22
population over 24 weeks of age. weeks. If necessary, the third (last) dose
may be given up to the age of 32 weeks.
 RV5 is NOT indicated in the paediatric
population from 33 weeks to 18 years.
 Diarrhoea and vomiting < 1:10*  Fever ≥ 1:10

Undesirable effects  Diarrhoea and vomiting ≥ 1:10*
 Irritability < 1:10
 Abdominal pain, flatulence < 1:100  Upper respiratory tract infection < 1:10
 Dermatitis < 1:100  Rash < 1:100
 Intussusception <1:10 000**  Nasopharyngitis <1:100
 Apnoea in very premature infants (≤ 28  Otitis media <1:100
weeks of gestation)***  Abdominal pain upper <1:100
 Haematochezia***  Bronchospasm < 1:1 000
 Gastroenteritis with vaccine viral shedding  Urticaria < 1:1 000
in infants with Severe Combined Immuno-  Intussusception < 1:10 000**
deficiency (SCID)***  Apnoea in very premature infants (born
≤28 weeks of gestation)***
 Haematochezia***
 Anaphylaxis***
 Irritability***
 Angioedema***
ǂ US ACIP recommends that the first dose of rotavirus vaccine, irrespective of product, is administered from 6 weeks through 14
weeks, six days of age.
* In the event of an infant spitting out or regurgitating most of the vaccine dose, a single replacement dose may be given.
** Updated 14 May 2014: up to six additional cases of intussusception per 100 000 infants within seven days of vaccination
observed in observational studies conducted in Australia and the US. See Chapter 6 for further details.
*** Frequency cannot be estimated based on available data.
9
Vaccination of infants with immunodeficiency and immunodeficient

close contacts
Excretion of live vaccine virus has been shown to occur after vaccination of healthy infants with both rotavirus vaccines
(69). Approximately 50% of RV1 vaccine recipients were shown to excrete vaccine virus after the first dose of RV1 and
4% after the second dose (1) while approximately 9% of RV5 vaccine recipients excreted vaccine virus after dose 1 (2)
and 0.3% after dose 3 (70). Peak viral shedding generally occurs around 7 days after the first dose. Transmission of
vaccine virus to healthy individuals has been observed with limited or no clinical symptoms (71).
Live rotavirus vaccines should always be administered with caution in individuals with congenital or acquired
immunodeficiency, as well as to infants in close contacts with immunodeficient patients. Following identification of
chronic rotavirus secretion, EMA and other global regulatory agencies have approved a labelling change in the SPC
for the two (RV1 and RV5) vaccines contraindicating administration to individuals with a history of severe combined
immunodeficiency (SCID) (72). Safety and efficacy have not been established for use of RV1 and RV5 in other
immunocompromised infants, including those with blood dyscrasias, leukaemia, lymphoma, malignant neoplasms
affecting bone marrow or the lymphatic system, infants on immunosuppressants including high-dose
corticosteroids, or infants with primary and acquired immunodeficiencies, including cellular immune deficiencies,
hypogammaglobulinemic and dysgammaglobulinemic states. Specific recommendations for use of rotavirus
vaccines in immunocompromised patients with asplenia, cancer, symptomatic HIV infection, cerebrospinal fluid
leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ
transplant (prior to or after), those receiving immunosuppressive therapy for chronic conditions and contacts of
immunocompromised patients are available from the Infectious Diseases Society of America (IDSA). They are
based on international consensus, however, often with limited evidence (73). An individual benefit-risk assessment
taking into account the risk of natural infection vs. vaccination could guide clinical decisions.
Children with asymptomatic and mildly symptomatic human immunodeficiency virus (HIV) infection can be offered
rotavirus vaccines (74), however, there are differing indications in the EU/EEA SPCs of RV1 and RV5 and
vaccinators should consult their respective SPC before considering administration of rotavirus vaccines to infants
diagnosed with HIV.
Vaccination of infants with other underlying medical disorders

With the exception of vaccination of premature infants, no experience has been obtained from clinical trials to
vaccinate infants with underlying medical disorders including gastrointestinal disease, growth retardation, or having
received blood transfusion, plasma or immunoglobulins within 42 days since they were all excluded from the trials.
However, a prior intussusception is listed as a contraindication against RV vaccination.
In one retrospective review of nine infants with functional short gut syndrome secondary to an ileostomy who had
received RV5, vaccination in eight out of the nine infants did not alter expected weight gain or body temperature (75).
However, one of the infants developed significant stomal losses, resulting in weight loss after vaccination. No other
reports on vaccination of infants with other underlying medical disorders was identified in the scientific literature.
Vaccination of infants exposed to biological therapy in utero

Women with inflammatory bowel disease (IBD) increasingly receive biological therapy (e.g. antibodies against tumour
necrosis factor, such as infliximab, or certolizumab), influencing their immune response. During pregnancy this treatment
will also impact the immune response of their new-born infants. A position statement by the World Congress of
Gastroenterology on biological therapy for IBD notes that infants exposed to biological therapy in utero should be given
routine vaccinations at standard schedules during the first six months of life, except for live-virus vaccines such as
rotavirus (76).
Interchangeability
Interchangeability between the two vaccines RV1 and RV5 has formally been evaluated (77-79). Mixed schedules
are safe and induce comparable immune responses when compared with vaccination with only one of the licensed
rotavirus vaccines given in the full series.
Vaccine-induced immunity
The immunological mechanisms by which rotavirus infection with either wild-type or vaccine strains protect against
subsequent rotavirus disease are not completely understood. Humoral and mucosal immunity is believed to play an
important role. Since no serological correlate of protection has been identified, serum IgA has been used as a
surrogate marker by both vaccine manufacturers in the clinical trials. A high level of serum IgA antibody has been
shown to correlate with clinical protection against rotavirus disease (80, 81). However, the IgA assays used by the
two manufacturers are different and not comparable. In addition, for RV5 neutralising antibodies directed against
rotavirus genotype G1 have been utilised (Goveia et al Poster ESPID 2014).
10
Table 2. Percentage of RV1-vaccinated subjects developing serum rotavirus-specific IgA antibodies antibody
titers > 20 U/mL post-immunisation, using different EU immunisation schedules (82)
Vaccine-recipients Placebo-recipients
Immunisation schedules Studies
evaluated conducted in % seropositive % seropositive
n n
[95% CI] [95% CI]
2, 3 months Germany 240 82.1 [75.1-87.7]

127 8.7 [4.4-15.0]
2, 3 months France 126 84.3 [74.7-91.4]
2, 4 months Spain 275 85.5 [79.6-90.2] 89 12.4 [6.3-21.0]
3, 5 months Finland 272 94.6 [90.0-97.5]

114 3.5 [1.0-8.7]
3, 5 months Italy 22 92.3 [64.0-99.8]
3, 4 months Czech Republic 272 84.6 [78.5-89.5] 90 2.2 [0.3-7.8]
Immunogenicity has been evaluated in many of the European childhood immunisation schedules. Both rotavirus
vaccines induce a high percentage of seropositive individuals after a complete vaccination course. The percentages
of seropositive infants following vaccination with the two available rotavirus vaccines used in different EU
immunisation schedules are presented in Tables 2 and 3.
Table 3. Percentage of RV5-vaccinated subjects developing at least a threefold rise in serum rotavirus-
specific IgA antibodies from baseline 42 days post-immunisation, using different EU immunisation
schedules (83,84)
Vaccine-recipients Placebo-recipients
Immunisation Studies
schedules evaluated conducted in % seropositive % seropositive
n n
[95% CI] [95% CI]
2, 4 and 6 months 11 countries 189 95.2 [91.2-97.8] 161 14.3 [9.3-20.7]
2, 4 and 6 months US, Finland* 67 95.5 73 12.3
* Study performed at end of shelf life
Storage of vaccines
Storage of RV1 and RV5 is recommended at 2–8ºC, but immunogenicity after seven days storage at 37ºC was
similar to that of vaccine stored at the recommended temperature (85).
Contamination of RV1 and RV5 vaccines with porcine circovirus

In 2010, the presence of whole porcine circovirus (PCV) was identified in RV1 and genome fragments from PCV1 and
PCV2 were identified in RV5. PCV are animal viruses infecting pigs. Human exposure to PCV is common due to its
presence in meat and other food products of pig origin. The origin of PCV contamination of the two rotavirus vaccines
was attributed to porcine trypsin, used during the manufacturing process to facilitate infection of the cell line to
propagate the rotaviruses. The EMA Committee for Medicinal Products for Human Use (EMA CHMP) reviewed the
contamination and, based upon the fact that PCV does not cause human disease, concluded that the benefit-risk balance
was not changed1. However, manufacturers were instructed to develop PCV-free vaccines. A similar recommendation was
issued in 2010 by WHO2.
1
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/07/news_detail_001059.jsp&mid=WC0b01ac058004d5c1 and
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001121.jsp&mid=WC0b01ac058004d5c1
2
http://www.who.int/immunization_standards/vaccine_quality/PCV1_Q_and_As_rotavirus_vaccines_3Jun10.pdf
11
Rotavirus vaccines authorised in non-EU/EEA countries and

vaccine candidates
Three additional rotavirus vaccines are authorised in China, India and Vietnam, respectively and additional several
vaccine candidates are at various developmental stages.
An oral, live lamb rotavirus vaccine, containing monovalent group A genotype G10 P[12] is being produced by Lanzhou
Institute of Biological Products, Lanzhou, China. The vaccine was approved in 1998 for prevention of rotavirus disease in
children aged 2 to 59 months in China. A case-control study conducted in Chinese children 9–11 months old showed that
one dose of the Lanzhou rotavirus vaccine provided 44.3% (95% CI, 28.4–56.7%) protection against laboratory-
confirmed rotavirus infection in an area where rotavirus is a notifiable disease; 52.8% (95% CI, 40.8–62.3%) protection
in children 12–17 months old, and 51.8% (95% CI, 11.6–73.8%) protection in children 18–35 months old (86). Uptake
of this vaccine in the routine immunisation programme has been limited (87).
Furthermore, an oral, live human-bovine reassortant rotavirus vaccine, derived from a neonatal group A rotavirus strain
isolated from an Indian infant (116E, genotype G9 [P11]), has been developed and is now being produced under the
trade name ROTAVAC by Bharat Biotech, Hyderabad, India (88-90). ROTAVAC was licensed in India in 2014 and is
currently being introduced into the Indian national immunisation programme. The vaccine was developed in collaboration
with the US National Institute of Allergy and Infectious Diseases (US NIAID), the US Centers for Disease Prevention and
Control (US CDC) and PATH (formerly Program for Appropriate Technology in Health) and the Indian vaccine producer.
NIAID sponsored early clinical trials in healthy adults and children and initial studies were conducted in the US. Overall
vaccine efficacy against severe rotavirus disease in Indian children up to two years was shown to be 55.1% (95% CI
39.9–66.4; p<0.0001); vaccine efficacy in the second year of life, 48.9% (95% CI 17.4–68.4; p=0.0056), was only
marginally less than in the first year of life [56.3% (95% CI 36.7–69.9; p<0.0001).
In Vietnam a live attenuated G1P[8] strain isolated and developed into an oral vaccine by the Center for Research and
Production of Vaccines and Biologicals in Vietnam is now authorised after having been tested in healthy Vietnamese
infants (89);
In total, four rotavirus vaccine candidates currently in human clinical trials can be identified on the website
ClinicalTrials.gov. Among them several candidate vaccines are being developed under non-exclusive licences for
technology transfer and production of the National Institute of Health human-bovine (UK) reassortant vaccine granted to
the Chengdu Institute of Biological Products (China), Instituto Butantan (Brazil), and Serum Institute of India Ltd. (India):
 a randomised, double blind, placebo-controlled phase 1 clinical trial assessing safety and immunogenicity of a
new 5-valent rotavirus vaccine candidate for oral use, produced by Instituto Butantan in Brazil, has been
conducted in healthy adults (n=80)3 (91). This vaccine candidate is receiving financial support from PATH and
the Bill & Melinda Gates Foundation;
 randomised, double blind, placebo-controlled phase 1 & 2 clinical trials assessing safety and immunogenicity
in adults, toddlers and infants of a new 5-valent rotavirus vaccine candidate (BRV-PV)4 for oral use produced
by the Serum Institute of India Ltd have been conducted (92). This vaccine candidate will now undergo a
large Phase 3 study to assess efficacy against severe rotavirus disease;
 a randomised, double-blind, placebo-controlled dose-escalation phase 1/2 descending age clinical trial,
assessing safety and immunogenicity of a VP8 subunit vaccine5 (a truncated VP8 subunit protein from the Wa
strain G1P8 fused to tetanus toxoid and adsorbed on aluminium hydroxide for intramuscular administration in
three concentrations 10, 30 or 60 μg), sponsored by the Bill and Melinda Gates Foundation/PATH non-
replicating rotavirus vaccine project. The study is being conducted in the US. First study results from healthy
adults were published in June 2015 (93);
 a randomised, double-blind, placebo-controlled phase 3 trial assessing efficacy of RRV-TV for the prevention
of rotavirus disease in Ghana, West Africa, with infants receiving the first dose of two during the neonatal
period, the second before they are 60 days old, and with follow-up to age 12 months. RRV-TV was, as
mentioned previously, licensed in the US in 1998 but withdrawn in 1999 due to a rare association with
intussusception, which occurred disproportionately in infants receiving their first dose at ≥90 days of age
(94). A vaccine efficacy of 63.1% against rotavirus disease of any severity was observed, which is similar to
the obtained efficacy acquired by RV1 and RV5 in similar African settings (95). Funding for this trial was made
available through the International Medica Foundation, a non-profit foundation.
3
Clinical trials registration NTC 00981669
4
Clinical trials registration NCT02133690
5
Clinical trials registration NCT01764256
12
In addition to the clinical trials listed on the ClinTrials.gov website, a neonatal rotavirus strain (RV3-BB isolated
from an Australian infant) candidate has been tested in a randomised placebo-controlled Phase I study that
evaluated safety and tolerability of a single oral dose of the RV3-BB rotavirus vaccine candidate in 20 adults, 20
children and 20 infants (10 vaccine recipients and 10 placebo recipients per age cohort) (96). Most infants (8/9)
who received RV3-BB demonstrated vaccine take developing IgA antibodies following a single dose. These data
support progression of the RV3-BB candidate to Phase 2I immunogenicity, safety and efficacy trials that will be
conducted by academic groups in New Zealand and Indonesia with funding from the Australian National Health and
Medical Research Council, New Zealand Health Research Council, the Bill and Melinda Gates Foundation and the
vaccine producer, Bio Farma in Indonesia. Neonatal and infant schedules will be evaluated.
Finally, in animal models both inactivated rotavirus whole virion and virus-like particles (VLPs) provided parentally
have been shown to provide protective immunity. No human clinical trials appear to have been initiated for any of
these technologies.
13
Overview of human rotaviruses6

Figure 2. Rotavirus particle
The virus particle consists of a triple-layered icosahedral protein capsid, composed of an outer protein (VP7 in yellow), an
intermediate protein (VP6 in blue) and an inner core (VP2 in green) layer.
From the smooth surface of the outer layer, sixty spikes extend ~12 nm (VP4 in orange).
Mature and infectious virus particles are approximately 70–75 nm in diameter. The infectivity of rotavirus particles depends
on the presence of the outer protein layer. Viral particles present on objects may be infectious for months.
Rotaviruses are relatively stable when inactivated. Infectivity is retained within pH range 3 to 9 and virus samples are
stable for months to years at + 4ºC.
The virus genome contains eleven segments of double-stranded RNA, providing a possibility for reassortment.
Rotaviruses are classified serologically into serogroups. A serogroup comprises viruses that share cross-reacting antigens
detectable by a number of immunological tests. Seven distinct serogroups have been identified (A–G). Serogroups A, B and
C cause disease in humans, while the others have primarily been identified in animals. Domestic animals commonly excrete
rotavirus of different types, which occasionally can be transmitted to humans as a zoonosis. Cross-immunity between
serotypes has been shown.
Rotaviruses may also be genotyped. Generally, genotyping is currently used for classification of circulating rotavirus strains
but must be correlated to the knowledge of serotypes/serogroups. Determination of the potential development of
protective immunity after vaccination to current and emerging new rotavirus strains is correlated to serotypes.
Serotype/genotype classification of group A rotaviruses uses the specificities of the two outer capsid proteins; viral protein
4 (VP 4) and viral protein 7 (VP 7). The VP7 specificity is referred to as G - type (glycoprotein) and the VP4 specificity as P-
type (protease-sensitive protein, trypsin cleavage of VP4 initiates penetration of intestinal epithelial cells). Both VP4 and
VP7 induce production of neutralising antibodies. 15 G-sero/genotypes have been identified in animals and humans, while
11 distinct P-serotypes and 28 P-genotypes have been described. Various combinations of G- and P-types have been
identified in field isolates from humans. Classification of rotaviruses is a binary system that includes both the VP4 and
VP7 types.
6
Knipe D, Howley P Rotaviruses Fields Virology 6th Edition 2012
14
Post-authorisation monitoring of circulating rotavirus

strains in EU/EEA countries
To exclude possible strain replacement induced by immunological pressure following vaccination, rotavirus strain
monitoring was requested in the EMA Risk Management Plan. The segmented genome of rotaviruses facilitates
genetic reassortment when intestinal epithelial cells are infected with more than one rotavirus geno-/serotype. This
property has the potential to generate many combinations of outer surface viral G- and P proteins (theoretically > 211
different combinations). However, the number of G and P combinations commonly detected is significantly less than
the theoretical number of possible reassortant combinations, although reassortant group A rotaviruses develop
regularly (see Figure 3). Reassortments may occur between two types of human rotaviruses or one human type and
one animal type of rotaviruses co-infecting one individual (50).
Figure 3. Schematic overview of the rotavirus reassortment process when two rotavirus sero-
/genotypes infect one enterocyte simultaneously*
* The uncoating process of each virus particle after entry into enterocytes expose the different segmented genes and provide the
possibility for reassortment of different genes that may result in new rotavirus geno-/serotypes with different surface proteins [G-
and P-types]. Infecting viruses enter the epithelial cell from the intestinal surface and new progeny viruses are released back into
the intestine resulting in epithelial cell death and subsequent villous atrophy.
Rotavirus strain surveillance to exclude strain replacement

Rotaviruses cause winter seasonal peaks of gastroenteritis in EU/EEA between December and May. However,
sustained transmission is identified all year round (see Figure 4) and variation in seasonality is observed (97).
Establishing the viral cause for a hospitalised case of diarrhoea is rare, since patient management of dehydration is
not influenced by the identified pathogen. Therefore, to ensure genotyping of a statistically sound and
geographically representative sample within the EU/EEA the European Rotavirus Surveillance Network
(EuroRotaNet)7 was formed to collect and genotype faecal samples from European children seeking medical advice
for rotavirus disease. This network is supported by producers of the RV1 and RV5 vaccines, to fulfil requirements in
the EMA Risk Management Plan agreed upon authorisation of the two new rotavirus vaccines RV1 and RV5 to
monitor possible strain replacement induced by immunological pressure following the use of rotavirus vaccines.
Participants in the network have mainly been public health institutes and academia in initially sixteen EU/EEA
Member States and since 2014 fourteen Member States after Bulgaria and Lithuania left the network. The
requirements from EMA will subside shortly and it is unknown whether the vaccine producers will continue to
7
www.eurorota.net
15
support the network long-term beyond 2017 and no formal surveillance of rotavirus infections and circulating
rotavirus strains are foreseen in the EU/EEA in the near future.
Rotavirus strain diversity

Results from the EuroRotaNet strain surveillance network on genotyping of rotavirus strains from ten consecutive
seasons (2006 – 2016) are now available (98, 99) (see Figure 5). Genotyping is performed in a standardised
manner across the countries by multiplex PCR and/or sequencing. Annual quality assurance programmes are
conducted.
Figure 4. Temporal distribution of rotavirus positive samples submitted to the EuroRotaNet strain
surveillance network database in consecutive seasons 2006 to 2016*
2500
2000
1500
Number
1000
500
0
May-09
May-14
Apr-07
Sep-07
Apr-12
Sep-12
Jan-06
Jan-11
Jun-06
Dec-08
Jun-11
Dec-13
Jan-16
Jun-16
Nov-11
Nov-06
Feb-08
Feb-13
Oct-09
Oct-14
Nov-16
Jul-08
Mar-10
Aug-10
Jul-13
Mar-15
Aug-15
Month/year
* With seven of the countries conducting rotavirus strain surveillance having introduced routine rotavirus vaccination for all
infants, an overall decline in number of samples sent for genotyping has been observed since 2014.
Source: Eurorotanet
The vast majority of human cases within EU/EEA and worldwide (more than 90% of all human rotavirus disease)
are caused by six genotypes within serogroup A rotaviruses, namely G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and
G12P[8]. Results obtained within the EuroRotaNet network confirm that G1P[8] was the most prevalent rotavirus
strain since its inception, but all six genotypes circulated in all countries (see Figure 5). However, for two seasons
G1P[8] was identified in < 50% of infected children and for the first time in the 2015/16 season G1P[8] was only
the fourth most prevalent strain and identified in only 13% of typed samples8. In the 2015/16 season G9P[8] was
the predominant strain, present in 34% of all specimen tested and the most common strain in five countries. This
change in predominant strain occurred in countries with and without routine rotavirus vaccination. Further analysis
of the 2015/16 season is on-going and expected to be published late 2017. A new emerging genotype G12P[8] was
identified in most seasons in the majority of participating EU/EEA countries in 0.5–0.8% of all stool samples and
other new emerging G8- and G10-containing strains were also identified, but with lower incidence. Vaccine efficacy
has been evaluated against G1P[8], G2P[4], G3P[8] and G4P[8] and G9P[8] in the clinical trials performed in the
Americas and Europe (1, 2)] for RV1 and in addition against G12P[8] for RV5.
Significant cross-protection is expected, also for new emerging genotypes, as suggested by clinical trials performed
in Malawi (RV1), South Africa (RV1) and Ghana (RV5), which are countries with a more diverse picture of co-
circulating rotavirus genotypes (100, 101). Vaccine efficacy in these studies ranged between 49.4% and 76.9%,
where only approximately 13% of the rotavirus strains were G1P[8]. However, the circulating genotypes may not
be the only reason for a lower efficacy observed in these countries. In a recent study genetics involving the histo-
blood group antigens appeared to play a role in susceptibility and vaccine take measured as an immunoglobulin A
response (102).
8
EuroRotaNet: Annual report 2016 (unpublished data)
16
Figure 5. Overall distribution of rotavirus genotypes by EU/EEA country reported to the EuroRotaNet
strain surveillance network 2006 to 2016 (n=61 959)
Source: Eurorotanet
In the data collection by EuroRotaNet, 1.5% of the rotavirus strains were reassortments among common human
strains, while 1.2% were likely to have emerged through zoonotic transmission or by reassortment between human
and animal rotavirus strains. Mixed infections with more than one genotype present in stool sample were detected
in 5.7% of cases and 3.8% of strains were only partially characterised.
However, until 2016 no novel emerging group A rotavirus strains causing larger outbreaks had been detected in
any of the countries under surveillance, although the time period surveyed is short for virus evolution. The number
of rotavirus positive cases available for typing has diminished in all the countries that have introduced rotavirus
vaccination, as a consequence of the reduction in rotavirus disease (see Figure 4). There is no evidence to date
that rotavirus vaccination programmes are driving the emergence of vaccine escape strains, and shifts in strain
distribution and predominant type in the post-vaccine era need to be interpreted with caution and in the context of
differences in distribution of genotypes according to age and seasonality9.
9
EuroRotaNet: Annual report 2016 (unpublished data)
17
Rotavirus immunisation programmes in EU/EEA countries

As of May 2017 a positive decision had been taken by the national health authorities in thirteen EU/EEA countries
regarding the introduction of rotavirus vaccination into routine paediatric immunisation programmes and
vaccination has already been implemented or is underway. Austria, Belgium, Estonia, Finland, Germany, Greece,
Ireland, Italy, Latvia, Luxembourg, Norway, Poland and the United Kingdom have introduced rotavirus vaccination
throughout the country, while Sweden has introduced vaccination in some regions.10 Among the eighteen Member
States that have not included rotavirus vaccination in the routine paediatric immunisation schedule, a positive
decision has been taken but not yet implemented in Ireland and Poland. A negative decision has been taken by
national health authorities in four countries (Cyprus, Denmark, France and Spain), while in the remaining countries
no decision (either positive or negative) has been made by national health authorities as to whether to introduce
rotavirus vaccination. Details on decisions made, year of introduction in countries with a positive decision,
recommended age groups, vaccine coverage obtained and the proportion of cost covered by public or insurance
funding are presented in Table 4.
Austria
Rotavirus vaccination was introduced into the national immunisation programmes in 2007. Both RV1 and RV5 are
being used in the country according to routine procurement practices. Optional, genotyping of rotavirus strains
isolated from children with breakthrough infections is available.
Belgium
Rotavirus vaccination was recommended at national level in 2006 but is not included in the vaccination
programmes at all regional levels. However, it is systematically offered (not free of charge, unlike other childhood
vaccines) during preventive consultations organised by the government agency ‘well-baby clinics’ at regional level.
Both RV1 and RV5 are used in the country. A network of laboratories is monitoring the number of stool samples
sent for rotavirus diagnostics.
Estonia
Rotavirus vaccination was initiated in 2014. RV5 is currently used in the country.
Finland
Germany
Rotavirus vaccination was initiated in 2013. Both RV1 and RV5 are being used in the country. Rotavirus disease is
notifiable in Germany.
Greece
Rotavirus vaccination was initiated in 2012. Rotavirus vaccination is only partially reimbursed. Both RV1 and RV5
are available in the country.
Ireland
Positive decision by national health authorities but no implementation yet.
Italy
Rotavirus vaccination was initiated in 2017. Both RV1 and RV5 are being used in the country according to routine
procurement practices.
Latvia
Rotavirus vaccination was initiated in 2015. Both RV1 and RV5 are being used in the country.
Luxembourg
Norway
Poland
Positive decision by national health authorities but no implementation yet
Sweden
Regional implementation started covering around 30% of the infant population. Rotavirus vaccination was initiated
in these regions in 2014. Both RV1 and RV5 are being used in the country according to routine procurement
practices.
10
VENICE III report on the current status of introduction of rotavirus vaccination into national immunisation programmes in
Europe, submitted to ECDC May 2016. Publication pending.
18
United Kingdom
Furthermore, it should be noted that rotavirus vaccine is being provided to additional European children through
the private sector, this being more common in southern Europe than in other parts of Europe, based on vaccine
distribution statistics.
The main reasons for not including the rotavirus vaccine into the national routine paediatric programme
investigated in the recent VENICE III survey (see footnote 11 above) were cost/cost-effectiveness ratio, insufficient
anticipated epidemiological impact, and other competing health priorities. Other reasons mentioned included risk of
emergence of serotypes not covered by the vaccine, improved clinical management preferred to vaccination, and
concerns regarding safety (intussusception).
As of mid-2016, 81 countries worldwide had introduced rotavirus vaccines into their routine immunisation
programme.
19
Table 4. Current status of rotavirus immunisation programmes in EU/EEA countries as of May 2017
Year of Proportion of
Stage of decision- Vaccine
introduction into cost covered
Member making Age group coverage
national by public or
State Positive/negative recommended reported
immunisation insurance
decision/not started (%)
programme funding
Positive decision by
D1-D3 7 weeks -
Austria national health 2007 77 100%
6 months
authorities
D1 8 weeks
national health
Belgium 2006 D2 12 weeks 86 75%
authorities (partly
D3 (16 weeks)
reimbursed)
No decision by national
Bulgaria - - - -
health authorities
Recommended for risk
Croatia - - - -
groups only
Negative decision by
Cyprus national health - - - -
authorities
Czech republic - - - -
health authorities
Denmark national health - - - -
authorities
Positive decision by D1 2 months
No data
Estonia national health 2014 D2 3 months 100%
available
authorities D3 4.5 months
Finland national health 2009 D2 3 months 93 100%
authorities D3 5 months
France national health - - - -
authorities
Positive decision by D1 6 weeks
No data
Germany national health 2013 D2 2 months 100%
available
authorities D3 (3-4 months)
No data
Greece national health 2012 D2 4 months 100%
available
authorities D3 (6 months)
Hungary - - - -
health authorities
Iceland - - - -
health authorities
national health
Ireland - - - -
authorities but no
implementation yet
No data
Italy national health 2017 - -
available
authorities
Positive decision by D1 8 weeks
No data
Latvia national health 2015 D2 12 weeks -
available
authorities D3 (16 weeks)
Lichtenstein - - - -
health authorities
Lithuania - - - -
health authorities
Positive decision by 89%
D1 2 months
Luxembourg national health 2006 measured in -
D2 3 months
authorities 2012
Malta - - - -
health authorities
Netherlands - - - -
health authorities
Positive decision by D1 1.5 months
No data
Norway national health 2014 D2 3 months 100%
available
authorities D3 (5) months*
20
Year of Proportion of
Stage of decision- Vaccine
introduction into cost covered
Member making Age group coverage
national by public or
State Positive/negative recommended reported
immunisation insurance
decision/not started (%)
programme funding
national health
Poland - - - -
authorities but no
implementation yet
Portugal - - - -
health authorities
Romania - - - -
health authorities
Slovakia - - - -
health authorities
Slovenia - - - -
health authorities
Spain national health - - - -
authorities
100% in these
Sweden
No decision by national two regions.
(two regions D1 6-8 weeks
health authorities Stockholm Partly (RV5) or
with ~30% of 2014 D2 3 months
Two regions – positive region 82% fully (RV1)
the paediatric D3 (5) months
decision reimbursed in
population)
other regions
England
Positive decision by 94.1% for
D1 2 months
UK national health 2013 dose 1 and 100%
D2 3 months
authorities 89.7% for
dose 2
Source: data adapted from national official websites and the 2016 VENICE III survey, submitted to ECDC according to contract
and available upon written request (publication pending).
21
2. Methods
The aim of this expert opinion is to provide EU/EEA Member States with relevant scientific information to support
the decision-making process on possible introduction and monitoring of routine vaccination to prevent rotavirus-
induced gastroenteritis.
The evidence presented in this document are based on reviews of the published literature in scientific journals,
grey literature and a search in the EMA Eudravigilance database for spontaneously reported cases of
intussusception following rotavirus vaccination. The information collected summarises:
 burden of rotavirus disease in the EU/EEA in children under five years of age
 rotavirus vaccine efficacy in countries with low mortality due to rotavirus infections (hereafter referred to as
‘low-mortality rotavirus countries’)
 rotavirus vaccine effectiveness in low-mortality rotavirus countries
 herd protection provided by infant rotavirus vaccination in low-mortality rotavirus countries
 rotavirus vaccine safety in low-mortality rotavirus countries
 cost-effectiveness using rotavirus vaccines in EU/EEA immunisation programmes
 attitudes to rotavirus vaccination among parents and healthcare workers.
The literature searches were conducted by ECDC library staff in PubMed, Embase and Cochrane databases to
collect relevant articles and systematic reviews published in English between 1 January 1995 and 14 February
2014. Search strategies and results are available in Annex 4 and 5. The systematic searches were complemented
by manual searches that included websites of public health institutes in the EU/EEA for current immunisation
schedules. An Endnote database was created and complemented with references identified using all search
strategies. Identified article titles with abstracts were reviewed by ECDC experts. Based on inclusion and exclusion
criteria taking into account the different search queries mentioned above, a second screening of selected full text
articles was performed. A decision on study inclusion was made jointly by ECDC staff (consensus of at least two
reviewers). For each study included, information on study design, number of participants, sampling and group
allocation, intervention if relevant, outcomes, and study results was extracted and summarised. All outcomes for
which meta-analysis was conducted were dichotomous (occurrence of the event or not, e.g. efficacy and
effectiveness).
Methodology used for evaluating burden of severe rotavirus

disease in EU/EEA
Burden of severe rotavirus disease was defined as rotavirus disease leading to hospitalisation. The search terms ‘rotavirus’,
‘rotavirus infection’, ‘disease outbreaks’, ‘epidemics’, ‘communicable disease’, ‘epidemiology’, ‘all EU/EEA countries by name,
e.g. Austria, Belgium, etc.’ and ‘hospitalisation’ were used to identify studies assessing burden of severe rotavirus disease
and hospitalisation in infants. Results of the burden of disease studies were not appropriate for a meta-analysis since no
uniform effect estimator was reported. Therefore, a descriptive summary of identified data is presented.
Methodology used for evaluating rotavirus vaccine efficacy

Since two recently published systematic reviews with meta-analyses were available and provided high-quality and
sufficient information on all relevant efficacy outcomes, results from these reviews were used. The review
published by the Cochrane Collaboration in 2012 and the German Standing Committee on Vaccination (STIKO) in
2013 have both assessed relevant outcomes in randomised controlled trials (RCTs) conducted until 2011. No
further RCTs have been conducted in rotavirus low-mortality countries. Results from the systematic review and
meta-analysis, conducted by STIKO, are presented in this expert opinion with permission.
Methodology used for evaluating rotavirus vaccine

effectiveness
Rotavirus vaccine effectiveness was defined as the relative reduction in rotavirus disease risk for a specified end point:
hospitalisation with regard to the rotavirus vaccination status of study subjects, based on odds ratio in case-control
studies and relative risk in cohort studies. Search terms such as ‘rotavirus’, ‘rotavirus vaccine’, ‘immunisation’ and ‘vaccine
effectiveness’ were used to identify studies that assessed effectiveness of rotavirus vaccines. Each study that was
included in the final analysis was assigned an acronym consisting of the author of the primary publication, year of
publication and vaccine brand tested.
Case-control or cohort studies were included if effectiveness of either RV1 or RV5 on at least one of the pre-defined patient-
relevant outcomes was reported for healthy children <5 years of age from developed countries (Europe, Australia, Canada,
USA, Latin America and Asia). Observational studies were excluded if a vaccine formulation was used that was different from
the vaccines licensed in the EU/EEA and if there was concomitant administration with OPV since this is not current practice in
22
the EU/EEA. Data for both vaccines were pooled, as the objective of this expert opinion was to evaluate the effectiveness of
rotavirus vaccination and not individual products. The final analysis presents pooled data for both vaccines.
Meta-analyses of effectiveness data from included case-control and cohort studies were performed in relation to rotavirus
vaccine status (at least two doses). Extracted data were entered into the computer software Review Manager (version
5.3, Nordic Cochrane Centre, Copenhagen, Denmark). Pooled estimates were calculated using random effects models.
The dichotomous data were analysed by calculating Mantel-Haensel random effects risk ratios (RR) or odds ratios (OR)
and corresponding 95% confidence intervals (95% CI) for rotavirus vaccine recipients versus placebo recipients in the
RCTs, or no vaccine in the observational studies. The pooled RR or were used to calculate pooled vaccine effectiveness
using the following formula: (1-[Relative Risk or Odds Ratio]) x 100 (103). Judgement of the extent of heterogeneity was
based on similarity of point estimates, extent of confidence interval overlap, and statistical criteria including tests of
heterogeneity and I2 (104).
Methodology used for evaluating rotavirus vaccine-induced

herd protection
Herd protection was defined as indirect protection of unvaccinated individuals in a population where rotavirus
vaccination is recommended and used. The search terms ‘rotavirus’, ‘vaccine’, ‘immunisation’, ‘herd-immunity’ were
used to identify studies assessing herd-immunity/herd protection induced by rotavirus vaccination in infants.
Results of the herd protection studies are reported as descriptive summary of identified data as well as results from
a meta-analysis.
Methodology used for evaluating rotavirus vaccine safety

Rotavirus vaccine safety was assessed by estimation of risk for development of specified end points in relation to
the rotavirus vaccination status of study subjects. The outcomes assessed were vaccine-induced intussusception
and Kawasaki disease, for which EMA had requested surveillance in their risk management plans. The risk window
used in the RCTs varied but most post-marketing observational studies of intussusception utilised the Brighton
Collaboration case definition levels 1–4, i.e. a risk window within 21 days of vaccination (see Annex 2) (105). No
similar generally agreed case definition was available for Kawasaki’s disease at the time of studies but has been
published subsequently (106).
Since a recently published systematic review with meta-analysis was available and provided sufficient, high-quality
information on all relevant safety outcomes in RCTs, results from this review were used. This Cochrane
Collaboration review published in 2012 assessed relevant outcomes in randomised controlled trials (RCTs)
conducted until 2011. No further RCTs have been conducted in rotavirus low-mortality countries.
Following introduction of rotavirus vaccines into routine immunisation programmes and the first vaccine safety signals,
observational studies assessing safety have been conducted in rotavirus low-mortality countries (mainly non EU/EEA
countries). Results based on odds ratios in case-control studies, relative risk in cohort studies, relative incidence in self-
control case series and standardised morbidity ratio in one observed versus expected analysis were identified and are
reported.
The search terms ‘rotavirus’, ‘rotavirus vaccine’, ‘immunisation’, ‘intussusception’, ‘Kawasaki disease’ were used to identify
studies that assessed safety of rotavirus vaccines.
Observational studies were included if safety of either RV1 or RV5 in relation to at least one of the pre-defined patient-
relevant outcomes was reported for healthy children <5 years of age from rotavirus low-mortality countries (Europe,
Australia, Canada, USA, Latin America and Asia). Only one smaller observational study from the EU/EEA using the
observed versus expected methodology was identified. Observational studies were excluded if a vaccine formulation was
used that was different from the vaccines licensed in the EU/EEA and if there was concomitant administration with OPV
since this is not current practice in the EU/EEA. A summary of identified studies are presented. Recently, a German group
published a systematic review and meta-analysis of ten studies that all used the self-control case series methodology and
obtained results on the outcome of intussusception risk related to age with rotavirus vaccination. Results from this
systematic review have been included.
In addition, since only one smaller observational study assessing intussusception in the EU/EEA was available,
information on intussusception cases spontaneously reported from EU/EEA Member States to the Eudravigilance (EV)
database was made available to the ECDC11 in accordance with EV access policy. The request was handled by EMA in
accordance with the ‘Rules for the implementation of Regulation (EC) No 1049/2001 on access to European Medicines
Agency (EMA) documents’ and ‘EudraVigilance access policy for medicines for human use’ EMA/759287/2009). EMA
provided line listings for case reports of intussusception submitted during the time period from authorisation of the two
rotavirus vaccines in 2006 until 1 July 2014. Data were partially redacted in accordance with Regulation (EC) No 45/2001
of the European Parliament and of the Council of 18 December 2000 on the protection of individuals with regard to the
11
N.B. The analysis and interpretation of Eudravigilance data presented in this expert opinion may not be understood or quoted
as being made on behalf of the European Medicines Agency or any of its working parties.
23
processing of personal data by the Community institutions and bodies and on the free movement of such data. The
information provided in the line listings was based on a query performed in EV using the following search criteria: all
reports submitted as spontaneous to EV up to 1 July 2014, where Rotarix or Rotateq were reported as a suspect or
interacting medicinal product. Line listings of IS cases were analysed for number of cases by product, gender, age at
vaccination, dose number in vaccine series, time to onset of IS from vaccination and clinical outcome. Chart review of
reported cases of IS to validate the diagnosis against a common case definition was not possible due to country-specific
and EU-level data protection laws. Number of vaccinated infants during the same time period is unknown but 9.7 million
doses of RV1 and 7.9 million doses of RV5 were distributed from the manufacturer.
Methodology used for evaluating rotavirus vaccine cost-

effectiveness in the EU/EEA
Rotavirus vaccine cost-effectiveness studies were defined as evaluation of cost-effectiveness for introduction of these
vaccines into national immunisation programmes. The search terms ‘rotavirus’, ‘rotavirus vaccine’, ‘immunisation’, ‘cost’,
‘cost analysis’, ‘economics’, ‘costs’, ‘price’, ‘pricing’, ‘pharmacoeconomics’, ‘cost-effective’, ‘cost-effectiveness’, ‘value for
money’, ‘budget’ and ‘all EU/EEA countries by name’ were used to identify studies assessing cost-effectiveness of
rotavirus vaccination in infants. Results obtained in the studies were not appropriate for a meta-analysis due to diversity
in assumptions and model structures. Therefore a descriptive summary of identified data is presented.
Methodology used for evaluating attitudes to rotavirus

vaccination
Attitude was defined as ‘parents’ and ‘healthcare workers’ attitudes to rotavirus vaccination. The search terms
‘rotavirus’, ‘rotavirus vaccine’, ‘attitude, ‘health behaviour’, ‘health promotion’, ‘health personnel attitude’, ‘family
attitude’, ‘parent attitude’, ‘patient non-adherence’, ‘patient noncompliance’, ‘refusal’, ‘compliance’, ‘wellness
programs’, and ‘health campaign’ were used to identify studies assessing attitudes to rotavirus vaccination in
infants. Results of the attitude studies were few and not appropriate for meta-analysis since no uniform effect
estimator was reported. Therefore a descriptive summary of identified data is presented.
Expert panel opinion

The opinion provided in this document is based on the identified evidence which was evaluated by a group of
independent EU/EEA experts. Scientific articles were summarised and discussed in two meetings and a series of
telephone conferences. Experts were also able to provide additional relevant literature.
Furthermore, based on the literature review, the experts suggested options for relevant data which could be
obtained by Member States before including rotavirus vaccination in a routine paediatric immunisation programme.
They also suggested indicators which could be followed after implementation to facilitate evaluation of impact of
vaccination and identified knowledge gaps are discussed.
The EU experts were selected based on the following criteria:
 experience in running and evaluating national routine immunisation programmes for children;
 experience in evaluating scientific evidence addressing vaccine safety, efficacy, effectiveness, and cost-
effectiveness;
 experience in issuing national recommendations for new vaccines to be included in routine immunisation
programmes.
Panel members’ declarations of interest were reviewed by ECDC and no potential conflicts of interest were found
that could influence the work of the panel.
Updated Expert Opinion following ECDC Advisory forum

review and public consultation
In 2016 and 2017, the Expert Opinion and its scientific advice was subject to discussion in ECDC’s Advisory Forum with a
round of public consultation in between. Following the public consultation procedure, nine responses with comments and
suggestions for edits were received from a variety of stakeholders including EU/EEA Member State Ministries of Health,
EU/EEA Member State Public Health Agencies, members of the academic community in EU/EEA Member States, WHO’s
Regional Office for Europe and the two vaccine manufacturers. The Expert Opinion was subsequently updated and
ECDC’s responses to the comments and suggestions provided during the consultation procedure are published in a
separate document on ECDC’s website. The final Expert Opinion was endorsed by the Advisory Forum in May 2017.
24
3. Results
Burden of rotavirus disease in EU/EEA countries
A number of prospective and retrospective epidemiological studies published between 1995 and 2014 described country-
specific burden of rotavirus disease in eighteen EU/EEA Member States (13, 107-137). Most studies focused on
describing severe rotavirus disease and addressed the burden of hospitalisation (see Table 5). A limited number of
European studies addressed deaths, the most severe outcome of rotavirus disease, nosocomial infections and burden in
out-patient facilities.
Hospital admissions
In the EU/EEA, all 49 studies identified from eighteen Member States reported that rotavirus is the most common
pathogen isolated from children hospitalised with AGE. The contribution of rotavirus as a cause of acute gastroenteritis in
hospitalised children < 5 years of age varied between years and between countries, ranging from 26 to 69% (see Table
5). The reasons for this wide range is not entirely clear, however there are probably some seasonal fluctuations. Methods
used for diagnostics (antigen-detection and more recently PCR) and differences in surveillance in Member States may
also influence results.
The number of children hospitalised per year also differs significantly; from 100 in Spain to 1 190 in Ireland per 100 000
children less than five years of age. However, in a majority of countries around 300–600 cases per 100 000 children <5
years are hospitalised per year (see Table 5).
In a review performed by WHO Regional Office for Europe hospital admission rates were similar across country income
groups (medians 200, 280, 420 and 190/100 000 per year in low-, lower-middle-, upper-middle- and high-income
countries in 49/52 WHO European Region countries, respectively) (6)].
The median duration of hospitalisation for rotavirus disease varied in the EU/EEA studies, ranging from 1.3 days in one
study conducted in nation-wide registries in Norway (127) to 9.5 days in one study hospital in Poland (128). The duration
of hospitalisation may also vary within countries, as observed in Italy (see Table 5).
By way of international comparison, studies among US children aged <5 years have shown that rotaviruses accounted
for 30–50% of all hospitalisations for acute gastroenteritis and approximately 70% of hospitalisations for gastroenteritis
during the seasonal peaks (138, 139). The US CDC researchers further estimated that in the first five years of life, four
out of five children in the United States will develop a symptomatic rotavirus disease, one in seven will require a clinic or
emergency department visit, and one in 70 will be hospitalised (3).
The need for intensive care in the EU/EEA setting has been evaluated in several studies. One study conducted in Sweden
suggests 1–2% of hospitalised children with rotavirus disease appear to be in need of intensive care, often due to very
severe dehydration (>10% of body weight) (15). In a prospective study by the German Paediatric Surveillance Unit,
assessing children with very severe rotavirus disease12 , 101 cases were identified during a two-year period (140). Based
on this the annual incidence of very severe rotavirus disease was estimated at 1.2 per 100 000 (95% CI 0.9–
1.4/100 000). Among the 101 children, 48 of the children were in need of intensive care, 12 suffered from necrotising
enterocolitis, and 58 had signs of encephalopathy.
Deaths
Five studies were identified addressing rotavirus-disease-associated deaths in the EU/EEA (6, 109, 141-143).
Using an adaptation of the U.S. CDC mortality model for Europe, an estimate was made of the number of RV-
associated deaths in children <5 years of approximately 200 deaths per annum (143). This study has been
criticised for over-estimating the mortality rate, as indicated by country-specific data presented below.
A study from the UK using national statistical reports from two different sources indicates 3.3 and 3.8 deaths per
year in children <5 years of age due to rotavirus disease, suggesting a mortality rate of <0.1 per 100 000 children
<5 years of age and a hospital case-fatality rate of around 0.2% (141).
A study from Germany, suggests a hospital case-fatality rate of 0.1% during a 10-year period of surveillance (142).
Additional data from Germany reveal that 1–2 deaths due to rotavirus disease are reported each year in children <5
years of age13.
Czech Republic reported three deaths in children <2 years over a nine-year period of surveillance but interestingly
also reported three deaths in elderly people related to rotavirus disease outbreaks in retirement homes (109).
Finally, in a study from the Netherlands RV-related mortality was determined for all children who had died within
three weeks of confirmed RV infection between 2000 and 2006 (144). Seven deaths were identified. All seven had
12
defined as in need of intensive care treatment, or hyper- or hyponatremia (>155 mmol/L or <125 mmol/L), or clinical signs of
encephalopathy (somnolence, seizures or apnoea) or RV-associated deaths
13
http://www.rki.de/
25
congenital pathology and two patients also had a history of low birth weight. One child died before 2 months of
age, the remaining six children died between 2 and 14 months of age.
In a review from 2009 of 49/52 countries of the WHO European Region, using published literature or WHO data
sources, rotavirus disease caused an estimated 6 550 deaths (range 5 671–8 989) and 146 287 (range 38 374–
1 039 843) hospital admissions each year in children aged <5 years (6). Seven countries, mostly in the low- and
lower-middle-income groups, accounted for 93% of estimated deaths. In total, three EU Member States - Slovakia,
Bulgaria and Slovenia - reported mortality data as part of this review. Bulgaria and Slovenia did not report any
deaths, while Slovakia reported a mortality rate of 0.1 per 100 000 children.
By way of international comparison, researchers from US CDC estimated in a study that one in 200 000 children
would die each year in the US from rotavirus disease(3).
Nosocomial infections
Evaluating the burden of intra-healthcare-acquired rotavirus disease suggests that up to ~25–30% of rotavirus
infections diagnosed in hospitalised children may be due to rotavirus infections acquired within the healthcare
system (27, 29, 145-153). Nosocomial rotavirus infections often occur in younger children than the community-
acquired rotavirus infections, and fewer complications develop (136, 154). Furthermore, nosocomial infections
often develop in children with underlying chronic diseases spending time in hospital settings where rotavirus is
easily transmitted.
In a German study assessing cases hospitalised during 2002–2008, 14% of reported cases were nosocomial (155).
A five-year (2006–2010) Polish study suggested that the mean proportion of nosocomial rotavirus disease among
all hospitalised rotavirus infected cases was 24% (156)]. A Spanish study reported an incidence of 59.0 nosocomial
cases per 100 000 children <5 years of age during 1998–2007(154). Another longitudinal prospective study in
paediatric in-patients 0–48 months old in Austria, Germany and Switzerland suggested that almost one third of
nosocomial cases occurred in infants aged two months or younger (149)].
In a review of nosocomial rotavirus disease in European countries (France, Germany, Italy, Poland, Spain and the
United Kingdom) rotaviruses were found to be the major cause of paediatric nosocomial diarrhoea (ranging from
31 to 87%) (27) and in a recent meta-analysis of twenty surveillance studies of nosocomial rotavirus disease, an
adjusted year-round incidence of 0.7 (95% CI 0.0–1.8) per 100 hospitalisations was calculated for children under
five years (157). Highest nosocomial rotavirus infection incidence rate was found in children <2 years of age,
hospitalised during the epidemic months (8.1/100 hospitalisations 95% CI 6.4–9.9). The authors conclude that
nosocomial rotavirus infections are an important problem for those children affected and for the quality of the
healthcare systems.
26
Table 5. Overview of EU/EEA studies evaluating percentage of children <5 years of age hospitalised due to
acute gastroenteritis in whom rotavirus excretion was identified, number of hospitalised children <5 years
of age per 100 000/year due to rotavirus disease and median duration of hospitalisation
% hospitalised
AGE with Number of
Median
laboratory- children
Country Authors Study year duration of
verified hospitalised <5
hospitalisation
rotavirus years per
(days)
disease <5 100 000/year
years
Austria Rendi-Wagner et al (107) 1997-2003 - 770 4.7
Van Damme et al, REVEAL (13) 2004-2006 58 990 -
Belgium Zeller et al (108) 1986-2006 19 - -
Bilcke et al (158)] 2004-2006 - 676 4.4
Czech
Pazdiora et al (109) 1998-2006 - 698 -
Republic
Fischer et al (110) 1995-1999 - 280 -
Denmark
Fischer et al (159) 2009-2010 39 380 -
Ryan et al (111) 1993-1994 43 520 2
England/Wales
Harris et al (112) 1995-2003 45 450 -
Vesikari et al (113) 1985-1995 54 600 2.3 for all AGE
Finland Rasanen (160)] 2006-2007 38 - -
Rasanen (160) 2007-2008 63 - -
Fourquet et al (114) 1997 51 210 -
France Van Damme et al, REVEAL (13) 2004-2006 56 870 -
Forster et al, SHRIK (115) 2005-2006 64 - -
Berner et al (142) 1987-1996 25 - 4
Poppe et al (116) 41 770 4.9
Germany* Van Damme et al, REVEAL (13) 2004-2006 66 500 -
Koch et al (117) 2001-2008 - 510 -
Kavaliotis et al (118) 2006 49 - -
Greece
Konstantopoulus et al* (119) 2008-2010 24 - 4
Ireland Lynch et al (120) 1997-1998 50 1190 4.1
Ruggeri et al (121) 27 - -
Gabutti et al (122) 2001-2005 36 - 5.7
Mattei et al (123) 2002-2005 - 157-204 -
Italy
Marsella et al (161) 2003-2005 - 154ǂ 5
Panatto et al (162) 2006 33 550 4.2
Forster et al SHRIK (115) 2005-2006 33 - -
Saia et al (163) 200-2007 - 196 3.5
Hungary* Szúcs et al (125) 1993-1996 21 840 -
de Wit et al (126) 1997-1998 32-58 90-340 3-4
Netherlands
Bruijning-Verhagen et al (164) - 510 -
Norway Flem et al (127) 2006-2008 63 300 1.3
Poland Mrukowicz JZ (128) 1994-1996 41 310 9.5
Romania Lesanu et al (165) 2011 58 - 6.4
Visser et al (129) 1999-2000 25 100 4.8
Luquero Alcade et al (130) 2000-2004 32 480 -
Cilla et al (166) 1996-2008 39 215 4.7
Spain Garcia-Basteiro et al (132) 2003-2008 22 104 3.2
Sanchez-Fauquier et al (167) 2006-2008 40 - -
Johansen et al (136)* 1993-1996 36-45 370 2.4
Sweden Van Damme et al, REVEAL (13) 2004-2006 62 770 -
Rinder et al (137) 2007-2008 41 388 -
United Van Damme et al, REVEAL (13) 2004-2006 61 290 -
Kingdom Forster et al, SHRIK (115) 2005-2006 51 - -
ǂ up to 14 years of age
* up to 4 years of age
27
Outpatient visits
Few European studies have focused on evaluating the burden of rotavirus disease handled within the healthcare
system in out-patient clinics/emergency departments. The large number of children being assessed in outpatient
settings (emergency departments or primary care) do contribute to the significant burden of rotavirus disease on
the healthcare systems and societal costs (112, 135, 168-170). The burden of rotavirus disease in the outpatient
setting was estimated in the REVEAL study and was observed to be 2–4 times higher than the incidence of children
hospitalisations due to rotavirus disease (13).
Conclusions
 Epidemiological studies conducted in eighteen EU/EEA Member States suggest that acute rotavirus disease
results in around 300–600/100 000 children under five years of age being hospitalised annually, however
significant variation occurs within and between countries. Extrapolating these data to the whole EU/EEA with a
birth cohort of around 5 million infants suggests that about 75 000–150 000 hospitalisations in children <5
years occur yearly.
 Further epidemiological studies in ten EU/EEA Member States suggest that around two to four times more
children seek medical evaluation for dehydration in outpatient settings, leading to significant burden on
healthcare systems.
 Finally, limited mortality due to rotavirus disease is reported in studies conducted in eight EU/EEA Member States. An
estimated mortality rate of <0.1 per 100 000 children <5 years and a hospital case-fatality rate of around 0.1–0.2%
is reported.
Identified knowledge gaps and needs for capacity building

 No case definition for disease surveillance of rotavirus disease exists in most EU/EEA countries and at the EU
level. Development and adoption of a suitable case definition would facilitate impact assessment of
implemented rotavirus immunisation programmes.
 Rotavirus disease is not a notifiable disease in most EU/EEA Member States, with the exception of Germany.
Initiation of EU/EEA Member State and EU-level routine or sentinel reporting of severe rotavirus disease leading
to hospitalisation and/or death would facilitate impact assessment of implemented rotavirus immunisation
programmes.
28
Rotavirus vaccine efficacy

The first randomised placebo-controlled clinical trials that served as the basis for licensure in the EU/EAA are briefly
described below (83, 171, 172). Subsequently 41 randomised placebo-controlled clinical trials were reviewed by the
Cochrane Collaboration (173).
RV1. A large randomised placebo-controlled clinical trial to evaluate efficacy of RV1 was conducted in Finland and 11 Latin
American countries (171). The study was designed to evaluate safety with respect to intussusception (n=63 225), and to
evaluate efficacy of the vaccine in reducing the need for hospitalisation related to rotavirus disease. The efficacy evaluated
in 17 867 infants (n=9 009 in the rotavirus vaccine recipient group) against severe rotavirus disease was 84.7% [95% CI:
71.7–92.4] during the first year of life, and 79% [95% CI: 66.4–87.4] during the second year of life. Serotype-specific rate
reductions against severe rotavirus disease were for G1[P8] 90.8% [95% CI 70.5–98.2], for G3[P8], G4[P8] and G9[P8]
86.9% [95% CI 62.8–96.6] and for G2[P4] 45.4% [95% CI -81.5–85.6]. In addition, studies involving 3 994 infants
(n=2 572 in the rotavirus vaccine group) were conducted in six European countries and showed that after two doses of
Rotarix, the vaccine efficacy estimated for the period between two weeks post-second dose and the end of two
consecutive rotavirus seasons (combined efficacy follow-up period; mean duration 17 months) was 83.8% [95% CI: 76.8–
88.9] against rotavirus disease requiring medical attention and 96.0% [95% CI: 83.8–99.5] against hospitalisation due to
rotavirus disease. Finally, 3-year efficacy estimated in Asia (Singapore, Hong Kong, and Taiwan) was 100% [95%CI 67-
100] (174). In this study RV1 efficacy against genotype G1 was 100.0% [95%CI 84.8-100] and pooled efficacy against
non-G1 rotavirus genotypes was 94.9% [95%CI 80.2-99.4].
RV5. A large randomised placebo-controlled trial was carried out to assess efficacy of RV5 with subjects < 8 weeks of
age from 11 countries including USA, several Latin American countries, Taiwan and Europe (Finland, Belgium, Germany,
Italy and Sweden) (83). The study was designed to evaluate safety with respect to intussusception, and efficacy of the
vaccine in reducing the need for hospitalisation and emergency department visits related to rotavirus disease. Sub-
studies nested within the large-scale study were designed to evaluate safety with respect to all adverse events, as well as
immunogenicity and efficacy against rotavirus disease of any severity. Efficacy was evaluated in 68 038 infants
(n=34 035 in the rotavirus vaccine group) and serotype-specific reduction in rotavirus disease was evaluated in a subset
of 5 673 infants (n=2 834 in the rotavirus vaccine group). The RV5 vaccine reduced hospitalisations and emergency
department visits related to G1–G4 rotavirus disease by 94.5% [95% CI 91.2–96.6]. The overall efficacy against any G1–
G4 rotavirus disease throughout the first rotavirus season after vaccination was 74% [95% CI: 66.8–79.9]; and against
severe gastroenteritis 98% [95% CI: 88.3–100]. The reduction in incidence of rotavirus disease caused by G1–G4 during
the second rotavirus season after vaccination was 88% [95% CI: 49.9–98.7] for severe disease and 62.6% [95% CI:
44.3–75.4] for disease of any severity. The duration of protection after a complete vaccination series has not been
studied beyond the third season after vaccination and, according to manufacturers, it will not be since studies have
been closed (175, 176). An extension study conducted in Finland, where 21 941 children were followed for up to
3.1 years after the third vaccine dose of RV5, revealed rate reductions in hospitalisations and emergency room
visits during the first, second and third years of life by 94.0% (95% CI 90.0–96.5), 94.7% (95% CI 90.7–97.2) and
85.9% (95% CI 51.6–97.2), respectively [201]. In this study the serotype-specific rate reductions in rotavirus
disease healthcare encounters (ED-visits and hospitalisations) in the per protocol population were: G1[P8] 95.3%
(95% CI 92.5–97.2), G2[P4] 66.8% (95% CI <0–75.8), G3[P8] 91.7% (95% CI 43.5–99.8), G4[P8] 66.8% (95%
CI <0–94.2) and G9[P8] 92.3% (95% CI 48.5–99.8). It is expected that reinfection with naturally circulating wild-
type rotavirus will boost the immune response in vaccinated individuals since vaccination will not induce sterilising
immunity. It is therefore essential that effectiveness and possible breakthrough infections are monitored.
A systematic Cochrane review published in 2012 evaluated 41 randomised controlled trials assessing efficacy of
rotavirus vaccines with 186 263 participants (173). The trials compared a rotavirus vaccine with placebo, no
intervention or another vaccine. The vaccines tested were RV1 (29 trials involving 101 671 participants) and RV5
(12 trials involving 84 592 participants). The large trials were conducted in low and high rotavirus-mortality settings
throughout the world. They showed that in the first two years of life, RV1 and RV5 prevented more than 80% of
severe cases of rotavirus diarrhoea in low-mortality developed countries.
29
Figure 6a. Rotavirus vaccine efficacy compared with placebo over a follow-up period of 2 years in
randomised control trials reported as risk ratio - RVGE leading to hospitalisation, first and second
year*
Figure 6b. Rotavirus vaccine efficacy compared with placebo over a follow-up period of 2 years in
randomised control trials reported as risk ratio- RVGE any severity, first and second year*
*X-axis in log scale

Adapted from: Background paper to the recommendation for routine rotavirus vaccination of infants in Germany (177, 178))
Further, systematic reviews were performed in support of the vaccine recommendation in Germany by STIKO
(Ständige Impfkommission) with a focus on efficacy, effectiveness, impact and safety of rotavirus vaccines (177,
178). Figure 6 presents the results obtained in the review of efficacy studies conducted in Europe, Australia,
Canada, USA, Latin America and Asia, indicating a vaccine efficacy of 92% (95% CI 82–96%) against rotavirus-
induced hospitalisation during the first and second year following vaccination as well as 74% (95%CI 61-83%)
against any rotavirus infection during the same time period.
Cross-protection against other genotypes

Cross-protection has been shown for both vaccines against the five most common genotypes (see above), which is
expected since antibodies to the common antigen VP6 have been shown in animal experiments to provide protection.
However, the number of cases with G2P4 has been very limited in the RCTs assessing RV1 and the confidence
intervals are wide. Effectiveness has been demonstrated for RV1 also against the less common genotypes
G9P[4]and G9P[6] and for RV5 and G12. Furthermore, there are no data available on new emerging genotypes
such as G8, and G10. None of these have so far been able to induce larger outbreaks in Europe or the US to
enable the evaluation of cross-protective immunity. However, studies performed in Africa and South East Asia
indicate statistically significant cross-protection for at least one of the genotypes G8 (101, 179).
Conclusions
 A Cochrane systematic review and meta-analysis published in 2012, evaluating 41 randomised controlled trials
with 186 263 participants, showed that in the first two years of life, the second generation rotavirus vaccines
RV1 and RV5 prevented more than 80% of severe cases of rotavirus diarrhoea in low-mortality developed
countries.
 A German systematic review and meta-analysis of RCTs conducted (published in 2013) suggests a vaccine
efficacy of 92% against rotavirus-induced hospitalisation during the first two years following vaccination (95%
CI 82–96%) as well as 74% (95%CI 61-83%) against any rotavirus infection.

 Vaccine efficacy data are limited in low-mortality rotavirus settings for cases induced by new emerging rotavirus
genotypes such as G8 and G10. Preparedness to conduct observational effectiveness studies should be
established should new emerging genotype/s cause larger outbreaks in the EU/EEA.
 Vaccine efficacy data are missing in chronically ill individuals and those with gastrointestinal malformations.
Observational studies can fill these gaps.
30
Rotavirus vaccine effectiveness

As of mid-2016, 81 countries worldwide had introduced rotavirus vaccines into their routine immunisation programme
(180). Vaccine effectiveness has been assessed for the two rotavirus vaccines in observational studies conducted in
rotavirus low-mortality settings in Australia, Belgium, Finland, France, Germany, Israel, Spain and the USA. Not all these
countries have introduced rotavirus vaccination in their national immunisation programmes, such as France and Spain. In
contrast to efficacy assessed in randomised controlled trials by administering vaccines and observing outcomes under
controlled conditions in a cohort of healthy participants, vaccine effectiveness is assessed in the general population after
the vaccine went into widespread use. Despite the inherent weaknesses of their study design, observational studies can
provide important additional evidence on the effects of the vaccine including population-effects (such as herd protection);
outcomes in population groups not included in the randomised clinical trials (e.g. chronically ill), and outcomes which are
rare in developed countries, such as rotavirus-induced deaths. We identified a total of 19 articles reporting results from
either case-control (n=15) or cohort studies (n=4) conducted in low rotavirus-mortality countries (181-196). Studies
were conducted between 2010 and 2013 and assessed effectiveness over 2–3 winter seasons.
Case-control studies conducted in low rotavirus-mortality settings

Pooled crude and adjusted odds ratios (ORs) from the 15 case-control studies showed that rotavirus vaccination is
effective in preventing rotavirus-induced gastroenteritis requiring hospitalisation in low rotavirus-mortality settings.
A forest plot with adjusted results is presented in Figure 7. After at least two doses of rotavirus vaccine, pooled
vaccine effectiveness to prevent severe rotavirus-induced gastroenteritis leading to hospitalisation was estimated at
84% (95% CI 75–89%) (181-192, 197). Pooled ORs were homogenous and consistent. This analysis suggests that
rotavirus-vaccination is also effective in the general paediatric population.
Figure 7. Forest plot of pooled odds ratios for the occurrence of hospitalisation due to rotavirus disease in fully
rotavirus-vaccinated children, as observed in case-control studies published between 2010 and 2013*
*X-axis in log scale
Cohort studies conducted in low rotavirus-mortality settings

Pooled risk ratios (RRs) from the four cohort studies (one study by Panozzo et al. reports results for four seasons)
confirmed that rotavirus vaccination is effective in preventing rotavirus-induced gastroenteritis requiring
hospitalisation (193-196). Pooled effectiveness was estimated at 91% (95% CI 88–94%) (see Figure 8). It should
be noted that there was greater heterogeneity among the cohort studies than the case-control studies.
31
Figure 8. Forest plot of pooled risk ratios for the occurrence of hospitalisation due to rotavirus disease in
fully rotavirus-vaccination children, as observed in cohort studies published between 2007 and 2011*
* X-axis in log scale
Effectiveness in high rotavirus-mortality settings

Whether rotavirus vaccines will provide protection against severe rotavirus disease caused by rotavirus strains that
did not circulate during the clinical trials conducted in Europe, Australia and North America has been addressed in
vaccine efficacy and effectiveness studies from Brazil (RV1), Nicaragua (RV5) South Africa (RV1), Malawi (RV 5),
Kenya (RV5) and Ghana (RV 1 and 5) (101, 198-201). Efficacy and effectiveness reported from these high
rotavirus-mortality countries is somewhat lower in the low-mortality countries, but still significant, taking into
account effects on both mortality and morbidity (101, 179, 198, 199). The study from Brazil (198) demonstrates
rather high vaccine effectiveness of RV1 against fully heterotypic circulating strains, but the authors discuss the
possibility of a more rapid decline of protective immunity against heterotypic strains. Of interest is also a recent
RCT conducted in rural Ghana, where three doses of RV 1 was compared to two doses, and resulted in increased
seroconversion frequencies and geometric antibody titers (201). However, since there is no correlate of protection,
a postmarketing effectiveness study is required to determine whether the improvement in immune response from
three doses of RV1 translates into a public health benefit in high rotavirus-mortality settings.
The first effectiveness study conducted in South Africa with broader range of circulating rotavirus strains has been
published and this also includes some children who are HIV-positive (202). South Africa introduced rotavirus
vaccine into its routine immunisation programme in August 2009 and it is administered at six and 14 weeks of age.
Extrapolation of these studies to the European paediatric population may not be valid and effectiveness studies,
including less frequently circulating rotavirus strains in European vaccinated settings, are warranted. In order to
obtain statistically-testable estimates, large paediatric populations need to be followed, which suggests that cross-
country border collaborations may be more valuable than country-specific studies.
Other studies of interest

Initial effectiveness data assessing reduction in mortality, available from Mexico after introduction of rotavirus vaccine in
their routine programme in 2007, suggest a 66% relative reduction in overall diarrhoea-related deaths in children <1 year
of age compared with baseline years (2003–2006) (203). Continued monitoring reveals that trends in hospitalisation and
deaths from diarrhoea among children younger than 5 years in Mexico before and 7 years after implementation of
rotavirus vaccination reveals a 53% reduction (95% confidence interval [CI], 47%-58%) in diarrhoea-related mortality
and a 47% reduction (95% CI, 45%-48%) in diarrhoea-related hospitalisations. This translates to 959 deaths and 5831
hospitalisations averted every year (204).
An observational cohort study conducted in the US investigated whether rotavirus vaccination prevents a known
complication associated with rotavirus disease, seizures (205). A full-course of rotavirus vaccination was statistically
associated with an 18–21% reduction in the risk of seizure requiring hospitalisation or emergency room attention (RR
0.79 95% CI 71–88) in the year following vaccination. Subsequently, several investigators have confirmed the reduction
in hospitalisation due to febrile seizures (206-208).
Data on long-term vaccine effectiveness beyond the first three years of life in vaccinated individuals after introduction of
rotavirus vaccines in paediatric routine immunisation programmes and in vaccinated populations are starting to become
available. In a Finnish test-negative case-control study effectiveness of RV5 was evaluated over four rotavirus seasons
and continued to show significant reduction: the crude estimate of the effectiveness of RV5 to prevent RV GE
hospitalisation in national immunisation programme age-eligible children was 94.4% (95% confidence interval, 79.8%-
98.4%) (209). Of note, vaccine-derived rotaviruses were detected in 8% of the children with rotavirus-induced
gastroenteritis, with a probable causal association in 2 children as assessed by the investigators. In addition, in repeated
surveys in one paediatric Finnish hospital the proportion of RVGE among all children with acute gastroenteritis cases
decreased from 52% (421 of 809 cases) in pre-introduction of vaccine years to 26% (86 of 330 cases) in post-
introduction of vaccine (years 2009 to 2011) and then falling to 12% (40 of 347 cases) in 2012 and 2014 (210). The
hospitalisations for RVGE were reduced by 90% and the outpatient clinic visits also by 90% in years 2012-2014. All acute
32
gastroenteritis cases were reduced by 59% in this study and norovirus was the major causative agent of acute
gastroenteritis identified in the post-introduction period. However, persistent rotavirus circulation was observed six years
post-introduction of vaccine in laboratory-investigated older children and elderly with acute gastroenteritis (211). Further
long-term studies of RV1 and RV5 in the US revealed statistically significant vaccine effectiveness for each year of life for
which sufficient data allowed analysis which was 7 years for RV5 and 3 years for RV1 (212). Both vaccines provided
statistically significant genotype-specific protection against predominant circulating rotavirus strains.
As observed above, it is expected that rotaviruses will continue to circulate in Europe and provide a natural immunity
boost to vaccinated individuals. Therefore the ultimate outcome of introducing rotavirus vaccines is containment and not
elimination/eradication.
Conclusions
Protection by the two rotavirus vaccines, RV1 and RV5, against severe rotavirus disease leading to hospitalisation,
was assessed in observational studies conducted in rotavirus low-mortality and developed countries, including:
Australia (RV1 and RV5), Austria (RV1 and RV5), Finland (RV5), France (RV5), Germany (RV1 and RV5), Spain
(RV5), and the US (RV1 and RV5). A meta-analysis of identified case control studies suggests a vaccine
effectiveness against severe rotavirus disease leading to hospitalisation of 84% (95% CI 75–89%) and a meta-
analysis of identified cohort studies suggests a vaccine effectiveness of 91% (95% CI 88–94%).

 Whether current rotavirus vaccines administered during the first six months of life will provide life-long
protection against severe rotavirus disease is unknown and needs to be monitored. Routine surveillance for
fully immunised and hospitalised children with breakthrough, laboratory-confirmed rotavirus disease infections
is a possible strategy. No known serological surrogate marker for correlates of protective immunity is
available, although serum IgA has been used in the RCTs and could possibly be explored as another tool for
monitoring the long-term response in sero-epidemiological studies.
 Whether current rotavirus vaccines will provide protective immunity to new emerging rotavirus strains in the
EU/EEA setting is unknown and needs to be monitored through routine or sentinel rotavirus strain surveillance
in the EU/EEA, and through observational studies should outbreaks occur.
Herd protection provided by infant rotavirus vaccination

The main aim for vaccines is to provide direct protection to immunised individuals. In addition, indirect protection of
unvaccinated individuals may be observed and may add to the impact achieved through population-wide vaccination
programmes. Possible mechanisms behind indirect effects may include transmission of vaccine virus to unimmunised
individuals inducing protective immunity, or reduced virus circulation/number of asymptomatic carriers in a defined
population through high vaccination coverage with vaccines that induce sterile immunity or significantly lower virus
excretion. Such indirect effects are often called herd, population or community immunity/protection and are beneficial to
individuals unable to be vaccinated due to contraindications. Herd protection may be demonstrated through detection of
a level of protection higher than expected from vaccine coverage achieved, or by observing any level of protection in
unimmunised subjects (205, 213, 214). The level of immunisation coverage required in a defined population for indirect
protection to become evident varies with disease and its corresponding vaccine.
One important factor for consideration when looking at the possibility of rotavirus vaccine-induced herd protection is that
catch-up campaigns of older age groups have not been possible due to the narrow age window for vaccination
recommended by regulatory agencies to minimise risk of intussusception (1, 2). Hence, population protection to
rotaviruses is either acquired through natural infection or vaccination of young infants.
Rotavirus vaccine viruses are known to be shed after vaccination with both RV1 and RV5. A randomised placebo-
controlled clinical trial evaluating transmission of RV1 vaccine virus among twins living in the Dominican Republic showed
that transmission of the vaccine strain occurred, from a vaccinated to an unvaccinated twin living in close contact, but
whether transmission leads to indirect protection is still unknown (71). Seroconversion occurred in the vaccinated twin in
62.5% (95% CI 51.0–73.1) and in 21.3% (12.9–31.8) of the unvaccinated twins. Transmission of vaccine virus to siblings
of RV5 vaccinated infants has also been described and resulted in limited clinical symptoms (80, 215).
A mathematical transmission model to project the impact of a rotavirus vaccination programme at the population level
was developed by Van Effelterre et al (216). The model was applied to five European countries using different expected
vaccination coverage rates; 70%, 90% and 95%. According to the model, herd immunity would induce a reduction of
any severity of rotavirus disease incidence by 25%, 22% and 20%, respectively, for the different levels of vaccine
coverage and for moderate-to-severe rotavirus disease by 19%, 15% and 13% five years after implementation of a
vaccine programme. These reductions are additional effects, on top the direct effect.
In addition to the observed direct effect, a number of effectiveness studies conducted in Australia, Austria, Belgium,
Brazil, El Salvador, Mexico, Panama and the United States also suggest an indirect effect of the second generation
rotavirus vaccines, implying that herd protection may occur also in older age groups (108, 193, 197, 203, 217-242).
33
Furthermore, Pollard et al. recently conducted a meta-analysis to estimate the herd protection effect in children aged
under one year in studies published between 2008 and 2014 (108, 193, 197, 203, 217-238, 243). The meta-analysis of
studies conducted in low-mortality rotavirus countries reporting on rotavirus-specific gastroenteritis outcomes suggested
a median herd effect on rotavirus-specific gastroenteritis morbidity/mortality of 22% (19–25%) for 12 study years
presented in five studies [(195, 197, 225, 237, 238).
Finally, first data on herd protection in older age groups have become available from a developing country using a time-
series analysis conducted in Rwanda. The greatest effect was recorded in children age-eligible to be vaccinated, but the
authors also noted a decrease in the proportion of children with diarrhoea testing positive for rotavirus in almost every
age group <5 years and eligible for the study (244).
Conclusions
Observational effectiveness studies suggest that herd protection in children of the same age group, as well as older
age groups, evolve after vaccination. Herd protection may contribute significantly to the overall impact of rotavirus
vaccination programmes.

 Whether rotavirus vaccine virus excreted by newly vaccinated infants and transmitted to older populations will
have any clinical impact for induction or maintenance of immunity, as natural disease has done, is unknown
and needs to be investigated further.
 Whether reduced circulation of rotavirus disease in the community will reduce burden of disease in other age
groups, particularly in the elderly, is unknown and needs to be monitored.
Rotavirus vaccine safety

Severe gastroenteritis with vaccine viral shedding in patients with
severe combined immunodeficiency
Post-authorisation spontaneous adverse event reports of severe gastroenteritis and chronic viral shedding in infants
later diagnosed with severe combined immunodeficiency (SCID) were received in countries that first introduced
rotavirus vaccines. Immunodeficiencies have often not been diagnosed at the time in life when rotavirus vaccines
are administered. In many of the EU/EEA countries rotavirus vaccines are the only live vaccines recommended for
all infants. BCG is recommended to all children in 10 EU/EEA Member States and to children with increased risk for
acquiring tuberculosis in all others. A review conducted in U.S. VAERS using MedDRA terms such as ‘combined
immunodeficiency’ or ‘SCID’ or ‘combined immunodeficiency’ from 3 February 2006 to 15 January 2010 following
rotavirus vaccination (RV1 and RV5) identified nine reports of SCID and rotavirus vaccination [(72). All infants but
one presented to the healthcare system with symptoms including diarrhoea and were hospitalised. Subsequent
investigations led to a diagnosis of SCID. Rotavirus diagnostics of stool samples were positive in all nine cases and
the virus was identified as the vaccine strain in six cases. Prolonged viral shedding was documented in five cases.
No deaths were reported.
Subsequently, EMA and other global regulatory agencies approved a labelling change in the SPC for the two (RV1
and RV5) vaccines contraindicating administration to individuals with a history of SCID (see Table 1 ‘Rotavirus
vaccine contents, indications, contraindications, route of administration, dose regimens and frequency of reported
undesirable effects’ and Section ‘Vaccination of infants with immunodeficiency and immunodeficient close contacts’
above). Early identification of SCID (e.g. new-born screening) could prevent inadvertent live rotavirus vaccine
administration (245, 246).
More recently RV1 vaccine strains have been identified in stool samples collected in the EuroRotaNet network14 in
participating centres in the UK following the introduction of rotavirus vaccination and RV5 vaccine strains have
been identified in immunocompetent children up to 3-6 months following vaccination and further investigations are
underway (247).
14
http://www.eurorota.net
34
Intussusception
Disease
Intussusception (IS) is a condition characterised by telescoping of the intestine onto itself. Intussusception
commonly occurs at the ileo-cecal junction (see Figure 9).
Figure 9. Schematic overview of the most common form of intussusception (when ileum enters cecum) and its
common treatments with air/barium enema.
NB. Other types of intussusception are known to occur, such as when a part (the intussusceptum) of the ileum or
jejunum prolapses into itself.
The incidence is about twice as high in male infants as female infants. IS can be treated by air/barium enema (see
Figure 9) or, if necessary, manual reduction during surgery. However, treatment traditions vary within the EU/EEA
and in some EU/EEA Member States or regions surgery may be the first treatment option. According to a recent
review, 77% of treatments provided in Europe are by air/barium enema (248).
There is an approximately 50% chance of success with a non-surgical reduction if it is initiated within 24–48 hours
from onset of symptoms. In a review of an IS case series, presence of reported symptoms for at least two days
before hospital admission was an independent predictor of the need for surgical reduction (adjusted odds ratio 2.7
95% CI 1.5–4.8) (249). If not repaired or repaired late, entrapment will lead to intestinal wall oedema, possibly
followed by necrosis and intestinal perforation. The latter leads to fever, peritonitis, septicaemia, shock and, if not
reversed, death. Moreover, in the above-mentioned case series fever at admission was noted to significantly
increase risk for need of surgical reduction (adjusted odds ratio 2.7, 95% CI 1.2–6.0). Mortality due to
intussusception is very rare in developed countries, estimated in the US at 2.1 per 1 million live births [(250). The
EU/EEA studies mentioned below confirm that mortality is very rare.
The pathogenesis of intussusception is not fully understood. IS may occur in any child, although a few
gastrointestinal malformations are known to induce intussusceptions, such as polyps, which are often referred to as
a ‘lead point’. Structural lead points were identified in 3% in a systematic review of IS cases reported in the WHO
European region from 1995 onwards (251). In this review recurrence was reported in approximately 1 in 10 IS
patients and only one death was reported. A few studies have identified the presence of wild-type rotavirus in the
stool or intestine of infants with intussusception; however this association seems uncommon, while adenovirus was
strongly associated (OR 44 reported from Australia) (252, 253).
Background incidence of IS in the EU/EEA

Eight European countries have assessed background incidence for intussusception in preparation for rotavirus
vaccine introduction (251, 254-262), see Table 6. The background incidence varies somewhat between countries,
ranging between 24 and 66 per 100 000 but not to the extent observed in other parts of the world (see p.38). In
addition, variation may be observed between studies conducted in the same country dependent on whether
validation according to the established Brighton Collaboration criteria (105) was conducted or not as in the case of
the United Kingdom when the study from 2013 only accepted validated cases and observed a lower incidence than
presented earlier (Table 6) (105, 255).
35
Table 6. Background intussusception incidence in eight European countries before rotavirus

vaccination
Country National/regional Incidence per 100 000 (95%CI)
Austria (258) National 42 NA*
Denmark (261) National 66 NA*
Germany (256) National 60.4 48.3–72.1
Germany (251) National 52.2 NA*
Ireland (255) National 24.2 15.0–37.0
Italy (263) National 20.2 NA
Netherlands (262) National 35.0 NA*
Switzerland (260) 38 (first year of life)
National 31 (second year of life) NA
26 (third year of life)
United Kingdom/England (254) National 66 NA
United Kingdom** (255) National 24.8 21.7–28.2
*Not available
** Validated cases only
Further assessment of the incidence of IS per month during the first year of life has been conducted in Germany
and the United Kingdom (England). Interestingly, the peak in Germany was noted to occur at the age of 180 to 269
days while in the United Kingdom (England) the peak was noted to be earlier, in infants aged 120–149 days (see
Table 7). The reason for such differences is unknown.
Table 7. Incidence of intussusception by month, first year of life assessed in two EU/EEA countries before
rotavirus vaccination
Germany United Kingdom (England)

Age/incidence per 100 000 (95% CI) (251) Age/incidence per 100 000 (95% CI) (256)
0-29 days 3.6 (0.4–13.0)
0-89 days 19.2 (12.5-30.4) 30-59 days 26.9 (15.1–44.4)
60-89 days 46.7 (30.5–68.5)
90-119 days 30.6 (17.8–48.9)
90-179 days 61.4 (48.0-79.4) 120-149 days 50.3 (33.4–72.7)
150-179 days 43.1 (27.6–64.2)
180-209 days 28.8 (16.4–46.7)
180-269 days 98.5 (80.9-120.6) 210-239 days 37.8 (23.4–57.7)
240-269 days 45.0 (29.1–66.4)
270-299 days 14.4 (6.2–28.3)

270-365 days 67.9 (53.6-86.5)
300-329 days 10.8 (4.0–23.5)
Few studies have assessed the treatment needed to resolve IS before rotavirus vaccine introduction. In a Swiss
study including 288 IS cases, confirmed with the Brighton Collaboration standardised case definition, spontaneous
devagination occurred in 38 patients, enemas reduced IS successfully in 183 cases, while surgical treatment was
required in 67 cases. In this series of cases all patients recovered without sequelae (260, 264). Management
practices have also been mapped in the United Kingdom and Ireland (264).
In a recently published international literature review the global intussusception incidence was estimated at 74 per
100 000, peaking at 3–9 months (248) (see Figure 10). However the variation was significant, with the lowest
incidence of 9 per 100 000 reported from Bangladesh compared to 328 per 100 000 reported from South Korea.
36
Figure 10. Global annual incidence of intussusception by month of life during first year of life
Global annual incidence <1 year of age estimated to 74 per 100 000
Source: (248)
Intussusception following vaccination with first generation of oral

live rotavirus vaccine
An earlier, now withdrawn, US-licensed rotavirus vaccine RRV-TV (Rotashield) used in 1998–1999 in the US routine
immunisation programme was associated with an estimated excess risk of one additional case of intussusception (IS) per
4 670 to 9 474 infants vaccinated (11–21 additional cases per 100 000 vaccinees) (61, 62). Regulatory agencies such as
EMA and FDA therefore requested clinical trials for new second generation oral live attenuated rotavirus vaccines (RV1
and RV5) large enough to be able to exclude the risk of one additional case of IS per 10 000 children (the definition for a
very rare adverse event) and >60 000 children were included in the randomised clinical trials conducted. Of particular
interest are the results from investigations that followed the use of RRV-TV and the contributing role of age to
development of intussusception. No child receiving dose 1 of RRV-TV before the age of 89 days developed
intussusception, in spite of 1 935 doses being administered to infants younger than 30 days and 69 123 doses
administered to infants aged 30–59 days (265). However, it should be noted that naturally occurring IS, although rare,
does occur in the very young (see Table 7). The biological mechanism behind development of IS following RRV-TV
vaccination is not yet fully understood.
No increased risk of intussusception with second generation of oral

live rotavirus vaccines (RV1 and RV5) in pre-authorisation
randomised controlled trials
The risk of intussusception was evaluated in RV1 recipients in a randomised double blind placebo-controlled clinical trial
conducted in Latin America and Finland with 63 225 children enrolled. This trial provided evidence of no increased risk of
intussusception in the RV1 group (n=31 673) receiving dose 1 at 6–13 weeks of age when compared to the placebo
group (n=31 552) within 31 days after each vaccine dose (171). The median age at study entry was 8.2 + 2.39 weeks.
The relative risk (RR) for intussusception post dose 1 was calculated to be 0.50 (95% CI 0.07–3.80) and post dose 2 was
0.99 (95% CI 0.31–3.21).
Similarly, the risk of intussusception was evaluated in RV5 recipients in a randomised double blind placebo-controlled
study in 6–12 week old infants (83). The median age at study entry was 10 weeks. During the combined 42-day period
following each dose, there were six cases of intussusception in 34 837 RV5 recipients compared with five cases in 34 788
placebo recipients. The relative risk (RR) for intussusception was calculated as 0.8 (95% CI 0.22–3.52).
No clustering of cases was identified in the early period after each dose with either vaccine or placebo (171, 172). In
conclusion, in the pre-authorisation trials which served as the basis for vaccine authorisation in the EU/EEA, no increased risk
of intussusception was observed in recipients of either rotavirus vaccine, RV1 or RV5, compared to the placebo groups.
This was also the conclusion in a Cochrane systematic review published in 2012 (173). However, a risk of IS lower than
one additional case per 10 000 vaccinated individuals could not be excluded in the conducted trials and further post-
licensure monitoring of intussusception was required by the European Medicines Agency in the risk management plans
for both vaccines.
37
Assessment of reports of intussusception following routine use of

second generation oral live rotavirus vaccines (RV1 and RV5) through
adverse event spontaneous reporting systems
Cases of intussusception in temporal relationship with the receipt of rotavirus vaccines were documented in the
routine monitoring systems of adverse events following immunisation in Australia, Brazil, Germany, Mexico and the
Unites States after the introduction of rotavirus vaccines into the national immunisation programmes. Subsequently
formal pharmacoepidemiological studies were initiated in all these countries. For results see section ‘Assessment of
intussusception reports following use of second generation oral live attenuated rotavirus vaccines (RV1 and RV5)
using observed versus expected analysis’ below.
The US experience from routine reporting has been summarised in the scientific literature: during the period
February 2006–April 2012 the Vaccine Adverse Event Reporting System (VAERS) received 584 confirmed
intussusception reports following RV5 administration (182 after dose 1) and 52 following RV1 administration (25
after dose 1). Clustering of cases was observed three to six days after administration of either vaccine (266). The
age of the children involved was not reported. Furthermore, there was no significant increase in reporting of cases
following dose 2 or 3. The authors conclude that this clustering can translate to a slightly increased risk of
intussusception, which is outweighed by the benefits of rotavirus vaccination.
Although there are several limitations assessing reports retrieved through spontaneous reporting of adverse events,
an extract of submitted spontaneous intussusception reports from the EMA Eudravigilance database following
rotavirus vaccination in EU/EEA countries was analysed for this ECDC expert opinion15. It is important to note,
however, that essential information was often missing in these submitted IS reports (e.g. age at vaccination, time
to onset of symptoms, treatment provided and clinical outcome of IS).
In total, 296 spontaneous reports of IS were reported from authorisation of the two rotavirus vaccines in 2006 until
1 July 2014 and retrieved from the Eudravigilance database: 198 following RV1 administration and 98 following
RV5. Time to onset of symptoms was known for 251/296 infants (85%). A total of 193 of these cases occurred
within 21 days of vaccination, the internationally accepted risk window, and a majority (159/193) occurred in
clusters during the first seven days following vaccination with dose 1 (see Figure 7) of both rotavirus vaccines.
The mean age for administration of dose 1 was known for 202/296 infants (68%). It was 92 d ± 33 for RV1 and 95
d ± 43 for RV 5. The observed mean age for infants that had received dose 1 and developed IS following either of
the two RV vaccines was significantly higher than the mean age in the conducted clinical trials that served as the
basis for authorisation.
The outcome of the IS cases at the time of reporting was known for 182/296 infants (62%). Cases were often
reported as resolved. However, 23/125 cases (18%) with known outcome following RV1 and 6/57 cases (10%)
following RV5 were unresolved at the time of reporting. Reported complications included ascites, intestinal
abscesses, intestinal necrosis, intestinal resection, hypotonia, bradycardia or shock. No cases with fatal outcome
were reported in the time period assessed (to 1 July 2014). Although no fatalities due to intussusception were
reported to the Eudravigilance database during the period assessed above, two cases of intussusception with fatal
outcome in rotavirus-vaccinated infants were subsequently reported from France in 201516.
Additional limitations of this review are that case confirmation by chart review at EU-level was impossible due to
data protection laws and that there was a lack of reliable denominator for rate calculation and lack of adjustment
for under- or over-reporting.
15
The analysis and interpretation of EudraVigilance data presented may not be understood or quoted as being made on behalf of
the European Medicines Agency or one of its committees or as reflecting the position of the European Medicines Agency, one of
its committees or one of its working parties.
16
http://ansm.sante.fr/S-informer/Actualite/Vaccins-contre-les-rotavirus-RotaTeq-et-Rotarix-et-rappel-sur-la-prise-en-charge-de-l-
invagination-intestinale-aigue-du-nourrisson-Point-d-Information
38
Figure 11a. Cases reported to the EMA Eudravigilance database (not validated with chart review)
until 1 July 2014 with known interval between dose 1 vaccination of RV1 and development of
intussusception (n=164)*
30
Number of reported IS cases
25
20
15
10
5
0
Day 11
Day 21
Day 31
Day 41
Day 51
Day 61
Day 71
Day 81
Day 91
Day 101
Day 110
Day 139
Day 149
Day 159
Day 169
Day 179
Day 189
Day 1
Day 120
Day 130
Days post-immunisation RV1 dose 1
*A cluster of IS cases is observed during first seven days following dose 1.
Figure 11b. Cases reported to the EMA Eudravigilance database (not validated with chart review) to
1 July 2014 with known interval between dose 1 vaccination of RV5 and development of
intussusception (n=86)*
Number of reported IS cases
30
25
20
15
10
5
0
Day 1
Day 101
Day 110
Day 139
Day 149
Day 159
Day 169
Day 179
Day 189
Day 61
Day 11
Day 21
Day 31
Day 41
Day 51
Day 71
Day 81
Day 91
Day 120
Day 130
Days post-immunisation RV5 dose 1
*A cluster of IS cases is observed during the first seven days following dose 1.
39
Assessment of intussusception reports following use of second

generation oral live rotavirus vaccines (RV1 and RV5) using observed
versus expected analysis
To conduct an observed versus expected assessment of a medical outcome requires knowledge of the background
incidence for this entity. This is commonly done using historical data, often from medical outcome databases in
countries where such population-based data is available. An alternative is to retrieve cases of intussusception
through an epidemiological study, engaging paediatric departments or paediatric radiology departments. Common
limitations for observed versus expected studies are the use of historical controls that do not check for temporal
trends and the use of unconfirmed cases not validated by chart review.
Three studies conducted in non-EU/EEA countries were identified assessing a possible association between
intussusception and rotavirus vaccination (RV1 and RV5) using the observed versus expected methodology (see Tables
8–9) (267-269). All studies used historical controls and validated their cases according to the Brighton Collaboration
criteria (see Annex 2) (105). The conducted studies showed an attributable risk ranging from 1 per 199 000 to no
elevated risk for RV5, while for RV1 the estimate was 1 per 19 000 vaccinated infants (see Tables 8–9).
The only assessment of the intussusception safety signal in the EU/EEA using the observed versus expected
methodology was conducted in Germany. In an analysis of 15 intussusception cases reported following vaccination
with RV1 and 12 cases reported following vaccination with RV5 in infants aged 3–5 months, a significantly
increased risk for intussusception was found in the risk window of 1–7 days after the first dose of either rotavirus
vaccine (standardised morbidity ratio for RV1 4.6 95% CI 1.5–10.7 and for RV5 5.8 95% CI 1.2–17.1) (269). Since
this risk was not observed in children vaccinated when aged under 89 days, the investigators, and subsequently
the German Standing Committee on Vaccination (STIKO), recommended initiation of rotavirus vaccination as early
as possible during the recommended age window of 6–12 weeks for dose 1 (177, 178, 269).
Assessment of intussusception reports following use of second

generation oral live rotavirus vaccines (RV1 and RV5) in formal
pharmacoepidemiological studies
Observational studies to assess a possible association between rotavirus vaccination and development of
intussusception have been conducted in non-EU/EEA countries (Australia, Brazil, Mexico and the Unites States)
using self-control case-series, case-control and cohort study designs (see Tables 8–9) (267-276). Although different
study methodology has been employed, they all report similar results and indicate an increased relative
risk/attributable risk of intussusception, mainly during the first seven days following dose 1, ranging from 1 per
20 000 to 1 per 69 000 for RV1 vaccinated infants and 1 per 14 000 to 1 per 67 000 for RV5 vaccinated infants in
the different studies, except in the first studies by Belongia et al, Shui et al and Haber et al, conducted using US
VAERS or US VSD data where no increased risk of intussusception following RV5 was observed, possibly due to
small sample size (266, 267, 277)]. A meta-analysis of studies conducted has been published (278) and showed
that the overall estimate of the relative risk of intussusception during the seven days post-dose 1 was 5.4 (95% CI:
3.9–7.4, three studies) for RV1 and 5.5 (95% CI: 3.3–9.3, three studies) for RV5. The overall estimate for relative
risk of intussusception during the seven days post-dose 2 was 1.8 (95% CI: 1.3–2.5, four studies) for RV1 and 1.7
(95% CI: 1.1–2.6, three studies) for RV5. These epidemiological studies carry a greater scientific weight than the
observed versus expected assessments mentioned above and suggest a class-specific effect.
Severity of intussusception observed following use of second

generation oral live rotavirus vaccines (RV1 and RV5)
Two retrospective studies have assessed the severity of intussusception that developed following vaccination with
either rotavirus vaccine (e.g. whether surgery was needed for reduction of the intussusception). In an observed
versus expected study from Germany reporting severity in 27 cases of IS following either RV1 or RV5 vaccination,
13 (48.1%) underwent surgical reduction (269) while in a self-case control study from Australia assessing severity
in 110 cases of IS rates of surgery were 39% (274). Both of these studies were rather small and therefore further
studies are needed, carefully considering treatment traditions in the area where the study is conducted.
40
Table 8. Risk estimates for intussusception and RV1

Country, source
Author, year Risk window*/dose Relative risk/ attributable
population and study 95% CI
(reference) no risk/incidence ratio
methods
1.9 cases per 100 000 vaccinated
Mexico partly funded from infants or 1 per 51 000 vaccinated
Days 1-7 following dose 1
Patel et al 2011 the US infants.
Days 1-7 following dose 2 Not available
(270) Hospital-based Self-controlled 1.4 cases per 100 000 vaccinated
case series and case control infants or 1 per 69 000 vaccinated
infants
Worldwide reports to the Incidence ratio of IS days
Escolano et al 2011
manufacturer 3-7 following dose 1 Incidence ratio 4.97 1.72-14.3
(279)
Case-series analysis versus 2
1.2–7.3 cases per
Mexico Mexican Institute of 100 000 vaccinated
infants
Velazquez et al Social Security infants or
Days 0-6 following dose 1 or
2012 (272) Hospital-based Self-controlled 1 case per 14 000 to
1 case per 27 000 vaccinated
case series 83 000 vaccinated
infants
infants
1.9-10.7 cases per
Australia TGA Days 1-7 following dose 1 100 000 vaccinated
Carlin et al 2013 (regulatory agency) Days 8-21 following dose infants or
infants or
(273) Hospital-based Self-controlled 1 1 per 9 000 to
1 per 20 000 vaccinated infants
case-series and case-control Days 1-7 following dose 2 53 000 vaccinated
infants
US VSD
Observed versus expected
5.34 cases per 100 000
Weintraub et al using historical rates Day 1-7 following dose 1 Not available
vaccinated infants or
2014 (268)] Total doses: 208 000 Day 1-7 following dose 2 Not available
1 per 19 000 vaccinated infants
Dose 1: 116 000
Dose 2: 92 000
Germany Paul Ehrlich
Institute (regulatory agency)
Oberle et al 2014
Hospital-based Observed Days 1-7 following dose 1 Standardised morbidity ratio 4.6 1.5-10.7
(269)
versus expected using
historical rates
Australia National Centre for
Immunisation Research and Days 1-7 following dose 1
Quinn et al 2014 Relative incidence 11.1 2.6 - 48.0
Surveillance (NCIRS) Days 1-21 following dose
(274) Relative incidence 5.5 1.7 - 17.8
Hospital-based Self-controlled 1
case series
Singapore Department of
Clinical Epidemiology,
Yung et al 2015 Communicable Disease
Day 1-7 following dose 1 Relative incidence 8.4 2.4 – 29.0
(280) Center
Hospital-based Self-controlled
case series
* based on Brighton Collaboration Level 1 case definition including surgical criteria, radiological criteria demonstration of intestinal
invagination by either air or liquid contrast barium enema, or demonstration of an intra-abdominal mass with specific features by ultrasound,
or autopsy criteria
41
Table 9. Risk estimates for intussusception and RV5
Author, year Country, source Risk Relative 95%CI

(reference) population and study window*/dose risk/attributable
methods no risk/incidence ratio
US VSD
2006-2008
Belongia et al using historical rates in VSD Day 1-30 following No elevated risk
-
2010 (277) Total number of doses: any dose identified
207 621
Total number of dose 1:
87 201
US VSD
2006 – February 2010
Day 1-7 following
Shui et al using historical rates in VSD 1 per 1.8 million
dose 1 Not reported
2012 (267) Total number of doses vaccinated infants
Day 1-30
786 725
Total number of dose 1:
309 844
0.24 – 1.71 cases per
0.74 per 100 000
100 000 vaccinated
US VAERS vaccinated infants
Haber et al Day 3-6 following infants
or
2013 (266) Self-controlled risk interval dose 1 or
1 per 135 000 vaccinated
1 per 58 000 to 417 000
infants
vaccinated infants
Days 1-7 following
Australia TGA 6.9 cases per 100,000 3.1-13.6 cases per
dose 1
(regulatory agency) vaccinated infants 100,000 vaccinated
Carlin et al Days 8-21 following
or infants
2013 (273) Self-controlled case-series dose 1
1 per 14 000 vaccinated 1 per 7 000 to 32 000
and case-control Days 1-7 following
infants vaccinated infants
dose 2
US VSD
Weintraub et 0-1.77 cases per
Observed versus expected 0.5 per 100 000
al. 2014 100,000 vaccinated
using historical rates AR estimate day 1-7 vaccinated infants or 1
(268) infants or 1 per 30 000
Total number of doses: 1.3 following dose 1 per 199 000 vaccinated
to infinite vaccinated
million infants
infants
Dose 1: 494 000
1.5 cases per 100 000
US PRISM
vaccinated infants
Self-controlled risk interval, 0.2 – 3.20 cases per
Day 1-7 following 1.1 cases per 100 000
Yih et al cohort study 100 000
dose 1 vaccinated infants
Total number of doses: or
2014 (276) Day 1-21 following or 1 per 67 000
1.28 million 1 per 30 000 to 520 000
dose 1 vaccinated infants
Total number of dose 1: vaccinated infants
1 per 91 000 vaccinated
508 000
infants
Germany Paul Ehrlich
Institute (regulatory
Oberle et al Days 1-7 following Standardised morbidity
agency) 1.2-17.1
2014 (269) dose 1 ratio 5.8
using historical rates
World-wide reports to Incidence risk ratio
Escolano et al Days 3-7 following
manufacturer relative to the control 1.84-6.55
2015 (271) dose 1
Self-controlled case series period 3.45
* based on Brighton Collaboration Level 1 case definition including surgical criteria, radiologic criteria demonstration of intestinal
invagination by either air or liquid contrast barium enema, or demonstration of an intra-abdominal mass with specific features by
ultrasound, or autopsy criteria.
42
Updates of the EU Summary of Product Characteristics on

intussusception in 2014
Benefit/risk assessments for the two rotavirus vaccines RV1 and RV5 have been formally conducted by the following
regulatory agencies: EMA (EU/EEA), FDA (United States), TGA (Australia) and found to be positive, given the severity of
rotavirus disease and availability of treatment for cases of intussusception. The EU Summary of Product Characteristics
has been updated as follows, in line with results obtained in the above-mentioned pharmacoepidemiological studies,
stressing that prompt attention should be given to infants with clinical symptoms indicative of intussusception.
EU SPC Section 4.4 (Warnings and precautions for use)
‘As a precaution, healthcare professionals should follow-up on any symptoms indicative of intussusception (severe
abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever) since data from
observational safety studies indicate an increased risk of intussusception, mostly within 7 days after rotavirus
vaccination (see section 4.8). Parents/guardians should be advised to promptly report such symptoms to their
healthcare provider’.
EU SPC Section 4.8 (Adverse events)
‘Data from observational safety studies performed in several countries indicate that rotavirus vaccines carry
an increased risk of intussusception, mostly within 7 days of vaccination. Up to 6 additional cases per
100,000 infants have been observed in the US and Australia against a background incidence of 33 to 101
per 100,000 infants (less than one year of age) per year, respectively. There is limited evidence of a smaller
increased risk following the second dose. It remains unclear whether rotavirus vaccines affect the overall
incidence of intussusception based on longer periods of follow up (see section 4.4)’.
Risk mitigation strategies aiming to further reduce the risk of

intussusception
Following the results of observed versus expected analyses and pharmacoepidemiological studies where a risk of
intussusception after rotavirus vaccination has been observed, public health agencies or national immunisation technical
advisory groups (NITAGs) in three EU/EEA countries have embarked on risk mitigation strategies. In 2013, the German
STIKO committee recommended that rotavirus vaccines should be initiated as early as possible from six weeks of age. In
Norway the first dose in the rotavirus vaccine series is offered at six weeks of age and the parts of Sweden (Stockholm and
Jönköping regions) that initiated rotavirus vaccination programmes in 2014, the first dose in the rotavirus vaccine series is
offered at six weeks of age in Jönköping and eight weeks of age in Stockholm. Whether these mitigation strategies using
early administration will have an impact on the incidence of intussusception following rotavirus vaccination is currently
unknown. Studies have been initiated in Norway and Sweden. A recent meta-analysis indicates that if the first dose of
rotavirus vaccination is given at less than 12 weeks of age, around 1 in every 50 000 children vaccinated may suffer from
intussusception as a result (AR 1.7 (1.1 - 2.7)), while if the vaccine is administered later, >3 months, 1 in every 20 000
children are at risk (AR 5.6 (4.3 – 7.2)) (281).
Kawasaki disease
During review of RV5 clinical trial data a higher, though not statistically significantly rate of Kawasaki Disease (KD)
was observed among RV5 vaccinees than placebo recipients. Therefore risk management plans for both rotavirus
vaccines included post-authorisation requirements to monitor KD. In a review of all KD reports received by US
Vaccine Adverse Event Reporting System (VAERS) from 1990 to mid-October 2007, no clustering of cases and no
increased risk of KD in the post-authorisation phase for the RV5 vaccine was observed (282 ). Instead, the
reporting rate for RV5 (1.47/100 000 person-years) was lower than the US background rate.
Other adverse events

Other undesirable effects noted in the initial RCTs are listed in Table 1.
Conclusions
Severe gastroenteritis with vaccine viral shedding in patients with severe combined immunodeficiency
 A review of US VAERS identified nine reports of severe gastroenteritis with vaccine viral shedding in patients who were
subsequently diagnosed with severe combined immunodeficiency (SCID). This observation resulted in a label change
in the SPCs in 2013 for both rotavirus vaccines, stating that SCID is a contraindication for rotavirus vaccination.
Intussusception
 In pre-authorisation RCTs with these second generation rotavirus vaccines, which served as the basis for vaccine
authorisation in 2006 in the EU, no increased risk of intussusception was observed in recipients compared to the
placebo groups. This was also concluded in a 2012 Cochrane systematic review assessing vaccine safety in
randomised placebo-controlled clinical trials published in 2012. However, a risk of IS lower than one additional case
in 10 000 vaccinated individuals could not be excluded and risk management plans from regulatory agencies
requested post-authorisation monitoring.
43
 After the introduction of rotavirus vaccines into routine immunisation programmes, IS cases following vaccination
with RV1 and RV5 were initially reported in early adopter countries (Australia, Brazil, Mexico and the Unites States).
Similarly, IS cases have been reported to the EU/EEA Eudravigilance database following vaccination with both
rotavirus vaccines.
 Formal observational studies conducted in non-EU/EEA countries such as Australia, Brazil, Mexico, Singapore
and the US indicate that rotavirus vaccines carry an increased risk of intussusception, mostly within seven
days of vaccination with dose 1. An observational study conducted in one EU/EEA country, Germany confirms
the reported increased risk. Following these studies the EU/EEA SPCs have been updated accordingly: ‘Up to
6 additional cases per 100,000 infants have been observed in the US and Australia against a background
incidence of 33 to 101 intussusception episodes per 100,000 infants per year, respectively’.
 Strategies for IS risk minimisation are currently being explored, with vaccinators and healthcare workers
caring for affected children being trained for early recognition of symptoms suggestive of intussusception and
vaccines being provided early in the recommended age window from six weeks of age. However, no results
are available yet on the impact of these strategies. A recent meta-analysis indicates that if vaccination with
first dose is given at less than 12 weeks of age around 1 in every 50 000 children vaccinated may suffer from
intussusception due to vaccination, while if the first dose of vaccine is administered later 1 in every 20 000
children will be at risk.
 Regulatory agencies in low-mortality rotavirus countries such as those in the EU/EEA have concluded that the
benefits of rotavirus vaccination outweigh the risks.
Kawasaki disease
No increased risk of Kawasaki disease has been observed in the post-authorisation period.

Published background incidence of IS by month during the first year of life is lacking in most EU Member States.
Developing these data in more Member States will be useful for observed versus expected analysis of IS.
Risk minimisation strategies, to reduce IS incidence following rotavirus vaccination, are being undertaken in
three countries. The impact of these strategies is currently unknown and studies of their effect would be
useful to inform others.
Training material for vaccinators/healthcare personnel is needed to educate parents on IS risk, symptom
recognitions and emergency measures to ensure adequate and prompt treatment, should an IS case be
encountered.
In the EU/EEA reporting of IS cases by vaccinators following RV vaccination could be improved. Future
monitoring of adverse events would benefit from completeness of reporting by vaccinators and chart review
for validation.
Protocols for observational studies to assess IS risk, should be developed for conduct in early adopter EU/EEA
countries if needed. Multi-country EU/EEA studies could enhance sample size and speed of results.
The question of whether new (third generation) rotavirus vaccines/vaccine candidates (e.g. live oral neonatal
rotavirus strains, inactivated parenteral whole virus or subunit) will offer better benefit-risk profiles than the
current second generation oral live vaccines needs to be investigated in continued randomised clinical trials.
44
Rotavirus vaccine cost-effectiveness in EU/EEA countries

In an economic context, where public funding is scarce, the need to adopt more efficient strategies for all public
interventions is paramount. Population health can be influenced directly by many different factors (behaviour,
environment, etc.) or indirectly (education, unemployment, etc.), therefore the impacts of public health
intervention are not straightforward. As a consequence, there is a need for a sound framework to assess the
potential impacts of different policy interventions. Economic assessments help facilitate the decision making
process in EU/EEA Member States.
There are several types of economic analytical models for prioritising different policy interventions; cost-benefit and
cost-effectiveness analyses being the most commonly used.
Cost-benefit analysis is a formal technique to summarise the health benefits and resources utilised by public health
interventions so that decision-makers can select appropriate options. It appraises in monetary value the overall
expected costs and benefits of an intervention in order to choose the best or most beneficial solutions. However,
costs and benefits may occur in different time frames, hence the monetary value of both is expressed in present
value using a discounting factor. Cost-benefit analysis is often utilised when there is only one policy intervention
option, however when there are many different policy alternatives then cost-effectiveness-analysis is the technique
of choice.
Contrary to cost-benefit analysis, for cost-effectiveness analysis, the expected benefits from the intervention do not
need to be expressed in monetary value and the number of cases or other indicators can also be adopted. Rules
are then determined in order to facilitate decision-making based on the cost-effectiveness-analysis. In Europe,
cost-effectiveness analysis is widely adopted as the technique to identify the most effective utilisation of limited
resources.
Furthermore, in cost-effectiveness studies epidemiological outcomes, such as the number of cases prevented,
number of life years gained, or so-called ‘utility’ indicators, such as quality-adjusted life years (QALY) gained or
disability adjusted life years (DALY) prevented are often used. The latter two capture the impact of the
intervention, both for mortality and morbidity outcomes. QALYs are the product of the time spent in a certain
health state and of a quality of life utility weight corresponding to this health state. DALYs reflect the total amount
of healthy life year(s) lost, whether from premature mortality or from some degree of disability.
There is no EU-wide adopted threshold for cost-effectiveness analysis, and only a few countries have set a formal
threshold defining a cost-effective intervention. For example, in England and Wales, the Joint Committee on
Vaccination and Immunisation (JCVI) to assess the vaccination program in the UK adopts the threshold of
interventions from the National Institute for Health and Clinical Excellence (NICE)17 which currently equals GBP 30 000
(EUR 35 000) for health services and personal services. In the Netherlands the threshold used is often set at EUR
20 000 per life year or QALY gained.
To the best of the authors’ knowledge, no similar thresholds have been adopted in northern, central, eastern or
southern Europe and they would probably vary significantly anyway, as such a threshold depends on the wealth of
the country and organisation of the healthcare system.
Assessing cost-effectiveness is often one of several important factors considered when a new vaccine is evaluated for
possible introduction into a routine programme. However, the measurement of the reduction in quality of life for a
disease affecting young children, such as in the case of rotavirus vaccines, poses unsolved methodological challenges.
This is particularly relevant because any assessment has to be made by proxy through a caregiver. With the high
morbidity but low mortality attached to rotavirus-induced gastroenteritis in EU/EEA countries, estimation of cost-
effectiveness ratios based solely on life years gained would lead to an underestimation of the benefits of vaccination.
This chapter summarises published evaluations of cost-effectiveness for the introduction of rotavirus vaccines into
national immunisation programmes in the EU/EEA.
17
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/224864/JCVI_Code_of_Practice_revision_2013_-
_final.pdf
45
Cost-effectiveness studies conducted in EU/EEA countries

Cost-effectiveness studies from Belgium, England and Wales, Finland, France, Germany, Ireland, Italy, the
Netherlands, Spain and the United Kingdom, have been identified with the appraisal of cost-effectiveness for universal
infant rotavirus immunisation based on use of either RV1 or RV5 vaccines (132, 158, 168, 283-299). To date no
EU/EEA Member States in central or eastern Europe have published cost-effectiveness data for rotavirus vaccines.
Study methodology and results are summarised in Tables 10 and 11.
Studies used static or dynamic models and included a variety of main assumptions and parameter values and are
therefore not comparable. The assumptions and parameter values that varied were the perspective of analysis
(healthcare provider costs only or societal costs in addition), whether quality of life (QALY) was included, different
discount rates, whether nosocomial infections were included, varying vaccine efficacy assumptions, and expected vaccine
prices. Studies were either commissioned by the pharmaceutical industry and conducted by academia or by public health
experts/academia independent of industry.
Based on the list price in respective countries for a complete course of rotavirus vaccination with two or three
doses available at the time of analysis (range EUR 75–187), only one study in Finland deemed the intervention to
introduce rotavirus vaccine to be a cost-saving over the current practice of managing cases of rotavirus infection,
which includes rehydrating severely affected children as in-patients. Cost-effectiveness estimates varied widely, as
did the assumptions and parameter values underlying their calculation, ranging from lower estimate range values
of below EUR 20 000 per QALY gained to upper range values of over EUR 200 000 per QALY gained (285), (299)
(see Table 11). The choice of different end-point measurements in the clinical trials complicates the analysis (see
Annex 1 for a comparison of the two severity scales used in the clinical trials). This is accounted for in the tables by
showing ranges of results, depending on the vaccine costs and effectiveness values considered in the studies for each
vaccine. For the sake of simplification, although all studies included sensitivity analysis, only results for the base-case
scenarios are presented.
The main differences between studies lie in:
Scope of analyses. Four types of costs can be distinguished; direct medical costs (costs of treatment), direct
non-medical costs (home assistance, transportation, etc.), indirect costs (care-providers leave of absence due
to disease in child or disease in care-provider, etc.) and intangible costs (loss in quality of life, etc.). The societal
perspective usually includes the non-medical direct costs borne by the families and the indirect costs, resulting
from time off work inducing loss in productivity and/or loss in wages for the carers whereas the healthcare
associated cost perspective takes into account the medical and non-medical costs only.
Rates of discounting (i.e. conversion of future values of costs or health effects to their present values). The
impacts of a public health intervention are usually not observed at the same time as the funding of the
intervention, hence usually both intervention benefits and costs are discounted to their present values. All studies
but one discounted the costs at a rate between 3 and 4% but the rates used for the benefits vary more widely
(1.5–5%). The range of discounting rate adopted is in line with results from different economic studies. It is worth
noting that the higher the discounting rate the lower the present value. In many studies (mainly for the
Netherlands and Belgium), asymmetric discounting rates have been adopted with a higher discounting rate for
costs of intervention than for the impact of the intervention, thus increasing the present value of related impacts
from an intervention. Such a choice favours vaccination rather than no vaccination.
Quality of the epidemiological parameters and cost estimates. Most RVGE are self-limiting and their true
incidence (see Table 5) and associated costs are often poorly measured. Acute gastroenteritis is frequent in
children under five years but the contribution of rotaviruses is not well quantified. Even for severe cases
leading to hospitalisations, the percentage attributable to rotaviruses is largely unknown, leading to varying
estimates, as the clinical management is independent of the pathogen causing the diarrhoea. Choices
regarding whether or not to include in the analysis cases for which no care is sought are likely to partially
explain the heterogeneity in the results of the different studies. This has been identified as the main factor
contributing to the discrepancy in the results obtained in two UK cost-utility studies. The burden of
nosocomial infections is very difficult to assess and many studies having neglected them on the basis of the
lack of data.
In addition, potential herd protection was considered in a dynamic transmission model assessing cost-effectiveness
of rotavirus vaccination in England and Wales (300). This model predicts that RV5 vaccination is likely to be cost-
effective in England and Wales at GBP 60 per course and in some scenarios the vaccination is predicted to be not
only cost-effective but also cost-saving.
Only one study by Bruijning-Verhagen et al conducted in the Netherlands suggests targeted rotavirus vaccination of
high-risk infants as a low cost and highly cost-effective alternative to universal vaccination (144).
46
Conclusions
Identified studies on cost-effectiveness of universal rotavirus vaccination in the EU/EEA provide discrepant
results. The inclusion of societal costs, and/or positive indirect benefits of the vaccines such as herd
protection, significantly affects the cost-effectiveness ratios.
There are differences among Member States, not only in the conclusions of the studies but also in the
impact of the studies on whether countries have introduced the rotavirus vaccine into their programmes.
Until now a recent survey in EU/EEA Member States found that eight out of eleven countries having
undertaken economic assessments have introduced rotavirus vaccines into their programmes while only six
have published their results (Belgium, Finland, Germany, Ireland, Italy and the United Kingdom)18.
First impact data after implementation of rotavirus vaccines in national immunisation programmes are now
becoming available and herd protection effect is significant. Countries still wanting to conduct cost-
effectiveness modelling should consider including herd effects in dynamic or semi-dynamic models.

Lack of a tradition for conducting cost-effectiveness analyses before introducing new vaccines was identified
in a majority of EU/EEA Member States.
Sharing available health economic models of rotavirus vaccination cost-effectiveness should be encouraged
so that they can be used in various settings in interested EU/EEA countries
Further impact studies in countries that have introduced rotavirus vaccines into their paediatric
immunisation programmes will enable comparison between the uncertain results obtained in the modelling
exercises to outcomes observed upon introduction.
18
VENICE III report on the current status of introduction of rotavirus vaccination into national immunisation programmes in
Europe, submitted to ECDC May 2016. In press but available upon request.
47
Table 10. Main assumptions and parameter values of cost-effectiveness studies conducted in the
EU/EEA on infant rotavirus vaccination – base case analysis
Country Author, year Perspective of Quality of Discount Nosocomial Vaccine Vaccine Vaccine
(reference) analysis1 life rates rotavirus efficacy coverage price
included disease against (%) (full series)
infections severe forms
included of rotavirus
disease
Belgium Bilcke et al 2008 HCP/societal Yes Cost: 3% Yes 96% to 100% 98 EUR 111
(158) Effect: 1.5% + waning rate
England & Jit et al 2007 (283) HCP/societal Yes Cost:3.5% Yes 94 % 95 GBP 70/75
Wales (in sensit. Effect: 3,5% ( EUR
analysis) (3% after 30 102/110)
years)
UK (1) Lorgelly et al 2008 HCP/societal No Cost: 3.5% No 92 % 91 GBP 60 (EUR
(168) Effect: 3.5 88)
%
UK (2) Martin et al 2009 HCP/societal Yes Cost: 3.5% Yes 100% year 1 88 GBP 83.76
(284) Effect: 3.5 92,2 % year 2 (EUR 122)
%
Finland Salo et al 2007 HCP/societal Yes Cost: 3% Yes (in 96% 100 EUR 79
(285) Effect: 3% sensitivity
analysis)
Finland Nohynek et al HCP/societal Yes - No 96% 100 EUR 79( RV1)
2009 (286) EUR 88.50
(RV5)
France (1) Melliez et al 2008 Societal (direct Yes Cost: 3% No 85 % 75 EUR 150
(287) costs) Effect: 3%
France (2) Standaert et al Societal (direct Yes Cost: 3% Yes 87% 85 EUR 114 (RV1)
2008 (288) costs) Effect: 1,5%
France (3) Yamin et al 2016 HCP/societal Yes Cost:4% Yes 62-65% first 2 75 EUR 115 (RV5)
(289) Effect: 2-4% years EUR 135 (RV5)
71-75% 10
years later
Germany Knoll et al 2013 HCP/Societal No Cost: 3% Yes 94% 87.5 EUR 102
(290)
Germany Aidelsburger et al HCP/societal Yes Cost:3% Yes 87% for 80 EUR 135
2014 (291) Effect: 3% Rotarix yr 2
92% for
RotaTeq yr 2
Ireland Tilson et al 2011 HCP/societal Yes Cost: 4% Yes 100% 90 EUR 100
(292) Effect: 4%
Italy Giammanco et al HCP/societal No Cost: 3 % No 85 % to 90 % 90 EUR 164.1
2009 (293) Effect: 3 % + waning rate EUR 65.6
(estimate used if
bought byNHS)
Netherlands Goossens et al Societal Yes Cost: 4% Yes 100 % 100 EUR 80/100
(1) 2008 (294) Effect: 1.5
%
Netherlands Zomer et al 2008 HCP /societal Yes Cost:4% Yes 84,7% to 97 EUR 135/138
(2) (295) Effect: 1.5% 94,5%
Netherlands Mangen et al 2010 HCP/societal Yes Cost: 4% Yes 88% 97 EUR 84(RV5)
(3) (296) Effect: 1.5% (RotaTeq) EUR 90(RV1)
92% (RotaRix)
Netherlands Rozenbaum et al Societal Yes Cost: 3.5% Yes 94.5% 95 EUR 75
(4) 2011 (297) Effect: 3.5%
Spain García-Basteiro et HCP No Cost: nd Yes 81.8-100% 96 EUR 187
(Catalonia) al 2011 (132) Effect: nd
Spain (Castilla Pérez-Rubio et al HCP/societal Yes Cost: 5% No 94% 100 EUR 139 (RV5)
y León) 2011 (298) Effect: 5% EUR 187.1
(RV1)
Spain Imaz et al 2014 HCP/Societal Yes Cost: 3% Yes 74% 96 EUR 133.5
(299) Effect: 3% (RV5)
1: HCP: healthcare payer, TP: third payer
48
Table 11. Main results of cost-effectiveness studies conducted in the EU/EEA of infant rotavirus
vaccination – base case analysis
Author, year
Country Main results
(reference)
Bilcke et al 2008 HCP: EUR 51 030 to EUR 65 767/QALY gained

Belgium
(158) Societal: EUR 7 572 to EUR 30 227 /QALY gained
HCP: GBP 61 000 to 79 900/QALY gained ( EUR 89 000 to EUR 116 600/QALY
England & Jit et al 2007 gained)
Wales (283) Societal: GBP 54 500 to GBP 74 000/QALY gained ( EUR 79 600 to
108 000/QALY gained)
Lorgelly et al 2008 HCP: GBP 177 212/life year saved
UK (1)
(168) ( EUR 258 700/life year saved)
Martin et al 2009 HCP: GBP 23 298/QALY gained ( EUR 34 015/QALY gained)
UK (2)
(284) Societal: GBP 11 459/QALY gained ( EUR 16 730/QALY gained)
HCP: EUR 20 359 to EUR 37 763 /QALY gained (base case)
Salo et al 2007 EUR 13 141 to EUR 26 678/QALY gained (incl. home treated and nosocomial
Finland
(285) cases)
Societal: cost saving to EUR 7 543/QALY gained
Nohynek et al
Finland HCP: RV1 25 218 EUR per QALY gained and RV5 45 199 per QALY gained
2009 (286)
Melliez et al 2008 Societal: EUR 138 690/QALY gained
France
(287) (EUR 298 000/life year saved)
Standaert et al
France Societal (direct costs): RV1 EUR 44 583 per QALY gained
2008 (288)
Yamin et al 2016
France Societal: RV5 dynamic model EUR 28 500, static model 34 000
(289)
Knoll et al 2013
Germany Cost per QALY not analysed
(290)
Aidelsburger et al HCP (Statutory health insurance): RV1 EUR 116 973 per QALY gained, RV5
Germany
2014 (291) EUR 142 732 per QALY gained
HCP: EUR 112 048/QALY gained (EUR 68,896/QALY gained if one caregiver
Tilson et al 2011
Ireland considered) Societal: EUR 72 736/QALY gained (EUR 43 916/QALY gained if
(292)
one caregiver considered)
Giammanco et al
Italy Cost per QALY not analysed
2009 (293)
Netherlands Goossens et al
Societal: EUR 21 900 to EUR 35 076/QALY gained
(1) 2008 (294)
Netherlands Zomer et al 2008 HCP: EUR 124 000/DALY prevented
(2) (295) Society: EUR 119 000/DALY prevented
TP: EUR 58 000/ DALY prevented (RV5); EUR 53 000/DALY prevented (RV1)
Netherlands Mangen et al 2010
Society: EUR 54 000/DALY prevented (RV5); EUR 49 000/DALY prevented
(3) (296)
(RV1)
Netherlands Rozenbaum et al
Societal: EUR 46 717/QALY gained; EUR 44 841/DALY prevented
(4) 2011 (297)
Spain García-Basteiro et
NA
(Catalonia) al 2011 (132)
Spain (Castilla Pérez-Rubio et al HCP: EUR 74 959/QALY gained (RV5); EUR 52,603/QALY gained (RV1)
y León) 2011 (298) Societal: EUR 45 624/QALY gained (RV5); EUR 23 435/QALY gained (RV1)
Imaz et al 2014 HCP: EUR 280 338/QALY gained
Spain
(299) Societal: EUR 210 167/QALY gained
QALY: quality adjusted life years

Exchange rates on 01/06/06: GBP 1 = EUR 1.46, USD 1 = EUR 0.78
49
Attitudes to rotavirus vaccination among parents and

healthcare workers
Knowledge and attitude towards rotavirus vaccination among parents and healthcare workers has rarely been
investigated in the EU/EEA. One study from the Netherlands addressing attitudes to rotavirus vaccination among
parents concluded that when deciding about vaccination against rotavirus, parents are mostly driven by the out-of-
pocket costs, vaccine effectiveness, protection duration, and frequency of severe side effects. The highest
vaccination coverage is expected for a vaccine with high effectiveness and protection duration that is implemented
within the current national immunisation programme context (301). Another study describing knowledge and
attitudes of public health residents (n=1 304) originating from five European countries (France, Italy, Portugal,
Spain and the United Kingdom) to immunisation programmes discussed self-reported knowledge on vaccines,
awareness of epidemics and prevention campaigns and attitudes towards vaccination (perceived importance)
(302). This group of healthcare workers in training will often be responsible for implementing and monitoring
immunisation programmes however around 25% of residents reported their own level of knowledge on vaccines to
be insufficient, with the lowest levels of knowledge in relation to the new vaccines: rotavirus, varicella, and HPV
vaccination for men. The authors of this study conclude that public health residents do not always feel sufficiently
educated to deal with vaccine-related issues and there is room for improvement.
The high vaccination coverage (60–90%) reported by EU/EEA countries that have initiated rotavirus vaccination is
an indirect indication of good acceptance, both among parents and healthcare workers (see Table 4).
Conclusions
A study from the Netherlands assessed parental attitudes to rotavirus vaccination and identified that vaccine
safety, effectiveness, duration of protection and whether the vaccine is offered free of charge were the most
important factors contributing whether they would vaccinate their children.
Limited information was identified addressing healthcare worker attitudes beyond a study among public
health residents and identified a need for further education.

Research addressing parental and healthcare worker attitudes towards rotavirus vaccination and other
vaccinations needs to be strengthened.
50
4. Options for monitoring and evaluating

impact of rotavirus vaccination
Building on the results obtained in the literature review, the experts identified options for monitoring and
evaluating the impact of rotavirus vaccination.
Information on efficacy, effectiveness and safety information for both RV1 and RV5 vaccines are available from
randomised clinical trials and from the initial phase of implementing the vaccines into routine paediatric vaccination
programmes in a number of countries in the Americas, Australia and Europe. However, information needs to be
collected systematically on long-term vaccine effectiveness, vaccine safety and possible rotavirus strain
replacement with clinical significance for continuous evidence-based benefit-risk assessments.
The main objective of vaccination against rotavirus in the paediatric immunisation programmes is to protect against
moderate-to-severe disease and thereby prevent hospitalisation and death. In addition, it is likely that consultancy
for moderate/severe rotavirus disease in emergency departments will be significantly reduced.
Preparing for rotavirus vaccine introduction

Before implementing rotavirus vaccination consideration should be given to how such a programme can be
prioritised within a wider public health context. It is therefore recommended that information is obtained on burden
of moderate-to-severe disease leading to hospitalisation and that circulating rotavirus genotypes are characterised.
Traditionally this has been done in epidemiological studies but another option is to establish routine or sentinel
surveillance systems for assessing burden of disease and circulating rotavirus strains. This may include:
development of a case definition for severe rotavirus disease;
establishment of universal or sentinel reporting of severe rotavirus disease leading to hospitalisation and/or
death;
establishment of sampling frames and genotyping methods which provide representative and comparable
data within each country and possibly across countries;
Furthermore, it is becoming more common for cost-effectiveness analyses to be required in the decision-making
process for introduction of new vaccines.
Monitoring impact of rotavirus vaccine programmes

Vaccine exposure/coverage
It advisable to collect individual exposure data, including:
name
gender
date of birth of infant
date of vaccination
which rotavirus vaccine was provided, including batch number
which dose in the series was administered.
It should also be ensured that rotavirus vaccines are administered timely in line with national vaccine programme
recommendations, particularly important for rotavirus vaccines to mitigate risk of intussusception, and that overall
vaccine coverage is monitored.
Monitoring of rotavirus vaccine safety

It should be considered to collect data on country-specific background incidence rate of intussusception to
facilitate observed-versus-expected assessment of reported intussusception cases, if needed.
Should intussusception cases occur, it should be ensured that vaccinators and healthcare workers responsible
for treatment of affected children report all the relevant information needed for regulatory, public health
agencies or market authorisation holders to assess the individual case in line with national and international
requirements (see checklist of information needed in Annex 3). In addition to the individual exposure data
mentioned above, the following information is suggested: date of onset of symptoms suggestive of
intussusception; detailed description of clinical symptoms and possible complications; detailed description of
diagnosis confirmation with radiology and/or ultrasound; treatments needed to resolve the intussusception
(date of interventions and, if several interventions were needed, dates for each one), and the final outcome
including any residual sequelae in each affected infant. It is most helpful for assessors if a copy of the
discharge note from the hospital stay is attached to the case report.
51
Monitoring of short-term rotavirus vaccine effectiveness

The second generation rotavirus vaccines will not induce sterilising immunity. Therefore rotaviruses will continue to
circulate in European populations and are expected to provide natural boosters to vaccinated individuals
throughout life. However, circulating viruses may reassort and new emerging strains may be imported, making it
essential to monitor rotavirus strains. Methods to assess the impact of rotavirus vaccines and the immunisation
programmes implemented in European settings at clinically-relevant disease endpoints may include the following
elements:
monitoring reduction in hospitalisations for rotavirus disease
monitoring reduction in number of laboratory samples sent for rotavirus diagnosis
sentinel surveillance of circulating rotavirus strains, including samples for genotyping from possible
breakthrough infections (breakthrough infections will occur since the vaccine does not provide 100%
protection and increases or clusters of breakthrough infections should be monitored)
specifically-designed impact studies (ECDC protocols available for case-control, cohort and impact studies.)19
When evaluating reduction in hospitalisation, historical controls are often useful, especially in countries that are
able to achieve high immunisation coverage from the initial phase of the routine programme.
Upon introduction of rotavirus vaccines in infants, it is expected that there will be a gradual reduction in the
number of children hospitalised with severe rotavirus disease, as follows:
first season - reduction expected in children aged 2–3 to 6 months
second season - reduction expected in children aged 2–3 to <12 months, perhaps also in the age group 12–
24 months
third season - reduction expected in children aged 2–3 to 24 months, perhaps also in the age group > 24
months.
A potential shift of the disease pattern to affect mainly older age groups (increased proportion of older children),
however likely not in any high numbers, ineligible for vaccination will naturally be seen during the initial phase but,
if the vaccines provide long-term protection as well as herd protection, this is expected to subside within four to
five years. It is common that epidemiological incidence monitoring is being done using the following age categories
< 1 year, < 2 years, < 5 years, 5-14 years, 15-49 years, >50 years.
Monitoring of long-term rotavirus vaccine effectiveness

In order to survey vaccine effectiveness in the long-term it is essential to use appropriate population-based
sampling procedures among vaccinated and unvaccinated individuals. Routine surveillance of hospitalised cases
caused by rotaviruses is encouraged. It is particularly important to test suspected rotavirus disease in fully
immunised children to monitor possible rotavirus strain replacement.
19
Three generic study protocols for rotavirus vaccine effectiveness and impact studies using different methodologies are available
on the ECDC website: http://ecdc.europa.eu/en/press/news/_layouts/forms/News_DispForm.aspx?ID=82&List=8db7286c-fe2d-
476c-9133-18ff4cb1b568
52
5. Conclusions and possible implications for

public health practice and research
Burden of disease studies assessing severe rotavirus disease leading to hospitalisation conducted in eighteen
EU/EEA countries before rotavirus vaccine introduction suggest that there are around 75 000–150 000
hospitalisations in children under five years annually, although mortality is low. Two rotavirus vaccines for use in
routine immunisation programmes have been authorised for prevention of RVGE and shown, in a series of studies,
to be effective in preventing hospitalisation. Vaccine effectiveness against rotavirus-related hospitalisation ranges
between 85–90% in countries with low mortality due to rotavirus disease (all EU/EEA countries are categorised as
low-mortality countries). Furthermore, herd protection contributes to the overall impact of vaccination
programmes. A risk of up to six additional intussusception cases per 100 000 vaccinated infants has been identified
for both rotavirus vaccines. Benefit-risk has been assessed by many regulatory agencies throughout the world
(including EU EMA, US FDA, and Australian TGA) and was found to be positive, given the severity of rotavirus
disease and availability of treatment for cases of intussusception. However, options for risk minimisation with the
current vaccines should be explored. It is important for parents and healthcare workers to be vigilant to ensure
that affected infants are promptly cared for, as recommended in the EU/EEA SPC. Research should be undertaken
to further reduce this risk, for example by developing new rotavirus vaccines. Finally, available health economic
models of cost-effectiveness for rotavirus vaccination should be shared so that they can be used by those EU/EEA
countries interested.
The expert panel suggests the following set of data and monitoring to be considered at the EU-level and in EU/EEA
Member States before and after introduction of rotavirus vaccine into a routine programme:
consider developing a case-definition for severe rotavirus disease relevant for disease surveillance and
epidemiological studies suitable to assess burden of disease and impact of implemented rotavirus
immunisation programmes;
consider organising case-based EU-wide, country-wide or sentinel surveillance of severe rotavirus disease
leading to hospitalisation and/or death before and after vaccine introduction;
consider investigating suspected and reported laboratory-confirmed rotavirus disease cases including
breakthrough infections, if observed number of cases exceeds the expected, in fully vaccinated individuals
(including genotyping and sequencing of causing rotavirus strain);
consider organising virological surveillance in a statistically sound and geographically representative sample of
circulating RV strains;
consider collecting data on individual rotavirus vaccine exposure (including age and batch number) and
overall rotavirus vaccine coverage;
consider compiling country-specific background incidence rates of intussusception (by month of age during
the first year of life) in additional EU/EEA Member States since geographical differences have been observed;
assess long-term impact (including monitoring for strain replacement, vaccine effectiveness and safety) of
rotavirus vaccines used in immunisation programmes from a statistically sound and geographically
representative sample within the EU/EEA.
53
6. Strengths of methodology used in this

expert opinion
The evidence for this report was collected using different methods: a literature review in PubMed, Embase and
Cochrane databases, referrals to additional literature identified by a panel of experts, AF members and public
consultation, as well as information on spontaneously reported cases of intussusception from the EMA
Eudravigilance database.
Meta-analyses of rotavirus vaccine efficacy and effectiveness data are provided. Further, meta-analysis data on
burden of nosocomial rotavirus disease and herd protection following rotavirus vaccination are presented
The opinion provided is based on scientific evidence identified in the literature review, the opinions of a group of
independent EU/EEA public health experts reviewing the evidence and discussions and the adoption of the ECDC
Advisory Forum.
7. Limitations of methodology used in this

expert opinion
The literature search was limited to publications released until February 2014. The additional literature provided by
the experts and the public consultation procedure proved useful as it allowed the inclusion of relevant evidence
that was published later and would have otherwise been omitted.
Although the literature search was made according to standards for a systematic review with meta-analysis, the
evaluation was conducted with less resources than recommended for a systematic review. Furthermore, it was not
possible to grade the quality of evidence.
Additional limitations are that cases reported spontaneously to the EMA Eudravigilance database could not be
confirmed by chart review due to national data protection laws and there was no reliable denominator of
vaccinated infants for rate calculations and no adjustment for under- or over-reporting.
8. Next steps
The final Expert Opinion with the scientific advice contained in this document will be disseminated by ECDC
through the European Commission’s Directorate General for Health and Food Safety (SANTE), the Health Security
Committee, the ECDC Advisory Forum and the ECDC Vaccine Advisory Group (EVAG). The document will also be
published on the ECDC website along with the comments/suggested edits provided by external stakeholders in the
public consultation phase and assessment by ECDC and possible implemented change to the Expert Opinion.
9. Expert opinion update

Should new information relevant to public health and the use of rotavirus vaccines in immunisation programmes in
the EU/EEA become available, this expert opinion will be updated.
54
10. Annexes
Annex 1. Rotavirus disease severity scales used in clinical
trials
Availability of objective clinical severity scales for assessing the disease is important for vaccine efficacy and
effectiveness studies. The two severity scales, the Vesikari 20-point scale and the Clark 24-point scale, used to
assess rotavirus gastroenteritis in clinical trials differ and have recently been compared (Table A1) (303)]. A
comparison of the severity assessment results revealed that more than 50% of the cases defined as severe by the
Vesikari scale were defined as moderate (63%) and mild (2%) by the Clark scale. Furthermore, 19% defined as
mild by the Clark scale were defined as severe by the Vesikari scale. It was also impossible to analyse the results
from the two severity scales statistically because the distribution categories were not even; the Clark scale is
divided into three ranges (<9, 9-16 and >16), while the Vesikari scale is divided into two ranges (<11 and >11).
The authors attempted to further divide the children in the study by creating three categories using the Vesikari
scale. This improved the correlation between the two scales but still did not achieve a high correlation, since only
55% of those with a scoring of >15 in the Vesikari scale were defined as severe by the Clark scale. The authors
concluded that future rotavirus vaccine trials should use only one severity scale for uniformity, or use clinical
parameters fitting to both the Clark and Vesikari scales, enabling the calculation of both severity scores. This would
facilitate the interpretation of efficacy/effectiveness results and comparisons between current and future rotavirus
vaccines.
Table A1. Overview of the Clark 24-point and the Vesikari 20-point severity scoring scales used in the
efficacy trials
Point values
1 2 3
Clark scale (ref)
Diarrhoea
Number of stools/day 2-4 5-7 >8
Duration in days 1-4 5-7 >8
Vomiting
Number of emeses/day 1-3 4-6 >7
Duration in days 2 3-5 >6
Rectal temperature
Temperature (C°) 38.1-38.2 38.3-38.7 >38.8
Behavioural symptoms/ signs
Description Irritable/less playful Lethargic/listless Seizure
Vesikari scale (ref)
Duration of diarrhoea (days) 1-4 5 >6
Maximum number of diarrhoea stools/24h 1-3 4-5 >6
Duration of vomiting (days) 1 2 >3
Maximum number of vomiting episodes/24h 1 2-4 >5
Temperature (C°) 37.1-38.4 38.5-38.9 >39.0
Dehydration - Mild Moderate to severe
Treatment Rehydration Hospitalisation -
According to the Vesikari scale, an episode of gastroenteritis with a score of >11 is considered severe, while the Clark scale
considers an episode with a score 9–16 as moderate to severe and an episode with a score of >16 as severe.
55
Annex 2. Brighton collaboration diagnostic criteria for

intussusception
Diagnostic certainty (105)
Level 1 • Surgical criteria – demonstration of invagination of the intestine at surgery

• Radiological criteria – demonstration of invagination of the intestine by air
or barium contrast enema or intra-abdominal mass, demonstrated by
ultrasound that is proven to be reduced by enema on post-reduction
ultrasound.
Level 2 • Two major or one major and three minor criteria (see below)
Level 3 • Four or more minor criteria (see below)
Major criteria Minor criteria
Evidence of intestinal obstruction Age <1 year

• History of bile-stained vomiting Male sex
• Abdominal distension or no bowel sounds Abdominal pain
• Radiograph showing fluid levels and dilated bowel loops Vomiting
Features of intestinal invagination Lethargy
• Abdominal mass or rectal mass or intestinal prolapse or Pallor
radiographs/ultrasound showing a visible intussusceptum or soft Hypovolemic shock
tissue mass. Radiograph showing abnormal but non-
Evidence of intestinal vascular compromise or venous congestions specific bowel-gas pattern.
• Passage of blood per rectum or blood detected on rectal
examination or passage of stool containing ‘red currant jelly’
material.
56
Annex 3. Checklist for vaccinators submitting

intussusception ADR reports
The following information will be helpful for assessors of ADR reports:
Date of birth
Gender of infant
Vaccine provided, including batch number
Vaccine dose number in series provided
Date of vaccination
Date of onset of symptoms suggestive of intussusception
Intussusception confirmed by radiology or surgery
Date of first treatment, please specify treatment (e.g. barium/air enema or surgery)
Date of second treatment if needed, please specify treatment (e.g. barium/air enema or surgery)
Other treatments provided
Clinical complications observed, please specify complications
Need for intensive care
Any sequelae (including if and how much intestinal resection was needed)?
Length and dates of hospitalisation
Copy of discharge note
Copy of confirmatory radiology/ultrasound test and, if available, surgical report.
57
Annex 4. Overview of literature search strategies and results

IDENTIFICATION RECORDS IDENTIFIED THROUGH DATABASE
SEARCHING
Rotavirus burden/outbreaks in EU/EEA
Embase 352
Pubmed 260
388 records after duplicates removed
Rotavirus vaccines
Embase 1259
Pubmed 931
Cochrane Library. Cochrane reviews 3
Cochrane Library. Other reviews 5
Cochrane Library. Trials 183
Cochrane Library. Technology assessments 4
Herd immunity induced by vaccination
Embase 59
Pubmed 41
Economic evaluations of rotavirus vaccination
Embase 892
Pubmed 720
Cochrane Library. Economic Evaluations 84
NHS EED 88
Attitudes to rotavirus vaccination
Embase 188
Pubmed 38
194 records after duplicates
EXCLUDED RECORDS
removed Burden: 313
Vaccines: 1468
Herd immunity: 29
Economic: 929
TITLE/ABSTRACT SCREENING Attitudes: 175
FULL PAPERS/REPORTS ORDERED
TOTAL: 2914 excluded records
Burden: 75
Vaccines: 107
Herd immunity: 41
Economic: 61
Attitudes: 19
TOTAL: 303
EXCLUDED RECORDS
Burden: 20
Vaccines: 16
Herd immunity: 6
FULL PAPERS/REPORTS ASSESSED Economic: 44
Burden: 55 Attitudes: 175
Vaccines: 91 TOTAL: 261
Herd immunity: 35
FULL PAPER/REPORT SCREENING Economic: 19
Attitudes: 20
EXCLUDED RECORDS
TOTAL: 220
Burden: 9
Vaccines: 5
Herd immunity: 6
INCLUDED STUDIES Economic: 2
Burden: 46 Attitudes: 16
Vaccines: 86 TOTAL: 38
Herd immunity: 29 TOTAL:
Economic: 17
Attitudes: 3
TOTAL: 181
58
Annex 5. Search strategies by topic for rotavirus expert

opinion
Rotavirus burden of disease/outbreaks in Europe
Pubmed
#1 "Rotavirus Infections"[Mesh] OR "Rotavirus"[Mesh] OR rotavirus[tiab] OR rotaviruses[tiab] OR "rota virus"[tiab]
#2 "Disease Outbreaks"[Mesh] OR outbreak[tiab] OR outbreak*[tiab] OR epidemics[tiab] OR epidemic[tiab] OR
surveillance[tiab] OR "Communicable Diseases/epidemiology"[Mesh] OR "Communicable Diseases,
Emerging"[Mesh]
#3 "Europe"[Mesh] OR "European Union"[Mesh] OR Europe[tiab] OR (Europe*[tiab] AND (union[tiab] OR
community[tiab])) OR EU[tiab] OR Austria*[tiab] OR vienn*[tiab] OR austro*[tiab]) OR Belgium[tiab] OR
Belgian*[tiab] OR Brussels[tiab] OR Antwerp*[tiab] OR ghent*[tiab] OR Bulgaria*[tiab] OR sofia[tiab] OR
Cyprus[tiab] OR Cypriot*[tiab] OR Lefkosia[tiab] OR Nicosia[tiab] OR Czech*[tiab] OR prague[tiab] OR praha[tiab]
OR Denmark[tiab] OR Danish[tiab] OR copenhagen[tiab] OR Aarhus[tiab] OR Estonia*[tiab] OR Tallinn[tiab] OR
finland[tiab] OR finnish[tiab] OR finns[tiab] OR finn[tiab] OR Helsinki[tiab] OR france [tiab] OR French[tiab] OR
paris[tiab] OR Marseille[tiab] OR lyon[tiab] OR Toulouse[tiab] OR nantes OR Strasbourg OR lille OR Germany OR
german*[tiab] OR berlin*[tiab] OR hamburg[tiab] OR munich[tiab] OR munchen[tiab] OR cologne[tiab] OR
koln[tiab] OR Frankfurt[tiab] OR Stuttgart[tiab] OR dusseldorf[tiab] OR Greece[tiab] OR greek*[tiab] OR
Athens[tiab] OR Athenian[tiab] OR Thessaloniki[tiab] OR hungary[tiab] OR Hungarian*[tiab] OR Budapest[tiab] OR
Ireland[tiab] OR irish[tiab] OR eire[tiab] OR Dublin*[tiab] OR Italy[tiab] OR Italian*[tiab] OR rome[tiab] OR
roman[tiab] OR Milan[tiab] OR naples[tiab] OR turin[tiab] OR Latvia*[tiab] OR riga[tiab] OR lithuania*[tiab] OR
Vilnius[tiab] OR Luxembourg*[tiab] OR luxemburg*[tiab] OR malta[tiab] OR maltese[tiab] OR Mdina[tiab] OR
Notabile[tiab] OR Imdina[tiab] OR netherland*[tiab] OR Holland[tiab] OR dutch[tiab] OR Amsterdam[tiab] OR
Rotterdam[tiab] OR hague[tiab] OR Utrecht[tiab] OR Eindhoven[tiab] OR polish[tiab] OR Poland[tiab] OR
warsaw[tiab] OR Krakow[tiab] OR lodz[tiab] OR Wroclaw [tiab]OR Portuguese*[tiab] OR Portugal[tiab] OR
Lisbon[tiab] OR porto[tiab] OR Romania*[tiab] OR Bucharest[tiab] OR Slovakia*[tiab] OR Bratislava[tiab] OR
pozsony[tiab] OR slovenia*[tiab] OR Ljubljana[tiab] OR Spanish[tiab] OR spain[tiab] OR Madrid[tiab] OR
Barcelona[tiab] OR Valencia[tiab] OR Seville[tiab] OR Zaragoza[tiab] OR Malaga[tiab] OR Mallorca[tiab] OR
iberia*[tiab] OR iberica[tiab] OR Swedish[tiab] OR Sweden[tiab] OR swede*[tiab] OR Stockholm[tiab] OR
norland[tiab] OR svealand[tiab] OR gotaland[tiab] OR Britain[tiab] OR british[tiab] OR wales[tiab] OR welsh[tiab]
OR Scottish[tiab] OR scots[tiab] OR Scotland[tiab] OR England[tiab] OR English[tiab] OR Birmingham[tiab] OR
leeds[tiab] OR London[tiab] OR Liverpool[tiab] OR Manchester[tiab] OR Glasgow[tiab] OR Edinburgh[tiab] OR
Cardiff[tiab] OR Belfast[tiab] OR UK[tiab] OR GB[tiab] OR Aberdeen[tiab] OR "United Kingdom"[tiab] OR
Croatia*[tiab] OR Zagreb[tiab]
#4 #1 AND #2 AND #3
#5 "Animals"[Mesh] NOT "Humans"[Mesh]
#6 #4 NOT #5
Limits: English, date from 1995
Embase
#1 'Rotavirus infection'/exp OR 'Rotavirus'/exp OR rotavirus:ti,ab OR rotaviruses:ti,ab OR 'rota virus':ti,ab
#2 'disease surveillance'/exp OR 'epidemic'/exp OR outbreak:ab,ti OR outbreaks:ab,ti OR surveillance:ab,ti OR
epidemic:ab,ti OR epidemics:ab,ti OR 'communicable disease'/exp/dm_ep
#3 'European Union'/exp OR 'Europe'/exp OR Europe:ab,ti OR (Europe*:ab,ti AND (union:ab,ti OR
community:ab,ti)) OR EU:ab,ti OR Austria*:ab,ti OR vienn*:ab,ti OR austro*:ab,ti OR Belgium:ab,ti OR
Belgian*:ab,ti OR Brussels:ab,ti OR Antwerp*:ab,ti OR ghent*:ab,ti OR Bulgaria*:ab,ti OR sofia:ab,ti OR
Cyprus:ab,ti OR Cypriot*:ab,ti OR Lefkosia:ab,ti OR Nicosia:ab,ti OR Czech*:ab,ti OR prague:ab,ti OR praha:ab,ti
OR Denmark:ab,ti OR Danish:ab,ti OR copenhagen:ab,ti OR Aarhus:ab,ti OR Estonia*:ab,ti OR Tallinn:ab,ti OR
finland:ab,ti OR finnish:ab,ti OR finns:ab,ti OR finn:ab,ti OR Helsinki:ab,ti OR france:ab,ti OR French:ab,ti OR
paris:ab,ti OR Marseille:ab,ti OR lyon:ab,ti OR Toulouse:ab,ti OR nantes OR Strasbourg OR lille OR Germany OR
german*:ab,ti OR berlin*:ab,ti OR hamburg:ab,ti OR munich:ab,ti OR munchen:ab,ti OR cologne:ab,ti OR
koln:ab,ti OR Frankfurt:ab,ti OR Stuttgart:ab,ti OR dusseldorf:ab,ti OR Greece:ab,ti OR greek*:ab,ti OR Athens:ab,ti
OR Athenian:ab,ti OR Thessaloniki:ab,ti OR hungary:ab,ti OR Hungarian*:ab,ti OR Budapest:ab,ti OR Ireland:ab,ti
OR irish:ab,ti OR eire:ab,ti OR Dublin*:ab,ti OR Italy:ab,ti OR Italian*:ab,ti OR rome:ab,ti OR roman:ab,ti OR
Milan:ab,ti OR naples:ab,ti OR turin:ab,ti OR Latvia*:ab,ti OR riga:ab,ti OR lithuania*:ab,ti OR Vilnius:ab,ti OR
Luxembourg*:ab,ti OR luxemburg*:ab,ti OR malta:ab,ti OR maltese:ab,ti OR Mdina:ab,ti OR Notabile:ab,ti OR
Imdina:ab,ti OR netherland*:ab,ti OR Holland:ab,ti OR dutch:ab,ti OR Amsterdam:ab,ti OR Rotterdam:ab,ti OR
hague:ab,ti OR Utrecht:ab,ti OR Eindhoven:ab,ti OR polish:ab,ti OR Poland:ab,ti OR warsaw:ab,ti OR Krakow:ab,ti
OR lodz:ab,ti OR Wroclaw:ab,ti OR Portuguese*:ab,ti OR Portugal:ab,ti OR Lisbon:ab,ti OR porto:ab,ti OR
Romania*:ab,ti OR Bucharest:ab,ti OR Slovakia*:ab,ti OR Bratislava:ab,ti OR pozsony:ab,ti OR slovenia*:ab,ti OR
59
Ljubljana:ab,ti OR Spanish:ab,ti OR spain:ab,ti OR Madrid:ab,ti OR Barcelona:ab,ti OR Valencia:ab,ti OR

Seville:ab,ti OR Zaragoza:ab,ti OR Malaga:ab,ti OR Mallorca:ab,ti OR iberia*:ab,ti OR iberica:ab,ti OR Swedish:ab,ti
OR Sweden:ab,ti OR swede*:ab,ti OR Stockholm:ab,ti OR norland:ab,ti OR svealand:ab,ti OR gotaland:ab,ti OR
Britain:ab,ti OR british:ab,ti OR wales:ab,ti OR welsh:ab,ti OR Scottish:ab,ti OR scots:ab,ti OR Scotland:ab,ti OR
England:ab,ti OR English:ab,ti OR Birmingham:ab,ti OR leeds:ab,ti OR London:ab,ti OR Liverpool:ab,ti OR
Manchester:ab,ti OR Glasgow:ab,ti OR Edinburgh:ab,ti OR Cardiff:ab,ti OR Belfast:ab,ti OR UK:ab,ti OR GB:ab,ti OR
Aberdeen:ab,ti OR 'United Kingdom':ab,ti OR Croatia*:ti,ab OR Zagreb:ti,ab OR (Schengen:ti,ab AND ('geographic
names'/exp OR (geographic:ti,ab AND (locations:ti,ab OR names:ti,ab)) OR 'geographic locations':ti,ab OR
'area':ti,ab))
#4 #1 AND #2 AND #3
#5 'animal'/exp NOT 'human'/exp
#6 #4 NOT #5
Limits: English, date from 1995, Embase
Vaccines: immunogenicity, safety, efficacy, effectiveness, risk benefit

studies, intussusception, Kawasakis disease
Pubmed
#1 (("Rotavirus Infections"[Mesh] OR "Rotavirus"[Mesh] OR rotavirus[tiab] OR rotaviruses[tiab] OR "rota
virus"[tiab]) AND ("Vaccination"[Mesh] OR "Vaccines"[Mesh] OR vaccine*[tiab] OR vaccination*[tiab] OR
immunization*[tiab] OR "Immunization"[Mesh] OR immunisation*[tiab] OR "Viral Vaccines"[Mesh])) OR "Rotavirus
Vaccines"[Mesh] OR "RIX4414 vaccine"[Supplementary Concept] OR "RotaTeq" [Supplementary Concept] OR
"rhesus rotavirus vaccine" [Supplementary Concept] OR "rotavirus vaccine 89-12" [Supplementary Concept] OR
rotarix[tiab] OR rotateq[tiab] OR Rotashield[tiab] OR "RIX4414 vaccine"[tiab] OR "RIX4414 vaccines"[tiab]
#2 "adverse effect"[tiab] OR "adverse effects"[tw] OR "side effects"[tiab] OR "side effect"[tiab] OR "adverse
reaction"[tiab] OR "adverse reactions"[tiab] OR "undesirable effects"[tiab] OR "undesirable effect"[tiab] OR
"injurious effect"[tiab] OR "Injurious effects"[tiab] OR "complication"[tiab] OR complications[tiab] OR
immunology[tw] OR pharmacology[tw] OR immunogenicity[tiab] OR toxicity[Tiab] OR toxicities[tiab] OR toxic[tiab]
OR contraindicat*[tw] OR hazard*[tiab] OR harm[tiab] OR danger[tiab] OR dangers[tiab] OR dangerous[tiab] OR
poisoning[tiab] OR safe[tiab] OR safety[tiab] OR safely[tiab] OR intussusceptions[tiab] OR "Intussusception"[Mesh]
OR Intussusception[tiab] OR "Treatment Outcome"[Mesh] OR efficacy[tiab] OR effective[tiab] OR
effectiveness[tiab] OR effectivity[tiab] OR efficiency[tiab] OR risk[tiab] OR risks[tiab] OR benefit[tiab] OR
benefits[tiab] OR "therapeutic use"[tw] OR unfavorable[tiab]
#3 "Practice Guideline" [Publication Type] OR "Practice Guidelines as Topic"[Mesh] OR "Guideline" [Publication
Type] OR "Practice Guideline"[tiab] OR "Practice Guidelines"[tiab] OR "practice parameter"[tiab] OR "practice
parameters"[tiab] OR guideline[tiab] OR guidelines[tiab] OR consensus[ti] OR recommendation[ti] OR
recommendations[ti] OR "Consensus Development Conference" [Publication Type] OR "Randomized Controlled
Trial"[Publication Type] OR "Controlled Clinical Trial"[Publication Type] OR randomized[tiab] OR placebo[tiab] OR
randomly[tiab] OR trial[ti] OR "Clinical Trials as Topic"[Mesh] OR "Case-Control Studies"[Mesh] OR (case[tiab]
control[tiab]) OR "Cohort Studies"[Mesh] OR (cohort[tiab] AND (study[tiab] OR studies[tiab])) OR (cohort[tiab]
analys*[tiab]) OR (follow*up[tiab] AND (sudy[tiab] OR studies[tiab])) OR (observational[tiab] AND (study[tiab] OR
studies[tiab])) OR longitudinal[tiab] OR retrospective[tiab] OR "Cross-Sectional Studies"[Mesh] OR (cross[tiab]
sectional[tiab]) OR "Meta-Analysis as Topic"[Mesh] OR "meta analysis"[tiab] OR "meta analyses"[tiab] OR
metaanal*[tiab] OR "Meta-Analysis"[Publication Type] OR (systematic[tiab] AND (review*[tiab] OR overview[tiab]))
OR "Review Literature as Topic"[Mesh] OR "Review"[Publication Type] OR review[ti] OR "systematic"[sb]
#4 #1 AND #2 AND #3
#5 "Animals"[Mesh] NOT "Humans"[Mesh]
#6 #4 NOT #5
Embase
#1 (('Rotavirus infection'/exp OR 'Rotavirus'/exp OR rotavirus:ti,ab OR rotaviruses:ti,ab OR 'rota virus':ti,ab) AND
('vaccination'/de OR 'vaccine'/exp OR vaccine*:ti,ab OR vaccination*:ti,ab OR immunization*:ti,ab OR
'immunization'/exp OR immunisation*:ti,ab OR 'virus vaccine'/exp)) OR 'Rotavirus vaccine'/exp OR rotarix:ti,ab OR
rotateq:ti,ab OR Rotashield:ti,ab OR 'RIX4414 vaccine':ti,ab OR 'RIX4414 vaccines':ti,ab
#2 'adverse drug reaction'/exp OR 'adverse effect':ti,ab OR 'adverse effects':ti,ab OR 'side effects':ti,ab OR 'side
effect':ti,ab OR 'adverse reaction':ti,ab OR 'adverse reactions':ti,ab OR 'undesirable effects':ti,ab OR 'undesirable
effect':ti,ab OR 'injurious effect':ti,ab OR 'Injurious effects':ti,ab OR 'complication':ti,ab OR complications:ti,ab OR
'immunology'/exp OR immunology:ti,ab OR 'pharmacology'/exp OR pharmacology:ti,ab OR immunogenicity:ti,ab
OR toxicity:ti,ab OR toxicities:ti,ab OR toxic:ti,ab OR contraindicat*:ti,ab OR hazard*:ti,ab OR harm:ti,ab OR
danger:ti,ab OR dangers:ti,ab OR dangerous:ti,ab OR poisoning:ti,ab OR 'safety'/exp OR safe:ti,ab OR safety:ti,ab
60
OR safely:ti,ab OR intussusceptions:ti,ab OR 'intussusception'/exp OR Intussusception:ti,ab OR 'treatment

outcome'/exp OR 'drug efficacy'/exp OR efficacy:ti,ab OR effective:ti,ab OR effectiveness:ti,ab OR effectivity:ti,ab
OR efficiency:ti,ab OR 'risk'/exp OR 'risk benefit analysis'/exp OR risk:ti,ab OR risks:ti,ab OR benefit:ti,ab OR
benefits:ti,ab OR 'therapeutic use':ti,ab OR unfavorable:ti,ab
#3 'practice guideline'/exp OR 'Practice Guideline':ti,ab OR 'Practice Guidelines':ti,ab OR 'practice parameter':ti,ab
OR 'practice parameters':ti,ab OR guideline:ti,ab OR guidelines:ti,ab OR consensus:ti OR recommendation:ti OR
recommendations:ti OR 'consensus development'/exp OR 'randomized controlled trial'/exp OR 'controlled clinical
trial'/exp OR randomized:ti,ab OR placebo:ti,ab OR randomly:ti,ab OR trial:ti OR 'clinical trial (topic)'/exp OR 'case
control study'/exp OR (case NEAR/3 control):ab,ti OR 'cohort analysis'/exp OR (cohort NEAR/3 (study OR
studies)):ab,ti OR (cohort:ab,ti AND analys*:ab,ti) OR (follow*up NEAR/3 (study OR studies)):ab,ti OR
(observational NEAR/3 (study OR studies)):ab,ti OR longitudinal:ab,ti OR retrospective:ab,ti OR 'cross-sectional
study'/exp OR (cross:ab,ti AND sectional:ab,ti) OR 'meta analysis'/exp OR 'meta analysis':ti,ab OR 'meta
analyses':ti,ab OR metaanal*:ti,ab OR 'systematic review'/exp OR (systematic NEAR/3 (review* OR overview)):ti,ab
OR 'systematic review (topic)'/exp OR 'review'/exp OR review:ti
#4 #1 AND #2 AND #3
#5 'animal'/exp NOT 'human'/exp
#6 #4 NOT #5
Limits: English, date from 1995 , Embase
Cochrane Library (Cochrane systematic reviews, other reviews, clinical trials)

#1 MeSH descriptor: [Rotavirus Infections] explode all trees
#2 MeSH descriptor: [Rotavirus] explode all trees
#3 rotavirus:ti,ab,kw or rotaviruses:ti,ab,kw or "rota virus":ti,ab,kw
#4 #1 or #2 or #3
#5 MeSH descriptor: [Vaccinnes] explode all trees
#6 MeSH descriptor: [Immunization] explode all trees
#7 vaccine*:ti,ab,kw or vaccination*:ti,ab,kw or immunization*:ti,ab,kw or immunisation*:ti,ab, kw
#8 #5 or #6 or #7
#9 MeSH descriptor: [Rotavirus Vaccines] explode all trees
#10 rotarix:ti,ab,kw or rotateq:ti,ab,kw or Rotashield:ti,ab,kw or "RIX4414 vaccine":ti,ab,kw or "RIX4414
vaccines":ti,ab,kw
#11 #10 or #9
#12 #4 and #8
#13 #11 or #12
Limits: EnglisH, date from 1995
Herd immunity
Pubmed
virus"[tiab]) AND ("Vaccination"[Mesh] OR "Vaccines"[Mesh] OR Vaccine*[tiab] OR vaccine*[tiab] OR
vaccination*[tiab] OR immunization*[tiab] OR "Viral Vaccines"[Mesh])) OR "Rotavirus Vaccines"[Mesh] OR
"RIX4414 vaccine"[Supplementary Concept] OR "RotaTeq" [Supplementary Concept] OR "rhesus rotavirus vaccine"
[Supplementary Concept] OR "rotavirus vaccine 89-12" [Supplementary Concept] OR rotarix[tiab] OR rotateq[tiab]
OR Rotashield[tiab] OR "RIX4414 vaccine"[tiab] OR "RIX4414 vaccines"[tiab]
#2 "herd immunity"[tiab] OR "Immunity, Herd"[Mesh]
#3 #1 AND #2
Embase
#1 (('Rotavirus infection'/exp OR 'Rotavirus'/exp OR rotavirus:ti,ab OR rotaviruses:ti,ab OR 'rota virus':ti,ab) AND
('vaccination'/de OR 'vaccine'/exp OR vaccine*:ti,ab OR vaccination*:ti,ab OR immunization*:ti,ab OR 'virus
vaccine'/exp)) OR 'Rotavirus vaccine'/exp OR rotarix:ti,ab OR rotateq:ti,ab OR Rotashield:ti,ab OR 'RIX4414
vaccine':ti,ab OR 'RIX4414 vaccines':ti,ab
#2 'herd immunity'/exp OR 'herd immunity':ab,ti
#3 #1 AND #2
61
Cost benefit analysis/burden

Pubmed
immunization*[tiab] OR "Viral Vaccines"[Mesh])) OR "Rotavirus Vaccines"[Mesh] OR "RIX4414
vaccine"[Supplementary Concept] OR "RotaTeq" [Supplementary Concept] OR "rhesus rotavirus vaccine"
[Supplementary Concept] OR "rotavirus vaccine 89-12" [Supplementary Concept] OR rotarix[tiab] OR rotateq[tiab]
OR Rotashield[tiab] OR "RIX4414 vaccine"[tiab] OR "RIX4414 vaccines"[tiab]
#2 Costs and Cost Analysis"[Mesh] OR ec[sh] OR "Economics"[Mesh] OR Cost[tiab] OR costs[tiab] OR
economic*[tiab] OR costly[tiab] OR costing[tiab] OR price[tiab] OR prices[tiab] OR pricing[tiab] OR
pharmacoeconomic*[tiab] OR (expenditure*[tiab] NOT energy[tiab]) OR "Cost effective"[tiab] OR "Cost
effectiveness"[tiab] OR "value for money"[tiab] OR budget*[tiab] OR burden[tiab] OR burdens[tiab]
#3 #1 AND #2
Embase
#1 'rotavirus infection'/exp OR 'rotavirus'/exp OR rotavirus:ab,ti OR rotaviruses:ab,ti OR 'rota virus':ab,ti AND
('vaccination'/de OR 'vaccine'/exp OR vaccine*:ab,ti OR vaccination*:ab,ti OR immunization*:ab,ti OR 'virus
vaccine'/exp) OR 'rotavirus vaccine'/exp OR rotarix:ab,ti OR rotateq:ab,ti OR rotashield:ab,ti OR 'rix4414
vaccine':ab,ti OR 'rix4414 vaccines':ab,ti
#2 'economic aspect'/exp AND 'economics'/exp AND 'economic evaluation'/exp OR Cost:ab,ti OR costs:ab,ti OR
economic*:ab,ti OR costly:ab,ti OR costing:ab,ti OR price:ab,ti OR prices:ab,ti OR pricing:ab,ti OR
pharmacoeconomic*:ab,ti OR (expenditure*:ab,ti NOT energy:ab,ti) OR 'Cost effective':ab,ti OR 'Cost
effectiveness':ab,ti OR 'value for money':ab,ti OR budget*:ab,ti OR burden:ab,ti OR burdens:ab,ti
#3 #1 AND #2
Cochrane Library
1 MeSH descriptor: [Rotavirus Infections] explode all trees
#2 MeSH descriptor: [Rotavirus] explode all trees
#3 rotavirus:ti,ab,kw or rotaviruses:ti,ab,kw or "rota virus":ti,ab,kw
#4 #1 or #2 or #3
#5 MeSH descriptor: [Vaccination] explode all trees
#6 MeSH descriptor: [Vaccines] explode all trees
#7 MeSH descriptor: [Immunization] explode all trees
#8 vaccine*:ti,ab,kw or vaccination*:ti,ab,kw or immunization*:ti,ab,kw
#9 #6 or #7 or #8
#10 MeSH descriptor: [Rotavirus Vaccines] explode all trees
#11 rotarix:ti,ab,kw or rotateq:ti,ab,kw or Rotashield:ti,ab,kw or "RIX4414 vaccine":ti,ab,kw or "RIX4414
vaccines":ti,ab,kw
#12 #11 or #10
#13 #5 and #9
#14 #12 or #13
CRD HTA
((rotavirus)) and ((Economic evaluation:ZDT and Bibliographic:ZPS) OR (Economic evaluation:ZDT and
Abstract:ZPS)) FROM 1995 TO 2014
62
Attitude to rotavirus vaccination

Pubmed
immunization*[tiab] OR "Immunization"[Mesh] OR immunisation*[tiab] OR "Viral Vaccines"[Mesh])) OR "Rotavirus
Vaccines"[Mesh] OR "RIX4414 vaccine"[Supplementary Concept] OR "RotaTeq"[Supplementary Concept] OR
"rhesus rotavirus vaccine"[Supplementary Concept] OR "rotavirus vaccine 89-12"[Supplementary Concept] OR
rotarix[tiab] OR rotateq[tiab] OR Rotashield[tiab] OR "RIX4414 vaccine"[tiab] OR "RIX4414 vaccines"[tiab]
#2 "Attitude"[Mesh] OR "Health Behavior"[Mesh] OR "Life Style"[Mesh] OR "Health Promotion"[Mesh] OR
attitude[ti] OR attitudes[ti] OR "health personnel attitude"[tiab] OR "health personnel attitudes"[tiab] OR "family
attitude"[tiab] OR "family attitudes"[tiab] OR "parental attitude"[tiab] OR "parental attitudes"[tiab] OR "paternal
attitude"[tiab] OR "paternal attitudes"[tiab] OR "staff attitude"[tiab] OR "staff attitudes"[tiab] OR behaviour[ti] OR
behaviours[ti] OR behaviors[ti] OR behavior[ti] OR perception[ti] OR perceptions[ti] OR acceptance[ti] OR "health
attitude"[tiab] OR "health attitudes"[tiab] OR "health behaviors"[tiab] OR "health behavior"[tiab] OR "health
behaviour"[tiab] OR "health behaviours"[tiab] OR "life style"[tiab] OR "life styles"[tiab] OR lifestyle[ti] OR
lifestyles[ti] OR "patient nonadherence"[tiab] OR "patient noncompliance"[tiab] OR refusal[tiab] OR
elopement[tiab] OR compliance[tiab] OR "promotion of health"[tiab] OR "health promotion"[tiab] OR "wellness
program"[tiab] OR "wellness programme"[tiab] OR "wellness programmes"[tiab] OR "wellness programming"[tiab]
OR "wellness programs"[tiab] OR "health campaign"[tiab] OR "health campaigns"[tiab]
#3 #1 AND #2
Embase
#1 'rotavirus infection'/exp OR 'rotavirus'/exp OR rotavirus:ab,ti OR rotaviruses:ab,ti OR 'rota virus':ab,ti AND
('vaccination'/de OR 'vaccine'/exp OR vaccine*:ab,ti OR vaccination*:ab,ti OR immunization*:ti,ab OR
'immunization'/exp OR immunisation*:ti,ab OR 'virus vaccine'/exp) OR 'rotavirus vaccine'/exp OR rotarix:ab,ti OR
rotateq:ab,ti OR rotashield:ab,ti OR 'rix4414 vaccine':ab,ti OR 'rix4414 vaccines':ab,ti
#2 'attitude'/exp OR 'health behavior'/exp OR 'lifestyle'/exp OR 'health promotion'/exp OR attitude:ti OR attitudes:ti
OR 'health personnel attitude':ab,ti OR 'health personnel attitudes':ab,ti OR 'family attitude':ab,ti OR 'family
attitudes':ab,ti OR 'parental attitude':ab,ti OR 'parental attitudes':ab,ti OR 'paternal attitude':ab,ti OR 'paternal
attitudes':ab,ti OR 'maternal attitude':ab,ti OR 'maternal attitudes':ab,ti OR 'staff attitude':ab,ti OR 'staff
attitudes':ab,ti OR behaviours:ti OR behaviour:ti OR behavior:ti OR behaviours:ti OR perception:ti OR perceptions:ti
OR acceptance:ti OR 'health attitude':ab,ti OR 'health attitudes':ab,ti OR 'health behaviors':ab,ti OR 'health
behavior':ab,ti OR 'health behaviour':ab,ti OR 'health behaviours':ab,ti OR 'life style':ab,ti OR 'life styles':ab,ti OR
lifestyle:ti OR lifestyles:ti OR 'patient nonadherence':ab,ti OR 'patient noncompliance':ab,ti OR refusal:ab,ti OR
elopement:ab,ti OR compliance:ab,ti OR 'promotion of health':ab,ti OR 'health promotion':ab,ti OR 'wellness
program':ab,ti OR 'wellness programme':ab,ti OR 'wellness programmes':ab,ti OR 'wellness programming':ab,ti OR
'wellness programs':ab,ti OR 'health campaign':ab,ti OR 'health campaigns':ab,ti
#3 #1 AND #2
63
11. References
1. EMA. European Public Assessment Report Rotarix. Available at:
http://wwwemaeuropaeu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000639/WC500054789pdf
2. EMA. European Public Assessment Report RotaTeq. Available at:
http://wwwemaeuropaeu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000669/WC500054185pdf
3. Parashar U, Gibson CJ, Bresee J, Glass R. Rotavirus and severe childhood diarrhea. Emerging Infectious
Diseases. 2006;12(2):304-6.
4. Tate J, Burton A, Boschi-Pinto C, Parashar U, Network WHOCGRS. Global, Regional, and National Estimates
of Rotavirus Mortality in Children <5 Years of Age, 2000-2013. Clin Infect Dis May 1; doi:
101093/cid/civ1013. 2016;62 Suppl 2:S96-S105.
5. Parashar UD, Burton A, Lanata C, Boschi-Pinto C, Shibuya K, Steele D, et al. Global mortality associated with
rotavirus disease among children in 2004. The Journal of Infectious Diseases. 2009 Nov 1;200 Suppl 1:S9-
S15. PubMed PMID: 19817620. Epub 2009/10/13.
6. Williams CJ, Lobanov A, Pebody RG. Estimated mortality and hospital admission due to rotavirus infection in
the WHO European Region. Epidemiology and Infection. 2009 May;137(5):607-16. PubMed PMID:
19134232. Epub 2009/01/13.
7. WHO. Rotavirus position paper. Weekly epidemiological record 2007;32(82):285-96.
8. WHO. Rotavirus position paper Weekly epidemiological record. 2009;51-52(84):533-40.
9. WHO. Rotavirus position paper. Weekly epidemiological record 2013;5(88):49-64.
10. Velazquez F, Matson D, Calva J, Guerrero L, Morrow A, Carter-Campbell S, et al. Rotavirus infections in
infants as protection against subsequent infections. The New England Journal of Medicine. 1996 Oct
3;335(14):1022-8. PubMed PMID: 8793926. Epub 1996/10/03.
11. Velazquez F. Protective effects of natural rotavirus infection. Pediatric Infectious Disease Journal.
2009;28(Suppl. 3):S54-S6.
12. Uhnoo I, Olding-Stenkvist E, Kreuger A. Clinical fetaures of acute gastroenteritis associated with rotavirus,
enteric adenovirus and bacteria. Archives of Disease in Childhood. 1986;61(8):732-8.
13. Van Damme P, Giaquinto C, Huet F, Gothefors L, Maxwell M, Van der Wielen M. Multicenter prospective
study of the burden of rotavirus acute gastroenteritis in Europe, 2004-2005: the REVEAL study. The Journal
of Infectious Diseases. 2007 May 1;195 Suppl 1:S4-S16. PubMed PMID: 17387650. Epub 2007/03/28.
14. Wildi-Runge S, Allemann S, Schaad UB, Heininger U. A 4-year study on clinical characteristics of children
hospitalized with rotavirus gastroenteritis. Eur J Pediatr. 2009 Nov;168(11):1343-8. PubMed PMID:
19205732. Epub 2009/02/12.
15. Johansen K, Hedlund KO, Zweygberg-Wirgart B, Bennet R. Complications attributable to rotavirus-induced
diarrhoea in a Swedish paediatric population: Report from an 11-year surveillance. Scandinavian Journal of
Infectious Diseases. 2008;40(11-12):958-64.
16. Ray P, Fenaux M, Sharma I, Malik A, S S, Bhatnagar S, et al. Quantative evaluation of rotaviral antigenemia
in children with acute rotaviral diarrhea. Journal of Infectious Diseases. 2006;194(5):588-93.
17. Blutt S, Kirkwood C, Parreno V, Warfield K, Ciarlet M, Estes MK. Rotavirus antigenaemia and viremia: a
common event? Lancet. 2003;362(9394):1445-9.
18. Nakagomi T, Nakagomi O. Rotavirus antigenemia in children with encephalopathy accompanied by rotavirus
gastroenteritis. Archives of Virology. 2005;150(9):1927-31.
19. Fischer T, Ashley D, Kerin T, Reynolds-Hedmann E, Gentsch J, Widdowson MA, et al. Rotavirus antigenemia
in patients with acute gastroenteritis. Journal of Infectious Diseases. 2005;192(5):913-9.
20. Chiappini E, Azzari C, Moriondo M, Galli L, de Martino M. Viraemia is a common finding in immunocompetent
children with rotavirus infection. Journal of Medical Virology. 2005;76(2):265-7.
21. Blutt S, Matson D, Crawford S, Staat MA, Azimi P, Bennett B, et al. Rotavirus antigenemia in children is
associated with viremia. PLoS Medicine. 2007;4(4):e121.
22. Robinson C, Hernanz-Schulman M, Zhu Y, Griffin M, Gruber W, Edwards K. Evaluation of anatomic changes
in young children with natural rotavirus infection: is intussusception biologically plausible? The Journal of
Infectious Diseases. 2004 Apr 15;189(8):1382-7. PubMed PMID: 15073674. Epub 2004/04/10.
23. Oishi I, Kimura T, Murakami T, Haruki K, Yamazaki K, Seto Y, et al. Serial observations of chronic rotavirus
infection in an immunodeficient child. Microbiology and Immunology. 1991;35(11):953-61.
24. Steele AD, Cunliffe N, Tumbo J, Madhi SA, De Vos B, Bouckenooghe A. A review of rotavirus infection in and
vaccination of human immunodeficiency virus-infected children. Journal of Infectious Diseases.
2009;200(SUPPL. 1):S57-S62.
25. Fischer SA. Emerging viruses in transplantation: There is more to infection after transplant than CMV and
EBV. Transplantation. 2008;86(10):1327-39.
64
26. Dennehy P, Peter G. Risk factors associated with nosocomial rotavirus infection. American Journal Dis
Children 1985;139(9):935-9.
27. Gleizes O, Desselberger U, Tatochenko V, Rodrigo C, Salman N, Mezner Z, et al. Nosocomial rotavirus
infection in European countries: A review of the epidemiology, severity and economic burden of hospital-
acquired rotavirus disease. Pediatric Infectious Disease Journal. 2006;25(1 Suppl.):S12-S21.
28. Widdowson MA, van Doornum GJ, van der Poel WH, de Boer AS, van de Heide R, Mahdi U, et al. An
outbreak of diarrhea in a neonatal medium care unit caused by a novel strain of rotavirus: investigation
using both epidemiologic and microbiological methods. Infection control and hospital epidemiology : the
official journal of the Society of Hospital Epidemiologists of America. 2002 Nov;23(11):665-70. PubMed
PMID: 12452294. Epub 2002/11/28.
29. Gianino P, Mastretta E, Longo P, Laccisaglia A, Sartore M, Russo R, et al. Incidence of nosocomial rotavirus
infections, symptomatic and asymptomatic, in breast-fed and non-breast-fed infants. Journal of Hospital
Infection. 2002;50(1):13-7.
30. Senecal M, Brisson M, Lebel MH, Yaremko J, Wong R, Gallant LA, et al. Measuring the Impact of Rotavirus
Acute Gastroenteritis Episodes (MIRAGE): A prospective community-based study. The Canadian Journal of
Infectious Diseases & Medical Microbiology = Journal canadien des maladies infectieuses et de la
microbiologie medicale/AMMI Canada. 2008;19(6):397-404. PubMed PMID: 19436568. Pubmed Central
PMCID: PMC2663469.
31. Grillner L, Broberger U, Chrystie I, Ransjo U. Rotavirus infections in newborns: an epidemiological and
clinical study. Scandinavian Journal of Infectious Diseases. 1985;17(4):349-55.
32. Bishop R, Barnes G. Neonatal rotavirus infection: possible effect on prevalence of severe diarrhoea in a
community. Journal of Pediatrics and Child Health. 1997;33(1):80.
33. Kirkwood CD, Coulson BS, Bishop RF. G3P2 rotaviruses causing diarrhoeal disease in neonates differ in VP4,
VP7 and NSP4 sequence from G3P2 strains causing asymptomatic neonatal infection. Archives of Virology.
1996;141(9):1661-76. PubMed PMID: 8893789. Epub 1996/01/01.
34. Ferson M, Stringfellow S, McPhie K, McIver C, Simos A. Longitudinal study of rotavirus infection in child-care
centres. Journal of Paediatrics and Child Health. 1997;33(2):157-60.
35. Phillips G, Lopman B, Rodrigues LC, Tam CC. Asymptomatic rotavirus infections in England: Prevalence,
characteristics, and risk factors. American Journal of Epidemiology. 2010;171(9):1023-30.
36. Barnes GL, Callaghan SL, Kirkwood CD, Bogdanovic-Sakran N, Johnston LJ, Bishop RF. Excretion of serotype
G1 rotavirus strains by asymptomatic staff: A possible source of nosocomial infection. Journal of Pediatrics.
2003;142(6):722-5.
37. Haffejee IE. Neonatal rotavirus infections Rev Infect Dis. 1991;13:957-62.
38. Jayashree S, Bhan M, Raj P, Kumar R, Svensson L, Stintzing G, et al. Neonatal rotavirus infection and its
relation to cord blood antibodies. Scandinavian Journal of Infectious Diseases. 1988;20(3):249-53.
39. Mukhopadhya I SR, Menon VK, Babji S, Paul A, Rajendran P, Sowmyanarayanan TV, Moses PD, Iturriza-
Gomara M, Gray JJ, Kang G. Rotavirus shedding in symtomatic and asymptomatic children using reverse
transcription-quantitative PCR. Journal of Medical Virology. 2013;85(9):1661-8.
40. Huppertz HI, Salman N, Giaquinto C. Risk factors for severe rotavirus gastroenteritis. Pediatric Infectious
Disease Journal. 2008;27(1 Suppl.):S11-S9.
41. Adlhoch C, Hoehne M, Littmann M, Marques AM, Lerche A, Dehnert M, et al. Rotavirus vaccine effectiveness
and case-control study on risk factors for breakthrough infections in Germany, 2010-2011. Pediatric
Infectious Disease Journal. 2013;32(2):e82-e9.
42. Dennehy P, Cortese M, Bégué R, Jaeger J, Roberts N, Zhang R, et al. A case-control study to determine risk
factors for hospitalization for rotavirus gastroenteritis in U.S. children. Pediatr Infect Dis J.
2006;25(12):1123-31.
43. Bishop R, Davidson G, Holmes I, Ruck B. Virus particles in epithelial cells of duodenal mucosa from children
with acute non-bacterial gastroenteritis. Lancet.1973;2:1281-3.
44. Bishop R, Davidson G, Holmes I, Ruck B. Detection of a new virus by electron microscopy of faecal extracts
from children with acute gastroenteritis. Lancet. 1974:149-51.
45. Estes MK, Morris AP. A viral enterotoxin. A new mechanism of virus-induced pathogenesis. Advances in
Experimental Medicine and Biology. 1999 (473):73-82.
46. Iturriza-Gomara M, Auchterlonie I, Zaw W, Molyneaux PJ, Desselberger U, Gray J. Rotavirus gastroenteritis
and central nervous system (CNS) infection: characterization of the VP7 and VP4 genes of rotavirus strains
isolated from paired fecal and cerebrospinal fluid samples from a child with CNS disease. Journal of Clinical
Microbiology. 2003;40(12):4797-9.
47. Teitelbaum J, Daghistani R. Rotavirus causes hepatic transaminases elevation. Dig Dis Sci.
2007;52(12):3396-8.
65
48. Kramer A, Schwebke I, Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A
systematic review. BMC Infectious Diseases. 2006;6.
49. Foster J, Chen J. General principles of disease transmission. Pediatric Annals. 2002;31(5):293-8.
50. Gentsch J, Laird A, Bielfelt B, Griffin D, Banyai K, Ramachandran M, et al. Serotype diversity and
reassortment between human and animal rotavirus strains: implications for rotavirus vaccine programs. The
Journal of Infectious Diseases. 2005 Sep 1;192 Suppl 1:S146-59. PubMed PMID: 16088798. Epub
2005/08/10.
51. Richardson S, Grimwood K, Gorrell R, Palombo E, Barnes G, Bishop R. Extended excretion of rotavirus after
severe diarrhoea in young children. Lancet 1998;351:1844-8.
52. Aggarwal S, Upadhyay A, Shah D, Teotia N, Agarwal A, Jaiswal V. Lactobacillus GG for treatment of acute
childhood diarrhoea: an open labelled, randomized controlled trial. Indian J Med Res Mar;.
2014;139(3):379-85.
53. Hidrasec. Summary Product Characteristics. 2015. Availble at: https://www.medicines.org.uk/emc/medicine/31232
54. Pammi M, Haque Khalid N. Oral immunoglobulin for the prevention of rotavirus infection in low birth weight
infants. Cochrane Database of Systematic Reviews [Internet]. 2011; (11). Available from:
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003740.pub2/abstract.
55. Ward R, Bernstein D. Protection against rotavirus disease after natural rotavirus infection. US Rotavirus
Vaccine Efficacy Group. Journal of Infectious Diseases. 1994;169(4):900-4.
56. Velazquez FR, Matson DO, Guerrero ML, Shults J, Calva JJ, Morrow AL, et al. Serum antibody as a marker of
protection against natural rotavirus infection and disease. Journal of Infectious Diseases. 2000;182(6):1602-9.
57. Johansen K, Hinkula J, Espinoza F, Levi M, Zeng C, Rudén U, et al. Humoral and cell-mediated immune
responses in humans to the NSP4 enterotoxin of rotavirus. J Med Virol. 1999;59(3):369-77.
58. Johansen K, Granqvist L, Karlén K, Stintzing G, Uhnoo I, Svensson L. Serum IgA immune response to individual
rotavirus polypeptides in young children with rotavirus infection. Arch Virol. 1994;138(3-4):247-59.
59. Arias C, López S, Mascarenhas J, Romero P, Cano P, Gabbay Y, et al. Neutralizing antibody immune response
in children with primary and secondary rotavirus infections. Clinical and Diagnostic Laboratory Immunology.
1994;1(1):89-94.
60. Staat M, Cortese M, Bresee J, Begue R, Vitek C, Rhodes P, et al. Rhesus rotavirus vaccine effectiveness and
factors associated with receipt of vaccine. The Pediatric Infectious Disease Journal. 2006 Nov;25(11):1013-
8. PubMed PMID: 17072123. Epub 2006/10/31.
61. Murphy T, Gargiullo P, Massoudi M, Nelson D, Jumaan A, Okoro C, et al. Intussusception among infants
given an oral rotavirus vaccine. The New England Journal of Medicine. 2001 Feb 22;344(8):564-72. PubMed
PMID: 11207352. Epub 2001/02/24.
62. Murphy T, Smith P, Gargiullo P, Schwartz B. The first rotavirus vaccine and intussusception: Epidemiological
studies and policy decisions. Journal of Infectious Diseases. 2003;187(8):1309-13.
63. Simonsen L, Morens D, Elixhauser A, Gerber M, Van Raden M, Blackwelder W. Effect of rotavirus vaccination
programme on trends in admission of infants to hospital for intussusception. Lancet. 2001;358(9289):1224-9.
64. Vesikari T, Prymula R, Schuster V, Tejedor JC, Cohen R, Bouckenooghe A, et al. Efficacy and immunogenicity
of live-attenuated human rotavirus vaccine in breast-fed and formula-fed european infants. Pediatric
Infectious Disease Journal. 2012;31(5):509-13.
65. Ciarlet M, He S, Lai S, Petrecz M, Yuan G, Liu GF, et al. Concomitant use of the 3-dose oral pentavalent
rotavirus vaccine with a 3-dose primary vaccination course of a diphtheria-tetanus-acellular pertussis-
hepatitis B-inactivated polio-haemophilus influenzae type b vaccine: Immunogenicity and reactogenicity.
Pediatric Infectious Disease Journal. 2009;28(3):177-81.
66. Omenaca F, Sarlangue J, Szenborn L, Nogueira M, Suryakiran PV, Smolenov IV, et al. Safety, reactogenicity
and immunogenicity of the human rotavirus vaccine in preterm European Infants: a randomized phase IIIb
study. The Pediatric Infectious Disease Journal. 2012 May;31(5):487-93. PubMed PMID: 22228231. Epub
2012/01/10.
67. Goveia M, Rodriguez Z, Dallas M, Itzler R, Boslego J, Heaton P, et al. Safety and efficacy of the pentavalent
human-bovine (WC3) reassortant rotavirus vaccine in healthy premature infants. The Pediatric Infectious
Disease Journal. 2007 Dec;26(12):1099-104. PubMed PMID: 18043445. Epub 2007/11/29.
68. Monk H, Motsney A, Wade K. Safety of rotavirus vaccine in the NICU. Pediatrics. 2014;133(6):e1555-60.
69. Anderson EJ. Rotavirus vaccines: viral shedding and risk of transmission. The Lancet Infectious Diseases.
2008 Oct;8(10):642-9. PubMed PMID: 18922486. Epub 2008/10/17.
70. Smith C, McNeal M, Meyer N, Haase S, Dekker C. Rotavirus shedding in premature infants following first
immunization. Vaccine. 2011 Oct 19;29(45):8141-6. PubMed PMID: 21856359. Epub 2011/08/23.
71. Rivera L, Pena LM, Stainier I, Gillard P, Cheuvart B, Smolenov I, et al. Horizontal transmission of a human
rotavirus vaccine strain-A randomized, placebo-controlled study in twins. Vaccine. 2011;29(51):9508-13.
66
72. Bakare N, Menschik D, Tiernan R, Hua W, Martin D. Severe Combined Immunodeficiency (SCID) and
rotavirus vaccination: Reports to the Vaccine Adverse Events Reporting System (VAERS). Vaccine. 2010.
73. Rubin L, Levin M, Ljungman P, Davies E, Avery R, Tomblyn M, et al. 2013 IDSA clinical practice guideline for
vaccination of the immunocompromised host. Clinical Infectious Diseases: an official publication of the
Infectious Diseases Society of America. 2014;58(3):309-18.
74. Steele A, Madhi S, Louw C, Bos P, Tumbo J, Werner C, et al. Safety, Reactogenicity, and Immunogenicity of
Human Rotavirus Vaccine RIX4414 in Human Immunodeficiency Virus-positive Infants in South Africa. The
Pediatric Infectious Disease Journal. 2011 Feb;30(2):125-30. PubMed PMID: 20842070. Epub 2010/09/16.
75. Fang A, Tingay D. Early observations in the use of oral rotavirus vaccination in infants with functional short
gut syndrome. Journal of Paediatrics and Child Health. 2012 Jun;48(6):512-6. PubMed PMID: 22107074.
Epub 2011/11/24.
76. Mahadevan U, Cucchiara S, Hyams J, Steinwurz F, Nuti F, Travis S, et al. The London Position Statement of
the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis
Organisation: pregnancy and pediatrics. The American Journal of Gastroenterology. 2011 Feb;106(2):214-
23; quiz 24. PubMed PMID: 21157441. Epub 2010/12/16.
77. Mohammed A, Immergluck L, Parker T, Jain S, Leong T, Anderson E, et al. Association between mixed
rotavirus vaccination types of infants and rotavirus acute gastroenteritis. Vaccine. 2015;33(42):5670-7.
78. Payne D, Sulemana I, Parashar U, Network NVS. Evaluation of Effectiveness of Mixed Rotavirus Vaccine
Course for Rotavirus Gastroenteritis. JAMA Pediatr Jul 1;1 doi: 101001/jamapediatrics20160014 No abstract
available 2016;70(7):708-10.
79. Libster R, McNeal M, Walter E, Shane A, Winokur P, Cress G, et al. Safety and Immunogenicity of Sequential
Rotavirus Vaccine Schedules. Pediatrics. 2016;137(2):e20152603.
80. Dennehy PH. Rotavirus vaccines: an overview. Clinical Microbiology Reviews. 2008 Jan;21(1):198-208.
PubMed PMID: 18202442. Pubmed Central PMCID: PMC2223838. Epub 2008/01/19.
81. Cheuvart B. Association of serum anti-rotavirus immunoglobulin A antibody seropositivity and protection
against severe rotavirus gastroenteritis: analysis of clinical trials of human rotavirus vaccine. Hum Vaccin
Immunother. 2013;10(2).
82. Vesikari T, Karvonen A, Ferrante S, Ciarlet M. Efficacy of the pentavalent rotavirus vaccine, RotaTeq(R), in
Finnish infants up to 3 years of age: the Finnish Extension Study. Eur J Pediatr. 2010; 169(11):[1379-86]
83. Vesikari T, Matson D, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a
pentavalent human-bovine (WC3) reassortant rotavirus vaccine. New England Journal of Medicine.
2006;354(1):23-33.
84. Block S, Vesikari T, Goveia M, Rivers S, Adeyi B, Dallas M, et al. Efficacy, immunogenicity, and safety of a
pentavalent human-bovine (WC3) reassortant rotavirus vaccine at the end of shelf life. Pediatrics.
2007;119(1):11-8.
85. Kerdpanich A, Chokephaibulkit K, Watanaveeradej V, Vanprapar N, Simasathien S, Phavichitr N, et al.
Immunogenicity of a human rotavirus vaccine (RIX4414) after storage at 37(degrees)C for seven days.
Human Vaccines. 2011;7(1):74-80.
86. Fu C, He Q, Xu J, Xie H, Ding P, Hu W, et al. Effectiveness of the Lanzhou lamb rotavirus vaccine against
gastroenteritis among children. Vaccine. 2012;31(1):154-8.
87. He Q, Wang M, Xu J, Zhang C, Wang H, Zhu W, et al. Rotavirus vaccination coverage among children aged
2-59 months: a report from Guangzhou, China. PLoS ONE. 2013;8(6):e68169.
88. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent
human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled
trial. Lancet. 2014;383(9935):2136-43.
89. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent
human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine.
2014;32(1):A110-A6.
90. Glass R, Bhan M, Ray P, Bahl R, Parashar U, Greenberg H, et al. Development of candidate rotavirus
vaccines derived from neonatal strains in India. The Journal of Infectious Diseases. 2005 Sep 1;192 Suppl
1:S30-5. PubMed PMID: 16088802. Epub 2005/08/10.
91. Luna E, Frazatti-Gallina N, Timenetsky M, Cardoso M, Veras M, Miraglia J, et al. A phase I clinical trial of a
new 5-valent rotavirus vaccine. Vaccine. 2013;31(7):1100-5.
92. Zade J, Kulkarni P, Desai S, Sabale R, Naik S, Dhere R. Bovine rotavirus pentavalent vaccine development in
India. Vaccine 2014;32(Suppl 1):A124-8.
93. Fix A, Harro C, McNeal M, Dally L, Flores J, Robertson G, et al. Safety and immunogenicity of a parenterally
administered rotavirus VP8 subunit vaccine in healthy adults. Vaccine. 2015;33:3766-72.
94. Simonsen L, Morens DM, Blackwelder WC. Ecological studies, rotavirus vaccinations, and intussusception.
Lancet. 2002;359(9311):1066-7.
67
95. Armah G, Kapikian AZ, Vesikari T, Cunliffe N, Jacobson R, Burlington D, et al. Efficacy, immunogenicity, and
safety of two doses of a tetravalent rotavirus vaccine RRV-TV in Ghana with the first dose administered
during the neonatal period. The Journal of Infectious Diseases. 2013;208(3):423-31.
96. Danchin M, Kirkwood C, Lee K, Bishop R, Watts E, Justice F, et al. Phase I trial of RV3-BB rotavirus vaccine:
a human neonatal rotavirus vaccine. Vaccine. 2013;31(23):2610-6.
97. Hahné S, Hooiveld M, Vennema H, van Ginkel A, de Melker H, Wallinga J, et al. Exceptionally low rotavirus
incidence in the Netherlands in 2013/14 in the absence of rotavirus vaccination. Euro surveillance : bulletin
europeen sur les maladies transmissibles = European communicable disease bulletin. 2014;19(43).
98. Iturriza-Gomara M, Dallman T, Banyai K, Bottiger B, Buesa J, Diedrich S, et al. Rotavirus surveillance in
europe, 2005-2008: Web-enabled reporting and real-time analysis of genotyping and epidemiological data.
Journal of Infectious Diseases. 2009; 200 (Suppl. 1):S215-S21.
99. Hungerford D, Vivancos R, Read J, Pitzer VE, Cunliffe N, French N, et al. In-season and out-of-season
variation of rotavirus genotype distribution and age of infection across 12 European coutnries before the
introduction of routine vaccination 2007/2008 to 2012/13. Eurosurveillance. 2016;21(2).
100. Armah G, Sow S, Breiman R, Dallas M, Tapia M, Feikin D, et al. Efficacy of pentavalent rotavirus vaccine
against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: A
randomised, double-blind, placebo-controlled trial. The Lancet. 2010;376(9741):606-14.
101. Madhi S, Cunliffe N, Steele D, Witte D, Kirsten M, Louw C, et al. Effect of human rotavirus vaccine on severe
diarrhea in African infants. New England Journal of Medicine. 2010;362(4):289-98.
102. Böhm R, Fleming F, Maggioni A, Dang V, Holloway G, Coulson B, et al. Revisiting the role of histo-blood
group antigens in rotavirus host-cell invasion. Nat Commun. 2015;6:5907.
103. Orenstein W, Bernier R, Dondero T, Hinman A, Mark J, KJ B, et al. Field evaluation of vaccine efficacy. Bull
World Health Organ 1985;63(6):1055-68.
104. Higgins J, Thompson S, Deeks J, Altman D. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60.
105. Bines JE, Ivanoff B, Justice F, Mulholland K. Clinical case definition for the diagnosis of acute
intussusception. Journal of Pediatric Gastroenterology and Nutrition. 2004 Nov;39(5):511-8. PubMed PMID:
15572891. Epub 2004/12/02.
106. Phuong LK, Bonetto C, Buttery J, Pernus Y, Chandler R, Goldenthal K, et al. Kawasaki disease and
immunisation: Standardised case definition & guidelines for data collection, analysis. Vaccine.
2016;34(51):6582-96.
107. Rendi-Wagner P, Kundi M, Mikolasek A, Mutz I, Zwiauer K, Wiedermann U, et al. Active hospital-based
surveillance of rotavirus diarrhea in Austrian children, period 1997 to 2003. Wiener klinische Wochenschrift.
2006;118(9-10):280-5.
108. Zeller M, Rahman M, Heylen E, De Coster S, De Vos S, Arijs I, et al. Rotavirus incidence and genotype distribution
before and after national rotavirus vaccine introduction in Belgium. Vaccine. 2010;28(47):7507-13.
109. Pazdiora P, Benes C. Rotavirus gastroenteritis in the Czech republic before the start of vaccination. Epidemiol
Mikrobiol Imunol. 2013;62(4):131-7.
110. Fischer TK, Nielsen NM, Wohlfahrt J, Paerregaard A. Incidence and cost of rotavirus hospitalizations in
Denmark. Emerging Infectious Diseases. 2007;13(6):855-9.
111. Ryan MJ, Wall PG, Adak GK, Evans HS, Cowden JM. Outbreaks of infectious intestinal disease in residential
institutions in England and Wales 1992-1994. Journal of Infection. 1997;34(1):49-54.
112. Harris JP, Jit M, Cooper D, Edmunds WJ. Evaluating rotavirus vaccination in England and Wales. Part I.
Estimating the burden of disease. Vaccine. 2007;25(20):3962-70.
113. Vesikari T. Rotavirus gastroenteritis in Finland: Burden of disease and epidemiological features. Acta
Paediatrica, International Journal of Paediatrics, Supplement. 1999;88(426):24-30.
114. Fourquet F, Desenclos JC, Maurage C, Baron S. Acute gastro-enteritis in children in France: Estimates of
disease burden through national hospital discharge data. Archives de Pediatrie. 2003;10(10):861-8.
115. Forster J, Guarino A, Parez N, Moraga F, Roman E, Mory O, et al. Hospital-based surveillance to estimate the
burden of rotavirus gastroenteritis among european children younger than 5 years of Age. Pediatrics.
2009;123(3):e393-e400.
116. Poppe M, Ehlken B, Rohwedder A, Lugauer S, Frank H, Stehr K, et al. Morbidity and hospital admissions due
to rotavirus infection in Germany. Monatsschrift fur Kinderheilkunde. 2002;150(4):491-6.
117. Koch J, Wiese-Posselt M. Epidemiology of rotavirus infections in children less than 5 years of age: Germany,
2001-2008. Pediatric Infectious Disease Journal. 2011;30(2):112-7.
118. Kavaliotis I, Papaevangelou V, Aggelakou V, Mantagou L, Trimis G, Papadopoulou V, et al. ROTASCORE
study: epidemiological observational study of acute gastroenteritis with or without rotavirus in Greek
children younger tha 5 years old. European Journal of Pediatrics. 2008;167(6):707-8.
68
119. Konstantopoulos A, Tragiannidis A, Fouzas S, Kavaliotis I, Tsiatsou O, Michailidou E, et al. Burden of

rotavirus gastroenteritis in children <5 years of age in Greece: hospital-based prospective surveillance
(2008-2010). BMJ Open 2013 Dec 11;3(12):e003570 2013;3(12).
120. Lynch M, O'Halloran F, Whyte D, Fanning S, Cryan B, Glass MRI. Rotavirus in ireland: National estimates of
disease burden, 1997 to 1998. Pediatric Infectious Disease Journal. 2001;20(7):693-8.
121. Ruggeri FM. Rotavirus infection among children with diarrhoea in Italy. Acta Paediatrica, International
Journal of Paediatrics, Supplement. 1999;88(426):66-71.
122. Gabutti G, Lazzara C, Marsella M, Bergamini M, Malaventura C, Borgna-Pignatti C. Burden of hospitalizations due
to Rotavirus infection in Emilia Romagna, Italy. Acta Biomedica de l'Ateneo Parmense. 2007;78(3):176-81.
123. Mattei A, Angelone AM, Sbarbati M, Di Orio F. Temporal trends in rate of hospitalisation for rotavirus
gastroenteritis in the paediatric population in Italy: Crosssectional study utilising national hospital discharge
database. Clinical Microbiology and Infection. 2012;18:226-7.
124. Panatto D, Amicizia D, Ansaldi F, Marocco A, Marchetti F, Bamfi F, et al. Burden of rotavirus disease and cost-
effectiveness of universal vaccination in the Province of Genoa (Northern Italy) (Structured abstract).
Vaccine [Internet]. 2009; 27(25-26):[3450-3 pp.].
125. Szucs G. Burden of human rotavirus-associated hospitalizations in three geographic regions of Hungary.
Acta Paediatrica, International Journal of Paediatrics, Suppl. 1999;88(426):61-5.
126. De Wit MAS, Koopmans MPG, Van der Blij JF, Van Duynhoven YTHP. Hospital admissions for rotavirus
infection in the Netherlands. Clinical Infectious Diseases. 2000;31(3):698-704.
127. Flem E, Vainio K, Dollner H, Midgaard C, Bosse FJ, Rognlien AGW, et al. Rotavirus gastroenteritis in Norway:
Analysis of prospective surveillance and hospital registry data. Scandinavian Journal of Infectious Diseases.
2009;41(10):753-9.
128. Mrukowicz JZ, Thompson J, Reed GW, Tollefson SJ, Kobayashi M, Araki K, et al. Epidemiology of rotavirus in
infants and protection against symptomatic illness afforded by primary infection and vaccination. Vaccine.
1999 Feb 26;17(7-8):745-53. PubMed PMID: 10067679. Epub 1999/03/06.
129. Visser LE. Impact of rotavirus disease in Spain: An estimate of hospital admissions due to rotavirus. Acta
Paediatrica, International Journal of Paediatrics, Suppl. 1999;88(426):72-6.
130. Luquero Alcalde FJ, Eiros Bouza JM, Rubio AP, Bachiller Luque MR, Castrodeza Sanz JJ, Ortiz De Lejarazu
Leonardo R. Gastroenteritis by rotavirus in Spanish children. Analysis of the disease burden. European
Journal of Pediatrics. 2008;167(5):549-55.
131. Cilla G, Montes M, Gomariz M, Alkorta M, Iturzaeta A, Perez-Yarza EG, et al. Rotavirus genotypes in children
in the Basque Country (North of Spain): rapid and intense emergence of the G12[P8] genotype.
Epidemiology and Infection. 2012 Jul 3:1-7. PubMed PMID: 22873952. Epub 2012/08/10.
132. Garcia-Basteiro AL, Bosch A, Sicuri E, Bayas JM, Trilla A, Hayes EB. Hospitalizations due to rotavirus
gastroenteritis in Catalonia, Spain, 2003-2008. BMC research notes. 2011;4:429. PubMed PMID: 22013948.
Pubmed Central PMCID: PMC3212997. Epub 2011/10/22.
133. Sanchez-Fauquier A, Montero V, Moreno S, Sole M, Colomina J, Iturriza-Gomara M, et al. Human rotavirus
G9 and G3 as major cause of diarrhea in hospitalized children, Spain. Emerging Infectious Diseases.
2006;12(10):1536-41.
134. Gil A, Carrasco P, Jimenez R, San-Martin M, Oyaguez I, Gonzalez A. Burden of hospitalization attributable to
rotavirus infections in children in Spain. Vaccine. 2004;22(17-18):2221-5.
135. Iturriza Gomara M, Simpson R, Perault AM, Redpath C, Lorgelly P, Joshi D, et al. Structured surveillance of
infantile gastroenteritis in East Anglia, UK: incidence of infection with common viral gastroenteric
pathogens. Epidemiology and Infection. 2008;136(1):23-33.
136. Johansen K. Incidence and estimates of the disease burden of rotavirus in Sweden. Acta paediatrica (Oslo,
Norway: 1992) Supplement. 1999;88(426):20-3.
137. Rinder M, Tran AN, Bennet R, Brytting M, Cassel T, Eriksson M, et al. Burden of severe rotavirus disease
leading to hospitalization assessed in a prospective cohort study in Sweden. Scand J Infect Dis.
2014;46(4):294-302.
138. Matson D, Estes M. Impact of rotavirus infection at a large pediatric hospital. J Infect Dis. 1990;162(3):598-
604.
139. Brandt C, Kim H, Rodriguez W, Arrobio J, Jeffries B, Stallings E, et al. Pediatric viral gastroenteritis during
eight years of study. Journal of Clinical Microbiology. 1983;18(1):71-8.
140. Shai S, Perez-Becker R, Von Konig CHW, Von Kries R, Heininger U, Forster J, et al. Rotavirus disease in
Germany-a prospective survey of very severe cases. Pediatric Infectious Disease Journal. 2013;32(2):e62-e7.
141. Jit M, Pebody RG, Chen AC, Andrews N, Edmunds WJ. Estimating the number of deaths with rotavirus as a
cause in England and Wales. Hum Vaccin. 2007;3(1):23-6.
69
142. Berner R, Schumacher RF, Forster J. Survey on rotavirus infections in a German pediatric hospital. European
journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical
Microbiology. 1997;16(6):479-81.
143. Soriano-Gabarro M, Mrukowicz J, Vesikari T, Verstraeten T. Burden of rotavirus disease in European Union
countries. Pediatric Infectious Disease Journal. 2006;25(1 SUPPL.):S7-S11.
144. Bruijning-Verhagen P, Mangen MJ, Felderhof M, Hartwig NG, van Houten M, Winkel L, et al. Targeted
rotavirus vaccination of high-risk infants; a low cost and highly cost-effective alternative to universal
vaccination. BMC Med. .2013;11:112.
145. Cunliffe N, Allan C, Lowe C, Sopwith W, Booth A, Nakagomi O, et al. Health-care associated rotavirus
gastroenteritis in a large paediatric hospital in the UK. Journal Hospital Infections 2007;67(3):240-4.
146. Thuret A, Patural H, Berthelot P, Benzait F, Martin I, Jusot J, et al. Prospective follow-up of hospital-acquired
diarrhoea in 28 paediatric wards of the south-east part of France during a winter season. Pathologie
Biologie 2004;52(3):131-7.
147. Sermet-Gaudelus I, DeLa Rocque F, Salomon J, Lachassine E, Lruz-Ville M, Baujat G, et al. Rotavirus
nosocomial infection in pediatric units. A multicentric observation study. Pathologie Biologie. 2004;52(1):4-10.
148. Pina p, Le Huidoux P, Lefflot S, Araujo EC, Bellaiche M, Harzig M, et al. Nosocomial rotavirus infections in a
general pediatric ward: epidemiology, molecular typing and risk factors. Archives de Pediatrie.
2000;7(10):1050-8.
149. Foppa IM, Karmaus W, Ehlken B, Fruhwirth M, Heininger U, Plenge-Bonig A, et al. Healthcare-associated
rotavirus illness in pediatric inpatients in Germany, Austria, and Switzerland. Infection Control and Hospital
Epidemiology. 2006;27(6):633-5.
150. Piednoir E, Bessaci K, Bureau-Chalot F, Sabouraud P, Brodard V, Andreoletti L, et al. Economic impact of
healthcare-associated rotavirus infection in a paediatric hospital. Journal of Hospital Infection.
2003;55(3):190-5.
151. Fruhwirth M, Berger K, Ehlken B, Moll-Schuler I, Brosl S, Mutz I. Economic impact of community- and
noscomially acquired rotavirus gastroenteritis in Austria. Pediatric Infectious Disease Journal.
2001;20(2):184-8.
152. Kinnula S, Renko M, Tapiainen T, Knuutinen M, Uhari M. Hospital-associated infections during and after care
in a paediatric infectious disease ward. Journal Hospital Infections. 2008;68(4):334-40.
153. Gutierrez-Gimeno M, Martin-Moreno J, Diez-Domingo J, Asensi-Botet F, Hernandez-Marco R, Correcher-
Medina P, et al. Nosocomial rotavirus gastroenteritis in Spain: A multi-center prospective study. Pediatric
Infectious Disease Journal. 2007;29(1):23-7.
154. Gil-Prieto R, San Martin M, De Andres AL, Alvaro-Meca A, Gonzalez A, De Miguel AG. Hospital-acquired
rotavirus infections in spain over a ten-year period (1998-2007). Human Vaccines. 2009;5(11):748-53.
155. Spackova M, Altmann D, Eckmanns T, Koch J, Krause G. High level of gastrointestinal nosocomial infections
in the German surveillance system, 2002-2008. Infection Control and Hospital Epidemiology.
2010;31(12):1273-8.
156. Nitsch-Osuch A, Kuchar E, Kosmala A, Zycinska K, Wardyn K. Nosocomial rotavirus gastroenterocolitis in a
large tertiary paediatric hospital in Warsaw, 2006-2010. Arch Med Sci. 2013;9(3):493-8.
157. Bruijning-Verhagen P, Quach C, Bonten M. Nosocomial rotavirus infections: A meta-analysis. Pediatrics.
2012;129(4):e1011-e9.
158. Bilcke J, Van Damme P, De Smet F, Hanquet G, Van Ranst M, Beutels P. The health and economic burden of
rotavirus disease in Belgium. European Journal of Pediatrics. 2008;167(12):1409-19.
159. Fischer TK, Rungoe C, Jensen CS, Breindahl M, Jorgensen TR, Nielsen JP, et al. The burden of rotavirus
disease in Denmark 2009-2010. Pediatric Infectious Disease Journal. 2011;30(7):e126-e9.
160. Rasanen S, Lappalainen S, Halkosalo A, Salminen M, Vesikari T. Rotavirus gastroenteritis in Finnish children
in 2006-2008, at the introduction of rotavirus vaccination. Scandinavian Journal of Infectious Diseases. 2011
Jan;43(1):58-63. PubMed PMID: 20807022. Epub 2010/09/03.
161. Marsella M, Raimondi L, Bergamini M, Sprocati M, Bigi E, De Sanctis V, et al. Epidemiology of rotavirus-
associated hospital admissions in the province of Ferrara, Italy. European Journal of Pediatrics.
2009;168(12):1423-7.
162. Panatto D, Amicizia D, Ansaldi F, Marocco A, Marchetti F, Bamfi F, et al. Burden of rotavirus disease and cost-
effectiveness of universal vaccination in the Province of Genoa (Northern Italy). Vaccine. 2009;27(25-
26):3450-3.
163. Saia M, Giliberti A, Callegaro G, Baldovin T, Busana MC, Pietrobon F, et al. Hospitalisation for rotavirus
gastroenteritis in the paediatric population in the Veneto Region, Italy. BMC Public Health. 2010;10:636.
PubMed PMID: 20969755. Pubmed Central PMCID: PMC2978151. Epub 2010/10/26.
70
164. Bruijning-Verhagen P, Sankatsing V, Kunst A, van den Born C, Bleeker E, Thijsen S, et al. Rotavirus-related
hospitalizations are responsible for high seasonal peaks in all-cause pediatric hospitalizations. The Pediatric
Infectious Disease Journal. 2012 Dec;31(12):e244-9. PubMed PMID: 22828647. Epub 2012/07/26.
165. Lesanu G, Vlad RM, Tincu IF, Smadeanu R, Iaru O, Simion I, et al. Burden of Rotavirus Gastroenteritis
Among Hospitalized Infants in Romania Poster presentation Abstract 701. Arch Dis Child 2012;97:A202
166. Cilla G, Gomariz M, Montes M, Mendiburu M, Perez-Yarza EG, Perez-Trallero E. Incidence of hospitalization
due to community-acquired rotavirus infection:a 12-year study 1996-2008. Epidemiology and Infection.
2010;138:1235-41.
167. Sanchez-Fauquier A, Montero V, Colomina J, Gonzalez-Galan V, Aznar J, Aisa ML, et al. Global study of viral
diarrhea in hospitalized children in Spain: Results of Structural Surveillance of Viral Gastroenteritis Net Work
(VIGESS-net) 2006-2008. Journal of Clinical Virology. 2011;52(4):353-8.
168. Lorgelly PK, Joshi D, Gomara MI, Gray J, Mugford M. Exploring the cost effectiveness of an immunization
programme for rotavirus gastroenteritis in the United Kingdom (Structured abstract). Epidemiology and
Infection. 2008;136(1):[44-55].
169. Iturriza-Gomara M, Elliot AJ, Dockery C, Fleming DM, Gray JJ. Structured surveillance of infectious intestinal
disease in pre-school children in the community: "The Nappy Study". Epidemiology and Infection.
2009;137(7):922-31.
170. Amar CFL, East CL, Gray J, Iturriza-Gomara M, Maclure EA, McLauchlin J. Detection by PCR of eight groups
of enteric pathogens in 4,627 faecal samples: Re-examination of the English case-control Infectious
Intestinal Disease Study (1993-1996). European Journal of Clinical Microbiology and Infectious Diseases.
2007;26(5):311-23.
171. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of
an attenuated vaccine against severe rotavirus gastroenteritis. New England Journal of Medicine.
2006;354(1):11-22.
172. Vesikari T, Matson D, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a
pentavalent human-bovine (WC3) reassortant rotavirus vaccine. New England Journal of Medicine.
2006;5(354):23-33.
173. Soares-Weiser K, MacLehose H, Bergman H, Ben-Aharon I, Nagpal S, Goldberg E, et al. Vaccines for
preventing rotavirus diarrhoea: vaccines in use. Cochrane Database of Systematic Reviews. 2012; (11).
Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008521.pub3/abstract.
174. Phua KB, Lim FS, Lau YL, Nelson EA, Huang LM, Quak SH, et al. Rotavirus vaccine RIX4414 efficacy
sustained during the third year of life: a randomized clinical trial in an Asian population. Vaccine. 2012 Jun
22;30(30):4552-7. PubMed PMID: 22497874. Epub 2012/04/14.
175. Vesikari T, Karvonen A, Ferrante SA, Kuter BJ, Ciarlet M. Sustained efficacy of the pentavalent rotavirus
vaccine, RV5, up to 3.1 years following the last dose of vaccine. The Pediatric Infectious Disease Journal.
2010 Oct;29(10):957-63. PubMed PMID: 20442684. Epub 2010/05/06.
176. Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor J, Cohen R, et al. Efficacy of human rotavirus vaccine
against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind
controlled study. Lancet. 2007;370(9601):1757-63.
177. Koch J, al. E. Background paper to the recommendation for routine rotavirus vaccination of infants in
Germany. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2013;56(7):957-84.
178. Recommendation for rotavirus vaccination standards for infants in Germany. Bundesgesundheitsblatt
Gesundheitsforschung Gesundheitsschutz. 2013;56(7):955-6.
179. Zaman K, Anh DD, Victor JC, Shin S, Yunus M, Dallas MJ, et al. Efficacy of pentavalent rotavirus vaccine
against severe rotavirus gastroenteritis in infants in developing countries in Asia: A randomised, double-
blind, placebo-controlled trial. The Lancet. 2010;376(9741):615-23.
180. Nguyen LT. VIEW-hub Report: Global Vaccine Introduction and Implementation International Vaccine. 2016.
Available at: https://www.jhsph.edu/research/centers-and-institutes/ivac/view-
hub/IVAC_VIMS_Report%202016Mar_public_FINAL.pdf
181. Bellido-Blasco JB, Sabater-Vidal S, Salvador-Ribera Mdel M, Arnedo-Pena A, Tirado-Balaguer MD, Meseguer-
Ferrer N, et al. Rotavirus vaccination effectiveness: a case-case study in the EDICS project, Castellon
(Spain). Vaccine. 2012 Dec 14;30(52):7536-40. PubMed PMID: 23103196. Epub 2012/10/30.
182. Boom J, Tate J, Sahni L, Rench M, Hull J, Gentsch J, et al. Effectiveness of pentavalent rotavirus vaccine in a
large urban population in the United States. Pediatrics. 2010;125(2):e199-e207.
183. Braeckman T, Herck K, Meyer N, Pircon JY, Soriano-Gabarro M, Heylen E, et al. Effectiveness of rotavirus
vaccination in prevention of hospital admissions for rotavirus gastroenteritis among young children in
Belgium: Case-control study. BMJ [Online]. 2012;345(7872).
71
184. Castilla J, Beristain X, Martinez-Artola V, Navascues A, Garcia Cenoz M, Alvarez N, et al. Effectiveness of
rotavirus vaccines in preventing cases and hospitalizations due to rotavirus gastroenteritis in Navarre, Spain.
Vaccine. 2012;30(3):539-43.
185. Cortese M, Immergluck L, Held M, Jain S, Chan T, Grizas A, et al. Effectiveness of monovalent and
pentavalent rotavirus vaccine. Pediatrics. 2013;132(1):e25-33.
186. Cortese M, LeBlanc J, White K, Jerris R, Stinchfield P, Preston K, et al. Leveraging state immunization
information systems to measure the effectiveness of rotavirus vaccine. Pediatrics. 2011;128(6):e1474-e81.
187. Desai SN, Esposito DB, Shapiro ED, Dennehy PH, Vazquez M. Effectiveness of rotavirus vaccine in
preventing hospitalization due to rotavirus gastroenteritis in young children in Connecticut, USA. Vaccine.
2010;28(47):7501-6.
188. Donauer S, Payne DC, Edwards K, Szilagyi P, Hornung R, Weinberg G, et al. Determining the effectiveness of
the pentavalent rotavirus vaccine against rotavirus hospitalizations and emergency department visits using
two study designs. Vaccine. 2013;31(24):2692-7.
189. Guh A, Hadler J. Use of the state immunization information system to assess rotavirus vaccine effectiveness
in Connecticut, 2006-2008. Vaccine. 2011 Aug 26;29(37):6155-8. PubMed PMID: 21723356. Epub
2011/07/05.
190. Martinon-Torres F, Bouzon Alejandro M, Redondo Collazo L, Sanchez Lastres JM, Pertega Diaz S, Seoane
Pillado MT, et al. Effectiveness of rotavirus vaccination in Spain. Human Vaccines. 2011;7(7):757-61.
191. Muhsen K, Shulman L, Kasem E, Rubinstein U, Shachter J, Kremer A, et al. Effectiveness of rotavirus
vaccines for prevention of rotavirus gastroenteritis-associated hospitalizations in Israel: A case-control study.
Human Vaccines. 2010;6(6):450-4.
192. Staat M, Payne D, Donauer S, Weinberg G, Edwards K, Szilagyi P, et al. Effectiveness of pentavalent
rotavirus vaccine against severe disease. Pediatrics. 2011;128(2):e267-e75.
193. Field E, Vally H, Grimwood K, Lambert P. Pentavalent rotavirus vaccine and prevention of gastroenteritis
hospitalisations in Australia. Pediatrics. 2010.
194. Gagneur A, Nowak E, Lemaitre T, Segura J, Delaperriere N, Abalea L, et al. Impact of rotavirus vaccination
on hospitalizations for rotavirus diarrhea: The IVANHOE study. Vaccine. 2011;29(21):3753-9.
195. Panozzo C, Becker-Dreps S, Pate V, Weber D, Jonsson Funk M, Sturmer T, et al. Direct, indirect, total and
overall effectiveness of the rotavirus vaccines for the prevention of gastroenteritis hospitalzations in
privately insured US children, 2007-2010 American Journal of Epidemiology. 2014;179(7):895-909.
196. Wang F, Mast T, Glass R, Loughlin J, Seeger J. Effectiveness of the pentavalent rotavirus vaccine in
preventing gastroenteritis in the United States. Pediatrics. 2010;125(2):e208-e13.
197. Payne DC, Staat MA, Edwards KM. Direct and indirect effects of rotavirus vaccination upon childhood
hospitalizations in 3 US counties, 2006-2009. Clinical Infectious Diseases: an official publication of the
198. Correia M, Patel A, Nakagomi O, Montenegro F, Germano E, Correia N, et al. Effectiveness of monovalent
rotavirus vaccine (rotarix) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil.
Journal of Infectious Diseases. 2010;201(3):363-9.
199. Patel M, Pedreira C, De Oliveira L, Tate J, Orozco M, Mercado J, et al. Association between pentavalent
rotavirus vaccine and severe rotavirus diarrhea among children in Nicaragua. JAMA - Journal of the
American Medical Association. 2009;301(21):2243-51.
200. Snelling TL, Andrews RM, Kirkwood CD, Culvenor S, Carapetis JR. Case-control evaluation of the
effectiveness of the G1P[8] human rotavirus vaccine during an outbreak of rotavirus G2P[4] infection in
central Australia. Clinical Infectious Diseases. 2011;52(2):191-9.
201. Armah G, Lewis K, Cortese M, Parashar U, Ansah A, Gazley A, et al. A Randomized, Controlled Trial of the
Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural
Ghanaian Infants. J Infect Dis. 2016;213 (11):1678-85.
202. Msimang V, Page N, Groome M, Moyes J, Cortese M, Seheri M, et al. Impact of Rotavirus Vaccine on
Childhood Diarrheal Hospitalization Following Introduction into the South African Public Immunization
Program. Pediatr Infect Dis J 2013.
203. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomez-Altamirano
C, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. The New England
Journal of Medicine. 2010;362(4):299-305.
204. Sánchez-Uribe E, Esparza-Aguilar M, Parashar U, Richardson V. Sustained Reduction of Childhood Diarrhea-
Related Mortality and Hospitalizations in Mexico After Rotavirus Vaccine Universalization. Clin Infect Dis. May
1; doi: 101093/cid/civ1205. 2016;62(Suppl 2):S133-9.
205. Payne D, Baggs J, Zerr D, Klein N, Yih K, Glanz J, et al. Protective association between rotavirus vaccination
and childhood seizures in the year following vaccination in US children. Clinical Infectious Diseases: an
official publication of the Infectious Diseases Society of America. 2014;58(2):173-7.
72
206. Sheridan S, Ware R, Grimwood K, Lambert S. Febrile Seizures in the Era of Rotavirus Vaccine. J Pediatric
Infect Dis Soc. 2016;5(2):206-9.
207. Pardo-Seco J, Cebey-López M, Martinón-Torres N, Salas A, Gómez-Rial J, Rodriguez-Tenreiro C, et al. Impact
of Rotavirus Vaccination on Childhood Hospitalization for Seizures. Pediatr Infect Dis J 2015;34(7):769-73.
208. Yeom J, Kim Y, Kim R, Park J, Seo J, Park E, et al. Impact of rotavirus vaccine introduction on rotavirus-
associated seizures and a related possible mechanism. J Child Neurol. 2015;30(6):729-34.
209. Hemming-Harlo M, Vesikari T, Uhari M, Renko M, Salminen M, Torcel-Pagnon L, et al. Sustained High
Effectiveness of RotaTeq on Hospitalizations Attributable to Rotavirus-Associated Gastroenteritis During 4
Years in Finland. J Pediatric Infect Dis Soc 2016.
210. Hemming-Harlo M, Markkula J, Huhti L, Salminen M, Vesikari T. Decrease of Rotavirus Gastroenteritis to a
Low Level Without Resurgence for Five Years After Universal RotaTeq Vaccination in Finland. Pediatr Infect
Dis J. 2016;35(12):1304-8.
211. Markkula J, Hemming-Harlo M, Salminen M, Savolainen-Kopra C, Pirhonen J, Al-Hello H, et al. Rotavirus
epidemiology 5-6 years after universal rotavirus vaccination: persistent rotavirus activity in older children
and elderly. Infect Dis (Lond). 2017;9:1-8.
212. Payne D, Selvarangan R, Azimi P, Boom J, Englund J, Staat M, et al. Long-term Consistency in Rotavirus
Vaccine Protection: RV5 and RV1 Vaccine Effectiveness in US Children, 2012-2013. Clin Infect Dis. Dec 15;
doi: 101093/cid/civ872 Epub 2015 Oct 8. 2015;6(12):1792-9.
213. Clemens J, Shin S, Ali M. New approaches to the assessment of vaccine herd protection in clinical trials. The
Lancet Infectious Diseases. 2011;11:482-7.
214. John T, Samuel R. Herd immunity and herd effect: new insights and definitions. J Epidemiology.
2000;16(7):601-6.
215. Payne D, Edwards K, Bowen M, Keckley E, Peters J, Esona M, et al. Sibling transmission of vaccine-derived
rotavirus (RotaTeq) associated with rotavirus gastroenteritis. Pediatrics. 2010;125(2):e438-41.
216. Van Effelterre T, Soriano-Gabarro M, Debrus S, Claire Newbern E, Gray J. A mathematical model of the
indirect effects of rotavirus vaccination. Epidemiology and infection. 2010 Jun;138(6):884-97. PubMed
PMID: 20028612. Epub 2009/12/24.
217. Anderson E, Reddy S, Katz B, Noskin G. Indirect protection and indirect measures of protection from
rotavirus in adults. The Journal of infectious diseases. 2012 Jun;205(11):1762-4; author reply 4-5. PubMed
PMID: 22457285. Epub 2012/03/30.
218. Begue R, Perrin K. Reduction in gastroenteritis with the use of pentavalent rotavirus vaccine in a primary
practice. Pediatrics. 2010;126(1):e40-e5.
219. Belshaw D, Muscatello D, Ferson M, Nurkic A. Rotavirus vaccination one year on. Communicable Diseases
Intelligence Quarterly Report. 2009 Sep;33(3):337-40. PubMed PMID: 20043605. Epub 2010/01/02.
220. Buttery J, Lambert S, Grimwood K, Nissen M, Field E, Macartney K, et al. Reduction in rotavirus-associated
acute gastroenteritis following introduction of rotavirus vaccine into Australia's National Childhood vaccine
schedule. The Pediatric Infectious Disease Journal. 2011 Jan;30(1 Suppl):S25-9. PubMed PMID: 21183837.
Epub 2011/01/13.
221. Chang H, Smith P, Tserenpuntsag B, Markey K, Parashar U, Morse D. Reduction in hospitalizations for
diarrhea and rotavirus infections in New York state following introduction of rotavirus vaccine. Vaccine.
2010;28(3):754-8.
222. Clark H, Lawley D, Mallette L, DiNubile M, Hodinka R. Decline in cases of rotavirus gastroenteritis presenting
to The Children's Hospital of Philadelphia after introduction of a pentavalent rotavirus vaccine. Clinical and
vaccine immunology : CVI. 2009 Mar;16(3):382-6. PubMed PMID: 19158283. Pubmed Central PMCID:
PMC2650872. Epub 2009/01/23.
223. Clarke M, Davidson G, Gold M, Marshall H. Direct and indirect impact on rotavirus positive and all-cause
gastroenteritis hospitalisations in South Australian children following the introduction of rotavirus
vaccination. Vaccine. 2011;29(29-30):4663-7.
224. Cortes J, Curns A, Tate J, Cortese M, Patel M, Zhou F, et al. Rotavirus vaccine and health care utilization for
diarrhea in U.S. children. New England Journal of Medicine. 2011;365(12):1108-17.
225. Cortese M, Tate J, Simonsen L, Edelman L, Parashar U. Reduction in gastroenteritis in United States children
and correlation with early rotavirus vaccine uptake from national medical claims databases. The Pediatric
Infectious Disease Journal. 2010 Jun;29(6):489-94. PubMed PMID: 20354464. Epub 2010/04/01
226. Curns A, Steiner C, Barrett M, Hunter K, Wilson E, Parashar U. Reduction in acute gastroenteritis
hospitalizations among US children after introduction of rotavirus vaccine: analysis of hospital discharge
data from 18 US states. The Journal of Infectious Diseases. 2010;201(11):1617-24.
227. Dey A, Wang H, Menzies R, Macartney K. Changes in hospitalisations for acute gastroenteritis in Australia
after the national rotavirus vaccination program. The Medical Journal of Australia. 2012 Oct 15;197(8):453-
7. PubMed PMID: 23072242. Epub 2012/10/18.
73
228. Eberly M, Gorman G, Eide M, Olsen C, Rajnik M. The effect of rotavirus immunization on rotavirus
gastroenteritis hospitalization rates in military dependents. Vaccine. 2011;29(4):650-9.
229. Hanquet G, Ducoffre G, Vergison A, Neels P, Sabbe M, Van Damme P, et al. Impact of rotavirus vaccination
on laboratory confirmed cases in Belgium. Vaccine. 2011;29(29-30):4698-703.
230. Lambert S, Faux C, Hall L, Birrell F, Peterson V, Selvey C, et al. Early evidence for direct and indirect effects
of the infant rotavirus vaccine program in Queensland. Medical Journal of Australia. 2009;191(3):157-60.
231. Lanzieri T, Linhares A, Costa I, al. E. Impact of rotavirus vaccination on childhood deaths from diarrhea in
Brazil International Journal of Infectious Diseases: IJID: official publication of the International Society for
Infectious Diseases. 2011;15(3):e206-e10.
232. Lopman B, Curns A, Yen C, Parashar U. Infant rotavirus vaccination may provide indirect protection to older
children and adults in the United States. The Journal of Infectious Diseases. 2011 Oct 1;204(7):980-6.
PubMed PMID: 21878425. Epub 2011/09/01.
233. Macartney K, Porwal M, Dalton D, Cripps T, Maldigri T, Isaacs D, et al. Decline in rotavirus hospitalisations
following introduction of Australia's national rotavirus immunisation programme. Journal of Paediatrics and
Child Health. 2011 May;47(5):266-70. PubMed PMID: 21244557. Epub 2011/01/20.
234. Molto Y, Cortes J, De Oliveira L, Mike A, Solis I, Suman O, et al. Reduction of diarrhea-associated
hospitalizations among children aged <5 years in panama following the introduction of rotavirus vaccine.
Pediatric Infectious Disease Journal. 2011;30(Suppl. 1):S16-S20.
235. Paulke-Korinek M, Kundi M, Rendi-Wagner P, de Martin A, Eder G, Schmidle-Loss B, et al. Herd immunity
after two years of the universal mass vaccination program against rotavirus gastroenteritis in Austria.
Vaccine. 2011;29(15):2791-6.
236. Raes M, Strens D, Vergison A, Verghote M, Standaert B. Reduction in pediatric rotavirus-related
hospitalizations after universal rotavirus vaccination in Belgium. The Pediatric Infectious Disease Journal.
2011 Jul;30(7):e120-5. PubMed PMID: 21436757. Epub 2011/03/26.
237. Yen C, Armero Guardado J, Alberto P, Rodriguez Araujo D, Mena C, Cuellar E, et al. Decline in rotavirus
hospitalizations and health care visits for childhood diarrhea following rotavirus vaccination in El Salvador.
The Pediatric Infectious Disease Journal. 2011 Jan;30(1 Suppl):S6-S10. PubMed PMID: 21048524. Epub
2010/11/05.
238. Yen C, Tate J, Wenk J, Harris Jn, Parashar U. Diarrhoea-associated hospitalization among US children over 2
rotavirus seasons after vaccine introduction. Pediatrics. 2011;127(1):e9-e15.
239. Anderson E, Shippee D, Weinrobe M, Davila M, Katz B, Reddy S, et al. Indirect protection of adults from
rotavirus by pediatric rotavirus vaccination. Clinical infectious diseases: an official publication of the
240. Mast T, Wang F, Su S, Seeger J. Evidence of herd immunity and sustained impact of rotavirus vaccination on
the reduction of rotavirus-related medical encounters among infants from 2006 through 2011 in the United
States. Pediatr Infect Dis J. 2015;34(6):615-20.
241. Gastanaduy P, Curns A, Parashar U, Lopman B. Gastroenteritis hospitalizations in older children and adults in
the United States before and after implementation of infant rotavirus vaccination. JAMA: the Journal of the
American Medical Association. 2013;310(8):851-3.
242. Sabbe M, Berger N, Blommaert A, Ogunjimi B, Grammens T, Callens M, et al. , et al. Sustained low rotavirus
activity and hospitalisation rates in the post-vaccination era in Belgium, 2007 to 2014. Euro Surveill.
2016;21(27).
243. Pollard S, Malpica-Llanos T, Friberg I, Fischer-Walker C, Ashraf H, Walker N. Estimating the herd immunity
effect of rotavirus vaccine. Vaccine. 2015;33:3795-800.
244. Ngabo F, Tate J, Gatera M, Rugambwa C, Donnen P, Lepage P, et al. Effect of pentavalent rotavirus vaccine
introduction on hospital admissions for diarrhoea and rotavirus in children in Rwanda: a time-series analysis.
Lancet Glob Health. 2016;4()(2):e129-36.
245. de Pagter A, Bredius R, Kuijpers T, Tramper J, van der Burg M, van Montfrans J, et al. Overview of 15-year
severe combined immunodeficiency in the Netherlands: towards newborn blood spot screening. Eur J
Pediatr. 2015.
246. Diamond C, Sanchez M, LaBelle J. Diagnostic Criteria and Evaluation of Severe Combined Immunodeficiency
in the Neonate. Pediatr Ann. 2015;44(7):e181-7.
247. Markkula J, Hemming M, Vesikari T. Detection of vaccine-derived rotavirus strains in
nonimmunocompromised children up to 3-6 months after RotaTeq® vaccination. Pediatr Infect Dis J Mar;
2015 34(3):296-8.
248. Jiang J. Childhood intussusception: a literature review. . PLoS One. 2013;8(7):68482.
249. Johnson B, Gargiullo P, Murphy TV, Parashar UD, Patel MM. Factors associated with bowel resection among
infants with intussusception in the United States. Pediatric Emergency Care. 2012 Jun;28(6):529-32.
PubMed PMID: 22653458. Epub 2012/06/02.
74
250. Parashar UD, Holman RC, Cummings KC, Staggs NW, Curns AT, Zimmerman CM, et al. Trends in
intussusception-associated hospitalizations and deaths among US infants. Pediatrics. 2000 Dec;106(6):1413-
21. PubMed PMID: 11099597. Epub 2000/01/11.
251. Huppertz H, Soriano-Gabarro M, Grimprel E, Franco E, Mezner Z, Desselberger U, et al. Intussusception
among young children in Europe. The Pediatric Infectious Disease Journal. 2006 Jan;25(1 Suppl):S22-9.
PubMed PMID: 16397426. Epub 2006/01/07.
252. Bines J, Liem N, Justice F, Son T, Kirkwood C, de Campo M, et al. Risk factors for intussusception in infants in
Vietnam and Australia: Adenovirus implicated, but not rotavirus. Journal of Pediatrics. 2006;149(4):452-60.
253. Chen Y, Beasley S, Grimwood K. Intussusception and rotavirus associated hospitalisation in New Zealand.
Archives of Disease in Childhood. 2005;90(10):1077-81.
254. Samad L, Bashir H, Marven S, Cameron JC, Lynn R, Sutcliffe A, et al. Intussusception in the first year of life:
A UK national surveillance study. Archives of Disease in Childhood. 2010;95:A1.
255. Samad L, Cortina-Borja M, Bashir H, Sutcliffe A, Marven S, Cameron J, et al. Intussusception incidence
among infants in the UK and Republic of Ireland: a pre-rotavirus vaccine prospective surveillance study.
Vaccine 2013;31(38):4098-102.
256. Weiss S, Streng A, Kries R, Liese J, Wirth S, Jenke A. Incidence of intussusception in early infancy: a
capture-recapture estimate for Germany. Klinische Padiatrie. 2011 Dec;223(7):419-23. PubMed PMID:
21698555. Epub 2011/06/24.
257. Bissantz N, Jenke AC, Trampisch M, Klaassen-Mielke R, Bissantz K, Trampisch H, et al. Hospital-based,
prospective, multicentre surveillance to determine the incidence of intussusception in children aged below
15 years in Germany. BMC Gastroenterology. 2011;11:26. PubMed PMID: 21435207. Pubmed Central
PMCID: PMC3079686. Epub 2011/03/26.
258. Zwiauer KF, Weinzettel R, Zwiauer VM. Clinical manifestation of intusseption before and after introduction of
an oral rotavirus vaccine in austria. Journal of Pediatric Gastroenterology and Nutrition. 2011;52:E165-E6.
259. Jenke A, Klaassen-Mielke R, Zilbauer M, Heininger U, Trampisch H, Wirth S. Intussusception: incidence and
treatment-insights from the nationwide German surveillance. Journal of Pediatric Gastroenterology and
nutrition. 2011 Apr;52(4):446-51. PubMed PMID: 21415671. Epub 2011/03/19.
260. Buettcher M, Baer G, Bonhoeffer J, Schaad U, Heininger U. Three-year surveillance of intussusception in
children in Switzerland. Pediatrics. 2007;120(3):473-80.
261. Fischer T, Bihrmann K, Perch M, Koch A, Wohlfahrt J, Kåre M, et al. Intussusception in early childhood: a
cohort study of 1.7 million children. Pediatrics. 2004;114(3):782-5.
262. Rotavirus report. Chapter 5.3.2.5 Rotavirus. Surveillance and developments in 2015-2016. 2016:67.
263. Restivo V, Costantino C, Tramuto F, Vitale F. Hospitalization rates for intussusception in children aged 0-59 months
from 2009 to 2014 in Italy. Human Vaccines & Immunotherapeutics. 2017 [online]: 11 Jan 2017:1-5.
264. Samad L, Marven S, El Bashir H, Sutcliffe AG, Cameron JC, Lynn R, et al. Prospective surveillance study of
the management of intussusception in UK and Irish infants. Br J Surg. 2012;99(3):411-5.
265. Simonsen L, Viboud C, Elixhauser A, Taylor R, Kapikian A. More on RotaShield and intussusception: The role
of age at the time of vaccination. Journal of Infectious Diseases. 2005;192(Suppl. 1):S36-S43.
266. Haber P, Patel M, Pan Y, Baggs J, Haber M, Museru O, et al. Intussusception After Rotavirus Vaccines
Reported to US VAERS, 2006-2012. Pediatrics 2013;131:1042.
267. Shui I, Baggs J, Patel M, Parashar U, Rett M, Belongia E, et al. Risk of intussusception following
administration of a pentavalent rotavirus vaccine in US infants. JAMA - Journal of the American Medical
Association. 2012;307(6):598-604.
268. Weintraub A, Weintraub ES, Baggs J, Duffy J, Vellozzi C, Belongia EA, et al. Risk of intussusception after
monovalent rotavirus vaccination. The New England Journal of Medicine. 2014;370(6):513-9.
269. Oberle D, Jenke A, Von Kries R, Mentzer D, Keller-Stanislawski B. Rotavirus vaccination: a risk factor for
intussusception? Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2014;57(2):234-41.
270. Patel M, Lopez-Collada V, Bulhoes M, De Oliveira L, Marquez A, Flannery B, et al. Intussusception risk and
health benefits of rotavirus vaccination in Mexico and Brazil. New England Journal of Medicine.
2011;364(24):2283-92.
271. Escolano S, Hill C, Tubert-Bitter P. Intussusception risk after RotaTeq vaccination: Evaluation fromworldwide
spontaneous reporting data using a self-controlled caseseries approach. Vaccine 33 (2015) 1017–1020.
2015;2015(1017-1020).
272. Velazquez F, Colindres R, Grajales C, Hernandez M, Mercadillo M, Torres F, et al. Postmarketing surveillance
of intussusception following mass introduction of the attenuated human rotavirus vaccine in Mexico. The
Pediatric Infectious Disease Journal. 2012 Jul;31(7):736-44. PubMed PMID: 22695189. Epub 2012/06/15.
273. Carlin J, Macartney K, Lee K, Quinn H, Buttery J, Lopert R, et al. Intussusception Risk and Disease
Prevention AssociatedWith Rotavirus Vaccines in Australia’s National Immunization Program. Clinical
Infectious Diseases. 2013.
75
274. Quinn H, Wood N, Cannings K, Dey A, Wang H, Menzies R, et al. Intussusception after monovalent human
rotavirus vaccine in Australia: severity and comparison of using healthcare database records versus case
confirmation to assess risk. Pediatr Infect Dis J. 2014;33(9):959-65.
275. Haber P, Patel M, Pan Y, Baggs J, Haber M, Museru O, et al. Intussusception after rotavirus vaccines
reported to US VAERS, 2006-2012. Pediatrics. 2013;131(6):1042-9.
276. Yih W, Lieu T, Kulldorff M, Martin D, McMahill-Walraven C, Platt R, et al. Intussusception risk after rotavirus
vaccination in U.S. infants. N Engl J Med. 2014;370(6):503-12.
277. Belongia E, Irving S, Shui I, Kulldorff M, Lewis E, Yin R, et al. Real-time surveillance to assess risk of
intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine. The Pediatric
Infectious Disease Journal. 2010 Jan;29(1):1-5. PubMed PMID: 19907356. Epub 2009/11/13.
278. Rosillon D, Buyse H, Friedland L, Ng S, Velázquez F, Breuer T. Risk of Intussusception After Rotavirus
Vaccination: Meta-analysis of Postlicensure Studies. Pediatr Infect Dis J. 2015;34(7):763-8.
279. Escalano S, Farrington C, Hill C, Tubert-Bitter P. Intussusception after rotavirus vaccination--spontaneous
reports. N Engl J Med. 2011;365(22):2139.
280. Yung C, Chan S, Soh S, Tan A, Thoon K. Intussusception and monovalent rotavirus vaccination in Singapore:
self-controlled case series and risk-benefit study. J Pediatrics. 2015;167(1):163-8.
281. Koch J, Harder H, Von Kries R, Wichmann O. Risk of intussuscpetion after rotavrius vaccination - a
systematic literature review and meta-analysis. Deutsches Ärtzeblatt International. 2017;114:255-62.
282. Hua W, Izurieta H, Slade B, Belay E, Haber P, Tiernan R, et al. Kawasaki disease after vaccination: Reports
to the vaccine adverse event reporting system 1990-2007. Pediatric Infectious Disease Journal.
2009;28(11):943-7.
283. Jit M, Edmunds W. Evaluating rotavirus vaccination in England and Wales. Part II: The potential cost-
effectiveness of vaccination (Structured abstract). Vaccine. 2007; 25(20):[3971-9].
284. Martin A, Batty A, Roberts J, Standaert B. Cost-effectiveness of infant vaccination with RIX4414
(Rotarix(trademark)) in the UK. Vaccine. 2009;27(33):4520-8.
285. Salo H, Ollgren J, Linna M, Sintonen H, Kilpi T. Economic evaluation of rotavirus vaccination in Finland
[poster]. Eur J Public Health. 2007;17(Suppl 2):S3-36.
286. Nohynek H, Salo H, Renko M, Leino T. Finland introduces rotavirus vaccine into the national vaccination
programme in September 2009. Euro surveillance : bulletin europeen sur les maladies transmissibles =
European communicable disease bulletin. 2009;14(35). PubMed PMID: 19728979. Epub 2009/09/05.
287. Melliez H, Levybruhl D, Boelle PY, Dervaux B, Baron S, Yazdanpanah Y. Cost and cost-effectiveness of
childhood vaccination against rotavirus in France (Structured abstract). Vaccine. 2008; 26(1):[706-15].
288. Standaert B, Parez N, Tehard B, Colin X, Detournay B. Cost-effectiveness analysis of vaccination against
rotavirus with RIX4414 in France. Applied Health Economics and Health Policy. 2008;6(4):199-216.
289. Yamin D, Atkins K, Remy V, Galvani A. Cost-Effectiveness of Rotavirus Vaccination in France-Accounting for
Indirect Protection. Value Health Sep - Oct; doi: 101016/jjval201605011 Epub 2016 Jul 15. 2016 19(6):811-9.
290. Knoll S, Mair C, Benter U, Vouk K, Standaert B. Will vaccination against rotavirus infection with RIX4414 be
cost-saving in Germany? Health Economics Review. 2013;3(27):1-11.
291. Aidelsburger P, Grabein K, Böhm K, Dietl M, Wasem J, Koch J, et al. Cost-effectiveness of childhood rotavirus
vaccination in Germany. Vaccine. 2014;32(17):1964-74.
292. Tilson L, Jit M, Schmitz S, Walsh C, Garvey P, McKeown P, et al. Cost-effectiveness of universal rotavirus
vaccination in reducing rotavirus gastroenteritis in Ireland. Vaccine. 2011;29(43):7463-73.
293. Giammanco M, Coniglio M, Pignato S, Giammanco G. An economic analysis of rotavirus vaccination in Italy.
Vaccine. 2009;27(29):3904-11.
294. Goossens L, Standaert B, Hartwig N, Hovels A, Al M. The cost-utility of rotavirus vaccination with Rotarix
(RIX4414) in the Netherlands. Vaccine. 2008 Feb 20;26(8):1118-27. PubMed PMID: 18215445. Epub
2008/01/25.
295. Zomer T, van Duynhoven Y, Mangen M, van der Maas N, Vennema H, Boot H, et al. Assessing the
introduction of universal rotavirus vaccination in the Netherlands. Vaccine. 2008;26(29-30):3757-64.
296. Mangen M, van Duynhoven Y, Vennema H, van Pelt W, Havelaar A, de Melker H. Is it cost-effective to introduce
rotavirus vaccination in the Dutch national immunization program? Vaccine. 2010;28(14):2624-35.
297. Rozenbaum M, Mangen M, Giaquinto C, Wilschut J, Hak E, Postma M. Cost-effectiveness of rotavirus
vaccination in the Netherlands; the results of a consensus model. BMC Public Health. 2011;11:462. PubMed
PMID: 21663620. Pubmed Central PMCID: PMC3129591. Epub 2011/06/15.
298. Perez-Rubio A, Luquero FJ, Eiros Bouza J, Castrodeza Sanz J, Bachiller Luque M, de Lejarazu R, et al. Socio-
economic modelling of rotavirus vaccination in Castilla y Leon, Spain. Le infezioni in medicina : rivista
periodica di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive. 2011
Sep;19(3):166-75. PubMed PMID: 22037437. Epub 2011/11/01.
76
299. Imaz I, Rubio B, Cornejo A, Gonzalez-Enriquez J. Budget impact and cost-utlity analysis of universal infant
rotavirus vaccination in Spain. Preventive Medicine. 2014;61:116-21.
300. Atkins K, Shim E, Carroll S, Quilici S, Galvani A. The cost-effectiveness of pentavalent rotavirus vaccination
in England and Wales. Vaccine. 2012;30(48):6766-76.
301. Veldwijk J, Lambooij M, Bruijning-Verhagen P, Smit H, de Wit G. Parental preferences for rotavirus
vaccination in young children: a discrete choice experiment. Vaccine. 2014;32(47):6277-83.
302. Peralta A. Knowledge and attitudes of public health residents to immunisation programmes from 5 European
countries European Journal of Epidemiology. 2012;27(1):S109.
303. Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of
diarrhoeal episodes. Scand J Infect Dis. 1990;22(3):259-67.
77
European Centre for Disease
Prevention and Control (ECDC)
Postal address:
Granits väg 8, SE-171 65 Solna, Sweden Subscribe to our publications
www.ecdc.europa.eu/en/publications
Visiting address:
Tomtebodavägen 11a, SE-171 65 Solna, Sweden Contact us
[email protected]
Tel. +46 858601000
Fax +46 858601001 Follow us on Twitter
www.ecdc.europa.eu @ECDC_EU
An agency of the European Union Like our Facebook page
www.europa.eu www.facebook.com/ECDC.EU
ECDC is committed to ensuring the transparency and independence of its work

In accordance with the Staff Regulations for Officials and Conditions of Employment of Other Servants of the European Union and the
ECDC Independence Policy, ECDC staff members shall not, in the performance of their duties, deal with a matter in which, directly or
indirectly, they have any personal interest such as to impair their independence. Declarations of interest must be received from any
prospective contractor(s) before any contract can be awarded.
www.ecdc.europa.eu/en/aboutus/transparency
HOW TO OBTAIN EU PUBLICATIONS

Free publications:
• one copy:
via EU Bookshop (http://bookshop.europa.eu);
• more than one copy or posters/maps:
from the European Union’s representations (http://ec.europa.eu/represent_en.htm);
from the delegations in non-EU countries (http://eeas.europa.eu/delegations/index_en.htm);
by contacting the Europe Direct service (http://europa.eu/europedirect/index_en.htm) or
calling 00 800 6 7 8 9 10 11 (freephone number from anywhere in the EU) (*).
(*) The information given is free, as are most calls (though some operators, phone boxes or hotels may charge you).
Priced publications:
• via EU Bookshop (http://bookshop.europa.eu).

Rotavirus-Vaccination-Expert Opinion-September-2017

Uploaded by

Copyright:

Available Formats

Rotavirus-Vaccination-Expert Opinion-September-2017

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Rotavirus-Vaccination-Expert Opinion-September-2017

Uploaded by

Copyright:

Available Formats

SCIENTIFIC ADVICE

Expert opinion on rotavirus

Expert opinion on rotavirus vaccination in

Stockholm, September 2017

© European Centre for Disease Prevention and Control, 2017

Cost-effectiveness in EU/EEA Member States

Rotavirus immunisation programmes in EU/EEA

Attitudes to rotavirus vaccination among parents and healthcare

Conclusions and possible implications for public health

*Further information available at www.eurorota.net

Infections in immunocompromised children

Infections in family and household members

Risk factors for severe disease

Infectious dose and virus shedding

Protective efficacy induced by natural disease against subsequent

Serological correlates for protection including cross-immunity

Rotavirus vaccines available in EU/EEA countries

Breastfeeding and rotavirus vaccination

Concomitant administration of other paediatric vaccines

Vaccination of premature infants

Table 1. Rotavirus vaccine contents, indications, contraindications, route of administration, dose

 Diarrhoea and vomiting < 1:10*  Fever ≥ 1:10

Vaccination of infants with immunodeficiency and immunodeficient

Vaccination of infants with other underlying medical disorders

Vaccination of infants exposed to biological therapy in utero

2, 3 months Germany 240 82.1 [75.1-87.7]

2, 4 months Spain 275 85.5 [79.6-90.2] 89 12.4 [6.3-21.0]

3, 5 months Finland 272 94.6 [90.0-97.5]

3, 4 months Czech Republic 272 84.6 [78.5-89.5] 90 2.2 [0.3-7.8]

2, 4 and 6 months 11 countries 189 95.2 [91.2-97.8] 161 14.3 [9.3-20.7]

2, 4 and 6 months US, Finland* 67 95.5 73 12.3

* Study performed at end of shelf life

Contamination of RV1 and RV5 vaccines with porcine circovirus

Rotavirus vaccines authorised in non-EU/EEA countries and

Overview of human rotaviruses6

Post-authorisation monitoring of circulating rotavirus

Rotavirus strain surveillance to exclude strain replacement

Rotavirus strain diversity

Rotavirus immunisation programmes in EU/EEA countries

Methodology used for evaluating burden of severe rotavirus

Methodology used for evaluating rotavirus vaccine efficacy

Methodology used for evaluating rotavirus vaccine

Methodology used for evaluating rotavirus vaccine-induced

Methodology used for evaluating rotavirus vaccine safety

Methodology used for evaluating rotavirus vaccine cost-

Methodology used for evaluating attitudes to rotavirus

Expert panel opinion

Updated Expert Opinion following ECDC Advisory forum

Identified knowledge gaps and needs for capacity building

Rotavirus vaccine efficacy

*X-axis in log scale

Cross-protection against other genotypes

Identified knowledge gaps and needs for capacity building

Rotavirus vaccine effectiveness

Case-control studies conducted in low rotavirus-mortality settings

*X-axis in log scale

Cohort studies conducted in low rotavirus-mortality settings

* X-axis in log scale

Effectiveness in high rotavirus-mortality settings