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Rotavirus future surveillance activities and nested studies
A discussion paper for consideration by the EuroRotaNet Steering Committee
and Collaborators.
Written by Dr Miren Iturriza and Prof Jim Gray
June 2011
EuroRotaNet, a network of 17 European laboratories, performs rotavirus strain characterisation in
order to identify novel rotavirus strains emerging in the population. To date more than 27,000 strains
have been characterised and several animal/ human hybrid reassortant strains have been identified
and their circulation in the European population monitored.
Since 2006, two rotavirus vaccines, RotaRix a monovalent live-attenuated oral vaccine and RotaTeq
a pentavalent live-attenuated oral vaccine have been introduced into the vaccination schedules of
some European countries either as a universal childhood vaccine or available in the health care
market for those parents who wish to protect their children against rotavirus gastroenteritis. For this
reason EuroRotaNet in collaboration with others should be designing and undertaking nested studies
in order to determine the following:
1. The effectiveness of a rotavirus vaccine in the general population, through monitoring the
reduction in disease associated with common rotavirus types;
EuroRotaNet in collaboration with EpiConcept and eCDC have developed a generic protocol for
monitoring the effectiveness and impact of rotavirus vaccines. EpiConcept specializes in
epidemiology and the development of IT systems. These protocols will be available though eCDC
shortly and are likely to be run by public health organizations within each country with EuroRotaNet
collecting and collating information on co-circulating genotypes.
2. The possible vaccine-induced emergence of antibody escape mutants;
In the presence of high vaccine coverage herd immunity may drive the selection of variant strains with
mutations resulting in antibody escape and therefore refractile to the immunity conferred by current
vaccines. These will be identified as vaccine failures. Syndromic surveillance will be required as any
episode of acute gastroenteritis in a vaccinated child should be explored in order to identify the
aetiological agent.
3. The possible emergence in the vaccinated population of genotypes other than those
included in the vaccine;
These may be identified as vaccine failures in countries with high vaccination coverage, and may be
identified simply by the addition of data relating to vaccination collected through EuroRotaNet strain
surveillance: Currently data collection forms include fields for this information, but systems are not in
place to link vaccination history with laboratory data.
EpiConcept are currently working with eCDC and European partners in countries in which rotavirus
vaccines are in use, to develop more robust data collection and analysis protocols and mechanisms.
A control group consisting of countries without rotavirus vaccination is provided by EuroRotaNet in
order to identify the emergence of unusual strains and zoonotic introductions in the absence of
vaccine.
4. The possible emergence in the general population of reassortants between vaccine and
naturally circulating wild-type strains.
In order to study the transmission of rotavirus vaccine strains or of vaccine-wild type hybrid strains,
specific targeted studies need to be performed. It is proposed that a family transmission study would
be the best approach by following vaccinees, their siblings and parents in order to detect onward
transmission and/or co-infections with the potential to generate efficiently replicating hybrid strains.
Existing data indicates that after the first vaccine dose ~9%-21% and ~35%-80% of children shed
Rotateq® and Rotarix® vaccine virus, respectively, for several days/weeks. Therefore, this provides
opportunities for onward transmission and reassortment in the event of co-infections. A family cohort,
studied for 3 years post vaccination, could also provide information on the possible emergence in the
vaccinated population of genotypes other than those included in the vaccine and the possible
emergence of vaccine-induced antibody escape mutants and be an adjunct to the wider EuroRotaNet
strain surveillance network utilising the existing expertise in virology, molecular epidemiology and
bioinformatics within EuroRotaNet (see Figure 1).
Developments proposed for EuroRotaNet
These proposed studies will require high throughput, state of the art genome sequencing and the
bioinformatic tools to accompany them.
The numbers of rotavirus-positive cases are expected to be very significantly reduced in countries
with high vaccine coverage. Current protocols will allow the detection of unusual strains, and detailed
characterisation though whole genome sequencing will allow the determination of possible zoonotic
introductions. Consideration needs to be given to the vaccine in use in the country in order to detect
vaccine derived strains. For those countries in which RotaTeq® is in use, it will be possible to perform
initial screening by RT-PCR targeting gene(s) of the bovine strain backbone. However, this will not
replace the need for detail genomic characterisation through sequencing in order to investigate for
possible reassortants. For monitoring Rotarix® derived strains, whole genome sequencing and
analysis will be required
It is proposed to develop, within the current EuroRotaNet web-enabled database, a sequence
database, linked to the current strain surveillance database to enable analysis of complete rotavirus
genomes and to monitor emergent and vaccine strains in the population. In addition, sequence
analysis tools will be developed to enable rapid and easy determination of strains and gene segments
that are vaccine derived. Such tools would be necessary to complete objectives 2 to 4. A common
sequence repository with linked epidemiological data will enhance the current database providing a
unique and valuable resource for future vaccine development.
Figure1: Impact of rotavirus vaccine: Study to detect intrafamilial spread, reassortment, vaccine failure
and strain replacement.
Epidemiological
data collection
Family members:
•Age/ sex
•Vaccine history
•Vaccine used
•No. doses
•Dates given
Date of onset
Symptoms
Duration of
symptoms
1A
Recruitment and
Sample collection
Laboratory work
EuroRotaNet
Surveillance:
Collect faecal samples
from family members
2, 5 and 101days after
each
vaccine dose
Rotavirus detection
(RT-PCR)
Rotavirus typing
Whole genome
sequencing
Develop and establish
Bioinformatic tools.
AGE Episodes:
Collect faecal samples
from symptomatic
family members at any
time during the study
Syndromic detection
by PCR and RT-PCR2.
Rotavirus strains:
Whole genome
sequencing
Paediatricians/GPs
to recruit families:
1 or more adults,
2 or more children
including vaccinee
Collect sequence
data on 11 genes of
vaccine strains
pilot study may be required in order to determined the most appropriate sampling protocol
viruses, bacteria and parasites associated with AGE are available
2Methods for common enteric
Notes on developing the proposal
1. Sample size to be calculated:
 Information is available on number of children likely to shed post 1st dose of vaccine.
 Horizontal transmission: With RotaRix among twins, ~19% transmitted virus to a twin
receiving placebo
2. Countries

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Those in which vaccine is used within a universal childhood program
Those with a significant private market using rotavirus vaccine
Control groups/ rotavirus strains from countries not using the vaccines
3. Costs
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Recruitment by Paediatricians
Data collection
Pathogen detection by molecular methods
Rotavirus characterization (1 centre for high throughput sequencing will suffice)
BioInformatics development (Within the sequencing centre)
Data analysis
Staff