Rotavirus Future Surveillance Activities and Nested Studies

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. 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

 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

 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