Background
Prior to the introduction of rotavirus vaccination, rotavirus was the leading cause of severe gastroenteritis in children under 5 years of age worldwide, resulting in approximately 453,000 deaths per year and 40% of diarrhoeal hospital admissions [
1,
2]. Two orally administered live-attenuated rotavirus vaccines, Rotarix® (GlaxoSmithKline Biologicals, Belgium) and RotaTeq® (Merck Vaccines, USA), have been introduced in over 90 countries worldwide [
3]. The global mortality from rotavirus gastroenteritis (RVGE) has subsequently more than halved (recently estimated at between ~120,000 and ~215,000) and the number of all-cause acute gastroenteritis (AGE) hospitalisations is estimated to have reduced by 38% [
4‐
7].
Although the majority of the severe disease burden is in developing countries, rotavirus was estimated to cause approximately 80,000 general practice (GP) consultations and 750,000 diarrhoea episodes each year in the UK [
8]; 45% of hospitalisations and 20% of emergency department (ED) attendances for AGE in children under 5 years of age were attributable to rotavirus [
9]. The National Health Service (NHS) in England is free at the point of use for all UK residents, with vaccinations included in the routine immunisation schedule also free of charge. The monovalent rotavirus vaccine (Rotarix®) was introduced into the UK childhood immunisation schedule in July 2013, with two doses delivered at 8 and 12 weeks of age [
10]. Vaccine uptake in England increased rapidly, reaching over 91% for one dose by February 2014 and over 94% by mid-2016 [
11]. To date, studies in the UK have separately, and for varied populations and time periods, analysed vaccine impact on rotavirus laboratory detections (77% reduction in infants) [
12], RVGE hospitalisations (> 80% reduction in infants) [
13], all-cause AGE hospitalisations (26% in infants) [
12] and GP attendances for diarrhoea related illness (20–30% in those under 5 years old) [
14].
This study aimed to assess the effect of rotavirus vaccination on multiple levels of the UK health-care system simultaneously, by examining the trends in hospitalisations, ED attendances, community health consultations and GP consultations for outcomes of gastroenteritis, diarrhoea and rotavirus gastroenteritis in a defined population before and after vaccine introduction. This approach will, for the first time, provide estimates of rotavirus vaccine impact in an entire health economy. Secondly, within the UK, children under 5 years of age are over-represented in the most socioeconomically deprived populations [
15,
16], and experience significantly higher incidence of all-cause AGE hospitalisations than more affluent populations [
17]. It is known that in the UK, the uptake of routine childhood vaccines (e.g. vaccines for measles, mumps and rubella, human papillomavirus and influenza) is lower in socioeconomically deprived populations [
18‐
20]. Thus, we examined the uptake and impact of rotavirus vaccination in Merseyside, an area with a wide variation in socioeconomic deprivation, to assess whether vaccine uptake and impact are equitable.
Discussion
In this study, which is one of the few studies to evaluate the impact of rotavirus vaccine introduction simultaneously across all levels of the health-care system in a defined geographic area, we have demonstrated reductions in gastrointestinal disease burden across all levels of health-care and across all ages. Reductions were greatest for the most specific and severe disease outcomes (rotavirus hospitalisations and AGE hospitalisations) during the rotavirus season and for the youngest children who were in vaccine-eligible age groups. Smaller reductions among older unvaccinated populations suggest herd protection. The impact of vaccination was also greater in the most socioeconomically deprived populations, despite lower vaccine coverage.
Most previous studies that evaluated rotavirus vaccine impact in high-income countries focussed on severe disease outcomes, with the magnitude of reductions similar to those described here for children in both vaccine-eligible and ineligible age groups [
12,
29‐
42]. The reduction in all-cause AGE of 46% (36–55%) for infants and 50% (38–60%) for children 12–23 months of age was also similar to that reported in earlier UK studies, as was the indication of herd protective effects in older adults and children [
12,
36].
For less severe disease outcomes (people with disease presenting to GPs and WICs), we demonstrated smaller relative reductions compared to more specific or severe disease outcomes. However, these reductions constitute a substantial contribution to the absolute number of health-care contacts averted through vaccination. The impact on non-specific outcome measures was consistently highest during the rotavirus season for children under 5 years, suggesting that the observed reduction in incidence of AGE is likely to be due to a real reduction in incidence of rotavirus disease. The smaller reductions seen in consultations in primary care (WICs and GPs) are likely explained by the non-specific gastroenteritis outcome measure and also because of the presumed lower effectiveness of rotavirus vaccine against milder disease [
43,
44]. Furthermore, the reductions in GP consultations for infectious gastroenteritis observed for children in vaccine-eligible age groups (19% for infants and 13% for 12–23 months) are epidemiologically plausible, since a study from the pre-vaccine period estimated that rotavirus was detected by enzyme-linked immunosorbent assay (ELISA) in 14% and by ELISA and/or PCR in approximately 19% of infectious intestinal disease cases seen in GP consultations for UK children under 5 [
45,
46], with this estimate likely to be higher in infants. Furthermore, the estimated reductions in WIC attendances and GP consultations are comparable to that reported from an analysis of UK syndromic surveillance of GP consultations for gastroenteritis, diarrhoea and vomiting (26% reduction for infants) [
12]. They are also comparable with reductions in AGE outpatient attendances reported in Finland (13% reduction in infants) [
33,
47] and all-cause AGE community clinic visits in Israel (19% reduction in infants and 16% for 12–23-month-olds) [
48].
We have shown that the most deprived populations were at the greatest risk of all-cause AGE prior to vaccine introduction, with the highest rates of disease occurring in infants in the most deprived populations. This supports previous findings from a lower-resolution national study, which showed that the rate of hospitalisation with all-cause AGE increased with increasing deprivation [
17]. The uptake of rotavirus vaccination in our study population was also associated with neighbourhood-level deprivation, with a significantly lower uptake of the first dose of the vaccine and lower completion of the full two-dose schedule in the most deprived populations. Similar findings have been shown in Merseyside for measles, mumps and rubella vaccination, and locally and nationally for childhood influenza vaccination [
18,
19].
We were able to overlay a combination of small-area-level deprivation status, vaccine uptake and all-cause AGE hospitalisations to estimate the disease averted per first vaccine dose delivered for different deprivation strata. In infants, disease averted by vaccination was higher in the most deprived areas, suggesting that even with lower vaccine uptake, the most deprived populations benefit the most from the vaccination programme. The higher rates of disease averted in infants < 12 months of age living in the most deprived populations is likely to reflect the higher baseline burden of disease in this group and the relative inequity of hospitalisation rates prior to vaccine introduction. However, for 12–23-month-olds, there is a smaller difference in incidence of disease averted between the least deprived and the most deprived areas, reflecting the lower baseline inequity in disease burden between the deprivation strata.
Nationally, there are disproportionately more infants and young children living in the most deprived quintile (26%) compared to the least deprived (15%) [
15,
16]. With individual-level vaccine effectiveness known to be lower in persons with a lower socioeconomic status from studies conducted in high-income settings [
49,
50], improving vaccine uptake in the most deprived populations will have the biggest impact towards reducing rotavirus-associated disease. We estimate that over 41% of all-cause AGE hospitalisations averted in infants due to rotavirus vaccination would be averted in the most deprived populations if vaccine uptake was equitable across deprivation strata at the WHO vaccine uptake target of 95% [
27,
28].
Strengths and limitations
This ecological study using routine health service data is subject to a number of limitations. There is an inherent problem with clinical coding of rotavirus gastroenteritis in UK hospitals. A quality analysis at Alder Hey Children’s Hospital showed that only 39% of laboratory-confirmed rotavirus hospitalisations were coded as ICD-10 rotaviral enteritis (A08.0), and this figure is lower in other UK hospitals [
51]. Therefore, in this study, for the RVGE hospitalisation outcome measure, we used hospitalisations that were laboratory-confirmed rotavirus from Alder Hey rather than ICD-10 codes.
In the context of this outcome measure, it is important to acknowledge the change in rotavirus diagnostic testing methods that occurred at Alder Hey during the study period (Table
1). An enzyme immunoassay was used for 10 of the 14 study years, whilst immuno-chromatography was utilised between 2005 and 2008. The immuno-chromatographic method used (VIKIA®, Rota-Adeno) has a slightly lower diagnostic accuracy compared to enzyme immunoassay methods [
52,
53]. However, the pre-vaccine introduction time series spanned 11 years, and since the change in testing practices was not accompanied by a clear non-secular variation in RVGE hospitalisation rates, we would not expect this change to have impacted significantly on effect estimates.
Since rotavirus detection is not routinely undertaken in community settings, such as GP and WICs, syndromic and non-specific outcomes related to gastroenteritis were used, and we were, therefore, unable to account for the contribution of other pathogens causing AGE. However, the predictable seasonality of rotavirus infection allowed the analysis to focus on the rotavirus season, which should improve the robustness of reduction estimates in age-eligible children. In older children and adults, the estimates are more uncertain because there is limited laboratory testing and surveillance data on rotavirus seasonality and disease burden in these age groups in the pre-vaccine period. The lack of routine testing is evidenced by the recommendation in the
Standards for Microbiology Investigation S7: gastroenteritis and diarrhoea that rotavirus testing is only standard for sporadic cases of gastroenteritis under the age of 5 years and immunocompromised cases [
54].
Because of these limitations, the model fit was less good for older populations due to the less seasonal and more random incidence of gastroenteritis disease, and in these situations the analysis may have overestimated the impact of vaccination. Furthermore, we used a non-dynamic regression fit and so we did not account for changes in the force of the infection due to a reduction in the number of cases. We were, therefore, not able to adjust the predicted incidence to account for current levels of infection. A full transmission model would be required to describe fully the reduction in the transmission rate and associated case reduction due to vaccination. Despite these limitations, studies in the UK, Australia, Europe and the US also show an impact in older populations [
12,
36,
37,
42,
55‐
57]. The number of hospitalisations averted nationally under a uniform 95% vaccine uptake was made using two main assumptions. Firstly, that the population of Merseyside is representative of the national population and secondly, that the relationship between vaccine uptake and the herd protective effect of vaccination is linear. Therefore, the estimates are likely to be conservative as a consequence of assuming a linear relationship, particularly if the level of rotavirus vaccine uptake required for population protection is reached before 95% uptake.
Finally, the novelty of measuring vaccine impact on multiple levels of a health system simultaneously in a defined population provides robustness that any detected changes are due to rotavirus vaccination rather than idiosyncrasies of one particular data set. For example, we detected delayed peak activity (April/May) in children aged 24–59 months across all outcome measures in season 2014/15, strengthening the evidence that the data sets used in this study were useful in detecting rotavirus activity in non-specific outcomes. This delayed peak is also observed in laboratory-confirmed rotavirus detections nationally.
Conclusion
This analysis identified the effect of rotavirus vaccination on health-care utilisation for acute gastroenteritis in the four major levels of the UK health system for five outcomes of varying specificity. The study strongly indicates that rotavirus vaccination has reduced the incidence of acute gastroenteritis across the health-care system in both vaccine-eligible and ineligible populations. Rotavirus vaccination will, therefore, contribute to alleviating the increasing pressures on acute services across a health system. With an impact greater than that predicted through cost-effective modelling in the UK [
58], these data strongly support the sustained use of the vaccine in the UK and continued expansion to other European countries.
We have also shown that prioritising vaccine uptake in the most socioeconomically deprived communities is likely to give the greatest health benefit in terms of population disease burden and can contribute to reducing health inequalities. Further studies are required to disentangle which factors related to socioeconomic deprivation have the greatest influence on vaccine acceptance, so that interventions to improve vaccine uptake can be targeted effectively.
Acknowledgements
The authors acknowledge the contributions of Fiona Hardiman, all staff in the microbiology department, Karl Edwardson from Alder Hey Children's NHS Foundation Trust and Sacha Wyke from Public Health England. The authors acknowledge the contributions of GPs and NHS CCGs in Liverpool, South Sefton, Wirral, Southport and Formby, and St Helens; Liverpool Community Health NHS Trust; Knowsley and St Helens Health Informatics; Wirral Community Health Trust and the Five Boroughs Community Health Trust.