Christina Atchison

Host, weather and virological factors drive norovirus epidemiology: time-series analysis of laboratory surveillance data in England and Wales.

Norovirus, the most commonly identified cause of both sporadic cases and outbreaks of infectious diarrhoea in developed countries, exhibits a complex epidemiology and has a strong wintertime seasonality. Viral populations are dynamic and evolve under positive selection pressure. Methods Time series-adapted Poisson regression models were fitted to daily counts of laboratory reports of norovirus in England and Wales from 1993 to 2006. Findings Inverse linear associations with daily temperature over the previous seven weeks (rate ratio (RR) = 0.85; 95% CI: 0.83 to 0.86 for every 1°C increase) and relative humidity over the previous five weeks (RR = 0.980; 95% CI: 0.973 to 0.987 for every 1% increase) were found, with temperature having a greater overall effect. The emergence of new norovirus variants (RR = 1.16; 95% CI: 1.10 to 1.22) and low population immunity were also associated with heightened norovirus activity. Temperature and humidity, which may be localised, had highly consistent effects in each region of England and Wales. Conclusions These results point to a complex interplay between host, viral and climatic factors driving norovirus epidemic patterns. Increases in norovirus are associated with cold, dry temperature, low population immunity and the emergence of novel genogroup 2 type 4 antigenic variants.

Understanding Reduced Rotavirus Vaccine Efficacy in Low Socio-Economic Settings

Introduction Rotavirus vaccine efficacy ranges from >90% in high socio-economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance. Methods We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy. Results Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES. Discussion The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements.

Effectiveness and impact of rotavirus vaccines in Europe, 2006-2014.

Prior to the introduction of rotavirus vaccines in 2006, rotavirus was the leading cause of severe gastroenteritis among European children <5 years of age. We conducted a systematic review of the published literature to examine the effectiveness and impact of rotavirus vaccines in Europe following the first eight years of routine use. Four publication databases were searched, yielding 276 unique citations from February 1st, 2006 to July 31st, 2014. Twenty four studies on effectiveness (n=9) and impact (n=15) met the inclusion criteria. Across Europe, vaccine effectiveness against rotavirus-related healthcare utilisation ranged from 68% to 98%, consistent with efficacy data from clinical trials. Reductions in rotavirus hospitalisations ranged from 65% to 84%, consistent with findings from post-marketing studies from the US and Latin America. We confirm the significant public health benefit of rotavirus vaccination in Europe and provide further evidence to support implementation of universal rotavirus vaccination in all European countries.

Modelling the seasonality of rotavirus disease and the impact of vaccination in England and Wales

Two rotavirus vaccines are currently recommended for inclusion in routine childhood immunization programmes. We developed a deterministic age-structured model of rotavirus transmission and disease to investigate the population-level effects of vaccination in England and Wales. The model explicitly captures the natural history of infection and uses realistic population mixing patterns. The model accurately reproduces the strong seasonal pattern and age distribution of rotavirus disease observed in England and Wales. We predict vaccination will provide both direct and indirect protection within the population. If coverage levels comparable to other childhood vaccines are achieved, we predict that vaccination will reduce rotavirus disease incidence by 61% resulting in a potential fall in burden on health-care services.

Temperature-dependent transmission of rotavirus in Great Britain and The Netherlands.

In Europe, rotavirus gastroenteritis peaks in late winter or early spring suggesting a role for weather factors in transmission of the virus. In this study, multivariate regression models adapted for time-series data were used to investigate effects of temperature, humidity and rainfall on reported rotavirus infections and the infection-rate parameter, a derived measure of infection transmission that takes into account population immunity, in England, Wales, Scotland and The Netherlands. Delayed effects of weather were investigated by introducing lagged weather terms into the model. Meta-regression was used to pool together country-specific estimates. There was a 13 per cent (95% confidence interval (CI), 11–15%) decrease in reported infections per 1°C increase in temperature above a threshold of 5°C and a 4 per cent (95% CI, 3–5%) decrease in the infection-rate parameter per 1°C increase in temperature across the whole temperature range. The effect of temperature was immediate for the infection-rate parameter but delayed by up to four weeks for reported infections. There was no overall effect of humidity or rainfall. There is a direct and simple relationship between cold weather and rotavirus transmission in Great Britain and The Netherlands. The more complex and delayed temperature effect on disease incidence is likely to be mediated through the effects of weather on transmission.

Direct and Indirect Effects of Rotavirus Vaccination: Comparing Predictions from Transmission Dynamic Models

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8–2.9 times more than expected from the direct effects of the vaccine alone (28–50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1–1.7 times more than expected from the direct effects (54–90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research.

Rapid Declines in Age Group–Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales

BACKGROUND The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction. METHODS We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE-associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013-2014 rotavirus season to the rate during the prevaccination era. RESULTS In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16-.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65-.84) in all-cause AGE-associated hospitalizations in 2013-2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE-associated hospital admissions were averted in 2013-2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014-2015 season. CONCLUSIONS The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries.

Evaluating the potential risks and benefits of infant rotavirus vaccination in England

Rotarix(®), a vaccine for the prevention of gastroenteritis in young children, was introduced in England in July 2013. At around this time, an elevated risk of intussusception (a cause of bowel obstruction) was reported among infants vaccinated in Australia and the USA. A risk-benefit analysis compared potential vaccine-related risks (additional intussusception admissions and deaths) with estimated vaccine benefits (prevented rotavirus general practitioner visits, emergency visits, admissions and deaths) in the 2012 birth cohort. Detailed data from England included the incidence of intussusception events aged <2 years by week of age, the coverage of vaccination aged <2 years by week of age, and the incidence of rotavirus gastroenteritis (RVGE) events aged <5 years by week of age. Recent estimates of vaccine-related risk from Australia were applied during the 1-21 day period after the first and second dose of vaccination. Rotarix(®) is estimated to cause one additional intussusception admission in every 18,551 vaccinated English infants (5th and 95th percentiles, 6728-93,952), equivalent to 35 (7-98) additional intussusception admissions each year. The vaccine is estimated to prevent three rotavirus deaths, 13,000 rotavirus admissions, 27,000 rotavirus emergency visits and 74,000 rotavirus GP consultations in children aged <5 years, and lead to annual savings of over £11 million, each year. We estimate 375 (136-1900) fewer RVGE admissions for every additional intussusception admission, and 88 (18-852) fewer RVGE deaths for every additional intussusception death. The estimated benefits of Rotarix(®) vaccination would greatly exceed the potential risk in England.

Season of birth and risk of rotavirus diarrhoea in children aged 5 years.

This study investigates whether a childs risk of rotavirus diarrhoea is associated with season of birth in England and Wales, countries where rotavirus infections are highly seasonal. Poisson regression models were fitted to weekly counts of laboratory-confirmed rotavirus infections from children aged <5 years born between 1998 and 2007. In the first year of life, the risk of a laboratory-confirmed rotavirus infection was significantly higher for children born in summer compared with winter [relative risk (RR) 2.13, 95% confidence interval (CI) 2.07-2.19]. In the second to fifth years of life, the pattern reversed (second year of life: RR 0.73, 95% CI 0.71-0.75). The cumulative risk up to age 5 years remained significantly higher for children born in summer compared with winter due to the increased risk for summer births during their first year of life. Maternal immunity and age-specific levels of exposure to rotavirus could explain our findings.

Quantifying Parameter and Structural Uncertainty of Dynamic Disease Transmission Models Using MCMC: An Application to Rotavirus Vaccination in England and Wales.

Background. Two vaccines (Rotarix and RotaTeq) are highly effective at preventing severe rotavirus disease. Rotavirus vaccination has been introduced in the United Kingdom and other countries partly based on modeling and cost-effectiveness results. However, most of these models fail to account for the uncertainty about several vaccine characteristics and the mechanism of vaccine action. Methods. A deterministic dynamic transmission model of rotavirus vaccination in the United Kingdom was developed. This improves on previous models by 1) allowing for 2 different mechanisms of action for Rotarix and RotaTeq, 2) using clinical trial data to understand these mechanisms, and 3) accounting for uncertainty by using Markov Chain Monte Carlo. Results. In the long run, Rotarix and RotaTeq are predicted to reduce the overall rotavirus incidence by 50% (39%−63%) and 44% (30%−62%), respectively but with an increase in incidence in primary school children and adults up to 25 y of age. The vaccines are estimated to give more protection than 1 or 2 natural infections. The duration of protection is highly uncertain but has only impact on the predicted reduction in rotavirus burden for values lower than 10 y. The 2 vaccine mechanism structures fit equally well with the clinical trial data. Long-term postvaccination dynamics cannot be predicted reliably with the data available. Conclusion. Accounting for the joint uncertainty of several vaccine characteristics resulted in more insight into which of these are crucial for determining the impact of rotavirus vaccination. Data for up to at least 10 y postvaccination and covering older children and adults are crucial to address remaining questions on the impact of widespread rotavirus vaccination.