Evaluating the potential risks and benefits of infant rotavirus vaccination in England
Introduction
Rotavirus is a leading cause of childhood diarrhoea in England. Although less than five children are estimated to die from rotavirus gastroenteritis (RVGE) each year [1], it is a common and painful illness and causes anxiety for parents. RVGE also represents a significant economic burden; one in seven English newborns will require a visit to their general practitioner (GP) before their 5th birthday, one in 22 will visit Accident and Emergency (A&E) and one in 45 will be admitted to hospital. The estimated cost to the English National Health Service (NHS) is over ten million pounds annually [2].
Rotarix® (GlaxoSmithKline), a vaccine for the prevention of severe RVGE in young children, was introduced in England in July 2013 [3]. The vaccine is administered orally, and is given in two doses at two and three months of age. The decision to introduce Rotarix® was made by the Department of Health in November 2012 after it became possible to procure the vaccine at a cost-effective price [4]. The Joint Committee on Vaccination and Immunisation (JCVI) had previously reviewed studies showing that Rotarix® would not be cost-effective unless priced at £19 per dose (£38 per course) or lower [5], [6]. At this price each year of full health gained by vaccination would cost the Government £30,000, the upper limit accepted by the National Institute for Health and Care Excellence (NICE) [7].
A randomised controlled trial of Rotarix® in six European countries reported vaccine efficacy of 90% against severe RVGE [8] and several high income countries, including Finland, Australia and the USA, have now introduced the vaccine with impressive declines in childhood rates of gastroenteritis [9]. There have however been concerns about the safety of rotavirus vaccines; the first rotavirus vaccine, RotaShield®, was withdrawn from the market after an association was found that was consistent with it causing intussusception, a rare bowel disorder, in one in every 4670 to 9474 infants vaccinated in the USA [10]. Intussusception, when the bowel telescopes into itself, is the most common cause of bowel obstruction in young infants. Large safety trials of both new vaccines, Rotarix® and Rotateq® (Merck) were able to exclude the level of risk associated with RotaShield® [11], [12], but were not powered to exclude a lower level of risk. The level of risk that may turn out to be associated with Rotarix® in England is difficult to predict. However recent post-licensure data from two other high income settings, the USA and Australia, indicates a risk of one vaccine-related intussusception case in every 20,000 vaccinated infants [13]. This overall estimate is not directly comparable to the risk reported for RotaShield® because the new vaccines have been administered within age restrictions designed to avoid the peak age of intussusception.
If left untreated, intussusception is a fatal condition. However, in England, where most children have access to timely health care, fewer than 0.5% of cases are estimated to die, and most cases will have an uneventful recovery following enema reduction or surgery [14]. That Rotarix® continues to be used in all settings where an elevated intussusception risk has been detected (USA, Australia, Mexico, Brazil) implies that the benefits are considered to greatly outweigh this risk [13]. The World Health Organisation (WHO) has taken a similar position by recommending the global use of rotavirus vaccines despite their small known risk of intussusception, and has further recommended the removal of age restrictions in countries with delayed vaccination and high RVGE mortality, so that more children can receive the benefits of the vaccine [15], [16]. These age restrictions are designed to ensure the vaccine is administered before the peak age of intussusception. In England, where vaccination is timely and RVGE mortality is low, health practitioners have been given clear advice to adhere to these age restrictions (first dose of Rotarix® given no later than 15 weeks and second dose of Rotarix® no later than 24 weeks) [4].
In England, the potential risk of vaccine-related intussusception is unlikely to become clear until at least 18 months after Rotarix® is introduced when the expected number of cases in the absence of a risk would be about two in the week after the first dose and five cases in the week after the second dose. In the interim, we aim to estimate the potential burden of vaccine-related intussusceptions each year, and try to balance this against the estimated health benefits of the vaccine. The aim of this analysis is not to alarm parents and health professionals about the, as yet unknown, risk of intussusception in England; rather we aim to help put the potential risk in context, so that both parents and policy makers can make an informed judgement about Rotarix® vaccination.
Section snippets
Methods
An Excel-based [17] cohort model with a finely disaggregated age structure (weekly to age one year, and monthly to age five years) was used to estimate the risks and benefits of Rotarix® vaccination in England. All parameter values, and uncertainty ranges are listed in Table 1.
Estimated risks of Rotarix®
With strict adherence to recommended age restrictions, introduction of Rotarix® could potentially cause 35 (7–98) additional intussusception cases in children aged <5yrs in England each year (Fig. 1). Without vaccination around 248 intussusception admissions are expected each year in children aged <2 years; with Rotarix® this is estimated to increase by 14% to 284. The number of excess cases associated with dose one and dose two was similar; dose two had a smaller relative risk but is
Discussion
Our analysis suggests a potential risk of one vaccine-related intussusception in every 18,551 vaccinated infants, equivalent to 35 additional intussusception admissions each year. We estimate that Rotarix® would prevent around 74,000 GP consultations, 27,000 emergency visits and 13,000 admissions each year. This is equivalent to undiscounted savings of over £11 million annually. There would be 375 fewer RVGE admissions for every additional intussusception admission, and 88 fewer RVGE deaths for
Funding
AC and CS were commissioned by WHO's Initiative for Vaccine Research (Vaccine Schedules Initiative) to develop a multi-country model for evaluating the risks and benefits of Rotavirus vaccines. The analysis is based on the principles established during this work.
Contributions
AC conceived the idea for the paper, developed the model, gathered the inputs, ran the analysis, drafted and revised the paper. MJ helped gather the inputs, updated a previous model to enable a comparison/validity check and provided edits and comments on the draft. NA (with Julia Stowe – see acknowledgements) organised the extraction and analysis of the intussusception and vaccination coverage datasets and provided edits and comments on the draft. CA provided the dataset on the age distribution
Acknowledgements
We would like to thank Dr Julia Stowe for extracting the information on timeliness and the incidence of intussusception hospital admissions. We would also like to thank Dr Lamiya Samad for commenting on an earlier draft.
Conflicts of interest: AC, MJ, NA, CA and CS declare no conflicts of interest. JE's partner is employed by GSK.
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