Original Title: Evaluación de distintas estrategias de vacunación frente a rotavirus en España. Seguridad, eficacia, efectividad y eficiencia

Authors' objectives: This report is carried out at the request of the Ministry of Health to evaluate the appropriateness of implementing different rotavirus vaccination strategies in Spain. The objectives of the report are: • To evaluate the safety, efficacy and effectiveness of rotavirus vaccines in children under one year of age. • To assess the efficiency of universal vaccination and vaccination of at-risk populations compared to non-vaccination. • To estimate the possible budgetary impact of the implementation of universal vaccination against rotavirus in Spain.

Authors' results and conclusions: RESULTS: Safety: Twenty-two RCTs were selected for safety assessment, 13 evaluating Rotarix® with 73,608 participants and 9 evaluating RotaTeq® with 76,752 participants. The quality of the studies was moderate-high. Certainty of the evidence was assessed as high for most outcomes. No significant differences were identified between the study groups (vaccine versus placebo) in any of the safety indicators (mortality, serious adverse events, intussusception and adverse events requiring discontinuation of vaccination). Four SRs providing data on the safety of rotavirus vaccines have been selected from observational studies. All of them show that there is no difference between vaccinated and unvaccinated in terms of mortality and serious adverse events. Efficacy: Twenty-two RCTs have been selected for efficacy evaluation. The main results by vaccine are described below. ROTARIX®: For severe acute rotavirus gastroenteritis (RV-AGE) the efficacy of Rotarix® after two years of follow-up is 87%, but decreases to 66% for all severities of RV-AGE. For RV-AGE requiring medical attention, Rotarix® has shown an efficacy of 77% with two years of followup. For hospital admissions for RV-AGE, the efficacy of Rotarix® is 83% at two years. ROTATEQ®: For severe RV-AGE, the efficacy of RotaTeq® is 94% after two years of follow-up, but decreases to 64% for RV-AGE of any severity at 2 years of follow-up. For those with severe RV-AGE requiring medical attention, RotaTeq® has shown an efficacy of 93%. For hospital admissions for RV-AGE, the efficacy of RotaTeq® is 96% after 1 year of follow-up. Effectiveness: Three SR were selected from observational effectiveness studies in countries with low RV-AGE mortality or high economic status. The effectiveness results of the vaccines for severe RV-AGE and hospital admission due to RV-AGE are between 65% and 87% for Rotarix® and between 73% and 96% for RotaTeq®. In our country, it is observed that, with a vaccination coverage of around 60%, a decreasing in the rates of hospital admission due to RVAGE of around 30% has been obtained in recent years. Systematic review of efficiency: Sixteen economic evaluations were selected because they met the selection criteria. The methodological quality was moderate/high. Regarding the comparison between universal vaccination and non-vaccination, a large majority of studies concluded that universal vaccination would be efficient. In only two of the 16 studies is the Incremental Cost-Utility Ratio (ICUR) obtained clearly unfavourable to the universal vaccination strategy. In five studies, separate results are given for Rotarix® and RotaTeq®, with the ICUR in all of them being more favourable to Rotarix®. A single study, carried out in the Netherlands, evaluates the vaccination strategy in at-risk populations, although it applies to a broader set of at-risk populations than those included in the strategy currently in force in Spain. The results of this study showed that vaccination of the atrisk population is more efficient than non-vaccination. However, the universal vaccination strategy compared to vaccination of at-risk population or non-vaccination was inefficient. Cost-utility analysis for Spain: Universal vaccination achieves higher average utility than the other two strategies evaluated, although at a higher cost. The increases in utility are the same with both vaccines, although the average cost is clearly higher with RotaTeq® than with Rotarix®. Vaccination of at-risk populations with Rotarix® is the only strategy that is efficient at current prices. With this vaccine, when comparing this strategy with non-vaccination under the social perspective an ICUR of €23,638/QALY is obtained. With the RotaTeq® vaccine for the same comparison and perspective, an ICUR of €32,008/QALY is obtained. Universal vaccination is inefficient with both vaccines compared to either of the other two strategies, both from a societal perspective and from an NHS perspective. Moving from at-risk population vaccination to universal vaccination under the societal perspective would achieve each additional QALY at an average cost of €57,631 with Rotarix® and €69,068 with RotaTeq®, values that are above the proposed costeffectiveness threshold for Spain. Analyses from the NHS perspective provide ratios above the threshold in all cases considered in the base case. However, the strategy of vaccinating at-risk populations would have a much lower impact on clinical events than universal vaccination. Switching from non-vaccination to vaccination of at-risk population would avoid between 2.9% and 3.4% of hospital admissions, depending on whether vaccination was with Rotarix® or RotaTeq®. Switching from vaccination of at-risk population to universal vaccination would reduce hospital admissions due to RV-AGE by 63.5% and 65.6% for Rotarix® or RotaTeq® vaccination, respectively. The sensitivity analysis performed on all the parameters of the model indicates that the evaluation is robust as there is no variable, except for price that within the ranges identified in the literature review modifies the results substantially. Vaccination of at-risk population with RotaTeq® would be efficient at a price between €184.9 and €192 for full vaccination. Universal vaccination would be efficient in Spain with prices for full vaccination between 111.85 and 118.20 € with Rotarix® and between 108.70 and 115.50 € with RotaTeq®. Budgetary impact analysis: The implementation of universal vaccination would, at current vaccine prices, have an annual budgetary impact for the NHS of between 49.3 and 56.7 million euros depending on whether vaccination is carried out with Rotarix® or Rotateq®. At the price resulting from our sensitivity analysis, the budget impact would be reduced to data that could range between 26.8 and 28.7 million euros if vaccination is with Rotarix® and between 27 and 29.1 million euros if vaccination is with Rotateq®. Patient and caregiver perspective: Relevant information has been identified in relation to the acceptability of new vaccines and in particular rotavirus vaccine. 52% of parents of children admitted for acute gastroenteritis (AGE) would have administered the rotavirus vaccine even if it was not funded. 93% of parents of children admitted to hospital thought it was necessary to include rotavirus vaccine in the childhood immunisation schedule, and 80% would be willing to recommend it to other parents. Moreover, Spain is among the European countries with high coverage and acceptability of vaccination programmes. Organisational, ethical and social aspects: Introduction of rotavirus vaccination would not entail major associated organisational changes, given that both vaccines can be administered concomitantly with other vaccines or at visits usually scheduled in paediatric follow-up schedules, and that both vaccines, Rotarix® and RotaTeq®, are kept at refrigerated temperatures (2-8ºC) and they are administered orally. The recommendations made by Spanish scientific societies have led to the private purchase of the vaccines by approximately 68% of families. The assessment of the inclusion of this vaccine in the lifelong vaccination schedule in Spain should take into account the current inequalities in access that occur as a result. CONCLUSIONS: The two rotavirus vaccines available in Spain, Rotarix® and RotaTeq®, have a good safety profile. The available evidence does not show a higher incidence of adverse events or higher mortality among those vaccinated compared to those in the placebo group. • These vaccines have demonstrated, with high/moderate certainty of the evidence, high efficacy in the prevention of RV-AGE. • The systematic review of vaccine effectiveness based on large observational studies estimates similar results to those obtained in the review of efficacy. • In Spain, there has been a significant decreasing in hospital admission rates for RV-AEV in recent years, which in turn coincides with a progressive increase in vaccination coverage to high levels in 2020, although this vaccination is mostly carried out privately. • The results of the economic evaluation indicate that in Spain, at current vaccine prices, only vaccination of at-risk population with Rotarix® would be cost-effective. Vaccination of at-risk population with RotaTeq® would be efficient at a price between €184.9 and €192 for the full schedule. • Compared to the no-vaccination scenario, universal vaccination would achieve a much greater impact than at-risk population vaccination strategy in terms of decreasing clinical events. • The sensitivity analysis, performed with all model parameters, indicates that the economic modelling is robust as there is no variable, except price, which, within the ranges identified in the literature review, modifies the results substantially. • Universal vaccination would be efficient with Rotarix® with prices between 111.85 and 118.20 € for full vaccination and with RotaTeq® between 108.70 and 115.50 € for full vaccination. • Implementation of universal vaccination would, at current prices, have an annual budgetary impact for the NHS of between 49.3 and 56.7 million euros, depending on whether vaccination is carried out with Rotarix® or with Rotateq®.With the decreasing price resulting from the economic model, the budgetary impact would be between 26.8 and 28.7 million euros per year with Rotarix® and between 27 and 29.1 million euros per year with Rotateq®. • From an ethical and social point of view, the introduction of universal vaccination would reduce the current inequalities in access.

Authors' methods: SYSTEMATIC REVIEWS: Systematic reviews (SR) on safety, efficacy, effectiveness and efficiency were carried out. Studies conducted in an Organisation for Economic Cooperation and Development (OECD) country were selected. The quality of the included SRs was assessed using the AMSTAR-2 tool. The risk of bias of the included randomised clinical trials was assessed with the Cochrane Risk of Bias 2 (RoB-2) tool. The GRADE methodology was used for the overall assessment of the quality of evidence. In the SR of economic evaluations, the ISPOR tool was used to select studies for their relevance and applicability to the context. The results were synthesised through meta-analysis when several homogeneous studies were available for the same indicator. The selection and quality assessment of studies was carried out independently by two reviewers. When there was disagreement between the two, this was resolved after discussion, and when there was no consensus, a third reviewer was consulted. ECONOMIC EVALUATION AND BUDGET IMPACT ANALYSIS: A cost-utility analysis has been carried out for Spain, through the de novo elaboration of a Markov model based on the Spanish context and including mostly information from our country. The model compares three strategies: 1) no vaccination; 2) vaccination of the population at risk; and 3) universal vaccination. The results obtained with both the RotaTeq® and Rotarix® vaccines are analysed from two perspectives, that of the National Health System (NHS) and that of society. The model is an annual cycle model and follows a cohort of newborns until the end of life. They all start in the uninfected state and can become infected, remain uninfected or die. The model has been validated by consultation with experts and by comparing its results in terms of incidences with data obtained from the literature. A willingness-to-pay threshold of €22,000 to €25,000/AVAC was assumed. A univariate deterministic sensitivity analysis was performed for all the variables underlying the model. The budgetary impact of implementing the vaccination strategies evaluated for the NHS was assessed.

Project Status: Completed

Year Published: 2022

URL for published report: https://redets.sanidad.gob.es/productos/buscarProductos.do?metodo=detalle&id=1098

Requestor: Spanish Ministry of Health

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Spain

Organisation Name: Agencia de Evaluacion de Tecnologias Sanitarias

Contact Address: Instituto de Salud "Carlos III", Calle Sinesio Delgado 6, Pabellon 4, 28029 Madrid, Spain. Tel: +34 9 1 822 2005; Fax: +34 9 1 387 7841;

Contact Name: Luis M. Sánchez Gómez

Contact Email: luism.sanchez@isciii.es

Copyright: <p>Agencia de Evaluacion</p>