We identified various models used to estimate the cost-effectiveness of rotavirus vaccination. From these, results using the standardized dataset could be obtained for three specific applications (the POLYMOD, Roxanne and CoRoVa models). Despite differences in the approaches, cost-effectiveness results of the models were quite similar. Differences between the outcomes of the specific building blocks of the cost-effectiveness (that is, vaccination costs, savings and QALYs gained) of the models currently investigated seem to relate to five aspects of the models: the multi-cohort nature of the POLYMOD model which assumed a step up in vaccination coverage (and hence in vaccination costs as well as cases prevented); the exact timing of the waning in the models and in particular the exact modulation of between-dose efficacies in the CoRoVa model; assumptions about the distribution of cases of different severity levels within the one-year age groups provided (for example, assuming a Weibull distribution in the Roxanne model); and the possibility in the models of experiencing subsequent episodes of rotavirus infections and/or experiencing episodes with multiple manifestations (for example, first moderate progressing to severe) and types of health-care use (for example, inpatient and outpatient, rather than just one of both).
Ergo, differences between the models on the individual components of cost-effectiveness could be related to some specific generic features of the models with regards to representing vaccine uptake and pricing, within age-group distributions, waning and between-dose efficacies and inclusion of additional groups and episodes in the general design of these models. Sensitivity analysis revealed that cost-effectiveness of rotavirus vaccination is highly sensitive to vaccine prices, rotavirus-associated mortality and discount rates, in particular that for effects. This is fully in line with other authors' findings [32
Unfortunately, we were not able to include a model with a transmission dynamic approach in our model comparison, instead of the cohort approach followed in the three models analyzed. Emerging evidence that herd immunity effects might be relevant for rotavirus transmission and vaccination enhances the relevance of considering populations and transmissions between cohorts [33
]. Inability to include these models was often related to the complexity of these models and the difficulties to adequately grasp these complexities in the standardized framework provided on inputs and outputs. However, for further work it is important to also analyze such dynamic models given their major advantage of incorporating infection dynamics including herd immunity effects and potential age shifts in epidemiology [36
]. Also, differences in uptake between high-, middle-, and low-income countries should be analyzed using dynamic models given the different impacts of coverage levels on herd immunity.
The three models selected for our analysis were all basically developed for high-income countries. For reasons stated previously, other models - inclusive of models developed initially for low- and middle-income settings - could unfortunately not be considered in our comparison. As one consequence, all the publications arising from these models involved costs per QALY gained rather than costs per DALY Disability Adjusted Life Year averted. Although not undisputed, for low- and middle-income settings DALYs rather than QALYs are the common metric used [27
]. We do note that one specific study showed that results differ only slightly if DALYs are used instead of QALYs; in particular, it showed slightly more favorable cost-effectiveness for DALYs as the outcome [16
]. However, it has been demonstrated that the decision about whether or not to include caregiver QALYs has a major impact on results [4
]. The appropriateness of including QALYs beyond the index case of disease is being debated; it could be argued that caregivers' QALYs are particularly important for rotavirus as they can be measured directly, and hence may be more valid than QALYs in small children with RVGE, where proxy measurements have to be used [7
Our findings for the regions Afr, Sear, Amr and Eur should not be considered as exact representative results and policy making should not directly be based on this. For example, it is very unlikely that the similarities assumed for the proportion of RVGE cases that are mild, moderate and severe are valid in real world. This simplifying assumption was made in order to test the models generically and consistently. Nevertheless, our results clearly indicate a general trend of increasingly more favorable cost-effectiveness when going from high- to middle- and on to low-income countries, respectively. As the sensitivity analysis shows, this is obviously primarily related to vaccine pricing and the QALY-impact of averted mortality due to rotavirus infection. However for actual policy making, countries will need to either further consider the results from existing studies and reviews, or initiate country-specific cost-effectiveness analyses. For countries that have the capacity and resources to model the cost-effectiveness of rotavirus vaccine, our comparative analysis can help inform the design of new models or selection of existing models to support national-level decision making.
Hence, although our analysis is not meant to directly inform policy making, it offers considerable guidance for design and/or selection of a model for adaptation to individual (low-income) countries that want to conduct cost-effectiveness analyses. Scarce resources in these countries may direct the choice towards adapting an existing model rather than initiating the development of a new approach. Reassuringly, our analysis suggests that different models produce similar cost-effectiveness estimates, illustrating that the exact choice of which model to adapt may not be as crucial as the choice of assumptions and parameter values to incorporate in the model.