*3.4. Summary of Study Findings on Cost-Effectiveness and Health Equity Impact*

The cost-effectiveness and health equity impact findings of vaccines are summarized in Table S6 in the Supplementary Materials. Subpopulation ICERs were estimated in ten studies that found similar findings of better cost-effectiveness results (lower ICERs) in equity-relevant subpopulations with higher disease burdens, especially the poorer-income groups and rural areas [23–25,27–32,34]. This demonstrated that introducing vaccines or improving vaccination coverage, compared to no vaccination, was more cost-effective in the more socially disadvantaged groups.

We found similar findings of more deaths averted and higher financial risk protection benefits in subpopulations with higher disease burdens, such as poorer income groups and those living in rural areas, across 21 studies [6–13,23–35]. However, higher household OOP expenditures were averted more in the wealthier income groups due to the aversion to private healthcare utilization [8,9,11].

Studies estimating the distributional impact of improving [7,25,31,33] or achieving [23,28–30] equitable vaccination coverage found that more deaths were averted in the more socially disadvantaged groups with higher disease burdens and lower vaccination coverage. Furthermore, one distributional cost-effectiveness analysis demonstrated that the pro-poor vaccination strategy of the rotavirus vaccine compared to the currently implemented program was a "lose-win" strategy as it showed a negative impact on total health despite a positive impact on health equity, which required a trade-off between efficiency and equity [33]. Interestingly, one study found that introducing rotavirus vaccine in the context of existing inequities in vaccination coverage across regions and socioeconomic subpopulations resulted in introducing disparities in the mortality reduction [23].

#### *3.5. Reporting Quality*

Reporting quality of the included studies, assessed using the CHEERS 2022 statement [21], is presented in Table S7 in the Supplementary Materials. Overall, most topics were adequately reported in the included studies. However, the health economic analysis plan and engagement with patients and others affected by the study were not reported in any study.

#### **4. Discussion**

Economic evaluations are typically performed to estimate the average incremental costs and effectiveness of interventions of interest. Equity-informative economic evaluations further provide a spectrum of impact across equity-relevant subpopulations to inform policy prioritization. This systematic review identified 21 equity-informative economic evaluations of vaccination programs to date, with progressively evolving methods to incorporate equity. The health equity impact of vaccines has been incorporated into economic evaluations by estimating the distributional health and non-health benefits of vaccination programs across equity-relevant subpopulations to better understand where and to whom more efforts and support should be provided. Extended cost-effectiveness

analyses of vaccines were generally performed in LMICs to reflect the importance of financial risk protection, which is one of the goals of the health system for achieving universal health coverage [6–12,36,37]. Distributional cost-effectiveness analyses of vaccines were performed to estimate the distribution of health opportunity costs [33,38]. Since a vaccination program generally involves a large cohort of the population, distributional cost-effectiveness analyses could inform the trade-offs between improving total population health and reducing health inequities.

Existing inequities related to vaccines were shown in the included studies, where disease burden and financial risk were generally higher in more socially disadvantaged groups. There was usually lower vaccination coverage in poorer income quintiles, along with higher disease incidence and mortality compared to richer income quintiles. Successfully implemented equitable vaccination programs could help decrease diseases, deaths, and costs to health systems and households, as we found that immunization programs informed by equity-informative economic evaluations of vaccines generally resulted in more deaths averted and higher financial risk protection benefits in socially disadvantaged subpopulations compared to regular immunization programs [7,25,31,33]. Thus, equity-informed vaccination programs could enhance access to life-saving immunization for disadvantaged populations and ultimately help achieve health equity, if specifically designed to address existing inequities in health systems.

Forceful national and global decision-making on how best to adapt and optimize the implementation of immunization programs to reach all vaccination target groups needs to be underpinned by robust and standardized equity-informative economic evaluations. To ensure the ubiquitous application of such evaluations, global guidance is needed to incorporate health equity into economic evaluations and to ensure standardization in conducting, reporting, and interpreting the analyses. In this review, we highlight a few methodological considerations on how to shape future equity-informative economic evaluations of vaccines. Firstly, the health equity impact of improving vaccination coverage should be conducted to provide information on the potential benefits of moving towards achieving equitable vaccination coverage across equity-relevant subpopulations. Many studies were conducted to estimate the impact of vaccines introduced to contexts with existing inequities in vaccination coverage without consideration of the potential benefits of equitable vaccination coverage. Hence, models should be developed considering improving vaccination coverage as a gradual change rather than an instantaneous change to fully capture the marginal benefits of improving vaccination coverage. Different levels of target vaccination coverage should also be explored to develop evidence-informed optimal implementation strategies, as attempts to improve coverage early on (e.g., from 10% to 20%) are expected to have higher marginal benefits compared to boosting coverage in contexts with existing higher vaccination coverage (e.g., from 75% to 85%).

Secondly, we emphasize the importance of incorporating and reporting all relevant aspects of equity, as improving equity in one aspect could potentially lead to inequities in other aspects. For example, a pro-poor vaccination program that improved equitable vaccination coverage can introduce disparities in mortality reduction given the existing inequities in the mortality risk at baseline. Thus, policy decision-makers will be wellinformed about both the positive and negative impacts of the vaccination programs.

Thirdly, a dynamic model should be developed to fully capture the distributional impact of most vaccination programs on the force of infection in susceptible individuals and indirect transmission-dependent effects [3]. Nevertheless, it is challenging to model herd protection between equity-relevant subpopulations—for example, modeling how higher vaccination coverage among the richer income groups will translate to herd protection for the unvaccinated in the poorer income groups.

Lastly, as highlighted by the CHEERS 2022 statement [21], stakeholder engagement is important to ensure that the studies align with needs of local stakeholders and policy decision-makers. De facto, none of the included studies reported the inclusion of stakeholder engagement. Thus, advocacy is needed to ensure that stakeholder engagement is

included and transparently reported in future equity-informative economic evaluations of vaccines. Likewise, the inclusion of stakeholder engagement in economic evaluations, especially local stakeholders, is highly encouraged to gain a better understanding of their needs, opinions, and perceptions of how health equity and inequities are defined, measured, monitored, interpreted, and achieved. This is particularly important as we found that assessment and measurement of health equity impact were affected when equity was not clearly defined.

We accentuated a few limitations of our review that are worth mentioning. First, no specific guidelines or checklists are available to directly evaluate the equity-relevant methodological quality of equity-informative economic evaluations. Thus, quality assessment of the included studies could be carried out only in terms of reporting quality. Furthermore, the implications and applications of this review should be carefully interpreted since its findings and conclusions were based on a limited number of equity-informative economic evaluations of vaccines published since 2011. Analytical techniques of incorporating health equity in economic evaluations are continuously evolving, and we expect more studies to be published in the future.
