The Value(s) of Vaccination: Building the Scientific Evidence According to a Value-Based Healthcare Approach

Objectives To provide a new value-based immunization approach collating the available scientific evidence on the topic. Methods Four value pillars (personal, allocative, technical, and societal) applied to vaccination field were investigated. A systematic literature review was performed querying three database from December 24th, 2010 to May 27th, 2020. It included studies on vaccine-preventable diseases (VPDs) that mentioned the term value in any part and which were conducted in advanced economies. An in-depth analysis was performed on studies addressing value as key element. Results Overall, 107 studies were considered. Approximately half of the studies addressed value as a key element but in most of cases (83.3%) only a single pillar was assessed. Furthermore, the majority of papers addressed the technical value by looking only at classical methods for economic assessment of vaccinations whereas very few dealt with societal and allocative pillars. Conclusions Estimating the vaccinations value is very complex, even though their usefulness is certain. The assessment of the whole value of vaccines and vaccinations is still limited to some domains and should encompass the wider impact on economic growth and societies.


INTRODUCTION
Optimization of the use of limited available resources has been one of the main topics of discussion in healthcare so far. Over the past few years, different techniques have been developed to solve the problem of healthcare systems sustainability including evidence-based decision making (to ensure that only interventions with strong evidence of effectiveness and cost-effectiveness are used), quality improvement, and cost reduction (1). The value-based healthcare approach also emerged in order to address this issue with the aim to increase the value that is derived from the resources available for the population (2). Michael Porter, in 2010, introduced the concept of value in healthcare describing it as the "health outcome achieved per dollar spent" (3). Given the characteristics of European health systems that aim to ensure equity, universality and solidarity to all, efficacy, and efficiency parameters highlighted by Porter's value paradigm are necessary but not sufficient (4). Allocation of resources should guarantee the highest level of quality and value in respect to the principles of equity in finance and distribution, hence a paradigm shift in the analysis of value was proposed by Sir Muir Gray (5), with the aim of integrating the programming of health services to the approaches of modern population medicine (5). The suggested triple value paradigm identified allocative, technical, and personal values as cornerstone of healthcare delivery (6). Subsequently, in 2019, the Expert Panel on Effective Ways of Investing in Health (EXPH) of the European Commission proposed a comprehensive concept built on four value-pillars to define "value(s)-based healthcare" for conveying the guiding principles of solidarity-based healthcare systems (1): -The personal value in terms of appropriate care to achieve patients' personal goals; -The allocative value, namely the equitable distribution of resources across all patient groups; -The technical value meant as the achievement of the best possible outcomes with available resources; -The societal value that is represented by the contribution of healthcare to social participation and connectedness.
Among health technologies, vaccines are one of the most successful of contemporary times. In the last 50 years, worldwide, the elimination and the control of many diseases was made possible by vaccines which drastically reduced mortality rate and related complications. According to the World Health Organization (WHO), vaccinations prevent 2-3 million deaths every year (7). Vaccinations also contribute to the sustainability of health systems thanks to the reduction in hospitalizations and required medical treatment, visits, and examinations and, therefore, direct medical costs (8). Moreover, through the avoidance of the disease occurrence and its consequences, vaccination promotes the overall economic growth of countries and counters poverty (9,10). Despite these important benefits vaccinations are currently challenged by several concerns, such as unequal access, lack of resources, and vaccine hesitancy. An exploitation of the broad value of vaccines and vaccination could help contrasting such concerns and strengthening vaccination policies and strategies. The aim of this study is to identify and systematically describe how the value of vaccine(s) and vaccination has been addressed in the academic literature considering the four EXPH value pillar framework. The description of the scientific evidence on the whole value of vaccination will be useful to foster a new value-based immunization approach.

METHODS
A systematic review of the academic literature was carried out bearing in mind the four pillars of value (personal, allocative, technical, societal) as defined by the document by the EXPH of the European Commission (1). The relevant dimensions considered within each pillar were based on a comprehensive reading of EXPH report (1) and were as follows: -Personal value: clinical and patients reported outcomes and experience measures, citizens' involvement and empowerment; -Allocative value: access to vaccination, equity in provision, affordability, unwarranted variations, innovation; -Technical value: health technology assessment (HTA) and models for assessing the economic evaluation of vaccines/vaccinations; -Societal value: impact on population's wellbeing, productivity, and social cohesion; indirect and community protection; accountability of the decision-making process.
The systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA) (11).

Search Strategy
For each pillar, a systematic review was carried out. Hence, four systematic reviews were conducted. PubMed and Web of Science databases were queried. For the technical value pillar, the University of York's Center for Reviews and Dissemination (CRD) database was also used.
The search strings-reported as Supplementary Materialswere launched on May 27th 2020. The systematic review was performed from December 24th, 2010 onwards as Michael Porter' article "What is value in health care?" was published December 23, 2010 (3). As described in introduction, this article was the first scientific contribution on the value of vaccination according to the conceptual framework of EXPH.
The articles records were entered in a work sheet and screened according to the inclusion/exclusion criteria.

Inclusion/Exclusion Criteria
Studies were considered eligible if they dealt with vaccinepreventable diseases (VPDs), were conducted in advanced economies according to the list of the International Monetary Fund 1 and mentioned the term "value" at least once in the entire text. The choice of including only studies conducted in advanced economies was made assuming that the basic necessities are fulfilled and thus the meaning of value could be more comparable. Only studies written in English were included. Commentary, editorials, conference presentation, and references not provided with full text were excluded as well as studies conducted in animals or in vitro.

Selection Process and Data Extraction and Synthesis
Five researchers (E.C., A.T., I.G., E.B., M.M.) independently screened titles and abstracts first and full texts afterwards. Any disagreement was resolved by discussion or by the involvement of two other researchers (G.E.C., C.d.W.).
The following data were extracted from all the articles eventually included: author, year, country, type of study, study objective (single vaccine/vaccination strategy), study aim, target population, setting, vaccination strategy (mandatory/recommended/other), vaccination policy (free/copayment/out of pocket), centrality of the value in the paper (main object of the study or not). Papers addressing the value as main object were further analyzed in order to collect information about the domains considered within each pillar. The additional information collected to disclose the different dimensions were as follows: -Personal value: clinical outcomes (efficacy, effectiveness, safety etc.), patients' reported outcomes (PROMs, PREMs, satisfaction, quality of life), patients' reported experience measures (preference, attitudes, perceptions, awareness, knowledge, confidence, convenience, complacency, wellbeing, productivity, etc.), citizens' involvement, and empowerment in vaccination (participation, engagement, empowerment, commitment); -Allocative value: accessibility (people possibility to obtain the services when needed) 2 , equity (absence of unfair and avoidable or remediable differences in vaccination provision among population groups) 3 , affordability (payment for healthcare services must be based on the principle of equity, ensuring affordable services for all), appropriateness (i.e., effectiveness of the service for a particular type of patient, from which the patient could find a benefit), unwarranted variations (overuse, underuse), innovation (in terms of organizational program or strategy set up to improve vaccination coverages); -Technical value: economic model (cost of illness, cost effectiveness, cost benefit, cost utility, budget impact, fiscal impact, other), general drivers of costs (direct healthcare costs, direct non-healthcare costs, indirect costs, intangible costs, tax revenue), vaccination/vaccine-related drivers of costs (vaccine safety, vaccine efficacy, costs of vaccine administration, costs of vaccination program), and HTA; -Societal value: population's wellbeing (productivity, social cohesion, etc.), indirect/community protection (herd immunity, social responsibility, etc.), shared decision-making process on (accountability, transparency, appraisal criteria, monitoring of the impact of the decision appraisal, etc.), and Health Impact Assessment (HIA). Tables 1-4 and summarized descriptively through frequencies.
Value was the main objective of the research in 54 studies (50.5%), nine among them addressing more than one value pillar. A description of the main findings for each pillar is reported hereafter.

Allocative Pillar
The search brought a total number of six articles addressing allocative value as main objective, among which three (50%) were primary studies (12, 28, 30) and three (50%) reviews (26, 27, 29). The studies were very heterogeneous in terms of vaccines taken into account and only few dealt with a specific vaccination, namely influenza in one case (16.7%) (28), and HPV in another one (16.7%) (27). None of the included articles addressed the issue of unwarranted variations. Three (50%) papers addressed the topic of the affordability (26,27,29), whereas four (66.7%) articles brought the attention on innovative aspects in terms of organizational delivery (28), informational model (12,30) or extension of the vaccination to previously excluded populations (27). Equity was addressed by two (33.33%) studies (26,27), while only one (16.67%) tackled accessibility and appropriateness (27).
With respect to specific dimensions considered within the pillar, a total of 19 (52.8%) papers focused on the costeffectiveness, including also the cost-utility (25, 27, 32, 34, 35, 37, 38, 40, 43, 44, 46-48, 50, 53, 56, 59-61). Six studies (16.7%) addressed the cost of illness (48-50, 54, 58, 62), two (5.6%) the cost-benefit (33,55), and one (2.8%) the budget impact (45). The study by Jiménez et al. (46) was a HTA report addressing also current use of the technology, technical characteristics, and the clinical effectiveness. Four papers (11.1%) considered alternative ways/models to assess the economic value of vaccination (31,39,41,42). One article assessed the economic surplus produced by vaccination defined as the sum of all health and economic benefits of vaccination, minus the costs of vaccine development, production, and distribution (42). One study developed a novel approach (using the payoff method) to value real options in health care (41). Quality of Care (QoC)-Isocurve Model and budget optimization model was used by one study (39), while one developed a new value-based incentive payment model for immunizations delivered in community pharmacies (31). Eventually, four studies (11.1%) either described or tried to identify the broader potential economic impacts of vaccination (26,29,36,57). In particular, Postma et al. (57) stressed the difficulty of assessing the full economic (and societal) value of the vaccination and suggested that wider economic and societal values should be integrated or at least considered in the economic values of vaccination programs. Lifelong benefits for individuals, the reduction of indirect costs, and improved quality of life should not be underestimated and should be captured as an integral part of the economic assessment of vaccination programs (57). Bloom et al. suggested an urgent need of concerted efforts to identify datasets that could estimate the full benefits of vaccination programs and fit the challenges. High-quality data are needed to support research to "enjoy gains in public health that are more transformational than incremental" (29).
Population's wellbeing was indirectly described as gain of productivity (10,26,29,57), healthy aging (57), as well as through social cohesion in terms of awareness of the population of being part of a community and of contributing to it (23,36,57). Of note, Barnighausen spoke about "outcome-related productivity, " which considers direct health care costs or loss of productive time and "long term mental, physical, or cognitive impairments" and "behavior-related productivity gains" brought by vaccination (10). Also benefits from reduction in the development of drug resistance was mentioned (10,36). Finally, shared decisionmaking was proposed by three articles in different forms: a set of core evaluation criteria to be applied to the vaccine evaluation procedure, with the ultimate aim to improve the accountability in vaccine decision-making (64); a community intervention to reduce vaccine hesitancy by providing pro-vaccine parents with tools to "engage in positive dialogue about immunization in their community, " so that pro-vaccine parents were empowered to be immunization advocates (23); and with the use of an interactive, internet-based decision tool that could help parents taking informed decisions about vaccination for their children (30).

DISCUSSION
Although the real and tangible benefits of vaccines are recognized globally, in many countries a decline in coverages has been observed in recent years and is still ongoing. Concerns or fears about vaccines safety, lack of trust, social norms, myths undermining confidence in vaccines, failure by some healthcare to provide evidence-informed advice, barriers in the access to vaccines (e.g., poor availability, co-payments), and failure to understand the underlying mechanisms that decrease vaccination confidence are some of the barriers to vaccination  (1). The understanding of the broad value of vaccination and the effective translation of this knowledge to the different stakeholders is therefore important to strengthen vaccination policies and strategies and counteracting disinformation and, misinformation. This systematic review has shown that the value of vaccine(s) and vaccination(s) was addressed by a few number of papers in the last 10 years. Only 54 out of the initial 7,122 articles (0.8%) addressed the topic in depth. The most studied vaccines were seasonal influenza, pneumococcal, and HPV vaccines. Most of the papers included in the systematic review addressed the technical value and then the personal one, while the allocative and societal values were addressed in very few papers. These results are noteworthy as it calls the attention on the need for more research on these dimensions that are relevant for fully addressing the value of vaccination also from the societal perspectives. Nonetheless, it should be pointed out that the assessment of the allocative and societal pillars poses several challenges. In fact, the allocative value encompasses many dimensions that cannot be assessed in a standardized way and are context-specific. The role played by equity, accessibility and appropriateness within the immunization agenda 2030 (65) and also in respect to COVID-19 vaccines emphasizes the importance of their evaluation (66).
As far as the societal value is concerned, several interesting suggestions for the development and the application of new methods and criteria emerged in respect to the impact of vaccination on social cohesion and Health Impact Assessment (AMR). In particular, with respect to AMR, vaccinations are still undervalued, even though they could reduce both the incidence of potential resistant infections and the inappropriate use of antimicrobials (67). Another important but still underinvestigated aspect is the patients/citizens' empowerment and engagement in the light of a shared decision-making, that is a key component of patient-centered health systems. An important point should be made also in regard to the evaluation of the technical value of vaccines and vaccination as the most of economic evaluations still adopt a narrow perspective on vaccines and vaccination benefits considering only health care cost savings and health gains. Nevertheless, a broader perspective should be undertaken, considering also outcome-related and care-related productivity gains, behavior-related output gains, health-based community externalities, risk reduction gains, reduction of comorbidities and other infections, and improvement in social equity (68). Nevertheless, also for this purpose, new tools are needed (68).
This systematic review has actually showed that there is room for improvements in regard to the concept of the value-based healthcare applied to vaccination.
To the best of our knowledge, this is the first systematic review that collated together the evidence on this topic shedding light on research gaps and needs. Evidence on the personal, allocative, technical, and societal value of vaccine(s)/vaccination published in the last decade and systematized in our review was described as foundation of a following consultation with international experts of the field. The result was the issuing of recommendations for research, decision-making, and public engagement to drive a value-based decision-making on vaccination (69). Further research activities would be desirable to address the same issues in low-and middle-income countries where the broad value of vaccines could be evaluated to a different extent.
Several limitations should be considered when interpreting results. Only articles published in English until May 27 th , 2020 were included, which might have led to fail identifying all the available evidence on the topic up to now. Furthermore, a selection bias could not be completed ruled out even though the screening process was performed by five researchers independently and based on a lenient criterion (value mentioned in any part of the text). The search strings as well as the synthesis of evidence was informed by the content of the document published by the EXPH of the European Commission but this cannot exclude that some dimensions could have been missed. Furthermore, in order to keep the systematic review strictly focused on the concept of value, articles were not included if they did not explicitly mention that word. We are aware that a lot of primary studies addressing the different dimensions of value of vaccines and vaccination have been published up to now, but our goal was not to make a systematic review of studies focused on single dimensions. A quality assessment of the included articles was not performed; therefore, we could not assess the methodological correctness of the included studies. However, in our opinion, this does not impair our work as we wanted to provide an overview of pillars and dimensions assessed without addressing the robustness of methods used to do it. Eventually, the heterogeneity of evidence limits the possibility to further elaborate on information and data coming from the studies and issue definite findings. Nevertheless, in our opinion, this first depiction could help bringing forward the assessment and the appraisal of the value of vaccines and vaccination in the field of both academic research and supranational, national and local decision-making.

CONCLUSIONS
Even though vaccines have contributed substantially to the reduction of the burden from infectious diseases, estimating their value is very complex. Each year, three million lives are saved thanks to vaccination. In developed countries, routine vaccinations have led to complete elimination or control of many diseases, drastically reducing their incidence, mortality rate and related complications (70). This article constitutes a comprehensive source of information on the value of vaccines/vaccinations and depicts the current evidence on the assessment of their personal, allocative, technical, and societal values. Increasing awareness of the true value of vaccines and vaccinations is of great importance as long as hesitation and underuse of vaccines may still lead to serious outbreaks. In fact, in a context of increasing pressure on healthcare budgets, vaccinations can contribute to the sustainability of health systems through a reduced and more efficient use of healthcare resources (71). As presented, the assessment of the whole value of vaccines and vaccinations needs to consider not just the direct impact on health and healthcare but also the wider impact on economic growth and societies. These wider impacts, although difficult to measure and still under-investigated, should be taken into consideration to better depict the whole values of vaccines and vaccinations and counteract vaccine hesitancy and misuse.

AUTHOR CONTRIBUTIONS
GEC, WR, and CdW conceptualized, designed, and supervised the study. AT, EC, MM, IG, and EB performed the data collection, screened the articles, and analyzed the data. AT and EC wrote the original draft of the manuscript that was revised and edited by GEC and CdW. All authors revised the manuscript and approved its submission for publication and certified that the work is original and their own.

FUNDING
This study was funded by VIHTALI (Value In Health Technology and Academy for Leadership & Innovation), Spin-Off of Università Cattolica del Sacro Cuore, Rome, Italy. This paper reports the results of a VIHTALI project entitled "The value(s) of vaccination: building the scientific evidence according to a value-based healthcare approach". The project was also funded by MSD.