A Structured Narrative Literature Review of the Broader Value of Adult Immunisation Programmes

Vaccine-preventable diseases continue to generate a substantial burden on health, healthcare systems, and societies, which is projected to increase with population ageing. There is a need to better understand the full value of adult immunisation programmes corresponding to the broader value of vaccine frameworks that are recommended for evidence-based decision-making. This review aims to summarise and map evidence for the value of selected adult immunisation programmes (seasonal influenza, pneumococcal disease, RSV, and HZ) in ten diverse countries. We conducted a structured literature review of evidence published from 2017 to 2023. An existing framework was used to structure the assessment, developing matrices demonstrating the elements of value evidenced for each vaccine and country of focus. Our analysis showed substantial evidence base on the value of adult immunisation programmes, but the availability of evidence varied by value element and by vaccine. The impact on the quality of life of the vaccinated individual was the most evidenced value element. Mortality benefits for vaccinated individuals and cost-offsets to healthcare systems were also well-evidenced. The availability of evidence for ‘broader’ societal value elements (such as transmission value, carer productivity and impact on social equity, and antimicrobial resistance prevention) varied. No evidence was identified relating to the broader value elements of macroeconomic effects, value to other interventions, or effects on the quality of life of caregivers. Robust evidence exists to show that adult immunisation programmes generate substantial value for population health and health systems, yet some elements of broader value remain underrepresented in the academic literature. Without such evidence, the full value of immunisation programmes is underestimated, risking suboptimal policy decisions.


Introduction
Vaccines are amongst the most effective interventions in medical history [1], having eliminated or even eradicated diseases like yellow fever, diphtheria, cholera, polio, measles, and rubella [2].Today, however, other vaccine-preventable diseases generate a substantial burden on health, healthcare systems, and societies around the world.Over 51 million deaths are expected to be averted due to vaccination against 14 pathogens between 2021 to 2030, which translates to about 5.2 million deaths averted per year [3].The prioritisation of preventive healthcare, including vaccines, is increasingly recognised as essential for supporting healthcare systems and societies to respond to these challenges [4].Yet, despite significant progress in ensuring global access to childhood immunisation programmes since the establishment of dedicated global initiatives and immunization goals, progress on vaccinating adults and older adults has been limited [5][6][7].
Vaccine-preventable diseases continue to produce substantial disease and mortality burdens in adult populations worldwide.For example, disaggregated data focusing on vaccine-preventable diseases estimated that one in five communicable-disease deaths among adults aged 60 and older were attributable to three priority vaccine-preventable diseases (influenza lower respiratory tract infections, pneumococcal pneumonia and meningitis, and herpes zoster) [8].Despite this, access to vaccinations varies widely, with many countries excluding adult vaccinations from routine schedules [9,10].For example, reported influenza vaccination coverage rates among older adults vary significantly, with rates as low as 9.2% in Saudi Arabia and as high as 81.9% in South Korea [11].
The value of adult immunisation programmes continues to be under-recognised in the academic literature and decision-making frameworks globally [12][13][14].Beyond preventing illness, vaccines can generate substantial 'externalities' (i.e., indirect spillover effects on third parties) [15].The Broader Value of Vaccines framework by Bell et al. [16] categorises and conceptualises the distinct elements of vaccines' value based on a synthesis of the literature.The framework distinguishes between 'narrow' effects of vaccines, concerning the impact of vaccines on the health of individuals and the health and economic effects on the health system, and 'broader' effects of vaccines, which include the effects of vaccines beyond those vaccinated, as well as various socio-economic effects outside of the health system [16].It has been widely debated in the literature that policy and decisionmakers typically only consider narrow health effects and economic effects within the health system, but not necessarily effects external to these [12,[16][17][18].This under-recognition of the value of adult vaccines may lead to suboptimal decision-making by policymakers and formulary decision-makers at the national or subnational level.
Aligning with calls to integrate recommended immunizations throughout the life course [19] and to expand on the narrow frameworks traditionally used to evaluate the value of immunization [17], this study aims to synthesise and categorise evidence from ten diverse countries on the value of various adult immunisation programmes for health, healthcare systems, and societies according to the Broader Value of Vaccines framework, and to identify under-recognised value elements of these adult immunisation programmes.

Materials and Methods
This targeted literature review sought to identify evidence on the value of four adult immunisation programmes (seasonal influenza, pneumococcal disease, respiratory syncytial virus (RSV), and herpes zoster (HZ)) which prevent infections due to seasonal influenza (flu), streptococcus pneumonia, RSV, and varicella zoster virus (VZV), respectively.The four adult vaccines were selected given their substantial and established disease burden now and in future projections [8].The selection allows us to differentiate between those vaccines that mainly generate value by preventing mortality (PD, influenza, and RSV) and those that mainly generate value by preventing morbidity (HZ).
We focused on ten countries, carefully selected to represent a diversity of immunisation schedules, healthcare systems, geographies, demographic contexts, and vaccine schedules: Australia, Brazil, France, Germany, Italy, Japan, Poland, South Africa, Thailand, and the United States of America.For a breakdown of the immunisation schedules of the selected countries at the time of analysis, see Table S1 in the Supplementary Materials.
The narrative synthesis looks beyond the traditional criteria used to estimate the cost-effectiveness of drugs, which typically focus on 'narrow' health and healthcare system effects.We focus on evidence within three key value domains: value for population health; value for healthcare systems; and value for society [14,16].Following Cafiero-Fonseca et al. and Bell et al. [12,16], we assessed the strength of the evidence base for the value of adult immunisation programmes by reviewing the papers identified in the search to determine which elements of value have been evidenced for each vaccine and country of focus.The Broader Value of Vaccines framework by Bell et al. [16] was used to structure the assessment.The definition and characterisation (narrow/broad) of each of the eleven value elements of the framework is explained in Table 1.According to the framework, narrow value elements include the impact of vaccines on the health of vaccinated individuals and on economic effects within the health system.Broad value elements include the effects of vaccines beyond those vaccinated, as well as various socio-economic effects outside of the health system (e.g., productivity).We developed evidence matrices to demonstrate evidence availability for the value of adult immunisation as characterised by the framework.We assessed evidence availability per value element for each immunisation programme, overall and for each country.We remained vaccine-agnostic within each disease area, and excluded evidence relating solely to the burden of disease.[16,20].This element is not relevant for the purpose of this paper of assessing the consideration of the value of vaccines in research studies.** AMR = Antimicrobial resistance.*** Macroeconomic effects not predicted to be relevant for vaccines of focus given low likelihood of major outbreaks.
The study design was a targeted literature review which employed the following inclusion criteria: quantitative and qualitative analyses, published from 1 January 2017 to 31 June 2023, full texts available, published in the English language, and studying adult human populations aged 18 and above.We excluded papers with only abstracts available, as well as case series, case reports, editorials or expert opinions.The initial search was restricted to evidence published since 2017 to prioritise the more recent literature showcasing the breadth of effects and given that very few studies published prior to 2017 considered effects beyond health benefits to the vaccinated individual and healthcare systems, such as population-level health benefits, productivity benefits, and other broader societal benefits [12].Further, we reviewed the reference lists in the articles identified by the database search to capture additional relevant studies, including those that fell outside the time range, but captured broader effects and for which no other or more recent data were available.
Two reviewers (H.B. and E.B.) independently screened the literature and extracted the following data: study type, author, study location, time frame of data collection, population considered, and study findings.We conducted the search in PubMed.The search strategy and search terms used are shown in Appendix A. We included evidence from a broad range of study types considering the breadth of the topic, as well as geographical differences, for example, in data availability and analytical capacity.To mitigate the risk of bias, we prioritised evidence from systematic reviews and excluded evidence from the lowest tiers of the evidence hierarchy (case series, case reports, editorials, or expert opinions) [21].
All results considering the relevant value elements, including those reporting null findings, were included in the matrices.Studies highlighted in the narrative synthesis on the value of vaccination were statistically significant with a confidence level of 95% or higher, unless otherwise stated.

Assessment of the Evidence Base for the Value of Adult Immunisation Programmes
We found 159 papers that fit our search criteria, 95 of which met the inclusion criteria for the value framework matrices for our countries and vaccines of focus.These are listed in Table S2 in the Supplementary Materials.Table 2 displays the matrix with the percentage of sample countries for which relevant evidence was identified on each value element by immunisation programme.Matrices showing results by country are presented in Appendix B.
The results showed that evidence availability for all vaccines was greatest for the 'narrow' benefits: quality of life and mortality benefits to vaccinated individuals and cost-offsets to healthcare systems.Across vaccines, evidence of these value elements was identified in each of the ten countries of focus.For each vaccine, effects on the quality of life of vaccinated individuals was the value element most consistently evidenced across countries (The definition of this value element in the Broader Value of Vaccines framework is the value of effects on the physical, mental, emotional, and social functioning of vaccinated individuals, and we include any outcomes relating to infections, morbidity and healthrelated quality of life within this definition).
A substantial evidence base exists on the value of vaccination for some 'broader' value elements.Productivity value was considered in at least one country for every vaccine except for RSV, although we identified evidence of the productivity burden associated with RSV [22].Evidence for transmission value exists for all relevant vaccines (i.e., influenza, pneumococcal, and RSV, as there is limited transmissibility of VZV between adults).
There is a paucity of evidence relating to other 'broader' value elements.Evidence for effects on the productivity of carers exists in a small proportion of the countries, for all vaccines except RSV.For effects on social equity, there is evidence relating to one of the included vaccines (pneumococcal) in one country (the United States).For effects on antimicrobial resistance, there is evidence relating to one of the included vaccines (influenza) in one country (Australia).No evidence was identified relating to macroeconomic effects, value to other interventions, or effects on the quality of life of caregivers in any country in the sample.
The value of influenza and pneumococcal vaccination was the most comprehensively evidenced, with evidence for seven value elements identified for each vaccine.Evidence of five value elements was identified for HZ vaccination and of four value elements for RSV vaccination.
The level of evidence availability differed across countries.The most comprehensive evidence was available in the United States, where evidence of seven of the eleven value elements was identified.The least comprehensive evidence was available in Poland and Thailand, where evidence of only two and three elements, respectively, was identified.For country-specific availability of evidence, see the full matrices presented in Appendix B. It is important to note that consideration of a value element may be through outcomes reflecting only partial value.For example, whilst effects on patient productivity were considered in the majority of countries, this was often measured solely in terms of absenteeism from formal workplaces, excluding effects on presenteeism and the value of informal market activity (for example, working in the informal economy) and informal non-market activity (for example, caregiving by unemployed or retired adults).

Value of Adult Immunisation Programmes for Vaccinated Populations
There is ample evidence (see Table 3) demonstrating the health value of adult immunisation programmes with respect to the prevention of disease, disease sequelae with major health consequences, and mortality in older adults (most commonly defined as adults aged 65 and older, but sometimes from the age of 50 and adults with risk factors).Vaccination was associated with a decline in the incidence of myocardial infarctions (HR, 0.73, 95% CI: 0.56-0.96)compared with no vaccination.Incidence of stroke did not differ between the two groups. [28] Mortality Systematic review and meta-analysis U.S.

Database inception-2022
Older adults (varies by study) Vaccination was associated with a decrease in the risk of all-cause mortality among adults (HR: 0.76, 95% CI: 0.66 to 0.87) compared with no vaccination.Incidence of cardiovascular mortality did not differ between the two groups.
[28] * HZ does not usually cause death, most studies of vaccine efficacy do not consider this outcome.

Value of Adult Immunisation Programmes for Reducing Disease Transmission
There is a small body of literature exploring the effects of adult immunisation programmes on broader disease transmission dynamics.We identified two studies which reported directly on the additional health benefits accrued to unvaccinated populations due to adult immunisation programmes.A study of the community effects of influenza vaccination in Australia and South Africa found that, compared with no vaccination, vac-cination of 15% of the population (prioritising HIV-positive individuals, adults aged 65 and older; and young children) could decrease the annual rate of symptomatic infection by over 47% and deaths by over 55% in both communities [37].

Value of Adult Immunisation Programmes for Healthcare Systems
There is good evidence that adult immunisation programmes avert substantial costs to healthcare systems and are cost-effective, and that increased uptake or coverage expansion would be more cost-effective for healthcare systems.This is summarized in Table 4.

Productivity Value of Adult Immunisation Programmes
There is evidence that vaccines avert major productivity losses, and that expansions of vaccination coverage would produce net gains for governments as a result of averted productivity losses among immunised populations (and the resulting fiscal implications, including increased income tax revenue as a result).This is summarized in Table 5.
There is limited evidence of the productivity value to caregivers.Three studies reported results incorporating productivity effects on caregivers.A cost-effectiveness analysis of influenza immunisation programmes in South Africa including adults aged 65 years and older reported productivity losses averted amongst their caregivers, and found the programme to be cost-effective [51].Similar analyses of pneumococcal and HZ immunisation programmes in adults aged 60 and over (some of whom had underlying conditions) in Japan reported productivity costs averted amongst caregivers and found the programmes cost-effective [52,53].
We did not identify any evidence valuing the productivity gains of vaccination amongst older adults in terms of the value of the informal care they themselves contribute (e.g., to grandchildren).Investment in this strategy would yield average per capita benefits of 16.2 times the value of the investment in terms of productivity impact and 3.1 times the value of the investment in terms of tax impact over the 1-year time horizon. [ RSV None identified

Herpes Zoster
Cost-benefit analysis Italy 1-year time horizon Adults aged 30 to 65 years A vaccination strategy resulting in a reduction in the number of individuals infected with HZ from 6400 to 6000 and with PHN from 1050 to 750 would result in a total annual reduction in productivity loss of EUR 640,000 and increase in tax revenue of EUR 63,000.Investment in this strategy would yield average per capita benefits of 20.0 times the value of the investment in terms of productivity impact and 1.7 times the value of the investment in terms of tax impact. [54]

Social Equity Value of Adult Immunisation Programmes
Vaccine programmes can contribute to improved health equity within countries, as well as a reduction in the financial risk associated with vaccine-preventable diseases, which is inequitably distributed.A systematic review of 'equity-informative' economic evaluations (i.e., evaluations which consider equity dimensions) of vaccines concluded that both the introduction of vaccine programmes and expanded vaccine coverage resulted in mortality reductions and financial risk benefits, which were relatively larger in subpopulations with higher disease burdens and lower vaccination coverage-in particular, poorer income groups and those living in rural areas [56].A modelling study exploring the expected equity effects of ten vaccines, including influenza and pneumococcal vaccines, in forty-one low-and middle-income countries between 2016 and 2030 estimated that the largest effects on averted deaths and cases of medical impoverishment would be in the lowest income quartile of the population across vaccines and countries [57].
Expanded vaccine coverage could further increase the equity value of vaccines, as well as their broader health and economic value to society.A modelling study in the US found that expanding the pneumococcal vaccination recommendation to all adults over the age of 50 (compared to the current recommendation of vaccination for adults aged 65 and older and high-risk adults) would reduce inequity in the pneumococcal disease burden between black and non-black populations [58].This is because, in the US, black populations aged 50 to 65 have a higher prevalence of risk factors, a higher probability of undiagnosed underlying medical conditions, and a greater risk of pneumococcal disease [59].The expanded recommendation would produce greater overall health and economic benefits, and be more cost-effective [58].

Role of Adult Immunisation Programmes in the Fight against Anti-Microbial Resistance (AMR)
Vaccines can affect antimicrobial resistance (AMR) directly via a reduction in the organisms and strains carrying resistant genes specifically targeted by a vaccine, and indirectly through a reduction in illnesses which require treatment with antibiotics.Evidence suggests that pneumococcal vaccines are associated with a direct and significant reduction in the number of antibiotic-resistant invasive pneumococcal disease episodes in vaccinated groups compared with unvaccinated controls [12,[60][61][62].While antiviral vaccines (e.g., influenza and RSV) do not directly affect organisms causing antibiotic-resistant disease, they reduce the incidence of illnesses for which antibiotics are inaccurately prescribed, as well as the risk of secondary bacterial infections which require antibiotic treatment.Significant reductions (11-50%) in the use of antibiotics have been observed in influenza-vaccinated adults compared with controls [61].One case-control study in Australia which assessed the effects of the influenza vaccine on antibiotic prescription for influenza-like-illness recorded a 22-23% reduction the likelihood of antibiotic prescribing in low-risk adults (aged 40-64 years and without comorbidities) [63].New vaccines targeting respiratory pathogens, such as RSV, would not only prevent the viral disease, but could potentially curtail subsequent antibiotic use and, consequently, induce AMR [64].

Discussion
This study shows that there is a substantial evidence base on the value of adult immunisation programmes, but the availability of evidence varies by value element and by vaccine.Evidence availability was greatest for the 'narrow' benefits of immunisation programmes: the quality of life and mortality benefits to vaccinated individuals and the cost-offsets to healthcare systems.The availability of evidence for 'broader' societal value elements (such as transmission value, carer productivity, and impact on social equity and antimicrobial resistance prevention) varied.No evidence was identified relating to the broader value elements of macroeconomic effects, value to other interventions, or effects on the quality of life of caregivers.
Quality of life and mortality were well-evidenced for each of the vaccines of focus, with demonstrated effectiveness in older adults and at-risk populations.While there is some evidence that some vaccines may be less effective in the oldest populations, due to the progressive decline of immunity with age, we found evidence of immune response and efficacy even in the frailest and most immunocompromised populations.This is important given that these populations often suffer the most severe consequences of vaccine-preventable diseases [33,36].These diseases can act in a costly 'vicious cycle', accelerating frailty and in turn making individuals more vulnerable to the health consequences of vaccinepreventable diseases [65,66].A well-functioning immune system (supported by adherence to vaccination schedules) can thus delay the acceleration of frailty to disability, highlighting the importance of vaccinating the oldest populations on an individual and societal level.Furthermore, new strategies are being developed to improve vaccine efficacy in adults aged 80 and over [67].With ageing global populations and higher healthcare resource utilisation and costs amongst older patients, as well as higher rates of co-morbidities, vaccines which are effective in-and widely used by-the oldest populations will be critical [22,68].
The value of adult immunisation programmes in off-setting costs to health systems is also well-evidenced.We found that all of the adult immunisation programmes considered are at least cost-effective (or have the potential to be, in the case of RSV) [38,[47][48][49] and can result in net cost savings to the healthcare system [39,40,45].Interventions to increase uptake can also be cost-effective [41] and even increase cost-effectiveness [45], potentially due to economies of scale in delivery, considering the relatively low variable costs compared with fixed costs, and in some cases population-level transmission effects (herd protection) [69,70].Expanding access to a broader adult population can potentially generate more value, especially given that the burden of vaccine-preventable diseases and rates of chronic diseases amongst younger age groups is projected to rise [71].
Vaccines provide important societal value.The most well-evidenced broader value element was the impact on productivity of the vaccinated, evidenced in 70% of our countries and for all of the vaccines of focus.Adult immunisation programmes provide a positive return on investment in the form of increased productivity (and subsequently, increased income tax revenues), which can outweigh their costs many times over [54].It is important to note, however, that the included studies only considered the productivity impacts of absenteeism, but not the potential effects of some vaccines, like pneumococcal and herpes zoster vaccines, on presenteeism [72].Additionally, they do not consider productivity effects on informal care delivered, for example, by older adults [73], nor the potential productivity value for younger adults in high-risk groups.
In recent years, academic publications have increasingly evidenced diverse elements of socio-economic value associated with adult vaccination.For example, in comparison with the studies on pneumococcal vaccination published between 2010 and 2016 reviewed by Cafiero Fonseca et al. [12], which identified evidence pertaining to six of the value elements in the framework, our research additionally identified evidence relating to two more value elements: social equity value and AMR prevention value.Whilst our results show that there is growing recognition of the broad societal value of vaccination, it is also clear that evidence gaps remain.Our review identified a paucity of evidence relating to broader value elements like AMR prevention and carer productivity, and we found no evidence relating to macroeconomic effects, value to other interventions, or effects on the quality of life of caregivers in any country in our sample.This can be explained partly by the methodological challenges involved in collecting and analysing evidence of broader value, and partly by the 'narrow' decision-making frameworks used to evaluate immunisation programmes [12][13][14]16].
It is important to recognise the broader value of vaccines, as oversight of some value elements risks the undervaluation of vaccination programs.For example, vaccination plays an important role in preventing AMR; thus, the exclusion of AMR prevention value in cost-effectiveness analyses may yield less favourable cost-effectiveness results [5,62,63].Investment in the development of novel antimicrobial vaccines can help to protect against the future progression of AMR, a value which may be complex to quantify given the technical challenges of measuring direct and indirect effects of vaccines on AMR and the lack of data availability [5,61,74].More comprehensive approaches to the design of cost-effectiveness studies, which simultaneously evaluate several criteria and in-corporate qualitative judgements where quantitative data may not be available, are increasingly possible and may be necessary to capture the broader value of vaccines [75].
The understanding and quantification of these broader value elements, and their incorporation into cost-effectiveness analyses, have important policy implications.For example, given that socioeconomically disadvantaged sub-populations have higher rates of underlying medical conditions-and subsequently a higher risk of vaccine-preventable disease and complications-the benefits of expanding adult immunisation programmes are particularly concentrated in these sub-populations [56][57][58][59].Capturing these contextdependent social equity considerations in cost-effectiveness analysis can enable the design of vaccine policies with the potential to reduce inequity in the distribution-and economic and societal burden-of vaccine-preventable diseases.
Existing methods and tools need to be adjusted to integrate these additional (broader) benefits for which empirical evidence has become increasingly available in recent years [17].More experimental and observational studies are also needed to expand the evidence base for the broader benefits of vaccination, beyond those included in existing conceptual frameworks.Gessner et al. [76] call for an inventory of evidence and regular monitoring of progress on completeness.Our research is a step in that direction.
The strengths of this review include a rigorous and structured search and literature evaluation by more than one person, enabling a comprehensive mapping of availability of evidence by value element in our selected countries.To our knowledge, this is the first use of the Broader Value of Vaccines framework by Bell et al. [16] to evaluate evidence availability and identify gaps by value element across the four selected immunisation programmes.We included a diverse set of countries and programmes to enhance the generalisability of the results and enable a better understanding of some contextual differences; however, our study has some limitations.Given the breadth of our scope, there is a trade-off with the systematic and comprehensive inclusion of evidence.We did not conduct a meta-analysis given the diversity of outcomes covered by the value elements considered and due to methodological heterogeneity in the studies included.Risk of bias was mitigated by excluding evidence from the lowest tiers of the evidence hierarchy.While this study includes a set of ten countries with various vaccination schemes, the generalisability of specific quantitative results is limited, as the magnitude of effects considered depends on contextual factors such as the uptake of both adult and child immunisation programmes [12].Further, our search was limited to the English literature.Therefore, public health reports or national studies that have not been published as scientific papers in English, but which may contain information on vaccination and quantification of its economic/societal value, are not reflected in our results.We also note that the majority of reported evidence pertains to the benefits of adult immunisation programmes, which may suggest publication bias.Finally, the evidence on RSV is limited given its novelty at the time of writing.
The combination of countries and immunisation programmes selected aims to provide a comprehensive picture of the recognition of the value of adult immunisation across a global context, balancing the breadth of adult vaccination programmes (e.g., those targeting fatal vs. non-fatal illnesses, which are less of a priority in low-income countries) with countries geographical (relevant for incidence rates of certain vaccine-preventable diseases), income, and data availability contexts.Our country selection includes ten diverse countries: while some middle-income countries were included, the implementation of immunisation programmes-and consequently, data availability-is often limited in low-income countries [17].Further research and investment are needed to specifically evaluate adult immunisation programmes in low-income countries and to generate focused analyses, for example, using the framework proposed by Hutubessy et al. [17], to help to improve the sustainability and equity of adult immunisation programmes.

Conclusions
Robust evidence exists demonstrating that adult immunisation programs can counter the increasing burden of vaccine-preventable diseases while being cost-effective for health systems.Expanding access to a broader adult population can generate greater value for society and net cost savings for healthcare systems.Further research evidencing the broader elements of the value of immunisation programmes where we identified gaps is essential to inform better decision-making and targeted policy interventions that aim to optimise the coverage of adult immunisation programmes and maximise their value to individuals, healthcare systems, and society.

Table 1 .
Value domains and value elements according to the Broader Value of Vaccines framework.

Table 2 .
Percentage of sample for which country-specific evidence of positive impact on value element was identified.

Table 3 .
Findings on the value of adult vaccination programmes in older adults and adults with comorbidities.

Table 4 .
Findings on the value of adult vaccination programmes to healthcare systems.

Table 5 .
Findings on the productivity value of adult vaccination programmes in immunised populations.