Vaccination programs for older adults in an era of demographic change

Vaccination programs for older adults in an era of demographic change Objectives Populations are aging worldwide. This paper summarizes some of the challenges and opportunities due to the increasing burden of infectious diseases in an aging population. Results Older adults typically suffer elevated morbidity from infectious disease, leading to increased demand for healthcare resources and higher healthcare costs. Preventive medicine, including vaccination can potentially play a major role in preserv- ing the health and independence of older adults. However, this potential of widespread vaccination is rarely realized. Here, we give a brief overview of the problem, discuss concrete obstacles and the potential for expanded vaccination programs to promote healthy aging. Conclusion The increasing healthcare burden of infectious diseases expected in aging populations could, to a large extent, be reduced by achieving higher vaccination coverage among older adults. Vaccination can thus contribute to healthy aging, alongside healthy diet and physical exercise. The available evidence indicates that dedicated programs can achieve substantial improvements in vaccination coverage among older adults, but more research is required to assess the generalizability of the results achieved by specific interventions (see Additional file 1). Keywords Demographic change · Healthy aging · Vaccines · Vaccination programs Abbreviations QALY Quality-adjusted life-year QoL Quality of life VPD Vaccine preventable disease Electronic supplementary material The online version of this HZ Herpes zoster article (https ://doi.org/10.1007/s4199 9-018-0040-8) contains supplementary material, which is available to authorized users. * T. Mark Doherty Institute for Biomedical Aging Research, University mark.x.doherty@gsk.com of Innsbruck, Innsbruck, Austria Center of Vaccinology, University of Geneva, Geneva, GSK, Wavre, Belgium Switzerland Global Market Access Solutions, St-Prex, Switzerland CNR Institute of Neuroscience, Aging Branch, Padua, Italy Unit of PharmacoEpidemiology and PharmacoEconomics, Health Sciences North Research Institute, Sudbury, ON, Department of Pharmacy, University of Groningen, Canada Groningen, The Netherlands Center for Pulmonary Diseases, National Hospital GSK, Siena, Italy Organization Tokyo National Hospital, Tokyo, Japan Department of Geriatric Medicine, University Hospitals Vanderbilt University School of Medicine, Nashville, TN, Leuven, Leuven, Belgium USA Division of Gerontology and Geriatrics, KU Leuven, Leuven, Department of Medicine, School of Medicine and Dentistry, Belgium University of Rochester, Rochester, NY, USA Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA Vol.:(0123456789) 1 3 290 European Geriatric Medicine (2018) 9:289–300 Only recently have the implications and the dimensions of Introduction the coming problems been more widely recognized, leading to various strategies being debated. These various measures Worldwide, populations are aging due to ever increasing life are aimed at keeping older adults economically and socially expectancy and decreasing birth rates. The United Nations active longer than has been common in prior generations on estimates that 15% of the world’s population will be over the the one hand—the concept of “adding life to years”—and age of 60 years by 2025 and that this proportion will rise to on the other to delay as much as possible the inevitable age- well over 20% by 2050 [1]. In Europe as well as Japan, the related increase in healthcare utilization—a concept desig- proportion of people aged 65 years or older will double from nated as “healthy aging” [4]. 2010 to 2060 and the proportion of people aged 65 years or older relative to the population of working age (15–64 years) is expected to double by 2060. Discussion This demographic development is already starting to put considerable strain on public finances in countries with Healthy aging state-financed pensions and healthcare systems and the effects can only be expected to increase [2 , 3]. Without sub- The World Health Organization has recently defined the stantial (and politically difficult) changes in policy, the tax concept of healthy aging as “the process of developing and base will diminish because of the fall in the proportion of maintaining the functional ability that enables well-being in working age (and tax-paying) adults while pension expenses older age” [4]. Healthy aging is obviously a laudable objec- will grow, both because of continued increases in life expec- tive on its own to improve welfare and quality of life (QoL), tancy and the sheer growth in the number of people eligi- but it is also specifically recognized as necessary to counter ble for pensions. Furthermore, it is expected that healthcare the anticipated surge in healthcare costs consequent on the expenditures will increase substantially, as individual need demographic change underway. for healthcare services rises markedly with advancing age. Contributorstorapid aging Acutestressors Intervenons • Chroniccomorbidies • Accidents • Counselling/social engagement • Loss of immune funcon • Acute illness • Improved nutrion • Loss of metabolic funcon • Socialstress • Exercise • Under-nutrion • Vaccinaon Fit Healthy aging Agingwith acute incidents Rapid aging Well Frail Dependent Dead 30 40 50 60 70 80 90 Fig. 1 Healthy vs premature aging. Typically, aging is associated through chronic inflammation, mitochondrial dysfunction and cellular with a decline in physical capability, during adulthood, from being senescence that may degrade the endocrine, hematologic and muscu- fit and physically active to being well (that is, without obvious physi- loskeletal systems, and secondly, by increasing susceptibility to infec- cal incapacity, but with reduced physical activity). In most adults, tions, which can further harm these physiologic systems. The ideal of the later phases of life are characterized by frailty and disability. healthy aging (living with as little time spent in frailty or disability) is Disability is simply enough defined as the inability to perform basic contrasted to rapid aging in this simple schematic. In reality, however, day-to-day functions without assistance. Frailty is more difficult to aging for most people is a nonlinear process. Acute incidents such as define, but is often identified as meeting 3 or more of the following physical trauma from falls, social stressors such as divorce or death of clinical criteria: a low level of physical activity, exhaustion or low a spouse, or acute illness (for example, from cardiac disease or infec- energy, muscle weakness, slowness, and unintentional weight loss. tion) can trigger sudden losses of capacity, which in older individuals, The underlying etiology of frailty is poorly understood, but includes become increasingly difficult to recover from. This places a priority comorbidities such as diabetes, obesity and respiratory illnesses. on intervention to prevent those acute incidents to prevent frailty/dis- Immune dysfunction also seems to be a key factor in two ways. First, ability and maintain quality of life 1 3 European Geriatric Medicine (2018) 9:289–300 291 Traditional stereotypes are no longer applicable to the dysregulation and chronic inflammation have been sug- current population of older adults, who are often healthier gested as primary drivers of frailty [15]. Consistent with and more active than prior generations and the focus today is this, biomarkers typically associated with increased not on chronological age but on functional ability and inde- inflammation appear to be predictive of frailty, mortality pendence [4]. In particular, there is consensus that we need and elevated disease risk [16, 17]. Since frailty appears to delay the onset of “frailty”, a common clinical syndrome to be a better predictor of disability, institutionalization in older adults that carries an increased risk for poor health and mortality than chronological age, the implications for outcomes including disability, hospitalization and mortality both healthcare costs and personal QoL, if we can under- [5, 6] (Fig. 1). Development of frailty is often associated stand how to delay the onset of frailty, are enormous. with a decreased ability to respond to immune stimuli, so- The elevated risk of infection and disease in older called immunosenescence (see Text Box 1). Lower immune adults, and especially in the frail elderly, correlates with responses in older adults correlate with higher susceptibility a decreased ability to respond to vaccination. It is also to infectious diseases and a higher risk of hospitalization or associated with a decreased pool of naive T cells, a rela- serious outcomes than in a younger person, further compli- tive increase in the proportion of memory T cells and cated by the higher prevalence of comorbidities common in an increased proportion of CD8+ T cells [18]. While it older adults [7]. reaches pathological levels in the frail elderly, immunose- For example, infections of the lower respiratory tract are nescence can be viewed as the culmination of a process now the fourth most frequent cause of death in developed that develops throughout life, in response to continuous countries, with approximately 75% of cases occurring in immunological stimulation: in some cases, decreased adults aged 60 years and older [8, 9]. As another example, immune responses to vaccination can be seen even in in the United States it is estimated that 40,000–80,000 peo- young adults compared to children [19, 20]. ple die annually from vaccine-preventable diseases (VPDs), while hundreds of thousands more are hospitalized [1, 10]. The majority of cases and 99% of the deaths from VPDs Vaccination—a tool for healthy aging are in older adults [11]. Given these numbers and existing trends in disease incidence, infectious diseases represent a Increasing vaccination coverage of older adults against major barrier to healthy aging and the burden of infectious VPDs can be expected to promote healthy aging. The VPDs diseases in adults over age 60 years is coming to represent particularly relevant for older adults currently include sea- a significant and increasing proportion of healthcare expen- sonal influenza, invasive pneumococcal diseases, pneu - ditures [12]. monia, herpes zoster (shingles), meningococcal diseases, pertussis, diphtheria, tetanus and hepatitis [21]. Numerous studies have been carried out to assess vaccination of older adults against these VPDs in terms of avoided cases and Text box 1. Immunological frailty savings in healthcare resources and costs (e.g., [10, 22–24]). As just one example, a Europe-wide study showed that vac- Frailty is a syndrome that covers the functional ability of cination coverage of 75% of adults over 65 against seasonal an individual in both mental and physical spheres, and influenza could result in 1.6–2.1 million cases prevented, increasing frailty is associated with decreased capacity in 25,000–37,000 influenza-related deaths avoided and savings these areas and an increased risk of mortality. Frailty can of healthcare costs amounting to €153–219 million annually be viewed as either an accumulation of comorbidities, or [22]. This is probably only the tip of the iceberg as there is as a loss of the ability to respond effectively to environ- substantial additional morbidity associated with infectious mental stressors [13, 14]. Regardless of definition, there diseases in terms of serious sequelae (see Text Box 2). Even is consensus that increasing frailty is associated with an when vaccination is not 100% effective in preventing infec- increased risk for further physiological decline, suggest- tion with a pathogen, it may still attenuate the course and ing a causal linkage [13]. severity of a disease [25, 26]. While aging is clearly linked to frailty, both terms are Despite the availability of effective and well-tolerated not synonymous. Some individuals become clinically vaccines against these diseases, many countries struggle to frail by the age of 70  years, while in others this may reach recommended coverage levels even when vaccination not happen until 90 years of age [14]. Frailty also seems is supported by national programs. The reasons include lack to be tightly linked to loss of immunocompetence and of knowledge, poor infrastructure for adult vaccination or greater susceptibility to infection (a combination referred perceptions that the benefits of vaccination of older adults to as immunosenescence), to the extent that immune may not justify the costs (see Text Box 3). 1 3 292 European Geriatric Medicine (2018) 9:289–300 Text box 2. The hidden costs of infectious disease Text box 3. Challenges for vaccination in older in older adults adults Cost‐effectiveness analyses of vaccination typically focus The most immediate challenge to vaccination in older on the morbidity and mortality directly attributable to a adults is the decreased immune response associated with specific pathogen and the percentage of this burden of aging. This is characterized not just by decreased spe- disease that can be prevented by a vaccination program. cific antibody titers generated by vaccination, but also However, in older adults, particularly those of advanced by a more rapid decline in titers, suggesting rapid loss of age, comorbidities such as cardiovascular disease, type‐2 immune memory [34]. The mechanisms involved are not diabetes, chronic obstructive pulmonary disease and renal yet fully defined, but do not appear to involve the loss of or hepatic dysfunction are common, and these can be immune cells capable of recognizing the response [35]. negatively impacted by infectious diseases [27]. In addi- Instead, it may reflect a change in the balance of existing tion, the course of disease in older adults is typically immune memory and a relative decline in the proportion more severe, the period of recovery more prolonged, and and types of memory T cells [36, 37]. If correct, this the risk of complications higher. As one example, herpes could explain the difficulty of generating durable mem - zoster (HZ) in younger adults is uncommon, typically ory responses with vaccines containing higher doses of transient and usually resolves without serious complica- antigen. This may simply boost an existing population tions. In older individuals however, not only does the of differentiated antigen‐specific cells which are already incidence of HZ increase significantly but so does the dysfunctional with regard to immune memory [36]. How- risk of complications such as postherpetic neuralgia, ever, the observation that adjuvanted vaccines can gener- which in some cases can cause chronic, debilitating pain ate stronger immune responses that apparently persist for lasting for months or even years [28]. Older HZ patients longer periods of time, even in individuals aged 70–90 also have an excess risk of stroke amounting to 30% in years, suggests that, given the correct stimuli, functional the year after HZ onset [29]. Combined, these factors memory responses can be generated de novo from the represent a significant risk to the patient’s QoL and their existing pool of T cells [38–41]. ability to continue working or living independently [30]. Improved vaccine efficacy has consequences beyond Similar data are available for other VPDs. One study those expected from a reduction in disease incidence of 36,636 outpatients aged ≥ 65  years with a chronic in vaccinated individuals. No vaccine is effective if not illness indicated that vaccination against influenza and used, and vaccination in older adults has been hampered pneumococcus reduced the risk of ischemic stroke and by concerns among some older adults, vaccinators and acute myocardial infarction by approximately a third. public health officials that it is ineffective or too short‐ Compared with unvaccinated individuals, the vacci- lived to be worth pursuing—in other words that the ben- nated persons had a substantially reduced risk of death efit/risk ratio is low [42]. Vaccines that can demonstrate and reduced risk of coronary and intensive care admis- enhanced efficacy and durable protection in older adults sions in the year following vaccination [31]. Indeed, the may therefore be key to persuading the population to commonest causes of severe disability in older adults request them and public health systems to deliver them. including strokes, congestive heart failure, pneumonia, ischemic heart disease, cancer, and hip fracture, have all been linked to influenza [18]. In the US, 90% of the Immunosenescence estimated 30–40,000 deaths linked to influenza occur in older adults and are related to cardiovascular and pulmo- Human aging is characterized by a chronic, low-grade nary complications [32]. inflammation, a phenomenon termed “inflammaging”, which The costs resulting from loss of employment, loss of is a highly significant risk factor for morbidity, frailty and independence and need for rehabilitation or inpatient care mortality in older adults as most, if not all, age-related dis- due to chronic disease arising subsequent to infection can eases share an inflammatory pathogenesis [ 43]. This low- be substantial. These risks can potentially be significantly grade inflammation not only accelerates tissue degeneration reduced by vaccination, but are typically not considered and wasting, but also influences adaptive immune responses in analyses of vaccine cost‐effectiveness [33]. which are at the core of generation of immune memory and, therefore, immunization. Activation of the innate immune system resulting in the production of cytokines during aging can be caused by waning control of latent infections, less effective physical 1 3 European Geriatric Medicine (2018) 9:289–300 293 barriers (more permeable skin, defective mucosal barriers costs that may be attributed to prevention of a single, spe- in gut and respiratory systems) or increase in overall tissue cific disease. The broader economic benefits to consider damage [44, 45]. In addition, age-associated intrinsic defects and attempt to quantify include improved educational in innate immune cells as well as accumulation and activa- attainment, productivity gains from ameliorated effects of tion of non-immune cells such as adipocytes contribute to multi-morbidity on general health and cognition, community inflammaging. externalities and political stability [50, 51]. The initiation of a T-cell response to a vaccine requires Intangible benefits of vaccination considered specifically activation of dendritic cells that present antigenic fragment in relation to vaccination of older adults, include attenuated peptides derived from the vaccine to T cells. This process, severity of disease in breakthrough cases [25] and reduc- which is the major target for the adjuvants in vaccines, tions in complications and comorbidities. Examples are stud- appears to be disturbed in an inflammatory environment or ies showing that influenza and pneumococcal vaccinations with older dendritic cells. Understanding of the mechanisms may reduce the incidence of myocardial infarction by up to of action of adjuvants and vaccine delivery systems and 50% [52]. Another example is that herpes zoster is strongly identifying those that are more effective in older individu- associated with an increased risk of stroke, an excess risk als remain an area of active research [46, 47]. which may be prevented by effective vaccines [29] (See Text The adaptive immune response of T and B cells, the back- Box 2). bone of a vaccine response, is also susceptible to aging [34] Another consideration is that vaccination may diminish and the previous decade has seen a surge in research on the problems related to polypharmacy in older adults with how and where this process is impaired in older individu- many comorbidities, which may lead to important adverse als. Defects in adaptive T-cell responses already begin to effects or lack of compliance [52]. Another intangible ben- become significant about the age of 50 years, in particular in et fi of vaccination, which is increasingly recognized (and not individuals with comorbidities. However, at least for healthy limited to vaccination of older adults), is that it may reduce individuals, the sizes and repertoires of antigen-specific the use of antibiotics [53–55] and thus diminish the growing CD4+ T cells and B cells do not appear to be decreased to a problems caused by the development of antibiotic-resistant biologically relevant extent in older adults [35]. strains of bacteria. The United Kingdom Joint Committee on Instead, at least part of the problem seems to be the Vaccination and Immunization has recently recommended reduced ability of antigen-specific lymphocytes to sur- that this effect be included in economic evaluations of new vive as long-lived memory T cells [36]. It is possible that vaccines and vaccination programs [56]. chronic infections such as cytomegalovirus may compromise The most widely used approach to economic evaluation antigen-specific responses and help drive the development of healthcare interventions (including vaccines) is cost- of immunosenescence [48, 49]. Whether this defect can be effectiveness or cost-utility analyses, which aim to assess the overcome by better vaccines or adjuvants or requires phar- incremental benefits of the intervention relative to its incre- macological intervention during the development of T-cell mental costs, usually taking the perspective of the healthcare responses after vaccination remains uncertain. In contrast system in estimating the costs. This type of economic assess- to CD4+ T cells, CD8+ naive and central memory T cells, ment is used in many countries by healthcare authorities for apparently the weak link in immune aging, are increasingly making decisions about reimbursement of new treatments. lost and become dysfunctional with age [37]. Depending on For preventive interventions like vaccines, the assessments the infection targeted by vaccination, it might be advanta- usually seek to estimate the loss of utility (QoL) avoided geous to generate an effective CD8+ memory population by the intervention and relate this to the incremental costs earlier in life, but induction of a CD8+ T-cell response incurred relative to no intervention. The result is expressed generally requires a live vaccine, whereas the inactivated as the incremental costs per quality-adjusted life-year or component vaccines previously developed preferentially (QALY) gained (or, more accurately, not lost), which may induce CD4+ T-cell and B-cell responses. then be compared to a benchmark to determine whether the intervention is cost-effective or not. Commonly used bench- The economics of adult vaccination marks in Europe range from 20,000 to 30,000 €/QALY, but few countries have set an explicit, official limit. Alongside investments in infrastructure to improve water A number of economic evaluations and reviews of vac- sanitation, vaccination programs are usually considered as cination of older adults have recently been published, for the most important factor in improved public health and example of pneumococcal conjugate vaccines [57] and her- longevity worldwide over the last century. It is increasingly pes zoster vaccine [58, 59]. Generally, these evaluations con- recognized that proper assessments of the economic value clude that vaccination is cost-effective but even taking the of vaccination needs to take a broader perspective than just narrow direct cost perspective there are important challenges focusing on the clinical benefits and the avoided healthcare to meet when making such assessments. Among these are 1 3 294 European Geriatric Medicine (2018) 9:289–300 heterogeneity between targeted older individuals in terms [65] and the government is proposing a Healthy Aging of risk of infection, response to vaccination and severity of program, which is projected to save 5 trillion yen (approx. disease, just as there may be age-related variations in dura- 40 billion Euros at current exchange rates) by 2025, with tion and level of immunity induced by vaccination [60]. almost a fifth of that coming from reduction in VPDs It is also of interest to note that, ignoring the difficult (primarily pneumonia) [65]. Other nations estimate assessment and valuation of health outcomes, studies of potential savings of a similar magnitude. For example a the costs of interventions show that the costs of vaccination recent study estimated that under-vaccination of adults are lower than those of many other preventive interventions costs the US 7.1 billion USD in healthcare expenditure and the potential benefits substantial (see Text Box  4). A per year [12]. recent study estimated that the total costs of fully adhering to recommended vaccinations over the full course of life in several European countries was much lower than those of Adult vaccination: recommendations and coverage many widely used preventive measures such as taking statins to prevent cardiovascular complications [61]. Despite the accumulating evidence of the benefits of vac - cination of older adults, vaccine uptake is generally lim- ited and far below targets [60]. To improve this situation, it Text box 4. Vaccination programs for healthy is necessary to identify the barriers to increased uptake of aging vaccinations among older adults and to modify these where possible. The proportion of the population over 65—and especially Vaccine programs for children and younger adults have over 85—years of age has increased dramatically over the shown that great declines in the incidence of infectious dis- last half century and this trend is only expected to accel- eases can be achieved if vaccination is properly implemented erate. While the decrease in mortality is to be celebrated, [25]. In the United States, coverage rates in children for most there is concern over the implication that a declining ratio recommended vaccines reach approximately 90% [66]. Euro- of those in employment to those no longer working will pean countries are more diverse, both in their recommended place stress on government budgets, and that the greater vaccines and the recommended schedules, but the coverage risk of illness in older individuals will place particular for the most common pediatric vaccines (measles, diphthe- stress on public health budgets [62]. Some steps have ria, pertussis, tetanus, tuberculosis, polio, etc.) reaches or already been taken to address the first of these concerns, exceeds 90% in most EU countries [67]. These programs as seen in the many countries raising the qualifying age indicate what is needed for successful disease control by for retirement and pension eligibility. However, for such vaccination and thus demonstrate the opportunities for adult policies to be successful, older individuals must remain vaccination programs. Comparing current pediatric vacci- healthy enough to continue working. Additionally, while nation programs with what is being done to enhance vacci- an increased demand for healthcare is unlikely to be nation of older adults also highlights important differences entirely avoidable in an aging population, there is grow- and the challenges that must be overcome to improve adult ing focus on ways of diminishing the burden of disease in vaccination rates. older people, a concept generally called “Healthy aging”. Where adult vaccination is recommended, there are wide A key component of healthy aging strategies is the divergences in what is recommended (Table 1) and in the recognition that infectious disease is likely to play an coverage levels reached. In a recent survey of immuniza- increasing role in morbidity among older individuals tion policies in 31 high-income countries [68], only 12 had ([63] and Text Box 2) and that vaccination is among the comprehensive adult vaccination policies, although all of most cost‐effective interventions. Consequently, we have them had recommendations for at least one adult vaccination seen expansion of vaccination programs and recommen- (influenza, with programs in place to monitor the vaccination dations shifting from a predominantly pediatric focus to coverage in adults in 29 of the countries). In two countries, one covering the whole lifespan, so‐called life course influenza vaccination is recommended for the entire popula- immunization, [64] as well as the development of vac- tion, whereas in the rest it was only recommended for risk cines specifically targeting diseases in older adults (see groups. Despite recommendations and public funding, only Text Box 3). The scale of the challenge—and the poten- one country in this study (the Netherlands) exceeded the tial benefits—are dramatic. In Japan, the currently most recommended level of coverage (75%) while many reached advanced country in the demographic transition, control less than 50% [68]. For the other vaccines, recommendations of infectious diseases and vaccination are among the are most common (26–27 countries) for adult immunization Ministry of Health, Labour and Welfare’s top priorities against hepatitis B, pneumococcus, tetanus and diphtheria, 1 3 European Geriatric Medicine (2018) 9:289–300 295 Table 1 Recommended vaccinations for adults in selected high-income countries [71–78] Vaccine Recommended vaccination Country Diphtheria No national recommendation Croatia, Czech Republic, Denmark, Hungary, Iceland, Ireland, Japan, Republic of Korea, Malta, Netherlands, Norway, Romania, United Kingdom Single booster Poland (in adulthood), Spain (at age 65) Adult, every 10 years Austria , Belgium, Bulgaria, Canada, Cyprus, Estonia, Finland, Germany, Greece, Italy, Latvia, Luxembourg, Slovenia, United States b b b c 65+, every 10 years France, Lichtenstein, Portugal, Switzerland Other New Zealand (every 20 years), Slovakia (50+, every 15 years), Sweden (50+, every 20 years) Tetanus No national recommendation Denmark, Hungary, Iceland, Ireland, Japan, Republic of Korea, Malta, Netherlands, Norway, Romania, United Kingdom Single booster Croatia (at age 60), Poland (in adulthood), Spain (at age 65) Adult, every 10 years Austria , Belgium, Bulgaria, Canada, Cyprus, Estonia, Finland, Germany, Greece, Italy, Latvia, Luxembourg, Slovenia, United States c b b c 65+, every 10 yearsCzech Republic, France , Lichtenstein, P ortugal, Switzerland Other Lithuania (every 5–10 years), New Zealand (every 20 years), Slovakia (every 15 years), Sweden (every 20 years) Pertussis No national recommendation Bulgaria, Canada, Croatia, Cyprus, Denmark, Estonia, Finland, Hungary, Iceland, Ireland, Latvia, Lithuania, Japan, Republic of Korea, Malta, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Slovakia, Spain, Sweden, Switzer- land, United Kingdom Single booster in adulthood Belgium, Czech Republic (at age 65), France, Germany, Greece, Slovenia, United States Adult, every 10 years Austria , Italy, Luxembourg 65+, every 10 years Lichtenstein Shingles (Herpes zoster) No national recommendation Bulgaria, Croatia, Cyprus, Denmark, Estonia, Finland, Germany, Hungary, Iceland, Ireland, Japan, Republic of Korea, Latvia, Lithuania, Luxembourg, Malta, New Zealand, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden Vaccination at 50+ Austria, Czech Republic Vaccination at 60+ Canada, Greece, United States d e Vaccination at 65+ Belgium, France , Italy Vaccination at 70+ Australia, United Kingdom Influenza (Trivalent) No national recommendation Sweden f f Annual vaccination at 60+ Germany, Greece , Hungary, Iceland, Netherlands, Slovakia f f f Annual vaccination at 65+Australia, Belgium, Bulgaria , Canada, Croatia, Cyprus, Denmark, Es tonia , f f f f f f Finland, France, Ireland, Italy , Japan, Republic of Korea, Latvia , Lithuania , f f f f Luxembourg, New Zealand, Norway , Portugal, Romania, Spain, Switzerland , United Kingdom f f f f f f All adults Austria , Czech R epublic, Malta, Poland, Slovenia , United States Pneumonia (S. pneumoniae) No national recommendation Bulgaria, Croatia, Estonia, France, Latvia, Lichtenstein, Lithuania, Netherlands, New Zealand, Portugal, Romania, Switzerland 50+, PPV Hungary 50+, PCV Poland 50+, PCV and PPV Austria 60+, PPV Germany, Iceland 60+, PCV Slovakia 60+, PCV and PPV Luxembourg 65+, PPV Australia, Canada, Cyprus, Ireland, Japan, Republic of Korea, Norway, Spain, Sweden, United Kingdom 65+, PCV Greece, Malta 65+, PCV and PPV Belgium, Czech Republic, Italy, United States 65+, PCV or PPV Denmark, Finland, Slovenia This table compiles recommended, age-specific vaccinations for older adults (from 50 years of age). It does not include catch-up vaccinations for vaccines typically given at younger ages, vaccines which are available but not recommended or reimbursed, vaccinations recommended for spe- 1 3 296 European Geriatric Medicine (2018) 9:289–300 Table 1 (continued) cific risk groups or vaccinations recommended in response to specific activities such as travel or transplantation PCV pneumococcal conjugate vaccine, PPV pneumococcal polysaccharide vaccine Every 5 years from age 65 Every 20 years for younger adults Every 10–15 years for younger adults Cap at 79 years of age Cap at 75 years of age Quadrivalent vaccine also available, though prioritization and access varies by region Initial dose is the conjugated pneumococcal vaccine, followed by the polysaccharide pneumococcal vaccine The use of PPV, with or without PCV, is being re-evaluated although again, these recommendations primarily focus Without funding, however, recommendations have lim- on risk groups and travelers [68] and coverage is generally ited effect. While most high-income countries have some poor [69]. Overall, the picture of adult vaccination is one of form of public funding in place for recommended vaccines fragmented recommendations, restricted coverage [70], and [82], cost can still be a barrier to access and may discour- significant data gaps [68]. age HCPs from recommending the vaccine. As one exam- ple illustrating this, moving from a partial to a full subsidy Adult vaccination: building effective programs of pneumococcal vaccination for older adults in Australia raised the uptake from 39 to 73% in patients attending a To understand why adult vaccination coverage is low, it is large public hospital [86]. Similarly, pediatric vaccination useful to examine those countries that have achieved the in the United States is financially supported by the Vaccines highest coverage and also to compare adult vaccination for Children initiative and this has virtually eliminated pre- programs with pediatric vaccination programs. Successful viously significant regional, ethnic and socioeconomic dis- pediatric vaccination programs generally recommend uni- parities in vaccination coverage [87]. In contrast, the same versal vaccination, they are supported by effective funding vaccines for adults can require substantial copayments, and mechanisms, and the outcomes are assessed (and the pro- ethnic and socioeconomic disparities in coverage rates are grams corrected, if needed) based on routine surveillance clearly visible [70]. of disease and vaccination coverage. These findings suggest that four things are necessary to The important role of recommendations is suggested by support effective vaccination programs, both in children and the observation that countries with comprehensive vaccina- in adults (Fig. 2). First, a clear commitment to vaccination tion recommendations for older adults tend to include more must be reflected in a coherent, comprehensive public policy. vaccines in their programs [68] and to reach higher levels of Second, a commitment to fund and deliver vaccines to the coverage with the recommended vaccines [67]. In addition, population is required, whether via predominantly public there is evidence that vaccination recommendations focusing funds as in the United Kingdom and the Netherlands, or a on groups at risk, although apparently offering an efficient mixture of public and private funds as in the United States. approach to vaccination, may actually inhibit uptake, since Third, effective surveillance of vaccination coverage and they may inadvertently send the message that the national the burden of disease is required, so that goals can be set, health system does not see the recommended vaccines as priorities established, and the effectiveness of the program important [79]. However, this evidence must be critically monitored and adjusted, if necessary. Finally, the safety and assessed in the light of economic evaluations, which often value of vaccination must be understood and appreciated conclude that universal vaccination of older adults against a both by the target population and by vaccinating healthcare particular VPD is not cost-effective and that programs must professionals. be targeted to specific, well-characterized groups to ensure The first three of these factors can be implemented by acceptable incremental costs per QALY gained [80]. public policy and the initial steps have already been taken As all the evidence identifies provider recommendation as in many countries. However, for adult vaccination programs the principal reason for adults to become vaccinated [1], this to achieve the same kind of success as pediatric programs implies that if few providers are convinced of the importance have, they need a similar degree of population acceptance. of adult vaccination the uptake will remain low. Numerous This is particularly an issue for adult vaccination because studies show that many primary-care physicians do not con- there is a widespread public perception that vaccination is sider vaccination of older adults a high priority [81–85]. not needed [90] and the decision of the individual to seek or accept vaccination is crucial. For infant vaccination, the 1 3 European Geriatric Medicine (2018) 9:289–300 297 Government Funds vaccine provision, establishes policy, establishes delivery and surveillance infrastructure Media Ask about vaccination Public Health Care Professionals Understand and accept the need for Recommend and provide vaccination, vaccination conduct public health surveillance Proactively recommend and offer vaccination Fig. 2 Components of successful vaccination programs. Healthcare and acceptance, as indicated by the labeled arrows. The media plays a systems are more than just government and business infrastructure: significant, but different role. While not (in theory) directly involved they comprise everyone involved in the process—politicians, health- in the process, it is the channel through which much of the dialogue is care providers and the general public. Each part of the polity engages conducted, and can also act as an “amplifier”—for example, increas- in dialogue with the other parts, and it is plain that for the establish- ing the visibility and impact of public concerns or hesitancy, or alter- ment of successful vaccination programs—whether in children or in natively promoting vaccination by reporting on disease-related deaths adults—all parts must be in general agreement [88, 89]. In addition, or vaccine benefits each part of the polity has specific roles in terms of delivery, dialogue messages are targeted at the parents. For adult vaccination, This implies that vaccination can serve as the third pillar the vaccine recipients must be reached with a message that of a strategy to support healthy aging, alongside healthy can convince them of the value and safety of vaccination diet and exercise. However, the uptake of vaccination by directly to themselves or to their family. Additionally, it is the target population is generally low and must be substan- important that vaccinating healthcare personnel understand tially improved if the potential of vaccines to reduce the the value of vaccination both for themselves and for patients. morbidity, mortality, loss of quality of life and healthcare These considerations are supported by interventions that costs caused by VPDs is to be realized [12]. The available have been associated with substantial improvements in adult evidence indicates that vaccination coverage in older adults vaccination coverage [88, 89]. Important common elements can be considerably improved, although there is a need for to improve coverage seem to be: clear national objectives further research into the generalizability of particular inter- and commitments; incentives for healthcare personnel to ventions to improve coverage. vaccinate; vaccination reimbursement systems; informa- Acknowledgements The authors would like to thank Nobuhiro Noro tion and awareness campaigns; clear coverage objectives. for his essential part in the success of the original meeting at which However, even programs considered as highly successful this manuscript originated. The authors also thank Business & Decision often plateau at a suboptimal level of coverage [89]. These Life Sciences platform for editorial assistance and manuscript coordi- plateaus vary between vaccine types thereby indicating that nation, on behalf of GSK. Carole Desiron coordinated the manuscript development and gave editorial support. The authors also thank Niels vaccine-specific issues must be addressed as well. Neymark, freelance scientific writer on behalf of GSK for providing medical writing support. Conclusion Authors’ contribution All authors reviewed the literature, provided substantial input, contributed to writing, and reviewed the paper. MD led the manuscript development. All authors gave their final approval All over the world, in rich and developing countries alike, and are accountable for all aspects of the work. a demographic shift towards an aging population is under- way. How we handle aging populations will have major eco- Funding GlaxoSmithKline Biologicals S.A. funded this study and all nomic and healthcare implications in the next few decades. costs related to the development of this publication. Many infectious diseases inflict a disproportionate burden of disease in older adults and can contribute to the onset of frailty, but may be prevented or attenuated by vaccination. 1 3 298 European Geriatric Medicine (2018) 9:289–300 8. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL Compliance with ethical standards (2006) Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet Conflict of interest GDG, ADP, RSO and MD are employees of the 367:1447–1457 GSK group of companies. ADP, RSO and MD hold restricted shares 9. Yoshikawa TT (1997) Perspective: aging and infectious diseases: in the GSK group of companies. MC received personal fees from the past, present, and future. J Infect Dis 176:1053–1057 GSK group of companies. JEM is an employee of The Health Sci- 10. McLaughlin JM, McGinnis JJ, Tan L, Mercatante A, Fortuna ences North Research Institute and her institution received an hono- J (2015) Estimated human and economic burden of 4 major rarium from the GSK group of companies for her attendance at an adult vaccine-preventable diseases in the US, 2013. J Prim Prev advisory board meeting and she received travel reimbursement during 36:259–273 the conduct of this work and outside this work. PHL, BGL and JF have 11. Office of Disease Prevention and Health Promotion. Immuniza- nothing to disclose. EW received consulting fees from Alios Pharma- tion and infectious diseases. https://www .health ypeople.go v/2020/ ceuticals outside this work. JG received grants from NIH during the t opic s-objec tives /t opic /immun izati on-and-inf ec tious -disea ses. conduct of this work and received personal fees from the GSK group of Last accessed 31 Mar 2017 companies for his attendance at an advisory board meeting during the 12. 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Bergman H, Ferrucci L, Guralnik J et al (2007) Frailty: an emerg- from the GSK group of companies for his attendance at an advisory ing research and clinical paradigm—issues and controversies. J board meeting during the conduct of this work and received personal Gerontol A Biol Sci Med Sci 62:731–737 fees from Pfizer and MSD outside of this work. 15. Fulop T, McElhaney J, Pawelec G et al (2015) Frailty, inflam- mation and immunosenescence. Interdiscip Top Gerontol Geriatr Ethical approval All procedures performed in this study were in 41:26–40 accordance with the ethical standards. 16. Johnstone J, Parsons R, Botelho F, Millar J, McNeil S, Fulop T et al (2014) Immune biomarkers predictive of respiratory viral Informed consent For a literature review, written consent is not infection in elderly nursing home residents. PLoS One 9:e108481 required. 17. 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Abstract

Objectives Populations are aging worldwide. This paper summarizes some of the challenges and opportunities due to the increasing burden of infectious diseases in an aging population. Results Older adults typically suffer elevated morbidity from infectious disease, leading to increased demand for healthcare resources and higher healthcare costs. Preventive medicine, including vaccination can potentially play a major role in preserv- ing the health and independence of older adults. However, this potential of widespread vaccination is rarely realized. Here, we give a brief overview of the problem, discuss concrete obstacles and the potential for expanded vaccination programs to promote healthy aging. Conclusion The increasing healthcare burden of infectious diseases expected in aging populations could, to a large extent, be reduced by achieving higher vaccination coverage among older adults. Vaccination can thus contribute to healthy aging, alongside healthy diet and physical exercise. The available evidence indicates that dedicated programs can achieve substantial improvements in vaccination coverage among older adults, but more research is required to assess the generalizability of the results achieved by specific interventions (see Additional file 1). Keywords Demographic change · Healthy aging · Vaccines · Vaccination programs Abbreviations QALY Quality-adjusted life-year QoL Quality of life VPD Vaccine preventable disease Electronic supplementary material The online version of this HZ Herpes zoster article (https ://doi.org/10.1007/s4199 9-018-0040-8) contains supplementary material, which is available to authorized users. * T. Mark Doherty Institute for Biomedical Aging Research, University mark.x.doherty@gsk.com of Innsbruck, Innsbruck, Austria Center of Vaccinology, University of Geneva, Geneva, GSK, Wavre, Belgium Switzerland Global Market Access Solutions, St-Prex, Switzerland CNR Institute of Neuroscience, Aging Branch, Padua, Italy Unit of PharmacoEpidemiology and PharmacoEconomics, Health Sciences North Research Institute, Sudbury, ON, Department of Pharmacy, University of Groningen, Canada Groningen, The Netherlands Center for Pulmonary Diseases, National Hospital GSK, Siena, Italy Organization Tokyo National Hospital, Tokyo, Japan Department of Geriatric Medicine, University Hospitals Vanderbilt University School of Medicine, Nashville, TN, Leuven, Leuven, Belgium USA Division of Gerontology and Geriatrics, KU Leuven, Leuven, Department of Medicine, School of Medicine and Dentistry, Belgium University of Rochester, Rochester, NY, USA Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA Vol.:(0123456789) 1 3 290 European Geriatric Medicine (2018) 9:289–300 Only recently have the implications and the dimensions of Introduction the coming problems been more widely recognized, leading to various strategies being debated. These various measures Worldwide, populations are aging due to ever increasing life are aimed at keeping older adults economically and socially expectancy and decreasing birth rates. The United Nations active longer than has been common in prior generations on estimates that 15% of the world’s population will be over the the one hand—the concept of “adding life to years”—and age of 60 years by 2025 and that this proportion will rise to on the other to delay as much as possible the inevitable age- well over 20% by 2050 [1]. In Europe as well as Japan, the related increase in healthcare utilization—a concept desig- proportion of people aged 65 years or older will double from nated as “healthy aging” [4]. 2010 to 2060 and the proportion of people aged 65 years or older relative to the population of working age (15–64 years) is expected to double by 2060. Discussion This demographic development is already starting to put considerable strain on public finances in countries with Healthy aging state-financed pensions and healthcare systems and the effects can only be expected to increase [2 , 3]. Without sub- The World Health Organization has recently defined the stantial (and politically difficult) changes in policy, the tax concept of healthy aging as “the process of developing and base will diminish because of the fall in the proportion of maintaining the functional ability that enables well-being in working age (and tax-paying) adults while pension expenses older age” [4]. Healthy aging is obviously a laudable objec- will grow, both because of continued increases in life expec- tive on its own to improve welfare and quality of life (QoL), tancy and the sheer growth in the number of people eligi- but it is also specifically recognized as necessary to counter ble for pensions. Furthermore, it is expected that healthcare the anticipated surge in healthcare costs consequent on the expenditures will increase substantially, as individual need demographic change underway. for healthcare services rises markedly with advancing age. Contributorstorapid aging Acutestressors Intervenons • Chroniccomorbidies • Accidents • Counselling/social engagement • Loss of immune funcon • Acute illness • Improved nutrion • Loss of metabolic funcon • Socialstress • Exercise • Under-nutrion • Vaccinaon Fit Healthy aging Agingwith acute incidents Rapid aging Well Frail Dependent Dead 30 40 50 60 70 80 90 Fig. 1 Healthy vs premature aging. Typically, aging is associated through chronic inflammation, mitochondrial dysfunction and cellular with a decline in physical capability, during adulthood, from being senescence that may degrade the endocrine, hematologic and muscu- fit and physically active to being well (that is, without obvious physi- loskeletal systems, and secondly, by increasing susceptibility to infec- cal incapacity, but with reduced physical activity). In most adults, tions, which can further harm these physiologic systems. The ideal of the later phases of life are characterized by frailty and disability. healthy aging (living with as little time spent in frailty or disability) is Disability is simply enough defined as the inability to perform basic contrasted to rapid aging in this simple schematic. In reality, however, day-to-day functions without assistance. Frailty is more difficult to aging for most people is a nonlinear process. Acute incidents such as define, but is often identified as meeting 3 or more of the following physical trauma from falls, social stressors such as divorce or death of clinical criteria: a low level of physical activity, exhaustion or low a spouse, or acute illness (for example, from cardiac disease or infec- energy, muscle weakness, slowness, and unintentional weight loss. tion) can trigger sudden losses of capacity, which in older individuals, The underlying etiology of frailty is poorly understood, but includes become increasingly difficult to recover from. This places a priority comorbidities such as diabetes, obesity and respiratory illnesses. on intervention to prevent those acute incidents to prevent frailty/dis- Immune dysfunction also seems to be a key factor in two ways. First, ability and maintain quality of life 1 3 European Geriatric Medicine (2018) 9:289–300 291 Traditional stereotypes are no longer applicable to the dysregulation and chronic inflammation have been sug- current population of older adults, who are often healthier gested as primary drivers of frailty [15]. Consistent with and more active than prior generations and the focus today is this, biomarkers typically associated with increased not on chronological age but on functional ability and inde- inflammation appear to be predictive of frailty, mortality pendence [4]. In particular, there is consensus that we need and elevated disease risk [16, 17]. Since frailty appears to delay the onset of “frailty”, a common clinical syndrome to be a better predictor of disability, institutionalization in older adults that carries an increased risk for poor health and mortality than chronological age, the implications for outcomes including disability, hospitalization and mortality both healthcare costs and personal QoL, if we can under- [5, 6] (Fig. 1). Development of frailty is often associated stand how to delay the onset of frailty, are enormous. with a decreased ability to respond to immune stimuli, so- The elevated risk of infection and disease in older called immunosenescence (see Text Box 1). Lower immune adults, and especially in the frail elderly, correlates with responses in older adults correlate with higher susceptibility a decreased ability to respond to vaccination. It is also to infectious diseases and a higher risk of hospitalization or associated with a decreased pool of naive T cells, a rela- serious outcomes than in a younger person, further compli- tive increase in the proportion of memory T cells and cated by the higher prevalence of comorbidities common in an increased proportion of CD8+ T cells [18]. While it older adults [7]. reaches pathological levels in the frail elderly, immunose- For example, infections of the lower respiratory tract are nescence can be viewed as the culmination of a process now the fourth most frequent cause of death in developed that develops throughout life, in response to continuous countries, with approximately 75% of cases occurring in immunological stimulation: in some cases, decreased adults aged 60 years and older [8, 9]. As another example, immune responses to vaccination can be seen even in in the United States it is estimated that 40,000–80,000 peo- young adults compared to children [19, 20]. ple die annually from vaccine-preventable diseases (VPDs), while hundreds of thousands more are hospitalized [1, 10]. The majority of cases and 99% of the deaths from VPDs Vaccination—a tool for healthy aging are in older adults [11]. Given these numbers and existing trends in disease incidence, infectious diseases represent a Increasing vaccination coverage of older adults against major barrier to healthy aging and the burden of infectious VPDs can be expected to promote healthy aging. The VPDs diseases in adults over age 60 years is coming to represent particularly relevant for older adults currently include sea- a significant and increasing proportion of healthcare expen- sonal influenza, invasive pneumococcal diseases, pneu - ditures [12]. monia, herpes zoster (shingles), meningococcal diseases, pertussis, diphtheria, tetanus and hepatitis [21]. Numerous studies have been carried out to assess vaccination of older adults against these VPDs in terms of avoided cases and Text box 1. Immunological frailty savings in healthcare resources and costs (e.g., [10, 22–24]). As just one example, a Europe-wide study showed that vac- Frailty is a syndrome that covers the functional ability of cination coverage of 75% of adults over 65 against seasonal an individual in both mental and physical spheres, and influenza could result in 1.6–2.1 million cases prevented, increasing frailty is associated with decreased capacity in 25,000–37,000 influenza-related deaths avoided and savings these areas and an increased risk of mortality. Frailty can of healthcare costs amounting to €153–219 million annually be viewed as either an accumulation of comorbidities, or [22]. This is probably only the tip of the iceberg as there is as a loss of the ability to respond effectively to environ- substantial additional morbidity associated with infectious mental stressors [13, 14]. Regardless of definition, there diseases in terms of serious sequelae (see Text Box 2). Even is consensus that increasing frailty is associated with an when vaccination is not 100% effective in preventing infec- increased risk for further physiological decline, suggest- tion with a pathogen, it may still attenuate the course and ing a causal linkage [13]. severity of a disease [25, 26]. While aging is clearly linked to frailty, both terms are Despite the availability of effective and well-tolerated not synonymous. Some individuals become clinically vaccines against these diseases, many countries struggle to frail by the age of 70  years, while in others this may reach recommended coverage levels even when vaccination not happen until 90 years of age [14]. Frailty also seems is supported by national programs. The reasons include lack to be tightly linked to loss of immunocompetence and of knowledge, poor infrastructure for adult vaccination or greater susceptibility to infection (a combination referred perceptions that the benefits of vaccination of older adults to as immunosenescence), to the extent that immune may not justify the costs (see Text Box 3). 1 3 292 European Geriatric Medicine (2018) 9:289–300 Text box 2. The hidden costs of infectious disease Text box 3. Challenges for vaccination in older in older adults adults Cost‐effectiveness analyses of vaccination typically focus The most immediate challenge to vaccination in older on the morbidity and mortality directly attributable to a adults is the decreased immune response associated with specific pathogen and the percentage of this burden of aging. This is characterized not just by decreased spe- disease that can be prevented by a vaccination program. cific antibody titers generated by vaccination, but also However, in older adults, particularly those of advanced by a more rapid decline in titers, suggesting rapid loss of age, comorbidities such as cardiovascular disease, type‐2 immune memory [34]. The mechanisms involved are not diabetes, chronic obstructive pulmonary disease and renal yet fully defined, but do not appear to involve the loss of or hepatic dysfunction are common, and these can be immune cells capable of recognizing the response [35]. negatively impacted by infectious diseases [27]. In addi- Instead, it may reflect a change in the balance of existing tion, the course of disease in older adults is typically immune memory and a relative decline in the proportion more severe, the period of recovery more prolonged, and and types of memory T cells [36, 37]. If correct, this the risk of complications higher. As one example, herpes could explain the difficulty of generating durable mem - zoster (HZ) in younger adults is uncommon, typically ory responses with vaccines containing higher doses of transient and usually resolves without serious complica- antigen. This may simply boost an existing population tions. In older individuals however, not only does the of differentiated antigen‐specific cells which are already incidence of HZ increase significantly but so does the dysfunctional with regard to immune memory [36]. How- risk of complications such as postherpetic neuralgia, ever, the observation that adjuvanted vaccines can gener- which in some cases can cause chronic, debilitating pain ate stronger immune responses that apparently persist for lasting for months or even years [28]. Older HZ patients longer periods of time, even in individuals aged 70–90 also have an excess risk of stroke amounting to 30% in years, suggests that, given the correct stimuli, functional the year after HZ onset [29]. Combined, these factors memory responses can be generated de novo from the represent a significant risk to the patient’s QoL and their existing pool of T cells [38–41]. ability to continue working or living independently [30]. Improved vaccine efficacy has consequences beyond Similar data are available for other VPDs. One study those expected from a reduction in disease incidence of 36,636 outpatients aged ≥ 65  years with a chronic in vaccinated individuals. No vaccine is effective if not illness indicated that vaccination against influenza and used, and vaccination in older adults has been hampered pneumococcus reduced the risk of ischemic stroke and by concerns among some older adults, vaccinators and acute myocardial infarction by approximately a third. public health officials that it is ineffective or too short‐ Compared with unvaccinated individuals, the vacci- lived to be worth pursuing—in other words that the ben- nated persons had a substantially reduced risk of death efit/risk ratio is low [42]. Vaccines that can demonstrate and reduced risk of coronary and intensive care admis- enhanced efficacy and durable protection in older adults sions in the year following vaccination [31]. Indeed, the may therefore be key to persuading the population to commonest causes of severe disability in older adults request them and public health systems to deliver them. including strokes, congestive heart failure, pneumonia, ischemic heart disease, cancer, and hip fracture, have all been linked to influenza [18]. In the US, 90% of the Immunosenescence estimated 30–40,000 deaths linked to influenza occur in older adults and are related to cardiovascular and pulmo- Human aging is characterized by a chronic, low-grade nary complications [32]. inflammation, a phenomenon termed “inflammaging”, which The costs resulting from loss of employment, loss of is a highly significant risk factor for morbidity, frailty and independence and need for rehabilitation or inpatient care mortality in older adults as most, if not all, age-related dis- due to chronic disease arising subsequent to infection can eases share an inflammatory pathogenesis [ 43]. This low- be substantial. These risks can potentially be significantly grade inflammation not only accelerates tissue degeneration reduced by vaccination, but are typically not considered and wasting, but also influences adaptive immune responses in analyses of vaccine cost‐effectiveness [33]. which are at the core of generation of immune memory and, therefore, immunization. Activation of the innate immune system resulting in the production of cytokines during aging can be caused by waning control of latent infections, less effective physical 1 3 European Geriatric Medicine (2018) 9:289–300 293 barriers (more permeable skin, defective mucosal barriers costs that may be attributed to prevention of a single, spe- in gut and respiratory systems) or increase in overall tissue cific disease. The broader economic benefits to consider damage [44, 45]. In addition, age-associated intrinsic defects and attempt to quantify include improved educational in innate immune cells as well as accumulation and activa- attainment, productivity gains from ameliorated effects of tion of non-immune cells such as adipocytes contribute to multi-morbidity on general health and cognition, community inflammaging. externalities and political stability [50, 51]. The initiation of a T-cell response to a vaccine requires Intangible benefits of vaccination considered specifically activation of dendritic cells that present antigenic fragment in relation to vaccination of older adults, include attenuated peptides derived from the vaccine to T cells. This process, severity of disease in breakthrough cases [25] and reduc- which is the major target for the adjuvants in vaccines, tions in complications and comorbidities. Examples are stud- appears to be disturbed in an inflammatory environment or ies showing that influenza and pneumococcal vaccinations with older dendritic cells. Understanding of the mechanisms may reduce the incidence of myocardial infarction by up to of action of adjuvants and vaccine delivery systems and 50% [52]. Another example is that herpes zoster is strongly identifying those that are more effective in older individu- associated with an increased risk of stroke, an excess risk als remain an area of active research [46, 47]. which may be prevented by effective vaccines [29] (See Text The adaptive immune response of T and B cells, the back- Box 2). bone of a vaccine response, is also susceptible to aging [34] Another consideration is that vaccination may diminish and the previous decade has seen a surge in research on the problems related to polypharmacy in older adults with how and where this process is impaired in older individu- many comorbidities, which may lead to important adverse als. Defects in adaptive T-cell responses already begin to effects or lack of compliance [52]. Another intangible ben- become significant about the age of 50 years, in particular in et fi of vaccination, which is increasingly recognized (and not individuals with comorbidities. However, at least for healthy limited to vaccination of older adults), is that it may reduce individuals, the sizes and repertoires of antigen-specific the use of antibiotics [53–55] and thus diminish the growing CD4+ T cells and B cells do not appear to be decreased to a problems caused by the development of antibiotic-resistant biologically relevant extent in older adults [35]. strains of bacteria. The United Kingdom Joint Committee on Instead, at least part of the problem seems to be the Vaccination and Immunization has recently recommended reduced ability of antigen-specific lymphocytes to sur- that this effect be included in economic evaluations of new vive as long-lived memory T cells [36]. It is possible that vaccines and vaccination programs [56]. chronic infections such as cytomegalovirus may compromise The most widely used approach to economic evaluation antigen-specific responses and help drive the development of healthcare interventions (including vaccines) is cost- of immunosenescence [48, 49]. Whether this defect can be effectiveness or cost-utility analyses, which aim to assess the overcome by better vaccines or adjuvants or requires phar- incremental benefits of the intervention relative to its incre- macological intervention during the development of T-cell mental costs, usually taking the perspective of the healthcare responses after vaccination remains uncertain. In contrast system in estimating the costs. This type of economic assess- to CD4+ T cells, CD8+ naive and central memory T cells, ment is used in many countries by healthcare authorities for apparently the weak link in immune aging, are increasingly making decisions about reimbursement of new treatments. lost and become dysfunctional with age [37]. Depending on For preventive interventions like vaccines, the assessments the infection targeted by vaccination, it might be advanta- usually seek to estimate the loss of utility (QoL) avoided geous to generate an effective CD8+ memory population by the intervention and relate this to the incremental costs earlier in life, but induction of a CD8+ T-cell response incurred relative to no intervention. The result is expressed generally requires a live vaccine, whereas the inactivated as the incremental costs per quality-adjusted life-year or component vaccines previously developed preferentially (QALY) gained (or, more accurately, not lost), which may induce CD4+ T-cell and B-cell responses. then be compared to a benchmark to determine whether the intervention is cost-effective or not. Commonly used bench- The economics of adult vaccination marks in Europe range from 20,000 to 30,000 €/QALY, but few countries have set an explicit, official limit. Alongside investments in infrastructure to improve water A number of economic evaluations and reviews of vac- sanitation, vaccination programs are usually considered as cination of older adults have recently been published, for the most important factor in improved public health and example of pneumococcal conjugate vaccines [57] and her- longevity worldwide over the last century. It is increasingly pes zoster vaccine [58, 59]. Generally, these evaluations con- recognized that proper assessments of the economic value clude that vaccination is cost-effective but even taking the of vaccination needs to take a broader perspective than just narrow direct cost perspective there are important challenges focusing on the clinical benefits and the avoided healthcare to meet when making such assessments. Among these are 1 3 294 European Geriatric Medicine (2018) 9:289–300 heterogeneity between targeted older individuals in terms [65] and the government is proposing a Healthy Aging of risk of infection, response to vaccination and severity of program, which is projected to save 5 trillion yen (approx. disease, just as there may be age-related variations in dura- 40 billion Euros at current exchange rates) by 2025, with tion and level of immunity induced by vaccination [60]. almost a fifth of that coming from reduction in VPDs It is also of interest to note that, ignoring the difficult (primarily pneumonia) [65]. Other nations estimate assessment and valuation of health outcomes, studies of potential savings of a similar magnitude. For example a the costs of interventions show that the costs of vaccination recent study estimated that under-vaccination of adults are lower than those of many other preventive interventions costs the US 7.1 billion USD in healthcare expenditure and the potential benefits substantial (see Text Box  4). A per year [12]. recent study estimated that the total costs of fully adhering to recommended vaccinations over the full course of life in several European countries was much lower than those of Adult vaccination: recommendations and coverage many widely used preventive measures such as taking statins to prevent cardiovascular complications [61]. Despite the accumulating evidence of the benefits of vac - cination of older adults, vaccine uptake is generally lim- ited and far below targets [60]. To improve this situation, it Text box 4. Vaccination programs for healthy is necessary to identify the barriers to increased uptake of aging vaccinations among older adults and to modify these where possible. The proportion of the population over 65—and especially Vaccine programs for children and younger adults have over 85—years of age has increased dramatically over the shown that great declines in the incidence of infectious dis- last half century and this trend is only expected to accel- eases can be achieved if vaccination is properly implemented erate. While the decrease in mortality is to be celebrated, [25]. In the United States, coverage rates in children for most there is concern over the implication that a declining ratio recommended vaccines reach approximately 90% [66]. Euro- of those in employment to those no longer working will pean countries are more diverse, both in their recommended place stress on government budgets, and that the greater vaccines and the recommended schedules, but the coverage risk of illness in older individuals will place particular for the most common pediatric vaccines (measles, diphthe- stress on public health budgets [62]. Some steps have ria, pertussis, tetanus, tuberculosis, polio, etc.) reaches or already been taken to address the first of these concerns, exceeds 90% in most EU countries [67]. These programs as seen in the many countries raising the qualifying age indicate what is needed for successful disease control by for retirement and pension eligibility. However, for such vaccination and thus demonstrate the opportunities for adult policies to be successful, older individuals must remain vaccination programs. Comparing current pediatric vacci- healthy enough to continue working. Additionally, while nation programs with what is being done to enhance vacci- an increased demand for healthcare is unlikely to be nation of older adults also highlights important differences entirely avoidable in an aging population, there is grow- and the challenges that must be overcome to improve adult ing focus on ways of diminishing the burden of disease in vaccination rates. older people, a concept generally called “Healthy aging”. Where adult vaccination is recommended, there are wide A key component of healthy aging strategies is the divergences in what is recommended (Table 1) and in the recognition that infectious disease is likely to play an coverage levels reached. In a recent survey of immuniza- increasing role in morbidity among older individuals tion policies in 31 high-income countries [68], only 12 had ([63] and Text Box 2) and that vaccination is among the comprehensive adult vaccination policies, although all of most cost‐effective interventions. Consequently, we have them had recommendations for at least one adult vaccination seen expansion of vaccination programs and recommen- (influenza, with programs in place to monitor the vaccination dations shifting from a predominantly pediatric focus to coverage in adults in 29 of the countries). In two countries, one covering the whole lifespan, so‐called life course influenza vaccination is recommended for the entire popula- immunization, [64] as well as the development of vac- tion, whereas in the rest it was only recommended for risk cines specifically targeting diseases in older adults (see groups. Despite recommendations and public funding, only Text Box 3). The scale of the challenge—and the poten- one country in this study (the Netherlands) exceeded the tial benefits—are dramatic. In Japan, the currently most recommended level of coverage (75%) while many reached advanced country in the demographic transition, control less than 50% [68]. For the other vaccines, recommendations of infectious diseases and vaccination are among the are most common (26–27 countries) for adult immunization Ministry of Health, Labour and Welfare’s top priorities against hepatitis B, pneumococcus, tetanus and diphtheria, 1 3 European Geriatric Medicine (2018) 9:289–300 295 Table 1 Recommended vaccinations for adults in selected high-income countries [71–78] Vaccine Recommended vaccination Country Diphtheria No national recommendation Croatia, Czech Republic, Denmark, Hungary, Iceland, Ireland, Japan, Republic of Korea, Malta, Netherlands, Norway, Romania, United Kingdom Single booster Poland (in adulthood), Spain (at age 65) Adult, every 10 years Austria , Belgium, Bulgaria, Canada, Cyprus, Estonia, Finland, Germany, Greece, Italy, Latvia, Luxembourg, Slovenia, United States b b b c 65+, every 10 years France, Lichtenstein, Portugal, Switzerland Other New Zealand (every 20 years), Slovakia (50+, every 15 years), Sweden (50+, every 20 years) Tetanus No national recommendation Denmark, Hungary, Iceland, Ireland, Japan, Republic of Korea, Malta, Netherlands, Norway, Romania, United Kingdom Single booster Croatia (at age 60), Poland (in adulthood), Spain (at age 65) Adult, every 10 years Austria , Belgium, Bulgaria, Canada, Cyprus, Estonia, Finland, Germany, Greece, Italy, Latvia, Luxembourg, Slovenia, United States c b b c 65+, every 10 yearsCzech Republic, France , Lichtenstein, P ortugal, Switzerland Other Lithuania (every 5–10 years), New Zealand (every 20 years), Slovakia (every 15 years), Sweden (every 20 years) Pertussis No national recommendation Bulgaria, Canada, Croatia, Cyprus, Denmark, Estonia, Finland, Hungary, Iceland, Ireland, Latvia, Lithuania, Japan, Republic of Korea, Malta, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Slovakia, Spain, Sweden, Switzer- land, United Kingdom Single booster in adulthood Belgium, Czech Republic (at age 65), France, Germany, Greece, Slovenia, United States Adult, every 10 years Austria , Italy, Luxembourg 65+, every 10 years Lichtenstein Shingles (Herpes zoster) No national recommendation Bulgaria, Croatia, Cyprus, Denmark, Estonia, Finland, Germany, Hungary, Iceland, Ireland, Japan, Republic of Korea, Latvia, Lithuania, Luxembourg, Malta, New Zealand, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden Vaccination at 50+ Austria, Czech Republic Vaccination at 60+ Canada, Greece, United States d e Vaccination at 65+ Belgium, France , Italy Vaccination at 70+ Australia, United Kingdom Influenza (Trivalent) No national recommendation Sweden f f Annual vaccination at 60+ Germany, Greece , Hungary, Iceland, Netherlands, Slovakia f f f Annual vaccination at 65+Australia, Belgium, Bulgaria , Canada, Croatia, Cyprus, Denmark, Es tonia , f f f f f f Finland, France, Ireland, Italy , Japan, Republic of Korea, Latvia , Lithuania , f f f f Luxembourg, New Zealand, Norway , Portugal, Romania, Spain, Switzerland , United Kingdom f f f f f f All adults Austria , Czech R epublic, Malta, Poland, Slovenia , United States Pneumonia (S. pneumoniae) No national recommendation Bulgaria, Croatia, Estonia, France, Latvia, Lichtenstein, Lithuania, Netherlands, New Zealand, Portugal, Romania, Switzerland 50+, PPV Hungary 50+, PCV Poland 50+, PCV and PPV Austria 60+, PPV Germany, Iceland 60+, PCV Slovakia 60+, PCV and PPV Luxembourg 65+, PPV Australia, Canada, Cyprus, Ireland, Japan, Republic of Korea, Norway, Spain, Sweden, United Kingdom 65+, PCV Greece, Malta 65+, PCV and PPV Belgium, Czech Republic, Italy, United States 65+, PCV or PPV Denmark, Finland, Slovenia This table compiles recommended, age-specific vaccinations for older adults (from 50 years of age). It does not include catch-up vaccinations for vaccines typically given at younger ages, vaccines which are available but not recommended or reimbursed, vaccinations recommended for spe- 1 3 296 European Geriatric Medicine (2018) 9:289–300 Table 1 (continued) cific risk groups or vaccinations recommended in response to specific activities such as travel or transplantation PCV pneumococcal conjugate vaccine, PPV pneumococcal polysaccharide vaccine Every 5 years from age 65 Every 20 years for younger adults Every 10–15 years for younger adults Cap at 79 years of age Cap at 75 years of age Quadrivalent vaccine also available, though prioritization and access varies by region Initial dose is the conjugated pneumococcal vaccine, followed by the polysaccharide pneumococcal vaccine The use of PPV, with or without PCV, is being re-evaluated although again, these recommendations primarily focus Without funding, however, recommendations have lim- on risk groups and travelers [68] and coverage is generally ited effect. While most high-income countries have some poor [69]. Overall, the picture of adult vaccination is one of form of public funding in place for recommended vaccines fragmented recommendations, restricted coverage [70], and [82], cost can still be a barrier to access and may discour- significant data gaps [68]. age HCPs from recommending the vaccine. As one exam- ple illustrating this, moving from a partial to a full subsidy Adult vaccination: building effective programs of pneumococcal vaccination for older adults in Australia raised the uptake from 39 to 73% in patients attending a To understand why adult vaccination coverage is low, it is large public hospital [86]. Similarly, pediatric vaccination useful to examine those countries that have achieved the in the United States is financially supported by the Vaccines highest coverage and also to compare adult vaccination for Children initiative and this has virtually eliminated pre- programs with pediatric vaccination programs. Successful viously significant regional, ethnic and socioeconomic dis- pediatric vaccination programs generally recommend uni- parities in vaccination coverage [87]. In contrast, the same versal vaccination, they are supported by effective funding vaccines for adults can require substantial copayments, and mechanisms, and the outcomes are assessed (and the pro- ethnic and socioeconomic disparities in coverage rates are grams corrected, if needed) based on routine surveillance clearly visible [70]. of disease and vaccination coverage. These findings suggest that four things are necessary to The important role of recommendations is suggested by support effective vaccination programs, both in children and the observation that countries with comprehensive vaccina- in adults (Fig. 2). First, a clear commitment to vaccination tion recommendations for older adults tend to include more must be reflected in a coherent, comprehensive public policy. vaccines in their programs [68] and to reach higher levels of Second, a commitment to fund and deliver vaccines to the coverage with the recommended vaccines [67]. In addition, population is required, whether via predominantly public there is evidence that vaccination recommendations focusing funds as in the United Kingdom and the Netherlands, or a on groups at risk, although apparently offering an efficient mixture of public and private funds as in the United States. approach to vaccination, may actually inhibit uptake, since Third, effective surveillance of vaccination coverage and they may inadvertently send the message that the national the burden of disease is required, so that goals can be set, health system does not see the recommended vaccines as priorities established, and the effectiveness of the program important [79]. However, this evidence must be critically monitored and adjusted, if necessary. Finally, the safety and assessed in the light of economic evaluations, which often value of vaccination must be understood and appreciated conclude that universal vaccination of older adults against a both by the target population and by vaccinating healthcare particular VPD is not cost-effective and that programs must professionals. be targeted to specific, well-characterized groups to ensure The first three of these factors can be implemented by acceptable incremental costs per QALY gained [80]. public policy and the initial steps have already been taken As all the evidence identifies provider recommendation as in many countries. However, for adult vaccination programs the principal reason for adults to become vaccinated [1], this to achieve the same kind of success as pediatric programs implies that if few providers are convinced of the importance have, they need a similar degree of population acceptance. of adult vaccination the uptake will remain low. Numerous This is particularly an issue for adult vaccination because studies show that many primary-care physicians do not con- there is a widespread public perception that vaccination is sider vaccination of older adults a high priority [81–85]. not needed [90] and the decision of the individual to seek or accept vaccination is crucial. For infant vaccination, the 1 3 European Geriatric Medicine (2018) 9:289–300 297 Government Funds vaccine provision, establishes policy, establishes delivery and surveillance infrastructure Media Ask about vaccination Public Health Care Professionals Understand and accept the need for Recommend and provide vaccination, vaccination conduct public health surveillance Proactively recommend and offer vaccination Fig. 2 Components of successful vaccination programs. Healthcare and acceptance, as indicated by the labeled arrows. The media plays a systems are more than just government and business infrastructure: significant, but different role. While not (in theory) directly involved they comprise everyone involved in the process—politicians, health- in the process, it is the channel through which much of the dialogue is care providers and the general public. Each part of the polity engages conducted, and can also act as an “amplifier”—for example, increas- in dialogue with the other parts, and it is plain that for the establish- ing the visibility and impact of public concerns or hesitancy, or alter- ment of successful vaccination programs—whether in children or in natively promoting vaccination by reporting on disease-related deaths adults—all parts must be in general agreement [88, 89]. In addition, or vaccine benefits each part of the polity has specific roles in terms of delivery, dialogue messages are targeted at the parents. For adult vaccination, This implies that vaccination can serve as the third pillar the vaccine recipients must be reached with a message that of a strategy to support healthy aging, alongside healthy can convince them of the value and safety of vaccination diet and exercise. However, the uptake of vaccination by directly to themselves or to their family. Additionally, it is the target population is generally low and must be substan- important that vaccinating healthcare personnel understand tially improved if the potential of vaccines to reduce the the value of vaccination both for themselves and for patients. morbidity, mortality, loss of quality of life and healthcare These considerations are supported by interventions that costs caused by VPDs is to be realized [12]. The available have been associated with substantial improvements in adult evidence indicates that vaccination coverage in older adults vaccination coverage [88, 89]. Important common elements can be considerably improved, although there is a need for to improve coverage seem to be: clear national objectives further research into the generalizability of particular inter- and commitments; incentives for healthcare personnel to ventions to improve coverage. vaccinate; vaccination reimbursement systems; informa- Acknowledgements The authors would like to thank Nobuhiro Noro tion and awareness campaigns; clear coverage objectives. for his essential part in the success of the original meeting at which However, even programs considered as highly successful this manuscript originated. The authors also thank Business & Decision often plateau at a suboptimal level of coverage [89]. These Life Sciences platform for editorial assistance and manuscript coordi- plateaus vary between vaccine types thereby indicating that nation, on behalf of GSK. Carole Desiron coordinated the manuscript development and gave editorial support. The authors also thank Niels vaccine-specific issues must be addressed as well. Neymark, freelance scientific writer on behalf of GSK for providing medical writing support. Conclusion Authors’ contribution All authors reviewed the literature, provided substantial input, contributed to writing, and reviewed the paper. MD led the manuscript development. All authors gave their final approval All over the world, in rich and developing countries alike, and are accountable for all aspects of the work. a demographic shift towards an aging population is under- way. How we handle aging populations will have major eco- Funding GlaxoSmithKline Biologicals S.A. funded this study and all nomic and healthcare implications in the next few decades. costs related to the development of this publication. Many infectious diseases inflict a disproportionate burden of disease in older adults and can contribute to the onset of frailty, but may be prevented or attenuated by vaccination. 1 3 298 European Geriatric Medicine (2018) 9:289–300 8. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL Compliance with ethical standards (2006) Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet Conflict of interest GDG, ADP, RSO and MD are employees of the 367:1447–1457 GSK group of companies. ADP, RSO and MD hold restricted shares 9. Yoshikawa TT (1997) Perspective: aging and infectious diseases: in the GSK group of companies. MC received personal fees from the past, present, and future. J Infect Dis 176:1053–1057 GSK group of companies. JEM is an employee of The Health Sci- 10. McLaughlin JM, McGinnis JJ, Tan L, Mercatante A, Fortuna ences North Research Institute and her institution received an hono- J (2015) Estimated human and economic burden of 4 major rarium from the GSK group of companies for her attendance at an adult vaccine-preventable diseases in the US, 2013. J Prim Prev advisory board meeting and she received travel reimbursement during 36:259–273 the conduct of this work and outside this work. PHL, BGL and JF have 11. Office of Disease Prevention and Health Promotion. Immuniza- nothing to disclose. EW received consulting fees from Alios Pharma- tion and infectious diseases. https://www .health ypeople.go v/2020/ ceuticals outside this work. JG received grants from NIH during the t opic s-objec tives /t opic /immun izati on-and-inf ec tious -disea ses. conduct of this work and received personal fees from the GSK group of Last accessed 31 Mar 2017 companies for his attendance at an advisory board meeting during the 12. Ozawa S, Portnoy A, Getaneh H, Clark S, Knoll M, Bishai D et al conduct of this work. SM received personal fees from the GSK group (2016) Modeling the economic burden of adult vaccine-preventa- of companies for her participation in a vaccine workshop in Brussels, ble diseases in the United States. Health Aff 35:2124–2132 Belgium, in February 2016 outside this work and received a grant from 13. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G (2004) Takeda outside this work. WS received a grant from Centers for Dis- Untangling the concepts of disability, frailty and comorbidities: ease Control and Prevention during the conduct of this work. WS also implications for improved targeting and care. J Gerontol A Bio received personal fees from Merck, Pfizer, Genentech, Dynavax and Sci Med Sci 59:255–263 Novavax during the conduct of this work. HN received personal fees 14. 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European Geriatric MedicineSpringer Journals

Published: Mar 19, 2018

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