Challenges in adult vaccination

Abstract

Life-long primary prevention interventions beginning and continuing throughout an individual’s lifetime are increasingly seen as key to meeting the global healthcare challenges that accompany demographic changes – a concept referred to as “Healthy aging”. In this perspective, vaccination is seen as part of a triad, together with healthy diet and exercise. Current adult vaccine coverage is lower than target vaccination rates in most developed countries, and so vaccine preventable diseases continue to present a substantial burden on health and healthcare resources, especially in older individuals. In part, this is due to lack of knowledge and understanding of the benefits of vaccination, inconsistent recommendations by providers and uncertainties about cost benefits. However, lower vaccine effectiveness in older adults plays a part, and new vaccines with novel characteristics to improve effectiveness in older adults are required. A life-course immunization approach to ensure optimal vaccine uptake across adults of all ages can be expected to reduce morbidity and mortality in later life. To achieve this, greater emphasis on public and healthcare provider education is necessary, based on appropriate economic analyses that demonstrate the overall value of vaccination. This article introduces the technical, economic, political and demographic issues that make establishing effective adult vaccination programs such a difficult, but pressing issue, and outlines some of the steps that are now being taken to address them.

Key messages

• Life-long preventive activities that start and continue throughout life are essential, especially as the world’s population is “getting older”. This “Healthy aging” approach includes not only healthy diet and physical exercise; vaccination is critical in reducing some infectious diseases and their complications. Many adults, especially older adults (who have lower immunity than younger people) develop infections such as influenza and shingles that could potentially be prevented through vaccination.

• This review provides a perspective on the challenges in delivering a life-course immunization program. While some vaccines are less effective in older people, newer vaccines have been developed which provide stronger and longer protection in older patients than standard existing vaccines. However, the benefits of vaccination can only be realized if the vaccines are recommended and used. For that purpose, greater education of patients and their healthcare providers is necessary.

• Better knowledge of vaccines and making sure that all adults are up to date with all their recommended vaccines is an essential part of “Healthy aging”. This should prevent not only vaccine-preventable diseases but also reduce the risk of complications in later life.

Keywords:

• Vaccine
• coverage
• effectiveness
• impact
• cost
• older adults
• healthy aging

Introduction

The burden of infectious disease falls most heavily at the extremes of life; the youngest and the oldest of the population typically have the highest incidence of many infectious diseases, are more likely to be hospitalized by infectious disease, and usually suffer the highest rates of complications and death. This susceptibility to infection often makes these two age cohorts a significant source of infections for the population as a whole.

Despite the age difference, the reason for susceptibility to infectious disease is the same: a reduced ability in some cases to mount protective immune responses to many infections. The cause, however, is very different [1]. In healthy infants, the underlying causes are the immaturity of the immune system and the lack of pre-existing protective memory responses, other than the normally short-lived immune factors inherited from the mother [1,2], although the subsequent immune response to vaccination or infection in children is normally more rapid and stronger than that seen in healthy adults. In older adults, and particularly in the oldest age cohorts, the opposite is true [3]. Despite the demonstrable presence of pre-existing immune memory, immune responses in older adults tend to be weaker, and generating effective immune responses against new targets appears to be more difficult. This phenomenon is labelled “immunosenescence” – a broad term, which essentially encompasses an age-related decline in immunity due to a number of causes [4–6] (Box 1). These reduced responses are seen not only following infection in older cohorts; vaccination responses are also lower.

Box 1 Immunosenescence*.

Table

In contrast to younger individuals, hematopoietic stem cells (HSCs) in older subjects show a greater differentiation into myeloid progenitors at the expense of lymphoid progenitors than in younger individuals [5]. This results in fewer circulating antigen presenting cells (APCs) and a relative shift in the proportions of naïve and memory cells within both B and T-cell populations (fewer naïve cells and a corresponding increase in memory T and B cells) [5,6]. As a result, overall antibody production and specificity is diminished. It is this shift which leads to impaired immunity against infection in older people, and also to reduced vaccine efficacy and shorter duration of vaccine response [5]. A general increase in pro-inflammatory cytokine levels is also seen (in particular IL-6 and TNF-α), secreted by aging HSCs, and by other tissue cells as part of a more generalized cellular senescence [4,5].

*It is important to realize that substantial variation exists in the relative contribution and extent of these mechanisms in individuals, and no direct correlation with specific chronological ages can be made.

Vaccination remains one of the most effective, and certainly the most cost-effective, medical interventions against infectious disease, at least for those diseases for which we have vaccines [7]. The ease with which immune responses can be generated in children and older infants, has been exploited by immunization programs to control or even eliminate many formerly common childhood diseases, in regions where high levels of vaccine coverage can be reached [8]. While infectious diseases – which a century ago contributed nearly half of all deaths in developed economies like the US – have been greatly reduced, [9] the remaining burden of infectious disease is now found disproportionately in older adults [10,11].

Analysis of the reasons suggests that immunosenescence is only part of the problem. Despite reduced effectiveness in older populations, recommended vaccines still provide significant protection – but only if they are used. Unfortunately, vaccination coverage is almost universally lower in adults than in infants or children in the same region, even where recommendations favour the use of the vaccine in different age groups [12–15]. The exact reasons vary from country to county, but they can basically be summed up as failures in provision (barriers due to cost of vaccination or access to vaccination services) and failures in demand; healthcare workers (HCWs) do not always ensure that their patients are vaccinated, and individuals frequently do not request vaccination.

This article reviews the challenges facing the expansion of adult vaccination programs, and the technological and programmatic advances being developed to face them.

The roots of the problem

The world’s population is aging. It is anticipated that before 2020, the number of individuals aged ≥65 will be greater than those aged <5 years of age, and by 2050, it is estimated that there will be two individuals aged ≥65 for every child <5 years [16,17]. While at present, those aged ≥60 years account for 12.5% of the overall global population, this is projected to rise to 22–25% by 2050 [17,18]. This will include an increasing number of older adults; with those aged >80 years increasing 3- to 4-fold from 125 million in 2015 to over 400 million by 2050 [17]. This change in population demographics is likely to be accompanied by an increase in the relative frequency of those conditions more commonly seen in older patients such as cancer, cardiovascular and respiratory disease and infectious disease, which brings substantial challenges to public health and allied health economic policy [18,19].

While non-communicable diseases (NCDs) such as cardiovascular disease (CVD), cancer, non-infectious lung disease and diabetes now represent the major causes of global disease morbidity and mortality in older adults [18,20], improvements in medical care and risk reduction have led to some reductions in mortality, which to a great extent contributes to longer lifespan and – at the population level – demographic changes. Recognition of the healthcare benefits of tobacco cessation, regular physical exercise, increased emphasis on healthy nutrition and the implementation of measures to promote this awareness (at the societal, medical and individual level), has played a substantial role in improving “healthy aging” [21]. Similarly, along with general public health measures (improved sanitation and clean water supplies), immunization against vaccine-preventable infectious disease and effective anti-infective therapies, have all led to significant reductions in mortality [22]. However, the benefits of vaccination are most obvious in children, whereas in older adults, mortality rates due to vaccine-preventable diseases such as influenza and pneumococcal disease have only modestly decreased in recent decades [7,10,23].

These observations apply primarily to higher-income countries; in low and middle income countries (LMICs), although NCDs are increasing, infectious diseases (including vaccine-preventable disease) continue to be major problems in both children and adults [21]. They do highlight however, the value and importance of identifying and implementing preventive healthcare strategies in anticipation of future benefits. In light of global demographic shifts to an older population, it is essential that similar foresight is applied. Key to realizing these benefits, however, is that such anticipation involves not only strategies directed at older individuals per se, but also those that promote disease prevention and wellbeing throughout life.

Healthy aging

A holistic approach to healthy aging involves the promotion of healthier lifestyles throughout life, via primary preventative interventions to reduce smoking, alcohol consumption, obesity, sedentary behaviour and infectious disease. The role of life-course immunization in positively impacting population health throughout life has been highlighted as an essential strategy, although as yet it remains poorly implemented [19,24].

Traditionally, most vaccine policies and initiatives are age-based with a focus principally on the paediatric population [chiefly children aged ≤6 years, and human papilloma virus (HPV) vaccination and tetanus, diphtheria and pertussis (Tdap) booster in adolescents] and a more selective vaccine policy for older adults (typically defined as over ≥60 or ≥65 years) at increased risk of certain infections (influenza, pneumococcal disease and herpes zoster) [12–15]. For healthy individuals not included in these age groups, recommended vaccinations are far fewer and may include “catch-up” vaccinations when prior immunization in childhood was missed, annual influenza vaccination (as recommended by many upper-income countries), and regular boosters against Tdap, hepatitis B and meningitis. Specific recommendations for selected vaccines may also be made for special populations. These include pregnant women, individuals considered at high risk of infection and significant morbidity and mortality due to co-existing medical conditions (e.g. chronic pulmonary, cardiovascular and renal disease, diabetes mellitus, and immunocompromised patients) or those with occupational risk, e.g. HCWs [13–15].

While compliance with vaccine recommendations in children is generally high, reaching coverage of over 90% in most high-income countries, compliance is far lower in adults [10,25]. Although differences exist for specific vaccines, adult vaccine coverage is consistently reported as below, and often substantially below, target vaccination rates [7,10,25–27]. Data from the Centers for Disease Control and Prevention (CDC) estimates that in 2015, 44.8% of adults ≥19 years of age had received annual influenza vaccination, while only 23% of adults at risk of pneumococcal disease were vaccinated. Furthermore, 30.6% of adults aged ≥60 years received immunization against herpes zoster, while 24.6% had hepatitis B vaccination (and only 65% of HCWs), and 23.1% of adults ≥19 years had Tdap coverage (Table 1) [25]. Differences persist at regional as well as national levels. In the US, coverage varies greatly in different states. For example, for herpes zoster vaccination in adults aged ≥60 years, coverage ranges from 17.8% (Mississippi) to 46.6% (Vermont) [28].

Table 1. Adult vaccine coverage in the Unites States in 2015 (NHIS) [25].

Vaccine	Vaccine coverage (%)
	All	By age group (years)								HCWs
	≥19	19–64	19–26	19–49	50–64	≥50	≥60	60–64	≥65	All	Direct care^a
Hepatitis A^b	9.0			12.3		5.5
Hepatitis B^c	24.6			32.0		16.5				64.7	74.1
HPV^d
Females			41.6
Males			10.1
Influenza^e	44.8			32.5	48.7				73.5	68.6	68.9
Pneumococcal^f		23^g							63.6
Tetanus (alone)^h	61.6			62.1	64.1				56.9
Tdap^h	23.1	24.7							16.5	45.6	51.1
Herpes zoster^i							30.6	21.7	34.2

^a HCWs with direct patient responsibilities.

^b Reported receipt of at least two doses of hepatitis A vaccine (ever).

^c Reported receipt of at least three doses of hepatitis B vaccine (ever).

^d Reported receipt of at least one dose of HPV vaccine (ever).

^e For the previous 2014–2015 season.

^f Reported receipt at least one dose of pneumococcal vaccine (ever).

^g Adults aged 19–64 years at increased risk of pneumococcal disease.

^h Within past 10 years.

ⁱ Reported receipt of herpes zoster vaccine (ever).

Tdap: tetanus, diphtheria and pertussis vaccine; HCW: health care worker; NHIS: National Health Interview Survey.

It should also be recognized that such adult vaccine coverage not only has a direct effect in reducing protection against target diseases in each unimmunized adult; it also contributes to lower population immunity thresholds, weakening herd immunity, which may impact upon infection risk in unvaccinated individuals [29,30].

As such, in contrast to the healthcare, social and economic benefits achieved with childhood vaccination [22], the burden of vaccine-preventable diseases in adults, in terms of morbidity, mortality and direct and indirect economic costs remains high [11,31–33]. In the US, it has been estimated that 99% of all deaths due to vaccine-preventable diseases occur in the adult population, with about 40,000–90,000 deaths each year. This is chiefly due to influenza and pneumococcal disease, although others such as hepatitis B and HPV also contribute [7,10,23].

Many factors may contribute to lower coverage in adults, including reduced awareness regarding recommendations and benefits for immunization, and concerns about costs, with these reported not only by patients who could benefit, but also by their healthcare providers [10,34–37]. While strategies to address the concerns of patients and providers are required, the poor rates of vaccine coverage in adults generally and older adults in particular, suggest that the burden of vaccine-preventable disease in older adults results in part from the consistent failure to address low vaccination coverage throughout life. Emphasizing the value of vaccination within the broader primary prevention activities used to promote healthy aging can hopefully remedy this legacy.

Age-related immune responsiveness and immunosenescence

Immune responses to vaccines differ throughout life. New-born (and pre-term) children show reduced immunogenicity and persistence of functional antibodies (Abs), and lower cell-mediated immune (CMI) responses to vaccines than older infants, with responses subsequently increasing with evolving maturity of innate and adaptive immune systems [2]. Indeed, vaccine responses influence timing of vaccinations and may also impact upon the protection conferred by specific vaccines.

For example, clinical studies evaluating responses to the HPV-16/18 AS04-adjuvanted vaccine (Cervarix, GSK) suggest that responses in adolescents aged 9–14 years receiving two doses are similar, if not stronger, and more rapid than those seen in the slightly older cohort (aged 15–25 years) receiving three doses [38–40]. Similar observations are also seen with other HPV vaccines [40] suggesting this is a class effect.

In vaccination against hepatitis A and B, use of a combination vaccine such as Twinrix (GSK) facilitates coverage in adults not adequately covered in earlier immunization schedules. Clinical data has shown that Twinrix provides high and persistent immunogenicity against both diseases similar to that of monovalent vaccines [41,42]. However, some age-related differences are seen. While data shows similar rates of seroconversion against hepatitis A in adults >40 years compared with younger subjects, differences are seen for responses against hepatitis B, where slightly lower rates of sero-protection (92–93% versus 96.6%) and lower antibody titres are observed. In addition, rates are lower in adults >50 years compared to those aged between 41 and 50 [41,43,44].

In herpes zoster, vaccination with the currently available live attenuated vaccine (Zostavax, Merck) shows lower vaccine efficacy in individuals aged ≥70 years than in younger subjects, and a decline in protection over time is seen in all ages [45–47]. This lower efficacy in older subjects is accompanied by lower CMI responses against varicella zoster virus (VZV) vaccine in this population (although antibody responses are similar in all ages) [48–50].

These examples illustrate two main points. First, an age-related decline in immunity (immunosenescence) is generally considered to be an important challenge to addressing the vaccine needs of the older population [4–6,50,51]. It is also important to realize that immune hypo-responsiveness begins in adulthood, not old age, and may also impact upon vaccine benefits in younger adults. Another key point, as shown in studies with Twinrix, is that immune responses at any given age may differ depending on the vaccine used; responses against hepatitis A are similar irrespective of age, whereas those against hepatitis B decline with age, with higher responses seen with combination compared with monovalent vaccines [41,43,44].

From this, we can see that different vaccines (and vaccine formulations) may and do differ in their effectiveness at any particular age, and so we cannot readily define the best age for targeting a broad adult vaccination catch-up policy. However, it is apparent that inclusion of vaccine planning and implementation within a broader prevention strategy towards individuals at any age is a desirable approach. Nevertheless, as highlighted in the example of herpes zoster, as a general rule, it can be assumed that immunosenescence in older adults impacts greatly upon the effectiveness of vaccines, especially in the oldest.

Designing vaccines for older adult populations

Adults, and in particular older adults, are an extremely heterogeneous population, with a far broader age-range than children targeted in immunization plans, and with a substantially greater burden of co-existing medical conditions. Another key difference is in immunology; infants have a very limited antigenic history, especially with regard to pathogens compared to older adults [1], while with increasing age, immunosenescence has an increasingly greater impact upon vaccine immune responses. Although this is not absolute, in that individual older adults may show comparable immune responses to younger adults, others are less responsive, and in general response declines with increasing age [4,5]. As such, strategies to improve vaccine success in older adults should consider this lower immune capability in the older population as a baseline from which to develop and deliver more effective vaccines. However, this task is complicated by the fact that there is no consensus on what constitutes “older adults” or “elderly” populations. Although the burden of many diseases clearly increases with increasing age, there is no clean cut-off: for example, an increased risk for pneumococcal infections starts to become visible in the people in their 40s and only increases further with age [52]. As a result, countries set their benchmarks at different ages, and this varies not only by country but also for different adult vaccine recommendations within the same country [27].

Vaccine efficacy is generally lower in older adults [53,54]. While influenza morbidity and mortality rates are highest in those aged ≥65 years, vaccine efficacy of traditional (unadjuvanted) vaccines is far lower (17–50%), compared with younger adults where efficacy is 70–90% [55]. In herpes zoster, in which disease burden is also greatest in the older, lower vaccine efficacy with increasing age is a feature of existing live attenuated herpes zoster vaccines; falling from 69.8% in those aged 50–59 years, to 37.6% in those ≥70 years and 18.3% in those aged ≥80 years [45,46].

Inevitably, lower effectiveness in older adults has an impact on cost-effectiveness analyses, which makes vaccination a less attractive intervention for healthcare providers. It may also adversely affect an individual’s perception (and that of their HCWs) of the benefits of vaccination, contributing to lower uptake, as seen in surveys for willingness to vaccinate against influenza and a range of other vaccines [36,56–62]. Another factor that may reduce uptake is the often short-duration of responses or other issues (such as shifting influenza antigenic strains) that mean that periodic boosting, or annual vaccination in the case of influenza, is necessary. This may further increase the perception that vaccines are relatively ineffective (or at least a temporary measure) although other considerations such as inconvenience in arranging vaccine visits may also further contribute to lower uptake [36,56,57,62,63].

These observations suggest that better vaccines would improve both vaccine impact and coverage, and identify two key challenges in developing newer vaccines for older adults: one is achieving greater efficacy and effectiveness, and the other is generating more persistent immune responses resulting in greater duration of vaccine protection. With changes to vaccine design and characteristics such as use of newer vaccine adjuvants, robust and sustained immune responses to vaccination in older ages, accompanied by improved clinical outcomes are possible [51,64–66]. Experience with the MF59 (squalene “oil-in-water”) adjuvanted trivalent influenza vaccines (TIVs) has shown that adjuvantation produces significantly higher immune responses in the very old, and greater responses to heterotypic strains, compared with unadjuvanted TIVs [67–69], and similar observations are seen with MF59-adjuvanted pandemic H1N1 vaccine [68]. In addition, adjuvanted TIVs have shown higher rates of vaccine effectiveness against laboratory-confirmed influenza (60%) and against pneumonia or influenza-related hospitalizations (51%) in comparison to unadjuvanted TIVs [69].

More recently, a herpes zoster subunit vaccine (HZ/su) has been developed which combines the VZV viral glycoprotein E (gE) antigen formulated with the Adjuvant System AS01_B, a liposomal-based formulation which includes both MPL (3-Odesacyl-4′-monophosphoryl lipid A) and QS-21 (Quillaja saponaria Molina, fraction 21) adjuvants, which act synergistically to induce robust antibody and CMI responses [70]. Phase II studies have shown that in older subjects aged ≥60 years, HZ/su vaccination elicits a sustained and persistent gE-specific activated T-cell and antibody response, with responses at 72-month post-vaccination remaining far higher than pre-vaccination levels, with no apparent influence of age at vaccination on the magnitude or duration of these responses [71,72]. This novel HZ/su vaccine has now been evaluated in two global phase III randomised controlled trials which were conducted concurrently at the same sites on comparable populations to evaluate the efficacy of the vaccine in adults ≥50 or ≥70 years of age from each study, or in adults ≥70 years of age in a pooled analysis involving both studies [73,74]. These studies showed remarkably high rates of vaccine efficacy against herpes zoster, and similar rates were reported regardless of age; adults aging 50–59 or 60–69 years showed efficacy of 96.6 and 97.4%, respectively [73], whereas adults aging 70–79 or ≥80 years from both studies showed efficacy of 91.3 and 91.4%, respectively, in the pooled analysis [74]. Moreover, for those aged ≥70 years, vaccine efficacy against post-herpetic neuralgia (the major complication), was 88.8% [74]. These efficacies, which persisted throughout the 4-year duration of these studies, are so far among the highest in vaccines targeting older adults [73,74].

Developing other vaccines with novel adjuvants may be an important route to improving vaccination effectiveness in older adults, while in future, novel vaccine combinations may also facilitate broader uptake [53,65]. Other strategies, such as higher antigen doses, and alternative delivery strategies (e.g. intradermal rather than intramuscular injection) or multiple booster dosing used in influenza vaccination may also play a role [75,76].

Turning vaccines into vaccination

No matter how effective a vaccine may be, vaccine uptake is influenced by public and physician or allied-HCW attitudes and choices. As mentioned above, perceptions regarding the need for and effectiveness of established vaccines are key factors in vaccine uptake. A relatively low rate of public awareness of the benefits of available vaccines has been reported for a wide range of vaccine-preventable diseases, including influenza, pneumococcal disease and herpes zoster [35,36,56,57,62,63,77–80]. This is associated with inconsistent or infrequent advice and recommendations by healthcare providers regarding the need and benefits of vaccination across all ages including the older adults [10,35], and a number of studies have identified uncertainty about vaccine effectiveness as a frequent reason for not recommending or accepting routine adult vaccination [36,62,79]. Other reasons for not recommending or providing adult vaccination include confusion or uncertainty regarding recommended schedules and a lower priority of adult vaccination within overall preventive measures [81].

Disparities in uptake exist, with some countries reporting lower vaccine coverage in ethnic minorities and in uninsured individuals, and this is typically accompanied by lower awareness in these populations, and also in differences in provider recommendations [10,25,35,37,81,82]. In older adults, living alone is also associated with lower uptake of influenza vaccination, suggesting a social dimension to the problem [83].

Clearly addressing these gaps in public and healthcare provider awareness of adult vaccination recommendations and benefits are crucial to improving vaccine coverage. This can be addressed by adopting a more comprehensive approach to vaccine education of both groups. National campaigns and initiatives such as the “The 4 Pillars Program” which includes provider and patient education, and use of practice-based immunization “champions” can be effective in improving adult vaccine uptake [84–86]. While broad educational campaigns are likely to be effective, these can be supplemented by more focused local campaigns. One example of the latter is that used to promote influenza vaccination in both older adults and pregnant women, following a switch from targeting only those with adverse risk factors to a universal immunization strategy in the UK [87]. In one city (Stockport), use of a coordinated multi-channel (print and digital media) community awareness campaign along with education of HCWs in primary care (physicians and pharmacists) led to increased vaccine uptake in older adults and pregnant women compared to the prior period, and levels which were significantly higher than the national average [87]. While immunization costs for the end user may be a barrier to vaccine uptake, they are almost certainly not always the deciding factor, as adult vaccine coverage is low even in countries which fully subsidize recommended adult vaccinations.

Beyond infectious disease – vaccination as an important tool for health management in adults

There has been increasing recognition and understanding of the important relationship between chronic and acute infection states and subsequent disease, and that vaccination can reduce the risk of adverse outcomes in patients with medical co-morbidities [88–90]. In addition, there is the risk that acute – but treatable – infections may have more sequelae in older patients. These include loss of function, and increasing risk of frailty (itself a risk factor for subsequent infections) which is associated with elevated risk for CVD and diabetes [91–93]. The goal of life-course immunization, and of the healthy aging agenda in general, is to prevent this downward spiral in older individuals. The goals of vaccination in this context include more than simply preventing disease, but also include quality of life issues including productivity and independent living.

Infections in older adults may also increase risk for cerebrovascular and cardiovascular events occurring in the period after infection, but where the infection may not be identified as a precipitating factor. An example of this is a potential link between herpes zoster and increased subsequent risk of strokes (post-herpes zoster attack stroke syndrome) which may be as high as 127% in the immediate post-zoster period [94].

A number of recent studies have shown influenza infection to be a potential trigger for cardiovascular conditions including acute coronary syndromes [95–97], and atrial fibrillation [98], with some studies showing that influenza vaccination can lower risk of acute cardiovascular events and mortality in patients with medical co-morbidities [89,92,98–101], and others demonstrating an association between influenza vaccination and a reduction in hospitalisations and deaths due to heart failure [102–105]. In their study evaluating the benefits of influenza and pneumococcal vaccination in individuals aged ≥65 years, Hung et al. found that while both vaccines reduced the risk of ischemic stroke, myocardial infarction and coronary care admissions, benefit was greatest in those receiving both vaccines [106]. In this study, the protective effect of vaccination was so prominent that the local government changed policy to make vaccination free for older adults – a policy that is potentially cost-saving when the downstream benefits are included.

Vaccination has also shown benefit in patients with other co-morbidities such as chronic obstructive pulmonary disease (COPD) and diabetes. A recently updated Cochrane review (involving 12 randomized controlled trials) evaluating benefits on pneumococcal vaccination concluded that vaccination results in significant protection against community-acquired pneumonia, and also reduces COPD exacerbations [107]. While most evidence for the benefits of vaccination in COPD patients comes from studies in higher-income countries, studies looking specifically at LMICs have also found that influenza vaccination is beneficial and cost-effective [108]. The benefits of a comprehensive vaccination program can be substantial: one Russian study in patients with COPD found combination vaccination against pneumococcal infection, Haemophilus influenza type b infection, and influenza resulted in a 3.7-fold reduction in COPD exacerbations and a 3.4-fold decrease in antibiotic use in the year-long follow-up period [109].

Patients with diabetes are not only more vulnerable to acquiring infections, but any infection can adversely affect sugar control, raising the likelihood of diabetic complications. Studies show that influenza vaccination reduces the incidence of pneumonia and influenza-related and all-cause hospitalizations in both working age adults (<65) and older adults (≥65 years) with diabetes [110,111]. A recent systematic review found that influenza vaccination in older diabetics prevented all-cause mortality (vaccine effectiveness (VE) 38%; 95% CI, 32–43%), all-cause hospitalization (VE 23%; 95% CI, 1–40%), and pneumonia and influenza-related hospitalization (VE 45%; 95% CI, 34–53%) [111].

Clearly, vaccination of older adults with such co-morbidities results in significant and substantial reductions in morbidity and mortality in these patients (and has the potential to reduce associated healthcare and indirect costs). Extending vaccination coverage to older adults thus provides an effective way to improve care and quality of life in this group.

Economic benefits of healthy aging

There is growing concern over the effect of aging populations on health budgets [18,112]. An additional worry may also be the relatively lower rate of investment in primary prevention measures, which, while understandable in light of the need to focus budget and resources on treating established illness, can only lead to further and more substantial medical costs in the future. While studies have shown that lifestyle measures are effective and cost-effective for a range of conditions e.g. hypertension in the prevention and control of diabetes [113–115], the overall economic benefits of some preventive measures in relation to direct treatment costs are uncertain and subject to interpretation [116–119]. This is particularly relevant in the context of an older population, due to their disproportionately high burden of disease.

In contrast, the economic benefits of vaccination are well established [7,22]. In the context of a life-long approach, a recent analysis from a European perspective suggests that life-course immunization costs for an individual are less expensive than other commonly used preventive measures such as use of bisphosphonates in preventing osteoporotic fractures or statins to reduce lipid levels [120].

Traditionally, vaccine-cost effectiveness has been estimated in terms of conventional health benefits such as quality- or disability-adjusted life-years (QALYs and DALYs), with interventions considered to be cost effective (or very cost-effective) if the incremental cost-effectiveness ratio (ICER) is below specified thresholds. These thresholds vary for individual countries, though for vaccination, the WHO thresholds are three times the gross domestic product (GDP) per capita (cost effective) or equal to the GDP per capita (very cost effective) [121].

However, there are limitations to this approach, which generally measure only short-term health and economic benefits. Newer methods that accommodate additional fiscal measures and cost-benefits may be more appropriate in evaluating overall vaccine benefits [122–124] One such approach is “cost optimization” modelling which incorporates these broader measures of overall health, social and economic benefits [125,126]. Rather than evaluating economic benefits in terms of an isolated cost threshold or ICER (i.e. conventional cost-effectiveness), cost optimization evaluates the broader overall value of vaccines in reducing overall medical cost within the parameters of specific healthcare budget, and allows more effective decision making on vaccine dosing and schedules within that budget. Essentially this measures the best way to obtain the maximum health benefit within a fixed budget and can be used for vaccines in different health economic settings (including LIMCs) [125,126]. Use of such approaches may show how increased vaccine coverage can produce long-term health and socio-economic benefits.

Conclusions

Infectious disease remains a significant problem in adults, even in high income countries, due to our failure to properly view vaccination as an important preventative measure throughout life, and to appreciate the downstream health risks attendant on infections such as influenza, pneumonia and zoster. Changing demographics threaten to make this problem even larger than it currently is, by increasing the population at risk of severe outcomes – precisely at a time when the aging population is going to place strain on budgets – including healthcare budgets.

Vaccination is an exceptionally cost-effective intervention and has the potential to reduce some of these foreseeable costs – but it also faces some major barriers: in particular, low coverage rates in adults and (for some current vaccines) reduced efficacy in older individuals. The issue of lower vaccine efficacy in older adults, in whom vaccine responses are lower as a consequence of immunosenescence, can be tackled by improved vaccine technology, as demonstrated by recent advances with adjuvanted vaccines (for example adjuvanted or high dose influenza vaccines, and the novel HZ/su vaccine against herpes zoster), which offer age-independent efficacy and longer duration of protection in the older adult population.

Turning existing vaccines into vaccination requires effective action at all levels of society. Although new technology can potentially improve outcomes in older individuals, we are failing to use existing technology effectively. It has been repeatedly shown that a doctor’s recommendation is the single most important factor in improving vaccination rates [29], but in the case of adult vaccination, it is particularly important that individuals understand what vaccination means to them at a personal level, since they are actively involved in making their own health decisions. Addressing the issue of low coverage therefore requires a concerted effort to improve public and healthcare providers awareness of vaccine preventable disease, and the benefits that can result from vaccination. Economic analyses that demonstrate overall value of vaccination (including future value) can also inform decision making regarding the benefits of a life-course immunization strategy. Support by the public and by healthcare providers is required if governments are to prioritize and financially support adult vaccination programs.

Trademarks

Zostavax is a trademark of Merck & Co, Inc.

Cervarix and Twinrix are trademarks of the GSK group of companies.

Acknowledgements

Authors would like to thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Vincent Laporte coordinated manuscript development and editorial support. The authors also thank Iain O’Neill (freelance on behalf of GSK) for providing medical writing support.

Disclosure statement

E. D. G., G. D. G. and T. M. D. are employees of the GSK group of companies. E. D. G., G. D. G. and T. M. D. additionally report ownership of stock/restricted shares/shares in the GSK group of companies.

Additional information

Funding

All costs associated with the development and publication of this manuscript was funded by GlaxoSmithKline Biologicals SA.