Vaccination in the elderly: what can be recommended?

Drugs Aging DOI 10.1007/s40266-014-0193-1

REVIEW ARTICLE

Vaccination in the Elderly: What Can Be Recommended? Pierre-Olivier Lang • Richard Aspinall

Springer International Publishing Switzerland 2014

Abstract The age-associated increased susceptibility to infectious disease would suggest that vaccination should be a route to promote healthy aging and keep our seniors autonomous and independent. While vaccination represents a cost-effective and efficient strategy at community level, the ability of the immune system to mount a protective immune response is still unpredictable at the level of the individual. Thus, at a similar age, some individuals, including the elderly, might still be ‘good’ responders while some other, even younger, would definitely fail to mount a protective response. In this review, the current burden of vaccine-preventable diseases in the aging and aged population will be detailed with the aim to identify the ideal vaccine candidates over the age of 50 years. This article will conclude with potential strategies to reduce, as best as possible, this burden and the imperative need to overcome barriers in extending current vaccine coverage towards to a lifelong vaccine schedule.

Key Points Age-related susceptibility to infectious disease and its associated burden make vaccination a costeffective and efficient public health strategy to promote healthy aging. While aged adults are usually considered to be immunocompromised and to respond poorly to vaccination, most of them will spend one-third of their lifespan over the age of 65 years, have a very active life, and travel more frequently and more widely than previous generations. Thus, providing vaccine candidates for individuals aged 50 years or over means to identify vaccines not only to control life-threatening infections, but also to prevent risks associated with recreational activities and travel, as well as sexually transmitted infections. We provide arguments for pragmatic vaccination for seasonal influenza virus infections; pneumococcal diseases; herpes zoster; diphtheria, tetanus, and pertussis; and hepatitis A and other vaccines for travelers.

P.-O. Lang R. Aspinall Translational Medicine Research group, Cranfield Health, Cranfield University, Cranfield, England P.-O. Lang (&) Nescens Centre of Preventive Medicine, Clinic of Genolier, Route du Muids, 3, 1272 Genolier, Switzerland e-mail: [email protected]

1 Introduction Were we to track the trajectory of the immune system in humans, we would see that it was shaped like an arc with the development of full function during the early years of life followed by a period of peak performance and then a

P.-O. Lang, R. Aspinall

decline of function towards the latter part of the lifespan. This decline affects everyone, but the rate of its onset is individual. It is the consequence of a compilation of events, including thymic involution with reduction in thymic output; the continuous re-shaping of the immune repertoire by persistent antigenic challenge; changes in antigen-presenting cells, including function of their Toll-like receptor ligands; the reduced production of new B cells and the intrinsic defects arising in resident B cells [1]. It is also affected by some age-associated chronic comorbid conditions [2], nutritional status (i.e. macro- and micro-nutrients) [3, 4], increases in the frequency of low-grade and chronic inflammation, and dysregulation in the hormonal pathway [5–7], as well as the role played by sarcopenia [8] and the frailty process [9–11]. The increased susceptibility to infectious disease would suggest that vaccination should be a route to promote healthy aging and keep our seniors autonomous and independent. In addition to its possible individual direct benefits, vaccination also yields social benefits, such as a lower overall cost of healthcare [12]. While vaccination represents a cost-effective and efficient strategy at community level [12–14], the ability of the immune system to mount a protective immune response is unpredictable as yet. This is because the deterioration of immunological systems with the passage of time does not occur at the same rate in all members of a population. While the majority of individuals over the age of 65 are currently physically more active than their counterparts a few decades ago [15], those over 80 are living with an increasing number of comorbidities [16]. Findings from the Swedish OCTA and NONA longitudinal immunological studies [17, 18] have confirmed that survival to the age of 100 years was associated with the selection of individuals with ‘inverted’ immune risk profile that was stable across time (i.e. avoidance of inverted CD4?:CD8? ratio and low numbers of senescent T cells). Moreover, there is a general misconception that the immune system becomes hypo-responsive or broadly non-functional with advancing age [13]. Although many compartments of the immune system decline, this does not occur uniformly [13], and some elements are preserved (e.g. CD8? T cell polyfunctionality) [19], while others are enhanced (e.g. pro-inflammatory cytokine production by macrophages) [20] or compensated by other immune compartments [21–23]. Finally, at a similar age, some elderly, including those over 80 years of age, might still be ‘good’ responders while others would definitely fail to mount a protective response. Although some promising markers have been identified and studied [24, 25], predicting individual responsiveness to vaccination using a robust method able to distinguish between a

healthy state and immunosenescence is still very challenging [26]. In answer to the current limited efficacy of current vaccines in some individuals and the lack of vaccines specifically designed for immunosenescent populations, some authors have suggested that the best protection might be in relying on herd protection to protect the most vulnerable population indirectly (e.g. those who are not or incompletely vaccinated and those in whom vaccination is contra-indicated or considered as less effective or ineffective) [1, 13, 27–30]. In this review, the current burden of vaccine-preventable diseases (VPDs) in the aging and aged population will be presented with the aim to identify the vaccine candidates for individuals aged 50 or over in terms of their appropriateness for use and issues with effectiveness and safety. This article will conclude with potential strategies to reduce, as best as possible, the burden of VPDs within this vulnerable population and the imperative need to overcome barriers in extending current vaccine coverage towards to a lifelong vaccine schedule.

2 Literature Search Strategy With the aim of identifying vaccine candidates for individuals aged 50 years or older, the criteria for adding vaccines to an immunization program were considered. Four domains were explored, including the pathogen, the vaccine, the burden of disease, and the cost effectiveness. They help considerably when collecting relevant scientific data for evaluation and decision making from the literature. The literature search was electronically performed in databases such as PubMed, Embase, Scopus, and Google Scholar. Appropriate publications were selected on the basis of title/abstract and full text. Reviews, meta-analyses, and clinical studies (randomized or not), and research articles were all considered. Current recommendations made for the targeted population at the country level for the European Community by the European Agency for the Evaluation of Medical Products (EMEA—http://www.ema. europa.eu) and the US FDA and the Centers for Disease Control and Prevention (CDC—http://www.cdc.gov) for the USA were, of course, also considered.

3 How Severe Is the Burden of Vaccine-Preventable Diseases in the Aging and Aged Population? Burden of illness includes both the impact on the wellbeing of the affected person, and the economic and social costs of managing the disease [31]. The mortality burden

Vaccination in the Elderly

of VPDs in the USA is especially poignant when you consider that, at the current time, approximately 200 children die and 70,000 adults die due to VPDs each year [32]. This stunning 250-fold difference is mainly the result of erroneous beliefs and attitudes of members of the general population towards vaccination programs, which have led to multiple resurgences and to fundamental changes in the epidemiology of common VPDs across the different age strata [1], not only in the USA [33], but worldwide [1, 29]. Finally, while vaccination programs have certainly contributed to saving many lives, VPDs still remain a major global public health concern for the aged adult population. With demographic changes indicating an increase in the elderly [29], the absolute and relative number of adults ill or dying of VPDs will probably continue to increase without any improvement in not only vaccine immunogenicity and efficacy [14] but also our understanding of the public, societal, cultural, and political barriers to vaccination.

3.1 Seasonal Influenza Virus Infections Foremost amongst infections controlled by vaccination is influenza [21]. It is a disease of viral origin commonly associated with a rapid onset of symptoms such as fever, chills, fatigue, headache, muscle and joint pain, and nasal congestion. However, the illness may be asymptomatic in many individuals, facilitating the spread of the virus. While influenza is usually a contagious illness of 1–2 weeks duration with full recovery in younger individuals, in some individuals and most particularly in frail and older adults it may lead to a period of prolonged bed rest, and be associated with considerable morbidity and mortality [21]. It may also act as a trigger for functional decline, even leading to disability in some individuals [34, 35]. Moreover, those aged over 65 years are more likely to develop complications such as pneumonia than their younger counterparts. Worldwide estimates indicate that influenza causes 3–5 million severe cases per year, resulting in 250,000–350,000 deaths. In the EU, between 40,000 and 220,000 deaths can be attributed to influenza infection yearly, depending on the pathogenicity of the circulating viral strain. The highest prevalence occurs among older adults, especially those with chronic medical conditions or immunological disorders, resulting in increased morbidity and mortality [11, 35]. Peak months of mortality due to respiratory illness, ischemic heart disease, cerebrovascular events, and diabetes in adults 70 years or older coincide with seasonal epidemics [36]. Such outcomes represent a considerable economic burden, amounting to approximately $US87 billion each year in the USA [35].

3.2 Pneumococcal Diseases Infection with Streptococcus pneumoniae is one of the main causes of not only bacterial pneumonia but also bacteraemia and bacterial meningitis amongst the elderly [29, 37–40]. The yearly average incidence of invasive pneumococcal disease (IPD) is 54 per 100,000 individuals aged 50 or over. Specifically for pneumonia, the incidence in general practice has been established at 17.5 per 1,000 patients aged 65–74 years and 31.4 per 1,000 patients aged 75 years or over [12, 41]. This includes not only pneumococcal infections but also all causes of pneumonia and, although exact figures of the incidence are difficult to establish, estimates suggest that between 12 and 48 % of all cases of pneumonia are pneumococcal pneumonias [42]. Partial data collected in a few European countries mentioned the existence of 77,778 cases of IPDs over the last 8 years [37]. On average, 590 per 100,000 population aged 50 years or older are admitted to hospital yearly for pneumococcal disease. The number of admissions to the intensive care unit is highest for meningitides (58 % for individuals aged both 50–64 years and 65 or over) and lowest for bacteraemia (18 % for both age groups). Bacteraemia and meningitides were associated with the highest fatality rates with, respectively, 40 and 39 % in adults aged 65 years and older compared with less than 1 % in children younger than 5 years [12]. It was estimated that 648 quality-adjusted life-years (QALYs) are lost due to pneumococcal infection in the elderly population [43]. During the period 1977–2006, Cabellos et al. [38] prospectively collected all community-acquired bacterial meningitis in the USA39. One-third of the 675 cases collected occurred in patients aged 65 years or older, and causative microorganisms were by far S. pneumoniae, followed by Neisseria meningitidis and Listeria monocytogenesis. S. pneumoniae and other causative pathogens can easily be spread from person to person through the exchange of respiratory and throat secretions even if fortunately, none are as contagious as influenza. During the year 2000 in England and Wales, there were 56,838 deaths from pneumonia and influenza and of these 53,833 occurred within the population over the age of 75 [44]. This is despite the fact that effective vaccines exist to fight these two pathogens [29]. 3.3 Varicella-Zoster-Virus Reactivation Herpes zoster (HZ) and zoster-related pain are frequent causes of morbidity in older adults. Epidemiological studies estimate the incidence of HZ in the general population to be between 3 and 4 per 1,000 population, with the sharpest increase of incidence occurring between 50 and 60 years of age and continues on an upward trend. This agerelated increase in incidence has been suggested to be due


to age-related immune remodelling and comorbid conditions [45, 46]. In the largest prospective observational study of HZ cases in community-dwelling patients, Chidiac et al. [47] supplied an objective measurement of the HZ-related burden on health-related quality of life (HR-QOL). A total of 8,103 patients with acute HZ and 935 with post-herpetic neuralgia (PHN) were seen over 1 year by 5,000 general practitioners and dermatologists. Patients enrolled in the study were classified into three groups according to the reason for their initial visit to their health practitioner: acute HZ; PHN, defined as the persistence of pain after healing of skin lesion; and other visceral and neurological complications. Each patient completed a questionnaire at the physician’s office, designed to evaluate perceived pain and HR-QOL with the Medical Outcome Study Short Form-36 (MOS SF-36). Pain-related disruption of life activities during the week prior to consulting the physician was more severe for the patients experiencing PHN. The 7,595 completed QOL questionnaires showed that HZ had an adverse impact in all MOS SF-36 dimensions, compared with questionnaires completed by a French control reference population, matched for age and sex. The lowest values were obtained in scores for physical functioning and emotional responses. Impact on HR-QOL in the PHN group was also shown by the high rate of alternative medical approaches. This finding emphasizes the significant distress experienced due to HZ-associated pain. Similarly, but more recently, the impact of HZ and PHN in HRQOL was described in Canada [48]. From October 2005 to July 2006, a total of 261 outpatients aged 50 years or older with HZ were recruited from the clinical practices of 83 physicians within 14 days after rash onset. HZ-related pain and discomfort and HR-QOL were assessed by means of the Zoster Brief Pain Inventory (ZBPI) and the EuroQol (EQ)-5D, respectively, at inclusion time, weekly during the first month, and monthly for the next 5 months of followup. Acute HZ interfered in all health domains but especially sleep (64 %), enjoyment of life (58 %), and general activities (53 %). The median duration of interference with activities of daily living because of pain varied between 27 and 30 days. Overall, 24 % of participants had PHN. Anxiety and depression, enjoyment of life, mood, and sleep were also most frequently affected during the painful period. The mean EQ-5D score was 0.59 at enrollment and remained at 0.67 at all follow-up points among participants who reported clinically significant pain and as long as pain persisted. Furthermore, even when anti-viral drugs are initiated within the first 72 h of the rash, both their analgesic and preventive effect on acute and chronic pain are modest [49, 50]. Thus, the combination of anti-viral therapy and analgesic drugs is often necessary in pain management. In the context of fail older patients, medication

selection, prescribed dosages, co-morbidities, and often polypharmacy must all be carefully considered. The complete control of pain with available analgesic drugs is still a considerable challenge for both patients and their physicians [49, 51]. This was recently illustrated in France with an observational and prospective study conducted in patients aged over 50 in whom, despite early diagnosis and treatment with anti-viral agents, many of the 1,358 patients experienced pain and marked long-term reduction in HRQOL [52]. The prevalence of HZ-related pain on day 0 and at months 3, 6, 9, and 12 was 79.6, 11.6, 8.5, and 6.0 %, respectively. In Australia, using retrospective data (1998–2005) from emergency department and hospital records, the authors evaluated the healthcare resource utilization associated with HZ [53]. The proportion resulting in hospital admissions increased from 6 % at ages 50–59 to 33 % in those aged 80 years or over. The annual rate of hospitalizations in subjects aged 50 years or older was 28/100,000 for those with a principal diagnosis of HZ, and 39/100,000 for those with both HZ and other diagnoses. The average length of stay was 6.8 days (6.0 for HZ without complications, and extended to more than 14 days for HZ encephalitis). The rate of total emergency visits increased with age. In a prospective study conducted in 96 community-dwelling patients with 8 months followup, Scott et al. [54, 55] described the economic and social burden associated with HZ onset [54, 55]. Hospitalizations, severe pain, and residual neurological deficit were more likely to occur in older patients, although two-thirds of cases occurred in those under 65 years. Severity was lower in this age group, but the costs to society tended to be higher due to absence from work. Health economic trials estimate that shingles and PHN cost the UK up to €108 million per year. However, while related pain is the most feared and studied complication, various other neurologic symptoms have been reported to occur with HZ. They include Bell’s palsy, the Ramsay Hunt syndrome, transverse myelitis, transient ischemic attacks, and stroke [46]. In addition, ophthalmologic complications of HZ occurring in the V1 distribution of the trigeminal nerve can include keratitis, scleritis, uveitis, and acute retinal necrosis [56]. More particularly in immunocompromised individuals, whatever the age, additional complications have been observed that result in a further increased burden [57]. Thus, disseminated skin disease, acute or progressive outer retinal necrosis, chronic HZ with verrucous skin lesions, and development of acyclovir-resistant varicella zoster virus (VZV) are described. Moreover, the disease can involve multiple organs (e.g. lung, liver, brain, and gastrointestinal tract), and patients may present with hepatitis or pancreatitis several days before the rash appears [46].


3.4 Bordetella pertussis Infection Pertussis, also known as whooping cough, is a highly contagious, acute respiratory illness caused by Bordetella pertussis, which is a bacterium easily transmitted from person to person. In the pre-vaccine era, the disease predominantly affected children below 10 years of age and usually manifested as a common cold with a prolonged cough illness with one or more of the classical symptoms, including inspiratory whoop, paroxysmal cough, and posttussive emesis. Since the introduction of pertussis vaccines, the epidemiology of reported pertussis infections has changed; in the USA in the 1990s, more than one-half of cases occurred in adolescents and adults [33]. Similar pictures have been observed in Canada [58] and European countries [59]. In the Netherlands from 2002 to 2005, a total of 4,963 cases leading to 10,338 general practitioner consultations and 28 hospital admissions were reported among adults aged 45 or over [60]. More globally, recent epidemiological studies have demonstrated a 115 and 400 % increase in pertussis prevalence in the non-immunized adolescent and adult populations [59, 61], and a 68 % increase in the population of individuals aged over 65 [62]. Clinical manifestations of pertussis in adolescents and adults are often less severe than in infants and children. Prior infection or immunization may attenuate the illness, but neither confers lifelong immunity [63, 64]. As a result, prolonged cough may be the only symptom in this population [65]. The presence or absence of classically described manifestations is only modestly useful to determine whether prolonged cough represents B. pertussis infection in this population [66]. However, morbidity of pertussis in old adults is substantial. A total of 86 % of infants younger than 6 months of age with pertussis had to be hospitalized; in adults aged 85 years or older, hospitalization rates reached 80 % [67]. The most common complications in adults with pertussis, whatever the age, are weight loss (33 %), urinary incontinence (28 %), syncope (6 %), and rib fractures from severe coughing (4 %). More severe complications can include encephalopathy (as a result of hypoxia from coughing or possibly from toxin), pneumothorax, rectal prolapse, subdural hematoma, and seizure [68]. A pertussis outbreak in a monastery in the Netherlands demonstrated the potential severity of the impact in the deaths of four individuals aged 55 years or older from intracranial bleeding [69]. None of the 75 residents and 19 of 24 non-resident personnel had been vaccinated against pertussis. In the older adult population, 7 % of individuals who get pertussis develop prolonged cough, and 20 % of unexplained chronic cough observed within this age group is linked to pertussis [70]. Adolescents and adults can also develop complications from pertussis, but they are usually

less severe in this age group, especially in those who have been vaccinated [67]. The under-recognized role of adolescents and adults in disease transmission, coupled with the reduced likelihood of correct diagnosis and waning immunity, all contribute to pertussis persistence [12] and the changed epidemiology [29]. Moreover adolescents and adults with no or low specific immunity may serve as a reservoir for infection of infants and children. Finally, the current attitudes towards vaccination [71, 72] in most industrialized countries have led to the considerable success of childhood vaccine schedules [44] but also to subsequent fundamental changes in the epidemiology of B. pertussis and, for similar reasons, tetanus and diphtheria [33]. All those infections that were thought of as VPDs of childhood are increasingly being recognized instead as adolescent and even adulthood diseases in populations that have not been properly immunized [1]. 3.5 Corynebacterium diphtheriae and Clostridium tetani Infections In 1980, the number of notified cases of diphtheria in Europe was just below 100,000, with a vaccine coverage rate of only 20–30 % [73]. Between 1999 and 2008, the total number of diphtheria cases within Europe was high, at 8,470, with cases mainly occurring in the Russian federation (5,148 cases), the UK (1,790 cases), and Latvia (625 cases). The main populations infected were unvaccinated adolescents, middle-aged adults, and those over 65 years of age [44]. Approximately 20–60 % of adults become susceptible to diphtheria because of waning vaccine-induced immunity and failure to receive recommended booster immunization. This was illustrated in the serologic survey conducted in the USA between 1988 and 1994, which revealed that fully protective levels of anti-diphtheria antibody were present in 61 % of individuals C6 years of age and only 30 % of adults over the age of 70 [74]. As in most industrialized countries, where expanded childhood immunization programs are high but boosting low [72], a large proportion of the adult population is gradually rendered susceptible to diphtheria as a result of waning immunity. Thus, a feature of recent outbreaks in Africa, Asia, Europe, and South America has been the high percentage of cases in adult populations [73]. In the 1990–1997 epidemic that caused 157,000 reported cases in countries of the former Soviet Union, 38–82 % of cases occurred in adults. At least up to 1986, most of these countries had high childhood immunization coverage, including a booster dose at 14–16 years of age. Again, it can be seen that diphtheria is a classic childhood VPD that


has become an adult and even older adult disease in the non-vaccinated population. A similar situation is observed with tetanus. Despite a very effective vaccine program, the annual number of tetanus cases did not change significantly between 1999 and 2008, with nearly 200 cases notified each year. The total number of cases over the last decade (1999–2008) was 2,039, mainly notified in Turkey (420 cases), the Russian Federation (285 cases), France (173 cases), and Italy (with 139 cases per year in both 2002 and 2003) [73]. Most of these cases affected adults over the age of 65 whereas, over the same 10-year period, neonatal tetanus has completely disappeared in Europe [44]. During the period between 2001 and 2008, the US CDC reported 233 cases of tetanus in the USA, with an annual incidence of 0.10 cases/million population overall, and 0.23 cases/million among individuals C65 years of age [33, 75]. Almost all reported cases of tetanus were in individuals who had either never been vaccinated or who had completed a primary series but not received a booster in the preceding 10 years. Thus, in the USA, many adults are inadequately vaccinated against tetanus. In the serologic survey conducted between 1988 and 1994, fully protective levels of anti-tetanus antibody were present in 72 % of individuals C6 years of age and only 31 % of those over the age of 70 [74]. Thus, if adults aged 65 years and older are at highest risk for both tetanus and tetanus-related death [75], this is mainly explained by the proportion of adults in the USA who have received tetanus toxoid in the previous 10 years, which decreased with age between 1993 and 1997: 65 % between the ages of 18 and 49; 54 % between the ages of 50 and 64; and 40 % aged C65 years (http://www.cdc.gov/mmwr/ preview/mmwrhtml/ss4909a3.htm). In combination, the B. pertussis, tetanus, and diphtheria epidemiology demonstrate that, although historically vaccines were deemed to be ‘just for children’, vaccines for adults (including aged adults) are becoming increasingly common and necessary [1, 76]. However, most adults think only of the tetanus booster recommended every 10 years and even then, many adults only get the vaccine if they injure themselves [77]. These figures highlight the need for renewed complete vaccination or booster doses in the sixth decade of life, after assessment of vaccine history and clinical status [78]. Furthermore, the occurrence of pertussis, diphtheria, and/or tetanus infection also reflects inadequate coverage of the national childhood immunization program [72]. Thus, in this particular case, obstacles to optimal vaccine delivery must be identified and forceful measures taken to improve immunization coverage [1, 79]. These data demonstrate the importance of a high vaccine coverage rate in newborns and infants, and the necessity to increase administration of booster doses in adults [78].

3.6 Hepatitis A Hepatitis A virus (HAV) causes jaundice, nausea, fever, and infection and can lead to liver failure. In many industrialized countries, HAV incidence rates have declined steadily, resulting in low endemicity in a large part of the world [80, 81]. This is the result of a safe and effective vaccine against HAV [82]. However, recent serological studies indicate that future cohorts of old adults will lack protection against the disease, due to less exposure to HAV at younger ages [83]. A recent study estimating the burden of HAV in the Netherlands suggested that, in the next 10 years, 60 % of the population of 60 years or over might be susceptible to HAV in the absence of vaccination or other exposure to HAV [82, 84]. The severity of the HAV increases with age at infection, leading to a higher number of hospitalizations and longer hospital stays [82]. Between January 2003 and May 2012 in the Netherlands, 436 cases were reported in total among those aged 50 or over, with a case fatality rate of 1.8 % [12]. In the USA, the HAV vaccine was licensed in 1995, and its routine use in 11 states with elevated transmission levels was recommended 4 years later. In 2006, this vaccine was recommended for all states, leading to a widescale reduction in hepatitis A throughout the country [33]. Recent research indicates that the mortality burden from viral hepatitis is growing in the USA, particularly among the middle-aged [85], and current transmission has shifted to older age groups [86]. It is thus now suggested that strategies to further reduce HAV transmission may require broadening the recommendations to include general adult populations without a previous vaccination history [82, 86]. 3.7 Vaccinations for Aging and Aged Travelers For some, it may appear that promoting travel-related vaccinations for aging and aged adults seems superfluous, but there is a considerable risk of becoming infected during periods of travel [87]. Indeed, one distinct change between older individuals compared with previous generations is a substantial increase in those who are international travellers [88]. This action as a potential route of infection also becomes important when one considers the survival of infectious organisms on inanimate surfaces. One recent study reviewed the survival of several infectious agents on seemingly dry inanimate surfaces and suggested that influenza could persist there for 1–2 days [89]. Throughout a period of travel, there will be times when individuals cluster together and enable airborne transmission as well as self-infection following transfer of the organism from an inanimate surface to the mouth through constant face touching [90, 91]. Because of immune decline, physiological changes, and the increased probability of


underlying medical conditions [45], older travelers are at higher risk than their younger counterparts (18–45 years) for at least some travel-associated diseases [88], and attention should be paid to reviewing their vaccination status.

4 What Are the Benefits of Vaccinating Aging and Older Adults? 4.1 With Trivalent Influenza Vaccines In developed countries, vaccination with the trivalent influenza vaccine (TIV) is considered the cornerstone to prevent influenza dissemination and is recommended annually for all adults over 60–65 years of age [92]. This immunization strategy is expected to facilitate healthy and independent living, but hospitalization and death rates from influenza in the USA have risen despite widespread influenza vaccination programs implemented in the 1990s [34]. On average, infection with influenza resulted in 36,000 deaths annually from 1990 to 1999, almost double that of the period from 1976 to 1990 [93]. A similar rise in hospitalization rates for acute respiratory illnesses and cardiovascular diseases during the influenza season was also observed over these periods [93, 94], and more recently over the 2005–2006 to 2010–2011 influenza seasons [95]. Whilst the immunization strategy has probably contributed to saving many lives, the exact magnitude of its benefits is still hotly debated [35]. The efficacy of the seasonal influenza vaccine has been mainly derived from observational studies using data research databases or healthcare utilization data systems. Subsequently, the accurate assessment of vaccine benefits in aged populations is fraught with considerable methodological and epidemiological challenges [35, 96, 97]. There is evidence that the immunogenic response to influenza vaccine is decreased among those aged 65 years and older [95, 97–99]. Even in years in which the vaccine is well matched and efficacious in young people, efficacy in older adults can be \20 % (vs. [70 % in their younger counterparts) [100, 101]. This lower performance of the TIV in providing protection in older individuals has been known for some time [102–109], but to date there has been no satisfactory resolution of the issue. The dramatic increase in rates of serious influenza illnesses is in part due to aging of the world population and the rising prevalence of high-risk conditions for influenza illness, including cardiovascular diseases and other underlying chronic comorbid conditions [1]. In addition, several studies have been undertaken on possible reasons for this problem and have produced a large number of studies on age-associated changes in the immune system [17, 18, 21, 110–112].

4.2 With Pneumococcal Vaccines The current licensed vaccine against S. pneumoniae in adults is the 23-valent polysaccharide vaccine (PPSV-23), which consists of free polysaccharides purified from the surface capsule of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F. Those serotypes correspond to 80–90 % of the serotypes causing the disease in Europe [113] in addition to strains responsible for multidrug antibiotic resistance [114, 115]. An effective vaccine should be able to induce functional, opsonophagocytic antibody responses against all major serotypes included in the vaccine and to boost immunity enough upon periodic vaccination [116]. Based on recent data about vaccine effectiveness, PPSV-23 appears to demonstrate minimal impact on invasive pneumococcal disease, no effect on pneumococcal nasopharyngeal carriage, and poor effectiveness and a lack of immunological memory in adults over 65 years of age [14, 39]. The evidence also noted the presence of hyporesponsiveness on revaccination that is currently one of the major concerns about this vaccine. In other words, while PPSV23 may produce a good response in terms of antibody production after the primary immunization, subsequent doses at a later date induce an antibody response that seems to be less robust than the primary dose [117–119]. Some recent data would suggest that this state of hyporesponsiveness is not always the case [120], and strong evidence of efficacy of PPSV-23 against IPD have been recently published [121]. Neither of the two most recent Cochrane systematic reviews provided compelling evidence to support the routine use of PPSV-23 to prevent all-cause pneumonia or mortality [121, 122]. Evaluation of the efficacy and effectiveness of PPSV-23 among individuals in the recommended target groups has yielded contradictory conclusions for prevention of non-bacteremic pneumococcal pneumonia; however, most study results are consistent with protection against IPDs among generally healthy young adults and among the general older population. Observational studies have suggested effectiveness estimates ranging from approximately 50 to 80 % for prevention of IPDs among immunocompetent older adults and adults with various underlying illnesses, supporting the recommendations for using PPSV-23 [119]. A recent metaanalysis of 18 randomized controlled trials (RCTs) (involving 64,852 participants) and seven non-randomized observational studies (involving 62,294 participants) of PPSV-23 efficacy and effectiveness suggested an overall efficacy of 74 % against IPD (95 % confidence interval [CI] 55–86) [121]. Analysis of the results from the seven observational studies yielded a pooled vaccine effectiveness estimate of 52 % (95 % CI 39–63). In contrast, another meta-analysis that included six RCTs estimated the


combined PPSV-23 efficacy against pneumococcal bacteremia at only 10 %, with a very wide CI (95 % CI -77 to 54) [123]. The large difference in findings from these two meta-analyses might be related to the inclusion of different trials. The strategy that has been taken to improve the quality of the immune response and the subsequent vaccine protection against S. pneumoniae has been to couple the pneumococcal polysaccharide antigen to an immunogenic protein carrier and hence to convert the polysaccharide antigen from a T-independent antigen to a T-cell-dependent antigen. This has led to the generation of specific antibody and memory B-cell responses [14, 124]. The early 7-valent pneumococcal vaccine (PCV-7) and the subsequent PCV-13, have considerably improved vaccine efficacy in infants [125], and has since become the recommendation. Interestingly, another important issue is that PCV-7 not only provided a direct protective effect for vaccinated individuals but it was able to interrupt circulation of the pathogen by reduction of human carriage and spread [1]. However, this selection pressure concerns only those strains included in the vaccine and subsequently has progressively resulted in altered carriage, in which disease resulted from pathogenic serotypes that were not included in the vaccine. This serotype replacement has become a major concern because very virulent strains such as 3, 7F, and 19A are increasing, as is multi-drug antibiotic resistance among the 19A serotype isolates [126–131]. In adults aged 50 and older, in both the main studies, PCV-13 vaccine produced an immune response that was at least as good as the 23-valent polysaccharide vaccine for all 12 of the S. pneumoniae polysaccharides they share in common (1, 3, 4, 5, 6B, 7F, 9 V, 14, 18C, 19A, 19F, and 23F; PCV-13 also contains serotype 6A), and for several of these serotypes the immune response was better with PCV13 [132, 133]. Adults aged 18 to 49 years had an immune response with PCV-13 that was as good as the response in adults aged 60–64. Subsequently, PCV-13 has been approved by the US FDA, and by the EMEA for the European community, for use in all adults aged 50 years or older in preventing invasive diseases caused by S. pneumoniae. However, in waiting for further evidence of the benefits of PCV-13, and because this vaccine does not cover 11 serotypes that result in 15 % of IPDs in the population aged C65 years (i.e. it contains 11 serotypes less than PPSV-23 and covers 65–77 % of the serotypes responsible for IPDs in Europe) [12, 14], PCV-13 and PPSV-23 must be considered together in the pneumococcal vaccine schedule for preventing IPDs and to cover the tremendous diversity of pneumococcal serotypes able to cause disease in adults [134, 135]. They should not be administered

simultaneously, as each may have a detrimental effect on the other (see Sect. 4.2 for further details). More recently, an RCT was conducted in the Netherlands to determine the effectiveness of the 13-valent conjugated vaccine in preventing community-acquired pneumonia (CAP) among 85,000 individuals aged 65 or older [136]. The CAPiTA (Community-Acquired Pneumonia Immunization Trial in Adults) is the largest doubleblind, randomized, placebo-controlled vaccine efficacy trial ever conducted in adults. The primary objective of the study was to demonstrate efficacy of PCV-13 against a first episode of vaccine-type (VT) CAP; the secondary objectives were efficacy against (1) a first episode of non-bacteremic/non-invasive VT CAP and (2) a first episode of VT IPD. VT CAP was defined as CAP caused by any S. pneumoniae serotype included in the vaccine. Non-bacteremic/non-invasive VT CAP was defined as CAP in which vaccine-type S. pneumoniae caused the pneumonia, but was not detected concurrently in the bloodstream or any other normally sterile site. Preliminary results, very recently published [137], demonstrated that PCV-13 prevented VT CAP in adults. These data will probably be an important component in any consideration of potential new or updated PCV-13 recommendations for adults. 4.3 With the Live Attenuated Herpes Zoster Vaccine The difficulties in effectively treating HZ and preventing the complications have provided strong arguments for the development of an effective immunization schedule against VZV [45, 138]. The currently available HZ vaccine is a live, attenuated virus vaccine, and a single 0.65 mL dose contains not less than 19,400 plaque-forming units (pfu) of the Oka/Merck strain of VZV, which is considerably more than the 1,350 pfu found in the vaccine for preventing varicella [45]. Its protective efficacy, immunogenicity, and tolerability has been recently evaluated from a systematic review of RCTs or quasi-RCTs comparing zoster vaccine with placebo or no vaccine to prevent HZ in older adults (mean age [60 years) [139]. Eight RCTs, with a total of 52,269 participants, were identified and published in 13 papers [140–152]. Six studies were excluded from the selection because they were without any clinical outcomes [153–155], tested another intervention and not the vaccine [156], evaluated HZ vaccine administered concomitantly with influenza vaccine [157], or included participants outside the age range of interest [158]. The main outcomes on effectiveness and safety were extracted from one clinical trial with a low risk of bias [147]. Four studies compared zoster vaccine versus placebo [144–147, 152]; one study compared high-potency zoster vaccine versus lowpotency zoster vaccine [151]; one study compared refrigerated zoster vaccine versus frozen zoster vaccine [142];


one study compared live zoster vaccine versus inactivated zoster vaccine, and one study compared zoster vaccine versus pneumococcal polysaccharide vaccine (pneumococcal polysaccharide vaccine 23-valent) [140]. Confirmed cases of HZ were less frequent in patients who received the vaccine than in those who received a placebo: risk ratio (RR) 0.49 (95 % CI 0.43–0.56), with a risk difference (RD) of 2 %, and number needed to treat to benefit of 50. Analyses according to age groups indicated a greater benefit in participants aged 60–69 years (RR 0.36; 95 % CI 0.30–0.45) and in participants aged 70 years and over (RR 0.63; 95 % CI 0.53–0.75). Vaccine-related systemic adverse effects were more frequent in the vaccinated group (RR 1.29; 95 % CI 1.05–1.57; number needed to treat to harm [NNTH] 100). The pooled data RR for adverse effects for participants with one or more inoculation site adverse effect was RR 4.51 (95 % CI 2.35–8.68), and the NNTH was 2.8 (95 % CI 2.3–3.4). Side effects were more frequent in younger (60–69 years) than in older (70 years and over) participants. The authors’ conclusions were that the HZ vaccine was effective in preventing HZ disease. Although vaccine benefits were larger in the younger age group (60–69 years), this was also the age group with more adverse events. In general, the vaccine was well tolerated; it produced few systemic adverse events, and the injection site adverse effects were of mild to moderate intensity. Recently, the STPS (Short-Term Persistence Study) [159] has also reported data concerning the persistence of vaccine effectiveness in a subsample of individuals enrolled in the SPS (Shingles Prevention Study) [147]. Thus, compared with the SPS, in the STPS vaccine, efficacy for HZ burden of illness decreased from 61.1 to 50.1 %, vaccine efficacy for the incidence of PHN decreased from 66.5 to 60.1 %, and vaccine efficacy for the incidence of HZ decreased from 51.3 to 39.6 %. Although the differences were not statistically significant, analysis of vaccine efficacy in each year after vaccination for all three outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5, but it is still uncertain beyond that point. Finally, many studies conducted in England and Wales [160], the USA [161–163], Canada [164, 165] and the Netherlands [166] analysed whether HZ vaccination was a cost-effective strategy [45]. They were all based on SPS vaccine efficacy data to determine the cost utility of the vaccine in the primary prevention of HZ and PHN. Costeffectiveness estimates in pharmacoeconomic analyses varied widely according to vaccine efficacy parameters, the incidence of HZ and HZ-related QALY losses, the healthcare systems considered, and what society is willing to pay for a QALY [160, 166–168]. However, all cost/

effectiveness studies suffer from limitations that are common to pharmacoeconomic analyses. Thus, cost-effectiveness estimates are consistently affected by parameters such as the lack of long-term vaccine efficacy data (i.e. waning vaccine protection and vaccine efficacy against HZ and PHN), a paucity of information on HZ-related healthcare and societal costs (i.e. vaccine unit cost; incidence, severity, duration, and associated cost/utilities of HZ and PHN) and benefits, and difficulties generalizing findings to other countries with differing healthcare systems and cost frameworks [138]. 4.4 With Acellular Pertussis, Tetanus Toxoid, and Reduced Diphtheria Toxoid Vaccine Initial vaccines developed following the isolation of the B. pertussis organism in the early 1900s contained killed whole cell B. pertussis organisms. Subsequently, the acellular pertussis (aP) vaccine containing purified components of the organism was developed. The acellular vaccine has a more favorable side effect profile, though the whole cell vaccine may induce more durable immunity [169, 170]. In countries with effective implementation of universal childhood vaccination programs, dramatic reductions in the incidence of pertussis have been observed. Otherwise, for the adult population aged 50 or over, strong evidence of effectiveness is still lacking [12]. For individuals aged 15–65, vaccination with aP vaccine reduced the risk of developing pertussis by 92 % [171, 172]. A single dose of the aP vaccine is likely to induce protection in individuals aged 55 or older. Further, in a recent pooled analysis of four trials [173–176], Van Damme et al. [177] estimated the immunogenicity of aP in older adults. The booster response rate, defined as initially seronegative subjects (\5 EU/mL) reaching C5 EU/mL or a twofold or greater increase in antibody concentration if initially seropositive, was 89.2 % for pertussis toxoid, 95.8 % for filamentous hemagglutinin, and 94.5 % for pertactin, suggesting that a single booster dose induced good immunological responses in most individuals. The majority of evidence about reduced diphtheria toxoid vaccine effectiveness comes from an outbreak setting, hence specific data for an aging or old adult population are lacking. During the epidemic in the 1990s in countries of the former Soviet Union, case control studies showed that three or more doses of Russian-manufactured toxoid induced 95.5 % (95 % CI 92.1–97.4) protective efficacy among children aged \15 years. Protection increased to 98.4 % (95 % CI 96.5–99.3) after five or more doses of the vaccine [73]. However, local diphtheria outbreaks in several developed countries not only demonstrated the importance of sustained high coverage of childhood immunization but also the precarious nature of


adult immunity. This waning of adult immunity is likely to proceed faster in areas where exposure to circulating strains of toxigenic Corynebacterium diphthariae no longer provide sufficient natural boosting of immunity. To compensate for the loss of natural boosting, industrialized countries add childhood and adulthood boosters of toxoid vaccine at about 10-year intervals to the primary immunization series of infancy to maintain long-life protection [73]. As demonstrated by the 1991–1997 epidemic, diphtheria may return as soon as vaccine coverage rates fall below critical limit [72]. Diphtheria toxoid is one of the safest vaccines available. Severe reactions are rare, and, to date, no anaphylactic reactions attributable to this vaccine have been described [73]. Currently, diphtheria toxoid (D) or reduced toxoid diphtheria (d) are almost exclusively available in combination with tetanus toxoid (T) as DT/dT, or with tetanus and pertussis vaccine as DTP (the origin of pertussis component often specified as whole-cell [wP] or aP) [73]. Similarly, waning immunity against tetanus is responsible for the recommendation for universal administration of Td boosters every 10 [10–178] or 20 years in some countries [179]. After a primary series (three properly spaced doses in children aged 7 years or older, and four doses in children aged less than 7 years), essentially all recipients achieve anti-toxin levels considerably greater than the protective level of 0.1 IU/mL. However, efficacy of the toxoid has never been studied in a vaccine trial. It can be inferred from protective anti-toxin levels that a complete tetanus toxoid series has a clinical efficacy of virtually 100 %; cases of tetanus occurring in fully immunized individuals whose last dose was within the last 10 years are extremely rare. Anti-toxin levels decrease with time. While some individuals may be protected for life, by 10 years after the last dose, most have anti-toxin levels that only approach the minimal protective level. In a small percentage, antitoxin levels fall below the minimal protective level before 10 years have elapsed [180]. To ensure adequate protective anti-toxin levels, individuals who sustain a wound that is other than clean and minor should receive a tetanus booster if more than 5 years have elapsed since their last dose. The combination vaccines Adacel (TdaP) and Boostrix (TdaP-IPV) have been registered as booster vaccines for the prevention of B. pertussis (aP) and diphtheria (d), tetanus (T), and poliomyelitis (IPV) infections in the USA and in Europe [12]. Boostrix was recently approved in the USA for use in individuals aged 65 or older, whereas Adacel has only been approved for those between the ages of 11 and 64 years [181]. Two studies have investigated the immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and aP (TdaP) vaccine in healthy C65 year olds

[182]. In the first, subjects received single doses of TdaP and seasonal influenza vaccine either co-administered or given 1 month apart, and in the second, participants received either TdaP or Td vaccine. TdaP was found to be immunogenic in subjects aged 65 years or over and noninferior to Td with respect to diphtheria and tetanus seroprotection, and anti-pertussis geometric mean concentrations were non-inferior to those observed in infants following a three-dose TdaP primary vaccination series in which efficacy against pertussis was demonstrated. Finally, in adults aged 65 years and older, Boostrix should be used when possible and this approach seems to be a cost-effective [183] and safe [182, 184] healthcare intervention. More recently, a study conducted in 252 healthy individuals aged 60 or over demonstrated that single-shot vaccinations against tetanus and/or diphtheria did not lead to long-lasting immunity in many elderly and that sufficient antigen-specific B-cell memory generated by adequate priming and consecutive booster vaccinations and/or exposure was a prerequisite for long-term protection [185]. Recruited participants were vaccinated with a booster against tetanus, diphtheria, pertussis, and polio; a subcohort was recruited to receive a second booster vaccination against tetanus, diphtheria, and pertussis 5 years later. Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had dropped below protective levels after 5 years. However protection was restored in almost all vaccinees after the second vaccination. 4.5 Hepatitis A The vaccine against HAV is highly effective in preventing infection [82], a protective efficacy up to 100 % in healthy individuals has been shown [186], and it provides high effectiveness when used as post-exposure prophylaxis [187]. The efficacy of these vaccines was demonstrated in the early 1990s in a double-blind RCT conducted in Thailand [188]. Following two doses of hepatitis A vaccine, protective efficacy was 94 % (95 % CI 79–99); cumulative efficacy following the booster dose at 12 months was 95 % (95 % CI 82–99). Two doses of the vaccine generated at least 25 years’ protection and is possibly life-long in immune-competent recipients. A prospective study in the elderly showed a seroprotection of approximately 65 % after a primary dose in subjects over 50 years of age compared with 100 % in the younger control group. However, seroprotection was 98 % in the older age group after receiving a booster dose [189]. The overall safety profile of inactivated vaccines administered to children and adults has proven to be good [82].


Fig. 1 Summarizing of candidate vaccines for individuals aged 50 years or older according to their way of living. For each vaccine, the main preventive goal (prevention of mortality or improvement of quality of life) is mentioned. PPSV-23 23-valent pneumococcal polysaccharide vaccine, aP acellular pertussis vaccine, PCV-13 13 valent pneumococcal conjugated vaccine, TIV trivalent influenza

vaccine. *Refer to official vaccine recommendations—The European Agency for the Evaluation of medical Products (EMEA) for the European community (http://www.ema.europa.eu) and the FDA and the Centres for Disease Control and Prevention (CDC—http://www. cdc.gov) for the USA. **Travelers and frequent travelers whatever the reason: holidays and/or business

5 What is the Ideal Vaccine Agenda for Promoting Healthy Aging?

strains) or quadrivalent (i.e. influenza A/H3N2, A/H1N1, Victoria, and Yamagata influenza B strains) influenza vaccine should be offered annually. Whether it is expected that by adding another B virus to the vaccine, quadrivalent vaccines may give broader protection, there is no recommendation to prefer one vaccine over another. Because influenza viruses are constantly changing [21], the vaccine is updated each year based on which influenza viruses are spreading, and how well the previous season’s vaccine protects against those viruses. It is therefore highly recommended that healthcare providers begin offering vaccination soon after the vaccine becomes available.

The lowest age at which most European countries offer the influenza vaccine for healthy old adults is 60 years, but considering the adverse impact of the immunosenescence process on vaccine response [13, 14, 45], the optimal timing to start a vaccine program for older adults may be earlier, possibly from the age of 50 [12]. Vaccinating before immunosenescence occurs might thus confer more effective specific immune protection. Vaccine candidates for those aged 50 years or older are presented in Fig. 1, according to lifestyles of targeted populations.

5.2 Pneumococcal Vaccines (PPSV-23 and PCV-13) 5.1 Inactivated Influenza Vaccines With respect to seasonal influenza infections, although a variety of vaccine products have been developed, only inactivated vaccines are registered in adults aged 50 or over in the USA and aged 60 or over in Europe. Live attenuated and recombinant hemagglutinin vaccines are not registered, whatever their route of administration, in these populations. Thus, one dose of either inactivated trivalent (i.e. influenza A/H3N2, A/H1N1, and Victoria influenza B

Pneumococcal vaccines are registered in Europe and in the USA for use in individuals aged 50 or over. Either PPSV23 or PCV-13 or both should be offered according to guidelines at country level because PCV-13 is not yet registered in European countries and PPSV-23 is not longer available everywhere. For example, it is not yet registered in Switzerland. In the UK, following a review of available evidence in March 2011, the Joint Committee on Vaccination and Immunization issued a statement on the routine PPSV-23 program for those aged 65 years or older,


advising that it be discontinued, with the vaccine continuing to be offered to those aged 65 or over in clinical risk groups only [1], although this was later amended. Where PPSV-23 is the only available vaccine, it is recommended in at-risk adult populations every 5 years until the age of 65. Over the age of 65, one dose only is recommended, whatever the medical condition. In countries where PCV13 is registered for adults appertaining to higher risk groups and older populations, PCV-13 and PPSV-23 should be considered together. However, they should not be administered simultaneously; each possible detrimentally affects the other. Thus, for individuals who have already had one or more doses of PPSV-23, it is recommended to wait 1 year or more before administering PCV13. If the patient is recommended to receive a second dose of PPSV-23, delay that second dose for 8 weeks or more following PCV-13 and 5 years or more following the first dose of PPSV-23. Patients who need both PCV-13 and PPSV-23 and who have received neither should receive PCV-13 first. 5.3 Herpes Zoster Vaccine Zostavax is now licensed to reduce the occurrence of HZ and PHN, and the burden of illness, severity and duration of the pain, and hospitalization rate, and enhance the HRQOL and activities of daily living in those from the age 50 years in some parts of Europe and 60 years of age in the USA. One dose is recommended, but while the vaccine is less effective in individuals aged 70 or older than in those aged 60–69, it is recommended that it be offered at the first available clinical encounter with general practitioners without upper limit of age, along with information about the duration of the protection and the timing for a booster dose if necessary [45]. It is usually described that a single dose conferred protection for approximately 6 years [190]. For the EU, the reimbursement/funding of the HZ vaccine is decided at a country level, and some differences are observed according to the healthcare system of the country (http://www.ema.europa.eu). 5.4 Tetanus, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine Tetanus and reduced diphtheria toxoid vaccination is normally part of the routine vaccine program in developed countries, without any upper limit of age. Two vaccines are available to protect people aged 7 years and older from these diseases: Td (tetanus-diphtheria) vaccine has been used for many years and protects against tetanus and diphtheria; TdaP vaccine was licensed in 2005 and is the first vaccine for adolescents and adults that protects against pertussis as well as tetanus and diphtheria. A Td booster

dose is recommended every 10 years after the age of 50 years; TdaP (tetanus, diphtheria, and aP) is administered only once in adults, without an upper age limit. While some countries (e.g. Switzerland [http://www.bag.admin. ch/themen/medizin/00682/00684/02535/index.html] and New Zealand [http://www.moh.govt.nz/moh.nsf/indexmh/ immunisation-handbook-2011?Open]) have increased the adult booster interval to 20 years in order to limit the risk of over immunization [179] and to improve vaccine coverage by optimizing Td booster doses; after the age of 60, every 10 years is the universally recommended interval. 5.5 What are Adverse Events and Contraindications of those Vaccines? Adverse events observed after vaccination against influenza, pneumococcal disease, HZ, pertussis, tetanus, diphtheria, and HAV are commonly mild and self-limiting [12]. However, more serious and long-term complications are reported but very rare (for further details refer to: http:// www.ema.europa.eu; http://www.cdc.gov). All these vaccines are contraindicated in individuals with hypersensitivity (i.e. severe allergy or anaphylaxis) to any toxoid and/ or antigen-containing vaccine, and/or any other vaccine components or those who experienced severe allergic reaction (i.e. anaphylaxis) after a previous vaccine dose. People who have high fever as a consequence of disease or any severe infections at the intended time of vaccination should not receive any vaccines until they are recovered. For vaccines such as influenza, which are produced from embryonated hen’s eggs, individuals with severe lifethreatening allergy to eggs are recommended to consult with a specialist with expertise in allergy prior to receiving the vaccine. Live attenuated influenza vaccines have been approved for use in healthy people aged 2 through 49 years who are not pregnant. Pneumococcal vaccines (PPSV-23 and PCV13) are contraindicated in people who are hypersensitive to diphtheria toxoid. The current HZ vaccine is not advised for use in individuals with primary or acquired immunodeficiencies, untreated active tuberculosis or those who are receiving immunosuppressive therapies or high doses of corticosteroids. There is no specific contraindication to the TdaP vaccine except obviously hypersensitivity to diphtheria and tetanus toxoid or pertussis antigen. Hepatitis A vaccine (i.e. Epaxal) must not be given to individuals aged 50 or older with known sensitivities to eggs and chicken proteins. HZ, PCV-13, and TdaP vaccines have been given concomitantly with the influenza vaccine and were well tolerated and effective [45, 132, 191]. TdaP has also been coadministered with the HAV vaccine (i.e. Havrix) and was well tolerated [12]. For optimal efficacy, the PPSV-23 and


HZ vaccines should be administered 4 weeks apart [45]. This is still a controversial issue, and the CDC Advisory Committee on Immunization Practices (ACIP) supports concomitant administration of these two vaccines (http:// www.cdc.gov). 5.6 Benefits of Herd Protection: Promoting a Life Course Vaccine Schedule Apart from possible direct benefits to vaccinated people, the greater beneficial effects on close contacts, neighbors, and at the community level have been measured [30] and are now well documented [1, 13, 27–30]. The herd protection theory proposes that in contagious diseases transmitted from person to person (e.g. influenza, pneumococcal and meningococcal diseases, measles, pertussis, and varicella) or for which humans are an important reservoir (e.g. diphtheria), the chain of infection is likely to be disrupted when a large number of the population are immunized (i.e. vaccine coverage rates are high enough to reach the herd immunity threshold) [1]. This has the effect of increasing the level of population (or herd) protection and reducing the likelihood that members of the vulnerable population will be infected. Indirect measures of controlling infections have been observed by vaccinating immunocompetent older adults, younger individuals, healthcare workers, or even schoolchildren, with pronounced positive effects on the incidence of infectious diseases within the general population and, more particularly, in the aging and aged population [1, 192–194]. However, the shifting of vaccine targets from poorer responders to groups with little direct benefit but better immune responsiveness represents a considerable societal challenge in view of the tension between individual rights and public health priorities [71, 72, 195]. One concern has been the adverse impact that herd protection may have on the increase in average age of infection, especially when the severity of the disease increases with age [1]. As already mentioned, measles, pertussis, and diphtheria were previously thought of as VPDs of childhood, but are now increasingly becoming adolescent and adult diseases in populations that have not been properly vaccinated [33, 44, 72]. This places a considerable burden not only on older adults but also on the adult populations and healthcare systems of most developed countries [32, 33, 196]. These trends are particularly observed when vaccine programs are predominantly childhood centered [29, 72]. Demographic projections indicate that, by 2025, the population aged over 65 years will have grown 3.5 times [1]. The first tenet of herd protection is that a beneficial effect is only obtained if a sufficient number of the population has been vaccinated so as to limit the transmission

from individual to individual. But our world will soon be composed of more people over the age of 65 than under the age of 5. Thus the population that is the most responsive to vaccinations and that has to be immunized to protect the most vulnerable population may not be sufficiently big. In addition, while herd protection is probably an effective approach in hospital and in long-term care settings to protect vulnerable populations [197], it does not seem to be a sustainable option in a world that is now more closely networked [1]. Indeed, the second argument for herd protection as a beneficial strategy is that aged individuals will be constrained in their movement and remain in close contact with a vaccinated population; however, as previously described, this is no longer the reality [87, 88]. In parallel, the current increased level of air travel means that the spread of any pathogen across the globe can occur within hours, as observed with recent influenza A/H1N1 and A/H5N1 pandemics [1]. Furthermore, across the world, vaccine coverage rates observed for the most common VPDs are far from uniform and often do not reach World Health Organization (WHO) goals [198]. In addition, while childhood vaccines are often required for entrance to schools [72], adult vaccines are not mandated; with no such requirements, there is often a lack of preventive healthcare and consequent low levels of vaccine use by most adults [1, 76]. Finally, while there is a certain truth to the statement that a good adult immunization program begins with a good childhood vaccine schedule, we must induce a shift in our thinking and make efforts to move away from a nearly complete childhood-centered immunization schedule toward a more balanced approach across the life span [1].

6 Conclusion Vaccine-preventable infectious diseases remain a major public health concern in adult populations across the world, and the overall body of evidence nevertheless suggests that vaccines are safe in most aged people. It also shows that currently we must keep in mind that certain aspects of vaccination should not be geographically limited, especially in our closely networked world. It is probably time to move towards strategies fitting the needs of globalization to overcome the burden of VPDs. Indeed, dealing with VPDs in the aging and aged populations means not only annual vaccination against influenza and updating pneumococcal and TdaP vaccinations, for which coverage rates are below the WHO goals, but also targeting hepatitis A and HZ infections in addition to vaccines for senior travelers. Questions about the necessity of boosters, and, if any, the number of doses that must be administered in order to confer an optimal and lasting immune response still remain


unclear for some vaccines (e.g. pneumococcal or HZ vaccine). One important question concerning the promotion of healthy aging through vaccination is whether populations aged 50 years or older would accept such an intervention. Thus, while the societal, cultural, and political barriers that limit vaccine uptake globally must be understood and broken down, it is also of utmost importance to develop specific knowledge about vaccine acceptance/reluctance in this specific population. Indeed, while the research is very active in better understanding skepticism about vaccines and parental refusal of vaccines, appropriate and rigorously designed studies investigating adults and elderly vaccine refusal and hesitancy are still lacking. This is an indication that our current way of thinking about prevention through vaccination is still too childhood-centered rather than lifelong oriented. Potential conflicts of interest P.-O. Lang (POL) and R. Aspinall (RA) have received consulting fees from Sanofi-Pasteur MSD (POL, RA) and Pfizer (POL) and attended sponsor-funded meetings (POL). POL reports serving on the Pfizer Advisory Board for Pneumococcal vaccination in the adult and Sanofi-Pasteur MSD Swiss board for Herpes Zoster.

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