Review

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Vaccine responsiveness in the elderly: best practice for the clinic Expert Rev. Vaccines 13(7), 885–894 (2014)

Richard Aspinall*1 and Pierre Olivier Lang1,2 1

Cranfield University, Cranfield, UK Nescens Centre of Preventive Medicine, Clinique of Genolier, Route du Muids 3 CP 100, 1272 Genolier, Switzerland *Author for correspondence: [email protected] 2

The success of vaccines developed since the beginning of the 20th century, has enabled the conquest of several childhood diseases preventing death and or disability for millions of children. But, globally, the number of children will soon be surpassed by the number of adults over the age of 65. The active lifestyle of these older individuals, coupled with a degree of immune deficiency recognised within this population will lead to a change in the profile of diseases affecting the elderly. The challenge for policy makers and also those involved in primary healthcare is how to protect this population from communicable diseases and keep them healthy, autonomous and independent when vaccines in the main have been developed for use on children and young adults. KEYWORDS: aging • immune profiling • immunity • immunosenescence • vaccination

Vaccination & the challenges to be addressed

The Population Reference Bureau estimates the global population size in 2013 was approximately 7137 million of which more than 570 million were over 65 years of age. Analysis of the projected increase in this older population suggests that their numbers would increase to around 1500 million by 2050. This increase will be largely due to an increase in the number of the ‘oldest-old’, often thought of as those over the age of 85 years. This oldest-old population has been predicted to increase by 351% by 2050, which is considerable compared with the 22% increase expected for the population under the age of 65 years [1]. While the aging process may be intrinsically linked with an ever-increasing incidence of chronic comorbid conditions [2,3], the current older generation has remained very active compared with generations a few decades ago [4]. For example, the availability of easy travel and the increase in the number of seniors travel clubs means that older individuals are considered to be at higher risk for some travelassociated diseases than their younger counterparts [5]. It is not just unusual infections, but familiar infections that are often associated with travel as well, and influenza is now informahealthcare.com

10.1586/14760584.2014.924403

considered to be the second most frequent infection in travelers [6]. Furthermore, the speed of travel and the sheer number of travelers means that any communicable disease arising in one region can be spread rapidly around the globe. This appears to be true even for infectious agents with a more sophisticated and less efficient mode of transmission such as mosquito-borne viruses and parasites. Evidence for this comes from studies on vector-borne infections such as West Nile Virus, Dengue Fever, Malaria and Chikungunya, which were considered to be largely absent as endogenous diseases in continental Europe, but have shown their return in recent years to Europe and the USA [7,8]. From a clinical perspective, the challenge for primary health care workers and public health policy makers is how to keep this everincreasing part of the population autonomous and independent and protect them efficiently from communicable diseases. At present, there is much reliance on vaccines and vaccination schemes whose success in eradicating lifethreatening and disabling diseases has demonstrated that they are one of the most effective interventions in modern medicine [9]. This has led to the development and design of vaccines against more and more diseases [10–12], and also to a widening of the age range at which they are administered from a predominantly


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childhood-centered vaccine schedule to a broader use across the lifespan [13]. The expansion of vaccine programs was based on the assumption that commercially available vaccines were effective; they always worked and produced protection irrespective of the age of the recipient. However, one of the most important considerations is that vaccine development was mainly driven by the aim to eradicate communicable diseases in children and in vulnerable younger adults [14]. In this review, we will focus on the evidence of how vaccines may contribute to the prevention of communicable diseases and facilitate healthy, independent living in older individuals. Immunosenescence

The inability of the immune response to provide adequate protection from infection is a feature of aging and aged adult populations. Such individuals are more susceptible to infection not only from emergent pathogens but also from infections they have overcome previously [2]. In addition, it is increasingly believed that these populations demonstrate less effective responses to vaccination [15]. Immunosenesence is a broad term which some consider to be the culmination of a series of agerelated changes in the adaptive and innate immune systems, leaving an individual with an immune response that is less effective than optimal. Many studies have been carried out to find the factors that contribute to the immunosenescence process, and the results have identified causes relating to Langerhans cells [16], dendritic cells, [17], T cell function [18], B cell function [19], the T and B cell repertoires [20,21], T cell production [22], B cell production [23], neutrophil dysfunction [24] and natural killer cells [25]. In addition, how all of these are affected by nutritional status [26] and comorbid conditions [27] have been investigated. For all individuals, the starting point (i.e., a fully functional immune system able to respond effectively either to vaccines and/or defined pathogens) is known and so is the end point, (i.e., an immunocompromised state unable to respond with a protective and durable response to either infection or vaccination), but the challenge is still to map the route from the start to the end. Without knowledge of this process, it is almost impossible for a clinician, presented with an older person requiring vaccination, to determine their immune status and then make clinical decisions on their vaccine choices. Consequently, both clinicians and policy makers involved in targeting vaccines to individual groups use age as a rough indicator. In the UK and in many other developed countries, all older individuals are considered to be at higher risk of some infectious diseases and so are recommended to receive specific vaccines. These include vaccines against influenza viruses, pneumococcal diseases, herpes zoster (HZ), tetanus, diphtheria and pertussis [28,29]. Influenza

Infection with influenza viruses produces a disease of limited duration in young adults with a functional immune system. 886

The disease trajectory is normally associated with a sudden onset of symptoms that can include fever, cough, nasal congestion and aching joints. Resolution is normally achieved within 7–14 days. In older individuals, the disease frequently presents in a different manner, often with cough as the most common presenting symptom. A plausible reason for this difference is the age-related remodeling of the immune system, and the outcome in older individuals is often more severe including an increased risk of mortality and a greater likelihood of hospitalization [2]. Moreover, older individuals are more liable to suffer complications associated with secondary bacterial infections of the pulmonary system, which can lead to increased morbidity [30]. The incidence of the disease is difficult to estimate globally because testing possible sufferers for the presence of the virus is rarely carried out; however, estimates suggest that infection with influenza virus is responsible for more than 250,000 deaths per year in addition to being associated with between 3 and 5 million cases of severe illness per year. Influenza vaccine: composition

The vaccine used for the majority of individuals usually contains three strains of the influenza virus (a quadrivalent vaccine is being used in the USA this year which contains a second influenza B strain [31]). For the Northern hemisphere, the decision is made in February of each year on the composition of that year’s vaccine in order for production plans to be put in place. Viruses to be incorporated into the vaccine are grown in the allantoic cavity of the embryonated eggs, harvested, inactivated with formalin or b-propriolactone, purified by ultracentrifugation and then treated with ether and a detergent or else solubilized using a detergent alone [32]. The amount of hemagglutinin antigen (HA) is quantified so that individuals are normally given a single intramuscular dose containing 15 mg of HA of each vaccine virus strain. An estimated 135–148 million doses of vaccine were required to be produced for use in the Northern hemisphere during the 2013–2014 season. The antigen used in the vaccine is usually derived from one influenza type A subtype H1N1 virus strain, one influenza type A subtype H3N2 virus strain and either one or two influenza type B viruses. The recommended strains for the trivalent vaccine in the 2013–2014 season for the Northern hemisphere were A/California/7/ 2009 as the H1N1-like component, A/Victoria/361/2011 as the H3N2-like component and B/Massachusetts/2/2012 as the influenza B component (and B/Brisbane/60/2008-like virus for the quadrivalent vaccine). Goal of vaccination, policy & expectation

Vaccination against influenza for those over 65 years of age is now recommended in the UK, most of Europe, USA and several other countries. The goal of vaccination with influenza is to provide protection against infection, and because direct testing of the vaccine to achieve this goal would be unethical, surrogate markers of protection are used. Expert Rev. Vaccines 13(7), (2014)

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Efficacy

Protective immunity in healthy young adults is normally achieved within 14–28 days, and so the ideal time for vaccination is September to early December [33]. Protection against infection has been related to antibody titer against the HA molecule and an antibody titer of the hemagglutinin inhibition (HAI) antibody of ‡40 is associated with approximately 50% clinical protection from infection [34]. The early protection studies to correlate antibody levels with protection from infection with the virus were carried out in healthy young adults [35], and there is little, if any, data to suggest that such antibody titer could be used as correlates of protection in older individuals. While it is widely believed that influenza vaccination saves many lives, prompting the widespread use of the trivalent inactivated influenza vaccine, the exact magnitude of the benefit of the current immunization strategy in the aged population is still controversial. Studies have shown that influenza vaccination leads to protection in more than 70% of younger individuals, but is ineffective in over half of the elderly population [36–38]. With the clear need to improve responses and increase the HAI titer following vaccination in older individuals, manufacturers have produced variants on the currently available vaccine. For those directed at an older population, most of the effort has been directed toward either increasing the amount of antigen [39] or the route of delivery, choosing intradermal rather than intramuscular delivery [40], or the addition of adjuvants to increase the response [41]. An early study in which graded doses of antigen were used, up to four-times the usual dose failed to show any significant effect of antigen dose on HAI titer in older individuals with a mean age of 81 [39]. A more recent study revealed a slight improvement on HAI titers at a higher antigen dose compared with the standard dose in older people, but the titers against the A strains within the vaccine were significantly lower than those found in younger individuals who received the standard dose [42]. The vaccine known as ‘Fluad’ contains the standard dose of influenza along with the adjuvant MF59C.1. A recent study compared responses based around HAI between older individuals receiving the standard vaccine with those receiving vaccine containing the MF59 adjuvant at 1 and 6 months after delivery. At 1 month after vaccination, individuals who received adjuvanted vaccine showed similar seroconversion rates and seroprotection rates across all three strains compared with recipients of the nonadjuvanted vaccine. After 6 months, a significantly greater seroconversion and seroprotection rate were only seen in the A/H3N2 response in recipients of the vaccine with adjuvant compared with recipients of the vaccine without adjuvant [43]. An alternative approach for older individuals has been to deliver the vaccine through the skin using a special delivery system. Comparison of the results from individuals who received the vaccine through the skin with those who received it via an intramuscular injection revealed that greater immune responses were seen with delivery through the intradermal route, especially after the second and third annual vaccinations [44]. informahealthcare.com

Review

Each of these vaccine variants has their advocates, but the problem for the clinician is: which is the most appropriate for an older patient who has asked for full influenza protection? The clinician may be aware that the current standard vaccine is not as effective as when given to the younger patients, but may be unwilling to order a battery of tests which might or might not identify the possible lesion in the immune response of the older individual. It would be difficult to support the view that the influenza vaccine ‘works’ in all older individuals to provide them with complete protection from influenza. Because of the failure of many older individuals to produce an antibody response commensurate with the proposed levels of protection [19], the goal of vaccination in older individuals may be different from that of younger adults. Rather than aim for complete protection from infection, the emphasis may be a shift toward preventing early mortality, reducing morbidity, especially periods of hospitalization, diminishing the risk of secondary bacterial infections or functional decline and sidestepping the exacerbation of chronic comorbidities. The current vaccine does provide some benefits and may reduce the risk of hospitalization for cardiac disease, cerebrovascular disease and pneumonia [45–47]. In addition, older recipients of the vaccine may also expect to have amelioration of influenza-associated disease. Pneumococcal diseases

Infection with Streptococcus pneumoniae is foremost among the causes of bacterial pneumonia, a disease associated with considerable morbidity and mortality in older populations [48]. Furthermore, resistance to antibiotics is increasing with 13% of the invasive isolates in England and Wales, reported to the Health Protection Agency in 2000, being resistant to erythromycin and some resistance to penicillin being present in 7% of these [33]. Pneumococcal vaccines: composition

The current licensed and registered vaccine for aged adults contains 23 immunochemically different polysaccharides from the approximately 90 existing serotypes of the bacterium. Production starts with individual cultures of the different strains grown in media, which does not contain polysaccharides of high molecular mass. Prior to harvesting, the purity of the culture is verified before the bacteria are inactivated with phenol, harvested and the polysaccharide isolated, purified then washed and dried to a specific moisture content. The individual monovalent bulk polysaccharides are mixed aseptically to produce the final bulk polysaccharide, and the mixture is dissolved in an isotonic solution so that one human dose of the pneumococcal polysaccharide 23-valent (PPV23) vaccine of 0.50 ml contains 25 mg of each polysaccharide [49]. In addition, a pneumococcal conjugate vaccine has been produced which contains 13 different serotypes (PCV13), which provokes a T cell-dependent response and also induces a recall response. In older individuals, a more robust response may be achieved if the polysaccharide antigens are conjugated to a 887

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protein in order to elicit a T cell-dependent response and produce immunological memory that can be provoked later.

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Goal of vaccination, policy & expectation

In the UK, a program of PPV23 immunization in older individuals was recommended to be introduced in 2003 by the Joint Committee on Vaccination and Immunisation (JCVI) partly because of the burden of invasive pneumococcal disease in that population. A repeat vaccination is recommended for all of those who received their first vaccination before the age of 65 years, but revaccination is not recommended for those who received their first vaccination after the age of 65 years. This is because of concerns over hyporesponsiveness. T-dependent immune responses result in the production of a pool of memory cells, and so restimulation of these through repeat exposure to antigen leads to an improved response. However, the true T-independent responses that result from vaccination with polysaccharides do not produce classic memory cells, and repeat exposure does not lead the expected improvement in antibody levels [48] although there are reports that this is not always the case [50]. In the USA, the Advisory Committee on Immunization and Practice advocates a single dose of 23-valent pneumococcal capsular polysaccharide vaccine for all persons aged 65 and older [48]. Efficacy

For healthy adults given the polysaccharide vaccine, a good antibody response should be developed in the third week after they have been given a single dose into the upper arm [33]. Antipneumococcal antibodies are known to protect against the disease, but the level of antibody titer associated with protection has not been established for adults. The functional capacity of the antibodies appears to decline with age so, for older individuals, the antibody potency measured by the opsonization titer to antibody concentration is significantly lower for all serotypes [51]. In a statement issued in March 2011, the JCVI was concerned that there had been no unambiguous decrease in the incidence of invasive pneumococcal disease in older populations after the introduction of the vaccine. In addition, they noted that the effectiveness of the PPV23 vaccine was poor and that revaccination may not provide improved responses but an impaired response due to immune hyporesponsiveness. As a consequence, they considered that vaccination of older individuals with PPV23 provided little benefit and should be discontinued [52]. In July of 2011 and in the light of new evidence, the JCVI suggested that the vaccine may be more effective against invasive pneumococcal disease than previously assumed and concluded that the PPV23 vaccine may provide some short-term protection in older individuals and was likely to be cost-effective. They recommended that the existing routine universal program for those aged 65 years and older should be continued [53]. 888

In the decades following the age of 65 years, the risk of pneumococcal infection increases and as time progresses, immunity wanes. There is a general feeling that the single dose of PPV23 currently [48] recommended for those over the age of 65 years in several European countries as well as in the USA does not provide extended protection into old age, which for some may extend for another 30 years or more. This is important given that the risk of infection with pneumococcus continues to rise with advancing age and highlights a significant unmet clinical need for the development of new vaccines for this population. In older individuals, a more robust response may be achieved if the polysaccharide antigens are conjugated to a protein in order to elicit a T cell-dependent response and produce immunological memory which may be provoked later. A pneumococcal conjugate vaccine has been produced which contains 13 different serotypes (PCV13) and which provokes a T celldependent response and also induces a recall response. When tested in vaccine-naı¨ve adults aged between 60 and 64 years and compared with PPV23, the PCV13 provided superior opsonophagocytic titers, suggesting a greater functional antibody response [54]. One concern is that many older individuals will have been vaccinated using the PPV23, and such recipients have been shown to provide a blunted response to subsequent vaccination [55]. A recent study showed that PCV13 was more immunogenic than the PPV23 vaccine for most of the common serotypes when used in individuals over 70 years of age. Moreover, the titer of opsonophagocytic antibody after a follow-on dose of PCV13 1 year later showed that a previous dose of PPSV23, but not PCV13, reduced the response to the subsequent administration of PCV13 [56]. Shingles & Postherpetic neuralgia

Shingles is a disease whose incidence is highest in the elderly and follows the reactivation of varicella-zoster virus (VZV), which has lain dormant in sensory neurons following primary infection in earlier life. While epidemiological studies estimate the incidence of HZ in the general population to be between 3 and 4/1000 persons, the sharpest increase of incidence occurs between 50 and 60 years of age and continues on an upward trend [57]. Relatively, recent estimates of the number of cases of shingles in England and Wales in those over 60 years of age suggest that there are more than 88,000 cases of which almost 20,000 were still in pain after 3 months [58]. The cost to the health service is estimated to be in excess of £17 million annually with almost half of the total costs associated with the disease in those over the age of 80 years [58]. Postherpetic neuralgia (PHN) is one of the debilitating complications of the disease, and the pain associated with this condition can be prolonged and very disabling, and while antiviral therapy can reduce the duration and severity of shingles, it fails to impact on PHN [59]. HZ vaccines: composition

This is a live vaccine and each dose contains not less than 19,400 plaque-forming units of the Oka/Merck VZV produced Expert Rev. Vaccines 13(7), (2014)

Vaccine responsiveness in the elderly

from MRC-5 human diploid fibroblasts. This is the sister vaccine to Varivax, which is given to children to prevent chickenpox and which contains approximately 1350 plaque-forming units of the Oka/Merck strain of virus, approximately 14-times less than the dose given to older individuals.

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Goal of vaccination, policy & expectation

The age-related decline in cell-mediated immunity to zoster virus is well documented [60] as is the age-related maintenance of zoster virus glycoprotein-specific antibody levels [61]. Vaccination leads to increases in the antibody titer against VZV glycoproteins and increases in T cell immunity measured as responder cell frequency to the infection and also by measuring the number of VZV-specific IFN-g-forming cells [61]. The HZ vaccine (Zostavax) is recommended to be given to older individuals, for example, those over 60 in the USA and over 50 in parts of Europe [62] and those aged 70 and 79 in the UK and can be obtained privately by anyone over the age of 50 in the UK [63]. Approaches to vaccination against shingles and PHN have a different rationale from other vaccines used in the older population. Influenza vaccine and the PPV23 vaccine aim to induce active immunity to prevent infection, but it is expected that individuals vaccinated against shingles are already infected with the VZV. The aim of the HZ vaccine is thus to provoke sufficient immunity against the dormant zoster virus such that when it is reactivated, the disease it normally induces is attenuated. Almost 3 years after the vaccine against the zoster virus was approved, the US FDA requested a change to its delivery asking that ‘Zostavax and Pneumovax 23 (PPV23) should not be given concurrently’ because concomitant use resulted in lower antibody titers to VZV. A follow-up study showed no evidence of an increased risk of shingles in those who received a zoster vaccine and pneumococcal vaccine on the same day [64]. This underlines the role of cell-mediated immunity in the response to zoster virus and the lack of any evidence to indicate that antibody titers against VZV are true measures of protection.

Review

Tetanus, diphtheria & pertussis

Symptoms of tetanus usually develop within 3 weeks of an individual being infected with Clostridium tetani in a deep wound and are characterized by contraction of the voluntary muscles, often those of the jaw or neck. The disease is caused by a toxin produced by the bacteria and may be fatal in those who have not been vaccinated. With diphtheria, the symptoms usually begin within a week of infection with the bacterium Corynebacterium diphtheriae which is normally spread by contact with or inhalation of the bacterium from infected individuals. The symptoms include a febrile response and a sore throat, breathing difficulties and in some instances the appearance of a gray white membrane in the throat. Pertussis, also known as ‘whooping cough,’ is a highly contagious, acute respiratory illness caused by the bacterium Bordetella pertussis. The bacteria are spread through close contact, and infection is known to predominantly affect children below 10 years of age. Vaccines against tetanus, diphtheria & pertussis: composition

The initial steps in the preparation of tetanus vaccine include the growth of toxic strains of Clostridium tetani in liquid media followed by the purification of the toxin they produce. This toxin is then deactivated by treatment with formaldehyde to produce the toxoid antigen. This toxoid antigen is further purified and sterilized and then mixed with aluminum or calcium salts to provide the correct formulation for the vaccine [66]. A protein with previous toxic properties is also at the center of the diphtheria vaccine. Liquid cultures of Corynebacterium diphtheriae are harvested, and the toxin is purified and converted to toxoid by treatment with formaldehyde. In the vaccine, this toxoid is adsorbed onto aluminum salt, which acts as an adjuvant [67]. Acellular pertussis vaccine is produced from cultures of Bordetella pertussis, and at present, there is no consensus about the antigenic composition of the ideal acellular pertussis vaccine. Consequently, vaccines from different manufacturers are considered as unique because of the presence of one or more different components [68].

Efficacy

Goals of vaccination, policy & expectation

A large clinical trial in more than 38,000 individuals over 60 years of age showed that vaccination reduced the burden of illness by 61%, a score derived from an amalgamated measure of the incidence, severity and duration of pain associated with shingles. The incidence of shingles was reduced by 51% and the incidence of PHN by 66.5% [65]. However, these figures are lower for those over the age of 70 years where the burden of illness was reduced by 55%, the incidence of shingles was reduced by 37% and the incidence of PHN was similar at 66.8%. The lack of clear and unambiguous correlates of protection for the response to zoster virus makes it difficult to identify approaches to improving the vaccine to ensure adequate protection, especially in the oldest old who are the ones with the most to benefit from protection.

The goal of vaccination is to provide protection from these diseases, and in the main, this has been achieved in children. In most industrialized countries, tetanus and diphtheria vaccination are part of the childhood and adulthood vaccine schemes. Where childhood programs of immunizations are good but boosting low, a large proportion of the adult population is gradually rendered susceptible to diphtheria and tetanus as a result of waning immunity [69,70]. Recently, pertussis has been reported to be the only vaccine-preventable disease, which is on the increase in the USA [71] and similar increases are seen in Europe [72]. The Advisory Committee on Immunization Practices in the USA recommended that the tetanus, diphtheria and acellular pertussis vaccine should be offered to all adults over 65 years of age [73]. In Europe, the situation is not the same, and recommendations differ between European countries.

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Efficacy

Hepatitis B

Older individuals often do not have protection against tetanus and diphtheria because of low titers of specific antibody [74]. Although vaccination of older individuals almost always leads to protective levels of antibody, a recent study revealed that protective levels after 5 years were only maintained for 90% against tetanus and for 55% for diphtheria. However, protective levels could be restored in almost all older recipients by a booster shot [74]. Reports suggest that most cases of pertussis occur in incompletely immunized infants and older persons whose immunity is in decline, with the latter often serving as the source of infection for the children [75]. Globally, recent epidemiological studies have demonstrated a 115 and 400% increase in pertussis prevalence in the nonimmunized adolescent and adult populations, and a 68% increase in the population of individuals aged over 65 years. 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 lacking. In individuals aged 15–65 years, the risk of developing pertussis is reduced by 92% after vaccination with acellular pertussis vaccine [75]. A recent report using pooled analysis of four trials suggested that a single booster dose induced good immunological responses mostly in older adults [76].

The Hepatitis B vaccine contains the cloned Hepatitis B surface antigen expressed in yeast and then adsorbed onto aluminum hydroxide as the adjuvant [33]. The response to this vaccine is age dependent as shown by an early study where 45 healthy elderly (average age 74 years) and 37 healthy young controls (average age 28) were vaccinated with hepatitis B. The results revealed that a protective titer was achieved by all young individuals but only 42% of the elderly cohort [80].

Travel vaccines

Susceptibility to infection during travel depends both upon the destination and also the behavior of the traveler. Older individuals are less likely to undertake risky behavior compared with younger individuals when travelling [77], but as mentioned previously are undertaking more travel and so provide greater opportunity for infection through close association with others and through transmission of potential pathogens present on inanimate surfaces [4,78]. Vaccinations provided for individuals prior to travel depend on the countries they are likely to visit, but the common vaccines may include those against Influenza, diphtheria, tetanus, Hepatitis A and B and yellow fever. The first three of these have been dealt with earlier and so we will just discuss the latter three. Efficacy Hepatitis A

Several vaccines are available, which provide protection against Hepatitis A and each contains an inactivated virus. For monovalent vaccines, the recommendation is a single dose which may be followed by a booster dose 6–12 months later [33]. Antibody is known to provide protection against the disease as individuals can be protected by passive transfer of antibody. Several studies have analyzed the effect of the vaccine in older individuals, and the consensus from these studies is that the speed of the antibody response seems to be less in older individuals which of course may impact on the timing of vaccination prior to travel. In addition, lower peak titers are attained after vaccine delivery in older individuals [79]. 890

Yellow fever

This vaccine is prepared by growing the 17D strain of this flavivirus on specific pathogen-free embryonated hens eggs. This is a live, attenuated vaccine normally given by deep subcutaneous injection [33]. In a recent study, young (18–28 years) and older (60–81 years) individuals were vaccinated with the YF-17D vaccine and their neutralizing antibody titers measured. Ten days after vaccination, there was a significant difference between the young and older age group with seroprotection attained by 77% of younger individuals and 50% of the older individuals. However, this difference was no longer statistically significant 28 days after vaccination [81]. Expert commentary

Few of the recommended vaccines provide a 100% success rate of protection in the older population, with some falling further from this target figure than others. Although an individual might be classed as potentially immunodeficient because of making an inadequate response to one of these vaccines, one could not infer that they would make a suboptimal response to the other vaccines. This is in part due to the different immune mechanisms associated with inducing protection in each case. For example, for tetanus, diphtheria and acellular pertussis, protection is provided by antibodies alone. This is also the case in younger recipients of the influenza vaccine where protection from subsequent infections is provided by neutralizing and receptor-blocking antibodies against the hemagglutinin molecule produced from a T cell-dependent B cell response [34]. While in older individuals, it is becoming increasingly clear from recent reports in the literature that factors other than specific antibody titer may be associated with protection against influenza viruses [82]. For the pneumococcal vaccine, protection is provided by antipneumococcal antibodies generated from a T cell-independent B cell response. Finally, for the HZ, vaccine protection is through T cell-dependent immunity [60]. With this in mind, it is clear that an older individual may be unable to mount protective response to one, two or all of these vaccines and in each case would be considered immunodeficient with their immune systems showing aspects of immunosenescence. Immunosenescence is a broad term without sharply defined boundaries and implies a reduction in immune function below a normally acceptable level. In order to assist clinicians in vaccinating their older patients and also vaccine designers and manufacturers in providing the correctly tailored Expert Rev. Vaccines 13(7), (2014)

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vaccine, we need to provide a concept of gradation or staging to the idea of immunosenescence. This would require providing some degree of immune profiling of this vulnerable older population. One of the problems associated with this approach is that there are currently no validated tests which could be used prior to vaccination to define an individual’s ability or inability to produce a protective response. Some efforts have been made in the past to identify individuals with some degree of immune dysfunction, resulting in the production of a scoring system for immunological vigor [83] or in the identification and characterization of an immune risk phenotype which includes T cell phenotypes, subset numbers, function, CMV status and cognitive impairment [84]. Others have suggested that TREC levels may be of interest in this classification [85]. More recently, in the systems biology approach, it is possible to analyze several parameters in individuals including cell subset phenotypes, antigen specificities of lymphocyte receptors as well as the extent of the repertoire, cytokine levels in the serum and sequence HLA types [86]. Such an approach has enabled the use of a large number of variables to predict the antibody response with some degree of accuracy [87]. However, predicting vaccine responses is less accurate in older people compared with younger individuals because of greater variability among the different parameters [86]. As we have seen from the studies already noted, there appears to be multiple causes of immune dysfunction in older individuals and so immune profiling in our view would use multiple parameters. These parameters should include classic immunological components as well as some indication of the physical robustness or frailty of an individual, their nutritional status and the number of comorbid conditions. The object would be to assign a score for an individual which could be used to allocate them to a specific stage of immunosenescence. This would enable us to classify immunosenescence into discrete stages on the basis of shared features with some recognized progression toward a final stage at which an individual would show a complete inability to respond optimally to any antigenic stimuli. Clustering of individuals into such stages would assist the design and development of new vaccines with higher efficacy through being directed at the features of that specific stage.

Review

Five-year view

In less than 5 years, the number of individuals over the age of 65 years will outnumber those under the age of 5 years in the world for the first time in recorded history. Moreover, the increase in the oldest old may mean that the age range within the population over 65 years may be considerable and for some this could encompass one-third of their lifespan. Making generalizations about people over the age of 65 years are clearly not useful and we should subdivide this category further. Previous concerns driving vaccine development were centered on preventing the death of young children from infectious disease and stopping them from acting as carriers of disease, but in a few short years, the emphasis will have to be changed. Maintaining the health of older people by protecting them from transmissible diseases, especially in view of the amount of international travel which this population now undertakes and stopping them acting as carriers for infectious organisms, will require the development of new vaccines. Because the number of variables that have an impact on immunity in older people is so diverse, single issue approaches such as increasing the amount of antigen or including adjuvants might provide some, but not all of this population with adequate protection. Advancing our understanding of how the immune system ages and how this aging process interacts with comorbidities and nutritional and environmental factors is imperative. Building on recent progress in the field should lead to the development of validated assays using strong biomarkers to identify and predict individual’s immune capacity. It might then be possible to offer older individuals a personalized vaccination program. Financial & competing interests disclosure

R Aspinall is an academic at Cranfield University and POL at the Clinique of Genolier, and this paper was written in between normal duties. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • The mean age of the global population is increasing because of a reduction in the number of children and more people living longer. • More individuals among the older section of the population travel more frequently and more widely than previous generations and so have greater exposure to familiar and unfamiliar pathogens. • Many older individuals are immunocompromised, respond poorly to vaccination and are more susceptible to infection. • Some individuals may spend one-third of their lifespan over the age of 65 years, and this population represents too great an age range for generalizations to be useful. • Many vaccines were developed with a view to preventing mortality in children from communicable diseases. • None of the current vaccines aimed at those over 65 years provide a 100% success rate of protection in all older individuals with some falling further from this target figure than others. • Introducing a system of immune profiling for older individuals would facilitate approaches to improve vaccine design and development. • Provision of protection through vaccination for older individuals requires both improvements in vaccine formulation and improvements in restoring immune capacity.

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