Vaccine effectiveness in older individuals: What has been learned from the influenza-vaccine experience

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Ageing Research Reviews 10 (2011) 389–395

Contents lists available at ScienceDirect

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accine effectiveness in older individuals: What has been learned from thenfluenza-vaccine experience

ierre-Olivier Langa,b,c,∗, Sheila Govinda, Wayne A. Mitchell a, Claire-Anne Siegrist c, Richard Aspinall a

Translational Medicine Group, Cranfield University, Cranfield, UKDepartment of Rehabilitation and Geriatrics, University Hospitals and Medical School of Geneva, Geneva, SwitzerlandWHO Collaborative Centre for Neonatal Vaccinology, Departments of Pathology-Immunology and Pediatrics,niversity Hospitals and Medical School of Geneva, Geneva, Switzerland

r t i c l e i n f o

rticle history:eceived 28 June 2010eceived in revised form0 September 2010ccepted 21 September 2010vailable online 1 October 2010

a b s t r a c t

Vaccination policies in most high-income countries attempt to reduce the adverse impact of influenzatargeting people aged at least 60 years. However, while it is widely believed that the current immu-nization strategy saves many lives, influenza infection still remains a severe burden in aged individualsleading to a wide debate on the exact magnitude of the benefit of vaccination in this population. Thefirst aim of the present review is to examine how effective current influenza-vaccine strategies are inaged adults, by analysing which are the most important factors modulating the interpretation of study

eywords:nfluenza vaccine effectivenessmmunosenescenceell-mediated immunity

nnate immunityemagglutinin inhibition

results in this population. Furthermore, consideration will be given to how immune factors influence themeasurement of vaccine efficacy/effectiveness, where advancing age leads to deleterious changes in theadaptive immune system, resulting in less than optimal responses to infectious agents and vaccination.Finally this review concludes with possible strategies to improve the ability of the senescent immunesystem to respond to vaccination.

© 2010 Elsevier B.V. All rights reserved.

lder adults

. Introduction

Vaccine preventable diseases (VPDs) remain a severe burdenn adult populations of developed countries (Michel and Lang,011). In the United States, they account for more than 70,000eaths per year in these populations compared with 200 deaths

n children (Poland et al., 2009). Aside from a 350-fold increasedikelihood of death, VPDs are also associated with an age-relatedncrease in serious adverse health events leading to hospitalization,ebilitating complications and/or death (Michel and Lang, 2011).eleterious changes in the adaptive immune system mainly asso-iated with advancing age are major contributors to a less thanptimal response either to the vaccination or to infectious agentsAspinall and Goronzy, 2010).

Foremost amongst VPDs is influenza. Worldwide estimates indi-ate that influenza infections cause 3–5 million of severe caseser year resulting in 250,000–350,000 deaths (Influenza, 2008). Inhe European Union, between 40,000 and 220,000 deaths per year

∗ Corresponding author at: Department of Rehabilitation and Geriatrics, Univer-ity Hospitals and Medical School of Geneva, chemin du Pont-Bochet 3, CH-1226hônex-Geneva, Switzerland. Tel.: +41 22 305 61 11; fax: +41 22 305 61 15.

E-mail address: [email protected] (P.-O. Lang).

568-1637/$ – see front matter © 2010 Elsevier B.V. All rights reserved.oi:10.1016/j.arr.2010.09.005

have been attributed to infection by influenza (Seasonal HumanInfluenza and Vaccination, 2010). The highest prevalence mainlyoccurs amongst older adults especially those with chronic medicalconditions or immunological disorders, resulting in increased mor-tality in these high risk groups (World Health Organization, 2005).However, mortality is just the tip of the iceberg in terms of dis-ease burden, as it can also act as a trigger for functional declineleading to disability in some aged individuals (Monto et al., 2009;McElhaney, 2005; Greenberg and Piedra, 2004; Gavazzi and Krause,2002). Such outcomes represent a considerable economic burdenamounting to $87 billion each year in the United States (Molinariet al., 2007). While it is widely believed that influenza vaccinationsaves many lives, prompting the widespread use of trivalent inac-tivated influenza vaccine (TIVs – 300 million doses produced eachyear) the exact magnitude of the benefit of the current immuniza-tion strategy in the aged population is still controversial (Jefferson,2006; Fireman et al., 2009; Jackson et al., 2006a,b, 2008; Simonsenet al., 2007, 2009). This review will aim to examine how effectivecurrent influenza-vaccine strategies are in aged adults and analysewhich are the most important factors modulating the interpreta-tion of study results in this population. Furthermore, consideration

will be given to how immune factors influence the measurementof vaccine efficacy/effectiveness. This review will conclude withpossible strategies to improve the ability of the senescent immunesystem to respond to vaccination.

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Table 1Age-specific immunogenicity criterions established by the Committee for Proprietary Medicinal Products of the European Medicines Evaluation Agency, based on seracollected at baseline and 3 weeks after immunization.

Immunogenicity criterion Definition Young adults (18–60years of age)

Old adults (>60years of age)

Seroprotective rate, % Proportion achieving reciprocal HAItiter of ≥40

>70 >60

Mean geometric increase n-Fold increase above baseline, ingeometric mean titers

>2.5 >2.0

Seroconversion rate, % Proportion with ≥4-fold rise abovebaseline HAI titers or an increase fromnegative prevaccination to

>40 >30

H

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seroprotection levels ≥40

AI = hemagglutination inhibition.

. Is current influenza vaccine actually effective in agedndividuals?

The current TIVs contain 15 �g of hemagglutinine (HA) of eachf the three influenza strains (A/H1N1, A/H3N2 and influenza B).umoral anti-HA antibody response is used as a surrogate marker

or vaccine efficacy (Fiore et al., 2008). To assist in the interpre-ation of influenza vaccine immunogenicity, the Committee forroprietary Medicinal Products (CPMP) describes a satisfactory HAnhibition (HAI) by serum anti-HA antibody response in the agedopulation (Note for Guidance on Harmonization of Requirementsor Influenza Vaccines, 1997), as shown in Table 1, by one of theollowing criteria: (i) >60% achieving a reciprocal HAI titre of ≥40considered as seroprotection rate); or (ii) a mean geometric – GMTf HAI antibody increase in titres of >2.0-fold (the seroprotectionate); or (iii) >30% achieving a 4-fold rise in HAI antibody titre (theeroconversion rate). TIV prevents laboratory-confirmed influenzallness in approximately 70–90% of healthy adults below the agef 60 years in randomized controlled trials when the vaccine andirculating viruses are antigenically similar (Centers for Diseaseontrol and Prevention, 2004; Jefferson et al., 2007). Whilst suchrotection occurs in young adults, the picture for the aged individ-als is not as clear and for obvious ethical reasons, it is not currentlyossible to resolve this issue by randomized placebo controlled tri-ls, although this has been done in the past (Goveart et al., 1994).o the efficacy of the vaccine, especially in the elderly, has mainlyeen derived from observational studies typically using data fromesearch databases or health care utilization data system (Nelsont al., 2009).

.1. What are the estimates given from observational clinical andmmunogenicity studies?

Observational studies have consistently reported reductions inll-cause mortality for vaccinated seniors during the influenza sea-on (Nelson et al., 2009). These results have been interpreted byome as evidence that vaccination reduces the risk of death andnfluenza-related hospital admission in the elderly (Fiore et al.,008) and have led to support of senior vaccination programs asoth cost-saving (Deans et al., 2010; Maciosek et al., 2006) and cost-ffective (Nichol et al., 2007). Indeed, some studies have indicatedhat vaccination can be up to 80% effective in preventing influenza-elated death (Monto et al., 2001; Jefferson et al., 2005; Patriarca etl., 1985), and up to 70% effective in preventing hospitalization forneumonia and influenza for older persons living in an institutionaletting (Nichol et al., 1998, 2007; Mullooly et al., 1994). How-ver, questions have arisen about whether these benefits have been

verestimated (Jefferson, 2006; Fireman et al., 2009; Jackson et al.,006a,b, 2008; Simonsen et al., 2007, 2009). In a recent Cochraneystematic review, authors were unable to reach clear conclusionsbout the exact benefit of the vaccine strategy against laboratory-

confirmed influenza cases or effectiveness against influenza-likeillness (ILI) in aged individuals, due to the likely presence of bias innon-randomized controlled trials (Jefferson et al., 2010). Similarly,immunogenicity studies do not seem to provide clearer outcomes.The early decrease in primary antibody responses (i.e. anti-HA anti-body responses induced in previously unvaccinated persons) hadbeen noted in older adult populations compared to younger adultsin two reviews (Goodwin et al., 2006; Beyer et al., 1989). However,both approaches highlight serious methodological flaws whichinclude a failure to exclude participants with (i) conditions thathave influence on the immune system; (ii) those previously vacci-nated and (iii) those with high pre-vaccination titers (Skowronskiet al., 2008) (see below).

2.2. Evidence of bias in estimates of influenza vaccineeffectiveness

Some reports (Jefferson, 2006; Fireman et al., 2009; Jackson etal., 2006a,b, 2008; Simonsen et al., 2007; Nelson et al., 2009) suggestthat selection bias may be responsible for the vaccine effectiveness(VE) estimates. It was reported that individuals selected for vacci-nation generally appeared “sicker” than unvaccinated individuals(Iezzoni et al., 2000; Chan et al., 1999; Xakellis, 2005; McGuireet al., 2007; Hak et al., 2002). However, recently from a cohortof 72,527 persons over 65 years of age followed over 8 years andincorporating a pre-influenza season analysis, Jackson et al. (2006a)demonstrated a preferential receipt of vaccine by relatively healthyseniors. This finding has also been noted by others (Jackson et al.,2006a,b, 2008; Simonsen et al., 2007; Nelson et al., 2009; Jackson,2008) and a curvilinear relation between predictors of mortalityand vaccination depicted (Fireman et al., 2009). Furthermore, func-tional limitations, such as requiring assistance for bathing, havebeen demonstrated to be associated with a decreased likelihoodof vaccination even in aged persons free of comorbid conditions(Jackson et al., 2006b). All together, these recent findings sug-gest that near the end of life, disability appears as a contributingfactor in the decision to receive or resist vaccination. Thus, pre-influenza season analyses seem to introduce biases that may notpresent in the influenza season analyses (Hak et al., 2006). Indeed,observational studies generally select subjects who are appropriatecandidates for the intervention, who all have similar access to theintervention. Thus, persons known to have a short life expectancymay not be offered vaccine, and a person dying before the endof the vaccination period may have had fewer opportunities toget vaccinated compared to individuals who are relatively healthythroughout the vaccination season (Nichol et al., 2007). In addition,the retrospective assessment of functional status is also a finding

leading to a healthy vaccine bias in observational studies (Jacksonet al., 2006b). Moreover, additional findings from Fireman et al.(2009) showed that after having adjusted for risk factors, (i.e. olderage, chronic conditions, and self-reported health status) mortality

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efore, during and after 9 influenza seasons increased by similarrajectory over time in both healthier and high-risk of death sub-roups. This provides strong evidence that selection bias is a fatalaw of many observational estimates in aged individuals and theseesults do not provide valid evidence on which to estimate the trueenefit that may be derived from influenza vaccination.

.3. How to differentiate vaccine effect from bias

To differentiate vaccine effects from bias, Fireman et al. (2009)as proposed a “difference in differences” approach. In other words,

f the flu vaccine really does prevent deaths, then in a large pop-lation there should be a detectable difference between: (i) theifference in the odds of prior vaccination between decedents andurvivors that is observed on days when influenza is circulating andii) the difference in the odds of prior vaccination between dece-ents and survivors that would be expected on the same calendarates if influenza were not circulating. Hence, influenza vaccineffectiveness reduced all-cause mortality among aged adults by.6% (95% CI 0.7–8.3) during 1996–2005 laboratory-defined flu sea-ons (Fireman et al., 2009). Whereas it has been found by Simonsent al. that influenza infection accounted at most for 10% of all deathsuring the influenza season (Simonsen et al., 2007), many cohorttudies reported a 50% reduction in the total risk of death in winterNichol et al., 2007; Voordouw et al., 2003).

However, as recently discussed by Nichol, the accurate excesseaths/winter-time deaths ratio attributable to influenza is chal-

enging to estimate, due to the lack of available individual-leveleasures (Nichol, 2009). This ratio uses a numerator that under-

stimates influenza-associated deaths due to the difficulty tonderstand the true disease burden caused by influenza and aenominator that over-estimates deaths during the influenza sea-on (Nichol, 2009; Thompson et al., 2009). As a result, this ratio doesot accurately reflect the absolute mortality burden attributableo influenza and is therefore a misleading number for judging thelausibility of influenza vaccine mortality benefit.

Similarly, in a recent large population-based nested case-controltudy, which incorporated a seasonally analysis, influenza vaccina-ion was not significantly associated with a reduction in the risk ofommunity-acquired pneumonia in the aged population (Jacksont al., 2008). While the VE estimate is consistent with approxima-ions from two recent meta-analyses demonstrating the VE againstneumonia hospitalization (Rivetti et al., 2006; Vu et al., 2002), theidth of its confidential interval demonstrates an imprecision andlack of statistical power (Nichol, 2009).

Thus, the influenza vaccine benefits “controversy” arises fromuestions about whether residual confounding and bias in observa-ional studies have resulted in VE estimates that misjudge the trueenefit. Without dramatic modification the current adjustmentethods will not adequately control for bias and the contro-

ersy will undoubtedly continue. New strategies are needed tomprove the accuracy of influenza VE estimates. Future studieshould include exploring the strengths and limitations of var-ous comparison periods for model validation, the influence ofmportant potential confounders, and other methods to quantifyhe impact of potential residual confounding such as sensitivitynalyses (Nichol, 2009). Complementarily, approaches for reduc-ng bias should include obtaining more accurate information ononfounders, such as functional status and life expectancy, avoid-ng all-cause death in favour of outcomes such as pneumonia ornfluenza-related pneumonia, and include prospective ascertain-

ent of influenza-specific outcomes to improve study sensitivity

o detect a true vaccine effect (Nelson et al., 2009). Age-relatedhanges in the immune system should be also considered. How-ver, while immunosenescence is undoubtedly a very real andmportant phenomenon adversely influencing vaccine response

Reviews 10 (2011) 389–395 391

(Grubeck-Loebenstein et al., 2009; Fulop et al., 2009; Sambharaand McElhaney, 2009; Siegrist and Aspinall, 2009), how it shouldbe measured and how it exactly influences changes in clinical pro-tection is still unclear.

3. How immune factors may influence influenza vaccineefficacy/effectiveness estimates

3.1. Do pre-vaccination HA-antibody titres influence the vaccineresponse?

Most adults have pre-existing levels of antibody because of priorinfluenza infection and/or flu vaccination but this will vary in speci-ficity depending on the age of the individual (Sasaki et al., 2008).Thus, young adults and elderly differ markedly for A/H1N1 strains(circulating between 1918 and 1957 and reintroduced in 1976), butare more similar for A/H3N2 strains (circulating since 1968). Olderindividuals with siblings infected during the influenza outbreak of1918 possess highly functional, virus-neutralizing antibodies to the1918 H1N1 virus, nearly 90 years after the pandemic (Yu et al.,2008). Complementarily, a cross-sectional serological survey con-ducted in 2008, before the first wave of A/H1N1 infection, showed apositive correlation between age and HAI and microneutralisationantibody titres to pandemic A/H1N1 (Miller et al., 2010). Similarly,prior year vaccination can also influence the HA-antibody and B-cell responses to re-vaccination. This has been demonstrated bySasaki et al. (2008) in young healthy adults (age range 22–49 years)where differing influenza vaccination histories in the prior year andin which the serum antibody and B-cells to TIVs or life attenuatedinfluenza vaccine (LAIV) were quantified during the 2005–2006influenza season. Lower levels of baseline anti-HAI titers were asso-ciated with a greater fold-increase of HAI titre and number ofantibody secreting cells number after vaccination. This suggeststhat prior history of influenza infection and/or vaccination affectsthe serum HA-antibody and the B-cell responses to subsequent vac-cination. As demonstrated by Feng et al. (2009), a similar pictureis observed in the aged population regarding the proportional folddecrease in antibodies after vaccination to the pre-existing levels ofHA-antibody. Thus, higher pre-immunization titres are associatedwith lower likelihood of demonstrating fold rises or seroconversionleading to the underestimation of vaccine efficacy whether the HAItitre is used as a surrogate marker of protection and the increasein HAI titre considered as a measure for predicting vaccine effi-cacy. These findings suggest that a clear inverse relationship existsbetween pre-immunization antibody levels and antibody increaseafter vaccination in elderly individuals and, that prior contact witheither influenza virus or vaccine may severely influence the inter-pretation of HAI titer following vaccination in this population.

3.2. Is the protective HAI titre decline throughout the influenzaseason?

Although the early decrease in protective anti-HA antibody lev-els (within 4 months following vaccination) is frequently raised as aconcern with respect to the timing of vaccination of elderly individ-uals (Smith et al., 2006), a recent review conducted by Skowronskiet al. (2008) suggests this may not be an issue. Amongst the 14 stud-ies included in this review, 8 reported seroprotection rates (Ruf etal., 2004; MacKenzie, 1977; Peters et al., 1988; Delafuente et al.,1998; Buxton et al., 2001; Brydak et al., 2003; Praditsuwan et al.,2005; Hui et al., 2006) and 6 seroconversion rates alone (McElhaney

et al., 1993; Powers et al., 1995; Van Hoecke et al., 1996; Minutelloet al., 1999; Mysliwska et al., 2004; Keylock et al., 2007). Seropro-tection rates according to CPMP criteria (Table 1) were maintained≥4 months after influenza immunization in all 8 for A/H3N2 com-

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onent and in 5 of 7 studies for the A/H1N1 and B components. Inetermining whether serological CPMP criteria were met at sea-on’s end, seroprotection rates of 70–100% were maintained notust at 4 months (Delafuente et al., 1998; Buxton et al., 2001) butlso at 5 months (Peters et al., 1988; Brydak et al., 2003) and, event >6 months (Ruf et al., 2004; MacKenzie, 1977; Praditsuwan et al.,005; Hui et al., 2006) for the A/H3N2 and A/H1N1 vaccine com-onents. In 2 of 6 studies reporting seroconversion alone, criteriaere still met at 4 months (Van Hoecke et al., 1996; Mysliwska et

l., 2004). Six studies had compared antibody persistence regardinghe age with no significant difference between groups (3 com-ared elderly with young adults (MacKenzie, 1977; Brydak et al.,003; McElhaney et al., 1993) and 3 compared aged individuals bydvancing age (Peters et al., 1988; Praditsuwan et al., 2005; Vanoecke et al., 1996)).

.3. Does innate immunity play a role in the response toaccination?

The primary interaction with the adaptive immune system isia the antigen presenting cells (APCs) and the decline in the num-ers of these cells with age may impact severely on the strategiesor coping with influenza. Further impact may follow because ofhe response to toll like receptor (TLR) ligands. In a recent study,anda et al. (2010) found substantial decreases in older comparedith young individuals in TNF-�, IL-6, and/or IL-12 (p40) produc-

ion in myeloid dendritic cells in response to TLR1/2, TLR2/6, TLR3,LR5, and TLR8 engagement and TNF-� and IFN-� production inlasmacytoid dendritic cells in response to TLR7 and TLR9 engage-ent. Authors also found higher intracellular cytokine production

n the absence of TLR ligand stimulation with APC from older com-ared with young individuals, suggesting some dysfunction in theegulation of cytokine production. Moreover they showed a strongssociation between poor antibody responses to influenza immu-ization and impaired TLR function in the older individuals.

.4. What is the effect of the age-related expansion ofysfunctional terminally differentiated T-cells?

Quantification of T-cell numbers throughout the lifespan showshat they are maintained in old mice (Aspinall et al., 2010) and inumans even in their tenth decade (Mitchell et al., 2010) at levelshich are comparable to those found in younger individuals. Thisould imply that there is no decline in the homeostatic mecha-isms which preserves the size of the peripheral T-cell pool withinefined boundaries. But such conservation may be achieved at thexpense of the content. With the age associated reduction in thymicutput and the proliferation of T cells driven either by antigen orytokines, the constituent T-cells of the pool must be progressingowards their replicative limit with age. Evidence of this comes withD28 expression. The CD28 marker is expressed on >99% of human-cells at birth, but with age there is a progressive increase in theroportion of CD28− T-cells, particularly within CD8+ T-cell sub-et which is the major immune mediator of viral clearance (Effros,007a; Hünig et al., 2010). The proliferative capacity of CD28−-cells is also limited, these cells have shortened telomeres, andhow increased resistance to apoptosis and restricted T-cell diver-ity (Vallejo, 2005). Proliferation within the peripheral T-cell pool ase age may be unbalanced and this is particularly when persistent

iral infection is involved. Infection with the Herpesviridae familyncluding human �-herpes viruses and with poliomaviruses, mayhape of the repertoire of the immune system with age (Weiskopf

t al., 2009; Lang et al., 2009; Virgin et al., 2009). Whilst someeports suggest that localized, niche limited, latent herpes virusHHV1) may not have any impact on immunosenescence (Lang etl., 2008), evidence implicates chronic cytomegalovirus (CMV or

Reviews 10 (2011) 389–395

HHV5) infection in the age-dependant expansion of dysfunctionalterminally differentiated T-cells (CD8+ CD28−). In CMV seroposi-tive older adults, up to 25% of the total CD8+ T-cells pool can bespecific for CMV immunodominant epitopes (Pawelec et al., 2009)and this expansion of CMV-specific CD8+ T-cells alters the capacityof the immune system to respond to other pathogens. These cellsare able to secrete pro-inflammatory cytokines and contribute toan ongoing inflammatory process (Pawelec et al., 2009). The rea-sons for the putatively unique effects of CMV compared with otherHerpesviridae and other pathogens are unclear at present. One pos-sibility may reside in the cell types acting as CMV reservoirs andtheir intimate interactions with immune cells (i.e. antigen present-ing cells such as DCs, as well as endothelial cells) (Pawelec et al.,2009).

4. How to improve the ability of the senescent immunesystem to respond to vaccination?

4.1. Is immunosenescence a quantifiable disorder?

Since the single preceding event in all cases of immunose-nescence is thymic involution, can we identify a specific thymicrate of output which is linked to a state of immunosenescence?Studies to identify recent thymic emigrants (RTEs) have shownthat the optimal means possibly uses a mixture of molecular andphenotypic techniques. Molecular techniques include PCR basedassays of populations of cells for their content of signal joint T-cell receptor gene excision circles (sj-TREC) which are circularDNA products of T-cell receptor � chain rearrangement (Aspinallet al., 2000). Recent phenotypic moieties include protein tyro-sine kinase 7 (PTK7) expression (Haines et al., 2009). PTK7 mainlyidentifies RTEs that are more recently produced by the thymus,PTK7+ naive CD4+ T-cells are uniformly CD31+ and a more pro-nounced and persistent loss of PTK7+ CD4+ than PTK7-CD31+ naiveCD4+ T-cells is observed after complete thymectomy. Indeed, mostadult circulating naive CD4+ T-cells are CD31+ and a CD31- sub-set describes lower sj-TREC content and less ��-TCR diversitythan CD31+ fraction and may be generated by foreign antigen-dependent homeostatic proliferation (Kohler et al., 2005). The useof a collection of markers to analyse thymic output in older indi-viduals has not been completed yet. However, recently, Mitchell etal. (2010) analysing peripheral blood mononuclear cells (PBMCs)from healthy individuals aged 60–104 years have shown an age-associated decline in sj-TRECs per 105 T-cells becoming significantduring the 9th decade.

4.2. How to identify individuals who are poor responders

Predicting individual responsiveness to vaccination using bio-logical markers that distinguish between healthy and immunose-nescent states is desirable. However achieving this goal with asingle and robust method is very challenging. Trzonkowski et al.(2003) suggest that a single marker which could identify the func-tioning of one compartment of the immune system, without takinginteraction with other components into account, might prove tobe insufficient. Indeed they are often affected by a wide range ofco-morbid conditions that influence the final outcome of the vacci-nation. Hirokawa et al. (2009) have proposed a T-cell immune scoreexpressing the immune status of individuals as a simple numeral.This score combines five T-cell related parameters: number of T-cells, ratio CD4+ to CD8+ T-cells, number of naïve T-cells (CD4+

CD45RA+), ratio of naïve to memory (CD4+ CDRO+) T-cells, andT-cell proliferative index (TCPI).

An alternative method has been to identify the immune risk pro-file (IRP), a condition consisting of high CD8+, low CD4+ numbers,

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haracterised by an inverted CD4+/CD8+ ratio and a poor mitogenesponse to concanavalin A (ConA) stimulation and, associated withersistent CMV infection leading to the expansion of dysfunctionalerminally differentiated CD8+ CD28− T-cells (Pawelec et al., 2009;trindhall et al., 2007). Interestingly, in an examination of immunearameters over the adult lifespan as a whole, Wikby et al. (2008)ave observed (i) an increase in the prevalence of individuals hav-

ng an IRP from about 8% in the age range of 20–59 years to about6% in the age range of 60–94 years of age, (ii) a higher mortalityate in individuals above 60 years of age who have an CD4+/CD8+nverted ratio, and (iii) a significant lowering of the numbers ofD3+, CD3+ CD4+ and CD3+ CD8+, and of CD8+ CD45RA+ CCR7+ells across the adult lifespan. Complementarily, findings from theONA immune longitudinal study confirmed the importance of

he IRP as a major predictor of mortality and suggested that sur-ival to the age of 100 years was associated with the selection ofndividuals with “inverted” IRP that was stable across the time (i.e.voidance of inverted CD4+/CD8+ ratio and low numbers of CD8+D28− T-cells) (Strindhall et al., 2007). However, concerning indi-iduals with a senescent immune system, a better understandingf the age-associated alterations to immunity is still necessary forelping to identify aged individuals requiring specific or additionalare during or in prevention of the influenza specific season. Thewareness of such changes would be vitally important for devel-ping new type of vaccines, adjuvants and modified protocols ofaccination designed for these immunosenescent individuals.

.3. What do we improve: the vaccine or the immune response?

As current TIV do not offer optimal protection in older adultsue in part to waning cell-mediated immunity, novel vaccineesigns and immunological therapeutic approaches to enhance-cell immunity have been proposed. New formulations alreadyested on older individuals include increasing the TIV dosage (60 �gersus 15 �g of HA) (Cate et al., 2009; Falsey et al., 2009); changesn the type of vaccine (live attenuated vaccines (LAVs) (De Villierst al., 2009); virosomal vaccines (Huckriede et al., 2005); anddjuvanted vaccines with MF59 or AS03) (de Bruijn et al., 2006;egliasco et al., 2001; Roman et al., 2010; Leroux-Roels et al., 2010).urther formulation changes which are at early stages of develop-ent include enhancing adjuvantation of current vaccines (Keitel

t al., 2008) or the development of novel adjuvant as the labilenterotoxin from E. coli, placed over the immunization site in aatch (Glenn et al., 2009); the use of life attenuated influenza vac-ines (LAIVs) in combination with current vaccines (Monto et al.,009); DNA vaccines (Drape et al., 2006) and recombinant vaccinesCox and Hollister, 2009; Treanor et al., 2007); the use of different

odes of delivery the viral antigens have been assessed such asntradermal (Holland et al., 2008; Leroux-Roels et al., 2008); andlternative antigens (use of highly conserved maturational cleav-ge site of HA precursor, the external domain of the M2 protein, andhe nucleoprotein) (Bianchi et al., 2005; Livingston et al., 2006).

In addition, it has been proposed to physically remove fromhe circulation and/or inducing the apoptosis of senescent CD8+D28− T-cells with the hope of inducing the homeostatic expan-ion of more functional population of memory T-cells (Effros,007a). Regarding the adverse impact of chronic CMV infection, aractical strategy might be the development of CMV vaccines pre-entively administrated during childhood (Pawelec et al., 2009).owever developing such a vaccine targeting a virus as complexs CMV may not be viewed as a priority compared with vaccinesgainst other pathogens. Different ways have also been explored

ow to rejuvenate the peripheral T-cell pool by reversing the thy-us atrophy. Several factors including IL-7, keratinocyte growth

actor and sex steroid ablation are currently taking centre stages potential immune rejuvenators (Mitchell and Aspinall, 2009).

Reviews 10 (2011) 389–395 393

Current strategy bolsters the immune response by altering themicroenvironment in which thymocytes develop. Treatment withrecombinant IL-7 reverses thymic atrophy, increases thymic out-put and subsequently improves immune response of old mice andold primates (Aspinall et al., 2010). The limited studies in humansreveal also an IL-7 mediated expansion of naïve T-cells (Rosenberget al., 2006). However, due to the interplay and regulation that existbetween these different factors future strategies combining two ormore of the factors which can reverse thymic atrophy will proba-bly impart greater insight into the best way of promoting thymicrejuvenation. Other strategies such as a pharmacologic approachto enhancing telomerase are currently being addressed as possiblemeans for the prevention or retardation of replicative senescentcells (Effros, 2007b). This follows proof-of-principle experimentsdemonstrating a small molecule telomerase activator (TAT2) onhuman CD8+ T-cells from HIV-infected donors in which positiveeffects have been observed (Fauce et al., 2008).

5. Conclusion

Influenza virus infection remains a major public health concernacross the world and the overall body of evidence neverthelesssuggests that influenza vaccination is also beneficial for aged indi-viduals. However, this review demonstrates that the achievementof an accurate assessment of vaccine benefits is still fraught withconsiderable methodological and epidemiological challenges. Ofcourse, designing new randomized placebo-controlled trials couldbe a solution but this would be also an expensive and an ethicallycomplex proposition. As, more immunogenic vaccines and otherstrategies for enhancing protection in this high risk population havealready been developed, to compare new and improved senior for-mulations with current formulations in head-to-head clinical trialswould appear as a competitive alternative. However, there is stillno gold standard against which to predict the impact of increas-ing age on vaccine response. Indeed, while immunosenescence isundoubtedly a real and important factor affecting vaccine response,methods for identifying and measuring it and for understanding itsimplications for vaccine response still require further evolution.

Conflict of interest

None is declared for this manuscript.

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