Antibody response to influenza vaccination in the elderly: A quantitative review

Vaccine 24 (2006) 1159–1169

Antibody response to influenza vaccination in the elderly:A quantitative review

Katherine Goodwina, Cecile Viboudb, Lone Simonsena,∗a National Institutes of Allergy and Infectious Diseases, Office of Global Affairs, 6610 Rockledge Drive, Room 2033, Bethesda, MD 20818, USA

b Fogarty International Center, National Institutes of Health, Bethesda, MD, USA

Received 2 June 2005; received in revised form 17 August 2005; accepted 26 August 2005Available online 19 September 2005

Abstract

We performed a quantitative review of 31 vaccine antibody response studies conducted from 1986 to 2002 and compared antibody responsesto influenza vaccine in groups of elderly versus younger adults. We did a weighted analysis of the probability of vaccine response (measuredas seroconversion and seroprotection) for each vaccine component (H1, H3 and B antigens). Using a multiple regression model, we adjustedfor factors that might affect the vaccine response. The adjusted odds-ratio (OR) of responses in elderly versus young adults ranged from 0.24t y in younga e concludet nic vaccinef©

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o 0.59 in terms of seroconversion and seroprotection to all three antigens. The CDC estimates of 70–90% clinical vaccine efficacdults and these estimates suggest a corresponding clinical efficacy in the elderly of 17–53% depending on circulating viruses. W

hat the antibody response in the elderly is considerably lower than in younger adults. This highlights the need for more immunogeormulations for the elderly.

2005 Elsevier Ltd. All rights reserved.

eywords: Influenza vaccine; Antibodies; Aging/immunology; Review

. Introduction

Influenza is an increasingly common cause of hospitaliza-ion and death in the elderly[1]. In recent severe, influenza/H3N2-dominated seasons, there were as many as 60,000

nfluenza-related deaths among persons over 65 years of age,nd the majority of these were among persons aged 75 andlder [2]. The current public health strategy for influenza

s to reduce severe outcomes such as hospitalizations andeaths, by recommending annual vaccination for people atlevated risk for such outcomes, including all persons over

he age of 65[3]. Observational studies suggest that influenzaaccination is associated with enormous reductions in allinter mortality among the elderly[4] but such studies may

Abbreviations: Ab, antibodies; GMT, geometric mean titre; HI, heam-gglutinin inhibition; OR, odds-ratio; CDC, Centers for Disease Control andrevention; WHO, World Health Organization∗ Corresponding author. Tel.: +1 301 402 8487; fax: +1 301 480 2954.

E-mail address: [email protected] (L. Simonsen).

be subject to self-selection bias and overestimation ofcine benefits[2]. However, because immune responses inelderly are known to be less vigorous than in younger adthere has long been concern about whether the vaccinesufficient protection in this age group[5,6].

In 1989, Beyer et al. published a review of studiescompared antibody responses to influenza vaccinationelderly to those of younger adults[7]. Of the 30 independestudies reviewed, the authors found that 10 reported a bimmune response in the young, 4 reported a better resin the elderly, and 16 did not find a significant differebetween the two groups. The authors concluded that seimportant factors, such as serious illnesses among studticipants, use of medications that inhibit immune responprevious influenza vaccination, and the presence of highvaccination antibody titres, could not be controlled for in treview. They suggested that future studies exclude subfor whom these factors exist. Since the 1989 review, sepublished studies have investigated the effects of thesefounding factors.

264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2005.08.105

1160 K. Goodwin et al. / Vaccine 24 (2006) 1159–1169

Table 1Description of adjustment factors suspected to affect vaccine antibody response and considered in multivariate analyses

Adjustment factors Definition Analysis

Living situation Community living: elderly live independently in the community Dichotomous; omitting ‘mixed’ residenceInstitutional living: elderly live in an institution and are dependent on careMixed living: elderly live in either an institution or in the community

SENIEUR Protocol SENIEUR Protocol: excluded subjects based on SENIEUR protocol orthose with chronic diseases

Dichotomous

Non-SENIEUR Protocol: applied other, less stringent health criteria, suchas those without immune disease and concurrent illness

Previous vaccination Proportion of subjects previously vaccinated in the group, continuousvariable ranging from 0 and 100%

Dichotomous;Previously vaccinated: >50% of subjectpreviously vaccinated;Previously unvaccinated: <50% of subjectspreviously vaccinated

New strain year New: strain was a novel vaccine component that study year, which had notbeen used in previous years

Dichotomous

Old: strain had been component in the previous years’ vaccine

Vaccine type Split: split-virus vaccine TrichotomousSub-u: sub-unit or sub-virosomal vaccineWhole: whole-virus vaccine

Dosage Continuous variable 10–50�g for each vaccine component H1, H3, and B DichotomousRegular dose: ≤15�gHigh Dose: >15�g

High pre-titre Continuous variables; values from seroprotection data measured beforevaccination, ranging from:

Dichotomous

H1N1: 0–82% H1N1H3N2: 0–94% High Pre-titre: % subjects seroprotected

pre-vaccination > 25%B: 0–93.7% Low Pre-titre: % subjects seroprotected

pre-vaccination < 25%H3N2 and B

High Pre-titre: % subjects seroprotectedpre-vaccination > 30%Low Pre-titre: % subjects seroprotectedpre-vaccination < 30%

We conducted a quantitative review of these more recentpapers. In particular, we compared the vaccine responses inthe elderly to those of control groups of younger adults. Addi-tionally, we compared responses in the younger elderly tothe very elderly to further gain insights into the impact ofage and vaccine response. We controlled for every factor forwhich we could obtain data that may have had an impact onvaccine response, including living situation (institutionalizedor community living), medical history, vaccine-specificfactors such as antigen dose and route of administra-tion, as well as all those suggested in the 1989 review(Tables 1 and 2).

2. Materials and methods

2.1. Source of literature

Published papers from 1989 onwards that evaluated theantibody response to the influenza vaccine in the elderlywere identified through a MEDLINE search using the terms

“influenza”, “vaccine”, “vaccination”, “elderly”, “antibodyresponse” and “humoral response”. We used Pubmed’sRelated Article feature and reviewed bibliographies of rel-evant studies to identify additional articles. Only studiesavailable through Pubmed and published in English wereconsidered. We used several inclusion criteria based on thestudy design and vaccine response measurements as detailedbelow.

2.2. Measurements of immune response

Haemagglutinin inhibition (HI) IgG antibody titre is themost established correlate with vaccine protectiveness[8,9].We studied three standard measures of vaccine response:

1. Seroconversion—the percentage of subjects with a 4-foldincrease in antibody titres.

2. Seroprotection—the percentage of subjects with HI anti-body titres≥ 1:40 post-vaccination.

3. Geometric mean titre (GMT) of HI antibody achievedpost-vaccination.

K. Goodwin et al. / Vaccine 24 (2006) 1159–1169 1161

Table 2Characteristics of immunization studies conducted in the elderly population since 1986 (N = 48)

Study design Elderly demographics Adjustment factors

Authora StudyYearb

Coc Young controlgroup under 65years

No. ofsubjects

Agerange

Meanage

Vaccinetyped

Vaccinedosage(�g)e

SENIEURProtocolf

Vaccinationstatus priorto studyg

Livingsituationh

Newstrainyeari

Gross[15] 1986 US 27 65–96 – Split 15 – 0%** M H3, BGross[15] 1986 US 113 65–96 – Split 15 – 100%** M H3, BPalache[12] 1988 NL/IL Y 67 68–99 – Sub-unit 10 – I H3, BPalache[12] 1988 NL/IL Y 64 68–99 – Sub-unit 20 – I H3, BZei [16] 1989 IT Y 24 60–77 70 Split 10 – 82%* C H3, BZei [16] 1989 IT Y 60 61–83 68 Sub-unit 10 – 77%* C H3, BChernsky[17] 1990 CA 90 >65 73.7 Whole 15 – 88%** C H3de Bruijn[18] 1990 NL Y 57 – 80 Whole 15 Y 0%* C H3McElhaney[19] 1990 CA Y 13 60–64 71 Whole 15 – C H3Remarque[20] 1990 NL Y 55 71–84 79 Whole 15 Y 0%* C H3de Bruijn[18] 1991 NL Y 55 – 79 Sub-unit 15 Y 0%* C H3, BGlathe[21] 1991 DE Y 58 – 80 Split 15 – 95%* I H3Glathe[21] 1991 DE Y 70 – 79 Split 15 – 30%* C H3Gross[22] 1991 US 30 – 75 – 50 100%** C H3, BGross[22] 1991 US 11 85 – 50 100%** I H3, BLina [23] 1991 FR Y 54 65–93 79.3 Split 15 100%** C H3McElhaney[19] 1991 CA Y 26 62–85 72 Split 15 42%* C H3, BPowers[24] 1991 US Y 17 65–92 79 Sub-unit 15 58.8%* C H3de Brujin[18] 1992 NL Y 26 – 78 Sub-unit 15 Y 0%* C NoneMinutello [25] 1992 IT 46 65–90 73.4 Sub-unit 15 72%* C NoneBernstein[26] 1993 US 233 67–95 80.7 Sub-unit 15 97%* C H3De Donato[27] 1993 IT 98 64–87 73 Sub-unit 15 86%** C H3Gardner[28] 1993 US 92 67–91 79.1 Sub-unit 15 – C H3Lina [23] 1993 FR 119 62–99 85.9 Split 15 84.9%** C H3Gardner[29] 1994 US Y 61 70–95 81 Sub-unit 15 100%* C H3Murasko[5] 1994 US Y 270 67–95 80.2 Sub-unit 15 97%* C H3VanHoecke[30] 1994 SK/HU 457 65–100 79.9 Split 15 – I NoneIorio [31] 1995 IT 51 60–84 73 Sub-unit 15 – 100%* C NoneIorio [31] 1995 IT 80 63–100 80 Sub-unit 15 – 100%* I NoneLina [23] 1995 FR Y 55 60–85 68 Sub-unit 15 89%** C H3, BMurasko[5] 1995 US Y 258 67–95 78.8 Sub-unit 15 97%* C H3, BBridges[32] 1996 US 86 – 82.5 – 15 – 72%* I H3Murasko[5] 1996 US Y 214 67–95 80.1 Sub-unit – 97%* C H3Muszkat[33] 1997 IL 62 – 68 Split – 74%* C H1Muszkat[33] 1997 IL 114 – 81.5 Split 15 98%* I H1Baldo[34] 1998 IT 93 65–100 – Split 15 81.7%** I H3, BBaldo[34] 1998 IT 93 65–100 – Sub-unit 15 88.2%** I H3, BMuszkat[35] 1998 IL 22 60–82 76.5 Split 20 100%* I H1, H3Pregliasco[36] 1998 IT 33 65–106 – Whole 15 – I H1, H3Pregliasco[36] 1998 IT 37 65–106 – Sub-unit 15 – I H1, H3Squarcione[37] 1998 IT 591 >65 73.3 Split 15 – C H1, H3Stepanova[38] 1998 SE Y 11 58–93 – Sub-unit 15 – 0%** C H1, H3Brydak[39] 1999 PO Y 45 62–93 77.4 Split 15 – – I NoneBelshe[40] 2001 US Y 50 61–91 69.8 – 15 – C BFrech[41] 2002 CH Y 55 >60 – – 15 – C NoneHara[42] 2002 JP Y 153 66–104 84.4 Split 30 100%** I NoneRuf [43] 2002 DE 273 >60 68.1 Split 15 0%* I NoneRuf [43] 2002 DE 272 >60 67.4 Sub-unit 15 0%* I None

(–) not available, Y = Yes, blank cell = No.a First author and reference number.b October or November of the study year.c Country where the study took place according to International Organization for Standardization abbreviations.d Spilt: split-virus vaccine; Sub-u: sub-unit or sub-virosomal vaccine; Whole: whole-virus vaccine.e Dosage of each vaccine component, H1, H3, and B.f Y: excluded subjects based on SENIEUR protocol; else used less stringent health criteria for inclusion and exclusion in the study.g *Percent of elderly having received influenza vaccination in the previous year; **percent of elderly having ever received influenza vaccination.h Community living elderly; I: institutionalized elderly; M: mixed, both institutionalized and community living elderly.i H1, H3, or B: strain was a novel vaccine component that study year; none: all strains had been components in the previous years’ vaccine.


Only papers reporting either seroconversion, seroprotec-tion, or GMT results for all three of the currently circulat-ing influenza (sub)types (A/H1N1, A/H3N2, and B) wereincluded in our review. If a paper presented data on twoinfluenza B strains, only the strain named first, usually labeledB1, was included. When serological results were only shownin figures, we carefully read numerical values from thegraphs.

Although the time to peak serum antibody response toinfluenza vaccine is not clearly defined, some publicationsreport the peak occurs between 2 and 6 weeks after vacci-nation [10,11]. All papers measured antibody responses atthe time of vaccination (pre-titer) and again 2–8 weeks post-vaccination (post-titer).

2.3. Primary factor of interest: age of study participants

We selected all papers that reported data on groups ofsubjects with a mean age of 65 and over. From these papers,information on younger control groups was included in ourdatabase whenever available. The presence of young controlgroups, however, was not a requirement for studies to beincluded in this review.

2.4. Adjustment factors

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2.4.4. Living situationWe included all studies without regard to whether the

elderly subjects were living independently in the community,in institutions dependent on care, or in a mixture of settings.

2.4.5. New vaccine componentDuring the 16-year period covered by this review

(1986–2002) the WHO changed the recommended vaccinecomponent for H3N2 approximately 12 times[14]; by con-trast, H1N1 and B viruses have slower evolution rates, andthe vaccine components were only changed 5 and 9 times,respectively, during the same time period[14]. Because useof a vaccine featuring a novel antigen might affect the anti-body response, we identified the presence or absence of anovel vaccine component in each study.

2.5. Statistical analysis

From the papers selected for this review, we recorded asbest as we could summary information on the outcomes, age,and adjustment factors listed above (Tables 1 and 2). We con-structed a database with separate entries of antibody resultsfor each group of elderly and control group of younger adults.When a study presented subgroup analyses based on vari-ous adjustment factors, for example, comparing the antibodyresponse to split virus versus whole virus vaccine, we enterede rtherr per.

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Table 1describes all the adjustment factors includeur analysis.

.4.1. Type, dose and number of shots of inactivatedaccine

We only included data from groups of persons thateceived a single, intramuscular dose of inactivated influaccine in our analysis. Inactivated vaccines come in seorms (split, whole, and sub-unit) all of which were includn our review. Researchers have proposed that increasinosage of the influenza vaccine would increase the antesponse[12]. Most studies used the recommended trivanfluenza vaccine dosage (15�g of each of the H1N1, H3N2nd B antigens), but we also included studies with dosanging from 10 to 50�g in order to assess the effectaccine dosage.

.4.2. Health status of the study participantsPapers that specifically studied groups of elderly sub

ith severe underlying conditions (e.g. where all subjectspinal cord injuries or were on dialysis) were not includost studies included in this review did not apply rigorealth inclusion standards; however, some studies applieSENIEUR Protocol”[13], which patients with any chronnderlying illness, abnormal laboratory tests, or medicase are eliminated from the study.

.4.3. Previous vaccinationStudies of groups of subjects were included regardle

ean pre-vaccination antibody titers and vaccination hies.

ach independent group observation separately. We fuefer to these entries as “sub-studies” throughout the pa

Our main analysis compared responses in the eldehose in younger adults. As a secondary analysis, weompared responses in the younger elderly to the very elll factors listed inTable 1were considered in both univariand multivariate analysis and we separately studied how

actors affected responses in the elderly.All statistical analyses were carried out with SAS vers

.02, SAS Institute Inc., Cary, NC, USA.

.5.1. Univariate analysesWe first conducted univariate analyses based on

tudies weighted by the number of study participantach group. We compared vaccine response in terms ofonversion, seroprotection, and GMT, in the elderly veounger adults (<58 years old). We then compared theine response in the younger elderly and very elderly bn the mean age of the sub-studies. The ‘younger eldroup was classified as sub-studies in which the meanf subjects was between 65 and 75 years, and thelderly’ were classified as sub-studies in which the mge of subjects was over the age of 75. We also comp

he vaccine response for each individual adjustment felated to the vaccine and study participants (vaccine: vaype, vaccine dosage, new vaccine component; participiving situation, health status, vaccination prior to study;ables 1 and 2).

We used chi-square tests to compare seroconvend seroprotection (binary outcomes) in each age cat


(young adults and elderly or young elderly and very elderly),by weighting the outcome of each sub-study by the numberof participants. By contrast, GMT was given in the originalpapers as a mean estimate for each sub-study and confidenceintervals were rarely available. Therefore, we could not cal-culate a summary estimate for GMTs that would truly reflectthe variability of this measure in the population. To comparethis outcome between young and elderly persons, we usedT-tests based on the logarithm of the mean GMT in the sub-study, with no weighting.

2.5.2. Multivariate analysisWe built logistic regression models to explain the weighted

antibody vaccine response using seroconversion or sero-protection as the outcome. We built separate models foreach combination of these two outcomes and three antigens(H1N1, H3N2 and B) for both age comparisons—young ver-sus elderly and younger elderly versus very elderly.

Using a stepwise regression modeling approach, weentered age as a covariate, along with all adjustment fac-tors, including those suggested in the 1989 review[7] (healthstatus, vaccination prior to study, high pre-vaccination titres)as well living situation, mean age, antigen dose, type of vac-cine (sub-unit or split), and novelty of vaccine antigen. TheP-value for entry in the model was set at 0.20 and theP-valuef

andG ul-t

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laterw diesw pan,I t intoi , prev and

dosage. In total, 48 independent sub-studies could be iden-tified (Table 2). The studies varied in size from 11 to 591elderly subjects and from 10 to 222 younger control subjects.Across all studies, the “young” age groups were comprisedof individuals aged 17–59. The “elderly” age groups werecomprised of individuals aged 58–104 years, with a meanage ranging from 68 to 86 years. The majority of elderlysubjects had been previously vaccinated, although eight stud-ies specifically selected for individuals that had not beenpreviously vaccinated. Elderly subjects were recruited fromeither the community (61% of sub-studies) or from institu-tions (36%), usually nursing homes. Only two sub-studies(3%) recruited a mixed population of community-dwellingand institutionalized elderly.

3.2. Vaccine response in the elderly versus youngeradults

3.2.1. Unadjusted responses (univariate regressionanalysis)

Prior to vaccination, the elderly and the young had sim-ilar antibody titres measured as GMT for all three antigens(Table 3). However, a larger proportion of the elderly wereseroprotected before vaccination, although these differenceswere not always statistically significant.

ther , sero-p ens( ero-p . Int argerf thed r int thep they

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or removing factors was 0.05.Since we did not have confidence intervals for GMT

MT values are widely distributed, we did not pursue mivariate models with this outcome.

. Results

.1. Study population and demographics

From our search of the literature published in 1989 ore retrieved 31 papers that fit our criteria. These 31 stuere conducted from 1986 to 2002 in North America, Ja

srael, and nine European countries. Several were splindependent sub-studies based on the year of the studyaccination prevalence, living situation, vaccine type,

able 3re-vaccination serological measures in the young and elderly across

accine component Age group Seroprotection (percentag

No. of subjects % Posit

1N1 Young 1124 28Elderly 3516 33

3N2 Young 1124 31Elderly 3516 32

Young 1124 25Elderly 3516 40

b: antibody; CI: confidence interval; Ref: reference.* P-value between 0.05 and 0.001.

** P-value < 0.001.

-

In univariate analysis, age had a significant impact onesponse to vaccination as measured by seroconversionrotection and GMT for each of the three vaccine antigTable 4). For all three antigens, seroconversion and srotection rates were significantly higher in the young

erms of seroconversion, age group differences were lor H1N1 and B antigens than for H3N2 antigens, butifferences between the two age groups were simila

erms of seroprotection for all three antigens. Similarly,ost-vaccination GMT levels were also always higher inounger adults.

To ensure that there was not an underlying bias in thees without young controls, whereby the elderly in these ses had abnormally low antibody responses, we perfor

univariate analysis that only included studies with yoontrol groups. In this sensitivity analysis we found that

dies, by influenza sub-type

bjects with Ab titers > 40) GMT

Unadjusted OR (95% CI) No. of subjects GMT P-value

Ref 814 241.3* (1.1–1.5) 3911 18 0.75

Ref 814 321.1 (0.9–1.2) 3911 25 0.53

Ref 814 312.0** (1.7–2.3) 3911 24 0.72


Table 4Post-vaccine response (unadjusted) in young vs. elderly across all studies, by influenza sub-type

Vaccinecomponent

Agegroup

Seroconversion (percentage of subjectswith 4-fold Ab increase)

Seroprotection (percentage of subjectswith Ab titres > 40)

GMT

No. ofsubjects

% Positive Unadjusted OR(95% CI)

No. ofsubjects

% Positive Unadjusted OR(95% CI)

No. ofsubjects

GMT P-value

H1N1 Young 913 60 Ref 1151 83 Ref 814 140Elderly 4492 42 0.48** (0.41–0.55) 4643 69 0.47** (0.40–0.55) 3997 83 0.02*

H3N2 Young 913 62 Ref 1151 84 Ref 814 162Elderly 4492 51 0.63** (0.55–0.73) 4643 74 0.53** (0.45–0.63) 3406 126 0.26

B Young 913 58 Ref 1151 78 Ref 814 234Elderly 4492 35 0.38** (0.33–0.44) 4643 67 0.58** (0.50–0.67) 3406 100 0.03*

Ab: antibody; CI: confidence interval; Ref: reference.* P-value between 0.05 and 0.001.

** P-value < 0.001.

antibody response in the elderly was substantially reducedwhen the studies without young controls were excluded.

3.2.2. Adjusted responses (multivariate regressionanalysis)

The models given by the stepwise regression procedurediffered somewhat for each of the six different combina-tions of three antigens and two outcomes (seroconversionand seroprotection) studied (Fig. 1). However, in all casesa remarkably robust effect was obtained when comparingthe adjusted responses of the elderly to those of youngeradults, which was the primary factor of interest. For sero-

F ightedr ed anda s-ratiob s thani ivid-uvt

protection, this adjustment reduced the odds-ratios (OR) forH1 and B antigens from around 0.5 to around 0.25, and 0.35,respectively, suggesting that the younger adults had a 3–4-fold better response to the vaccine than the elderly for theseantigens. For H3 antigen, the adjustment slightly lowered theodds-ratio from 0.53 to 0.48, suggesting that the youngeradults responded about twice as well to the vaccine as didthe elderly for this antigen. Overall, for all three antigens andboth outcomes studied, the adjusted antibody response to thevaccine was 2–4-fold higher among the younger adults thanthe elderly.

Three other factors—previous vaccination, high pre-vaccination titre, and institutional residence—also consis-tently influenced the antibody response and remained in mostmodels. Previous vaccination was associated with signifi-cantly lower rates of seroprotection for H3 and B antigens(OR: 0.76 and 0.24, respectively), while high pre-vaccinationtitre was associated with consistently higher seroprotectionrates for all three antigens (OR: 2.25–8.74). Institutionalresidence had the most consistent impact on the antibodyresponse in all models with significantly higher responserates both in terms of seroconversion and seroprotection(OR: 1.56–3.69) for all three antigens. Indeed, the antibodyresponse in groups of institutionalized elderly was quite sim-ilar to that of younger adults in the primary multivariateanalysis. As an example, for the H3 antigen, the young had a6 whilet ratea

3g

3onse

i erye er

ig. 1. Comparison of influenza vaccine adjusted and unadjusted weesponses in the elderly vs. young adults, measured as unadjustdjusted odds-ratio, by outcome and vaccine component. An oddelow 1 indicates that the vaccine response is better in young adult

n the elderly. Adjusted odds-ratios (OR) for age derived from ind
al multiple regression models that controlled for other demographic andaccine-specific factors that also affecting the outcome. The bars indicatehe OR point estimate and the ranges the 95% confidence limits.
r on forH tionf

2% seroconversion rate and 84% seroprotection rate,he institutionalized elderly had a 65% seroconversionnd 80% seroprotection rate for the same antigen.

.3. Vaccine response comparisons within the elderlyroups

.3.1. Unadjusted responsesIn a univariate analyses comparing the antibody resp

n the ‘younger elderly’ <75 years of age and the ‘vlderly’ ≥75, the ‘very elderly’ had a significantly lowesponses in terms of seroconversion and seroprotecti1, H3, and B antigens, with the exception of seroprotec

or the B antigen (Table 5).


Table 5Post-vaccine response (unadjusted) in elderly less than 75 years vs. elderly over 75 years across all studies, by influenza sub-type

Vaccinecomponent

Age group Seroconversion (% of subjects with 4-fold Ab increase) Seroprotection (% of subjects with Ab titres > 40)

Subject No. % Positive Unadjusted OR (95% CI) Subject No. % Positive Unadjusted OR (95% CI)

H1N1 <75 1945 55.1 Ref 1883 74.8 Ref>75 2492 31.7 0.38** (0.34–0.43) 2706 65.4 0.63** (0.58–0.70)

H3N2 <75 1945 57.9 Ref 1883 82.7 Ref>75 2492 46.4 0.63** (0.56–0.71) 2706 68.1 0.45** (0.40–0.50)

B <75 1945 41.4 Ref 1883 62.3 Ref>75 2492 29.2 0.58** (0.51–0.66) 2706 70.8 1.47** (1.34–1.60)

Ab: antibody; CI: confidence interval; Ref: reference.** P-value < 0.001.

Results for all factors related to elderly study participantsand vaccine response are shown inFig. 2. The antibodyresponse to vaccine did not vary significantly by vaccinetype (split, sub-unit, or whole) for any of the six combi-nations of outcomes (seroconversion or seroprotection) andantigens (H1N1, H3N2, and B) (P > 0.05). There is no indi-cation that increasing the dosage of antigen increases the

response to the vaccine in the elderly, but the data werescarce as only three sub-studies identified had used a sub-stantially elevated dosage (Table 2). High pre-vaccinationtitre was associated with a reduced seroconversion rate and anincreased seroprotection rate. Previous vaccination was alsoassociated with reduced seroconversion, but had a less sub-stantial impact on seroprotection. Notably, institutionalized

Fr

ig. 2. (�) yes; (�) no. Comparing elderly seroconversion and seroprotectiesponse, by six combinations of antigen and outcome studied.* P < 0.05;** P < 0.0

on rates (unadjusted, weighted) for each factor suspected to affect Ab vaccine01.


elderly responded remarkably better to the vaccine than didcommunity-dwelling elderly for all antigens and both out-comes measured (OR; seroconversion: 2.14–4.50; seropro-tection: 1.55–3.44) and consistently affected the OR for agein the model.

3.3.2. Adjusted responses (multivariate regressionanalysis)

In a multiple regression model, we found that the veryelderly had a reduced antibody response to all three anti-gens when measuring seroconversion (OR: 0.32–0.61) andto H1N1 and H3N2 when measuring seroprotection (OR:0.62 and 0.42, respectively) compared to the younger elderly.However, the antibody response to B as measured by sero-protection was significantly higher in the very elderly.

4. Discussion

The approach to influenza control typically aims at reduc-ing severe influenza-related outcomes largely by vaccina-tion of the elderly, who are at highest risk for influenza-related deaths. However, there is considerable evidence thatimmune responses to vaccination decline substantially withage[44,45]. Thus, it is not entirely clear how effective vacci-nation of the elderly against influenza is in terms of reducings dom-i pastt ffi-c sug-g er 70y eclin-i ereo ebo-c vac-c s ofs diesa fromt con-fl fitsm nterd

odyr dings t thee nset tingf derly( y 1/4a rig-o e iny icalt 90%e ill-n oure effi-

cacy in the elderly of about 17–53% efficacy for all threeantigens.

It is important to emphasize that this projected efficacycannot be compared to effectiveness measures from observa-tional studies in the elderly, which predict a 50% efficacy[4],as these studies measure highly non-specific outcomes, suchas reductions in all-cause mortality. Because most influenza-related severe outcomes occurs during A/H3N2-dominatedseasons[1,2], the result for the H3 component is of mostrelevance to the objectives of influenza control. For both sero-conversion and seroprotection, the elderly had a significantlyreduced response to the H3 antigen compared to the young(adjusted OR = 0.58 and 0.48, respectively).

We tested the robustness of these odds-ratio estimatesby trying various multiple regression modeling approachesand testing the effect of multiple factors in the models (seeTable 1). While the number of factors selected in the modelsfor various outcomes and antigens differed, the odds-ratioestimate for the age component remained remarkably sta-ble. Three other factors, namely previous vaccination, highpre-titres, and living situation, also influenced the antibodyresponse significantly. Because there was likely consider-able covariation between previous vaccination status andpre-titres, it was not possible to tease out this relationship fur-ther in the context of this review. Also, the model suggestedthat institutionalized elderly responded far better comparedt ll ast entedo g ini pos-sa pos-s thatt tibodyre thesev nsis-t cencei nzav

iedw diesi iffer-e otr ones dose( thed singd

r bys anal-y vereda y. Wec 989r nted

evere influenza outcomes. Unfortunately, only one ranzed placebo-controlled trial has been published in thehree decades[46]. Although this study measured 57% eacy among people over 60 years, an age stratificationested a far lower vaccine efficacy estimate for those ovears, but the study was not powered to demonstrate dng efficacy with age (only 10% of study participants wver 70). In the near absence of “gold standard” placontrolled trials, evidence for the benefits of influenzaination in the elderly has to be derived from other typetudies—including cohort studies, excess mortality stund studies of antibody (Ab) vaccine response. Data

hese varying types of studies, however, have producedicting results, ranging from astounding mortality beneeasured in cohort studies of 50% reduction in all wieaths[4], to marginal mortality benefits[2,47].

We undertook a quantitative review of vaccine antibesponse studies published from 1989 onwards (inclutudies conducted during 1986–2002). We report thalderly≥65 have a significantly reduced antibody respo

o vaccination compared with younger adults. After adjusor vaccine and host factors, vaccine response in the elseroprotection and seroconversion) was approximatels rigorous for H1 and B antigens and about 1/2 asrous for H3 antigens, compared to the Ab responsounger adults. In randomized placebo-controlled clinrials of healthy adults, the influenza vaccine was 70–ffective in preventing serologically confirmed influenzaess[3,48]. Taking this estimate as a gold standard,stimated OR corresponds to a projected clinical vaccine

o the community-dwelling elderly, in some cases as wehe younger adults. At least one other study has commn this phenomenon, suggesting that the elderly livin

nstitutions are better taken care of and, as a result,ibly enjoy better immune status[31]. This review, whichnalyzes only group data, cannot resolve this interestingibility. However, we believe we have clearly shownhese factors cannot alone explain the decreased anesponse in the elderly as some have hypothesized[7]. Ourstimated OR for age remained stable, even when allariables were taken out of the models. We believe this coently robust effect of age suggests that immune seness playing an important role in response to the influeaccine.

The question of effect of dosing could not be studith precision in our analysis, since only 5 of the 31 stu

ncluded in this review had groups receiving dosages dnt than the standard 15�g. Our finding that dose did nemain in our model could probably reflect that only inmaller study group had received a significantly higherTable 2). However, one reviewed study that examinedose–response effect found little or no benefits of increaoses[12].

Unlike the 1989 review by Beyer et al.[7], our quantitativeeview weighted the contributions of individual studiesize of the groups studied. And unlike these authors, oursis and multiple regression adjustment procedure uncorobust result of reduced vaccine response in the elderlonclude that the mixed findings by the authors of the 1eview may in part be explained by the lack of detail prese


in the studies it reviewed at the time, which made it difficultto characterize and control for factors that affected antibodyresponse. Furthermore, three of the four studies in the Beyerreview that found a better immune response among the elderlywere conducted under unique circumstances. In one case theelderly were compared to a group of younger adults withcystic fibrosis[49]. Two other studies involved elderly popu-lations that had been primed for a particular vaccine antigenearlier in life (A/H3N2 in 1968 and A/H1N1 in 1977) whereasthe younger group had not[50,51]. Adjusting for such a prim-ing effect was not an issue for our review, because during ourstudy period 1986–2002 there were no living elderly that havebeen primed to a particular strain for which the young are not.Thus, we believe the results from our review are more repre-sentative for the contemporary influenza vaccine response inthe elderly.

As a caveat, we note that our analysis was done at thegroup level, not individual records. In our multiple regres-sion models, we weighted the studies and generated andanalyzed summary values for age and adjustment factors foreach sub-study. This may have led to some loss of preci-sion, although the potential for misclassification bias seemslow. Most importantly, we do not expect bias due to mis-classification of age, because age was a selection criterionin the papers we reviewed. Also, our OR measurements maynot be a perfect measure of relative risk and may exagger-a te fort stud-i , notb nald odyt titre≥ naly-s hent

cur-rw se toi erly.W iesp rtici-p ciner rizedt ve orb vari-a thoseo lineds oura couldn thee erizet poset derlyb tel onses

Table 6Study design recommendations for future vaccine Ab response studies

Age sub-sets Report data in 5–10 year age groups in people over65 years

Pre-vaccination Report data on subjects that had been vaccinated inthe previous year

Serological data Report pre- and post-vaccination serological data forall three main measurements, seroconversion,seroprotection, and GMT

Residence Report data on residence, whether in an institutionor independently in the community

Selection criteria Select a study group that represents a realisticpopulation of the elderly

As antibody response is but one of several components ofthe immune response, in order to fully gauge vaccine effi-cacy in the elderly one should take into account changes notonly the adaptive immune system’s antibody response butalso age-related changes in the cellular response and the acti-vation of the innate immune system. Although the underlyingmechanism of T-cell responses to influenza infection is notfully understood they are clearly important. Several recentstudies have reported an age-related decline in the functionof a variety of T-cell sub-sets[5,52–54]. Due to concernsabout reduced vaccine response with age, several Europeancountries are already using an adjuvanted influenza vaccinespecifically designed for use in the elderly[25].

In the absence of further controlled clinical trials, andgiven the unresolved disagreement between cohort studiesand excess mortality studies[2], evidence from immunolog-ical studies and elucidation of the phenomena of immunesenescence are critical for our understanding of the likelyclinical response to influenza vaccine in the very elderly. Atbest, such studies should consider both antibody and cellularimmunity to the influenza vaccine. Until such a comprehen-sive understanding is achieved, we believe our finding in thisreview supports the need for further research into the phe-nomenon of immune senescence, with the hope that suchinsights will eventually lead to more immunogenic vaccineformulations.

A

hisa

R

er-tory

RJ,in

2.con-on

ep

te somewhat the projected low vaccine efficacy estimahe elderly. Some statistical power was lost because sixes only reported seroconversion or seroprotection dataoth. Additionally, some studies did not use the traditioefinitions for seroconversion (4-fold increase in HI antib

itres) and seroprotection (post-vaccination HI antibody40); but when these studies were taken out of the aes, the elderly responded slightly less vigorously than whese studies were included.

Since as many as 70% of all influenza-related deathsently occur among persons over the age of 75 in the US[2],e had initially planned to also study the antibody respon

nfluenza vaccination with increasing age among the elde were surprised to find that only 3 of the 31 stud

resented results for age breakdowns of the elderly paants. To study quantitatively the effect of age on the vacesponse based on the published literature, we categohe elderly study groups into those with a mean age aboelow 75, as a best proxy for age. In univariate and multite analysis, there was a significantly lower response inver 75 years of age, suggesting that Ab response decignificantly with age among the elderly. However, sincenalysis could only be based on group mean age, weot further quantify the impact of increasing age withinlderly age group. Therefore, in order to better charact

he likely age-dependence of vaccine response, we prohat future studies report vaccine response in the ely 5 or 10 year increments.Table 6 presents a comple

ist of suggestions to authors of future vaccine Ab resptudies.

cknowledgement

The authors would like to thank Mr. Robert Taylor forssistance in editing this manuscript.

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Antibody response to influenza vaccination in the elderly: A quantitative review