Vaccine 33 (2015) 4988–4993

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Prevention of serious events in adults 65 years of age or older:

A comparison between high-dose and standard-dose inactivated
influenza vaccines夽
Carlos A. DiazGranados a,∗ , Corwin A. Robertson a , H. Keipp Talbot b , Victoria Landolfi a ,
Andrew J. Dunning a , David P. Greenberg a,c
a
Sanofi Pasteur, 1 Discovery Drive, Swiftwater, PA 18370, USA
b
Vanderbilt University Medical Center, A2200 MCN 1161 21st Ave S, Nashville, TN 37212, USA
c
Department of Pediatrics, University of Pittsburgh School of Medicine, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: A recent study showed that a high-dose inactivated influenza vaccine (IIV-HD) was 24.2%
Received 23 April 2015 more efficacious than a standard-dose inactivated influenza vaccine (IIV-SD) in preventing laboratory-
Received in revised form 3 July 2015 confirmed symptomatic influenza in adults ≥65 years. Here we evaluate the effectiveness of IIV-HD
Accepted 6 July 2015
compared to IIV-SD in preventing serious illnesses considered potential sequelae or complications of
Available online 26 July 2015
influenza infection.
Methods: The original study was a double-blind, randomized, active-controlled, multicenter trial. Par-
Keywords:
ticipants were adults ≥65 years randomized to receive IIV-HD or IIV-SD, and followed for 6–8 months
Influenza vaccines, human
Vaccines, inactivated
post-vaccination for the occurrence of influenza and serious adverse events (SAEs). SAEs were events:
Clinical trial, phase III leading to death or hospitalization (or its prolongation); considered life-threatening or medically impor-
Aged tant; or resulting in disability. For the present analysis, reported SAEs were classified as possibly related
Aged, 80 and over to influenza by three blinded physicians and rates per 1000 participant-seasons were calculated. Relative
vaccine effectiveness (rVE) was estimated as (1 − Rate Ratio) × 100.
Results: 31,989 participants were enrolled, with 15,991 and 15,998 randomized to receive IIV-HD and IIV-
SD, respectively. IIV-HD was significantly more effective than IIV-SD in preventing SAEs possibly related
to influenza overall (rVE, 17.7%; 95% confidence interval [CI], 6.6–27.4%) and serious pneumonia (rVE,
39.8%; 95% CI, 19.3–55.1%). Borderline significance was observed for the efficacy of IIV-HD relative to
IIV-SD for the prevention of all-cause hospitalizations (rVE, 6.9%; 95% CI, 0.5–12.8%).
Conclusions: Compared to IIV-SD, IIV-HD reduced the risk of SAEs possibly related to influenza. The
observed relative effectiveness against serious pneumonia is particularly noteworthy considering the
burden of influenza and pneumonia in older adults.
© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

1. Introduction seasonal influenza-related hospitalizations and deaths [1,2]. The

Adults 65 years of age and older are particularly vulnerable
to complications from influenza infection, accounting for most
Abbreviations: IIV-HD, high-dose inactivated influenza vaccine; CI, confidence
interval; IIV-SD, standard-dose inactivated influenza vaccine; SAE, serious adverse
event; COPD, chronic obstructive pulmonary disease; RR, rate ratios; rVE, relative
vaccine effectiveness; FAS, Full Analysis Set; ITT, intent-to-treat; CAP, community-
acquired pneumonia.
夽 Presented in part at AMDA Long Term Care Medicine – 2014, Nashville, TN, 27
February–2 March 2014. Abstract available at: JAMDA 2014; 15(3): Page B28
(DOI: http://dx.doi.org/10.1016/j.jamda.2013.12.076).
∗ Corresponding author. Tel.: +1 570 9570745; fax: +1 570 9570934.
E-mail address: carlos.diazgranados@sanofipasteur.com (C.A. DiazGranados).
high burden of influenza in this population persists despite docu-
mented improvements in vaccination rates [3]. Accordingly, the
availability of improved influenza vaccines for older adults had
been considered an unmet medical need [4,5]. A recently completed
double-blind, randomized, controlled trial (NCT01427309) demon-
strated that a high-dose inactivated influenza vaccine (IIV-HD) was
24.2% (95% confidence interval [CI], 9.7%–36.5%) more efficacious
than a standard-dose inactivated influenza vaccine (IIV-SD) in pre-
venting laboratory-confirmed symptomatic influenza in adults 65
years of age and older [6].
In addition to the observed improvement in efficacy, 119 fewer
study participants developed at least one serious adverse event
(SAE) of any cause in the IIV-HD group compared to the IIV-SD
group. The risk of developing at least one SAE during the study was

http://dx.doi.org/10.1016/j.vaccine.2015.07.006
0264-410X/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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 C.A. DiazGranados et al. / Vaccine 33 (2015) 4988–4993
significantly lower among IIV-HD recipients than IIV-SD recipients
(relative risk 0.92, 95% CI, 0.85–0.99), suggesting that IIV-HD may
improve protection against the occurrence of influenza-related
serious events [6].
According to results from the last National Hospital Discharge
Survey conducted by the National Center for Health Statistics in the
United States, the top leading causes of hospitalization in adults 65
years or older are heart disease (including ischemic heart disease
and congestive heart failure), cerebrovascular disease, pneumonia,
and malignant neoplasms [7]. Excluding malignancy, influenza may
play an important role in the occurrence of these hospitalization-
related events, either by triggering exacerbations of pre-existing
conditions or by direct involvement of affected organs or tissues
[8–13]. It is therefore of particular interest for individual and public
health to evaluate the impact of influenza vaccines on the occur-
rence of serious cardio-respiratory events traditionally considered
potential complications or sequelae of influenza. To this end, the
present supplementary analysis of the original efficacy trial evalu-
ated the effectiveness of IIV-HD compared to IIV-SD in preventing
all-cause hospitalizations and serious cardio-respiratory events
possibly related to influenza infection.
2. Methods
2.1. Overall study design
Details of the original study design are presented else-
where [6]. Briefly, the study was a double-blind, randomized,
active-controlled, multicenter clinical trial, conducted during the
2011–2012 (Year 1) and 2012–2013 (Year 2) influenza seasons in
126 research centers in the United States and Canada. Adults 65
years of age and older were randomly assigned in a 1:1 ratio to
receive IIV-HD (Fluzone® High-Dose [Sanofi Pasteur, Swiftwater,
PA, USA], containing 60 ␮g of hemagglutinin per vaccine strain) or
IIV-SD (Fluzone [Sanofi Pasteur, Swiftwater, PA, USA], containing
15 ␮g of hemagglutinin per strain). Each season, participants were
followed for 6–8 months post-vaccination for the occurrence of
influenza and SAEs. SAEs were defined as events: leading to death or
hospitalization (or its prolongation); considered as life-threatening
or medically important; or resulting in disability [14]. Based on
available medical information, study investigators reported the
diagnoses associated with all SAEs.
2.2. Adjudication of SAEs as “serious events possibly related to
influenza”
Two physicians blinded to treatment group independently
reviewed all SAE diagnostic categories that were reported during
the study; these diagnostic categories had been coded as “preferred
terms” using the Medical Dictionary for Regulatory Activities [15]
versions 14.0 (for Year 1) and 15.0 (for Year 2) before study unblind-
ing. There were a total of 1347 SAE preferred terms reviewed.
Cardio-respiratory SAE categories considered as possibly related to
influenza infection were selected by each reviewer, based solely on
the medical nature of the reported preferred term for the diagnosis
(for example, SAEs with a diagnosis preferred term of “pneumo-
nia” were selected as possibly related to influenza, whereas SAEs
with a diagnosis preferred term of “hip fracture” were excluded).
The physician-reviewers then compared their respective selections
and exclusions to attempt consensus, which was attained for 1335
(99.1%) SAE preferred terms. The 12 remaining discrepant SAE
preferred term categorizations were arbitrated by a third blinded
physician-reviewer. Final adjudication of SAE categories as “possi-
bly related to influenza” was done before study unblinding, and
the selected categories were pre-specified in a supplementary
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4989
analysis plan. Adjudication was done without regard to influenza
confirmation in the study. Events were grouped in seven larger
categories: pneumonia events, asthma/COPD (chronic obstructive
pulmonary disease)/bronchial events, influenza events (serious
laboratory-confirmed influenza diagnosed outside study proce-
dures by a participant’s health-care provider), other respiratory
events, coronary artery events, congestive heart failure events, and
cerebrovascular events. The selected preferred terms and their clas-
sification are available in Supplementary appendix. All preferred
terms for the SAEs reported in the study (selected and not selected)
are publicly available at clinicaltrials.gov [16].
2.3. Statistical methods
Rates of all-cause hospitalizations and selected serious cardio-
respiratory events were calculated for IIV-HD and IIV-SD groups
as the number of hospitalizations or events per 1000 participant-
seasons. Rate ratios (RRs) and corresponding 2-sided 95% CIs were
estimated using the method given by Blackwelder [17]. Relative
vaccine effectiveness (rVE) was calculated as (1 − RR) × 100.
Analyses were done in the Full Analysis Set (FAS) according to
the vaccine assigned at randomization (intent-to-treat [ITT] analy-
sis). The FAS comprised all participants who received study vaccine.
Estimates were obtained for each study season and for both sea-
sons combined. Statistical significance was defined as a 2-sided 95%
CI excluding the null value (1 for RR and 0 for rVE).
3. Results
A total of 31,989 participants were enrolled in the study, of
whom 15,991 were randomized to IIV-HD (15,990 included in
the ITT analysis) and 15,998 were randomized to IIV-SD (15,993
included in the ITT analysis). Only 24 participants did not receive
the vaccine as randomized (0.08%). Enrollees included 14,500 par-
ticipants in Year 1 and 17,489 in Year 2.
Baseline clinical and demographic characteristics were well bal-
anced between groups [6]. In both groups, the mean age was
73.3 years, 56–57% of participants were female, approximately
67% had at least one high-risk pre-specified comorbid illness, and
approximately 74% had received influenza vaccination the previ-
ous season. The frequency of historical pneumococcal vaccination
prior to study start was essentially the same for IIV-HD (65.17%)
and IIV-SD (64.81%) recipients. Pneumococcal vaccination during
the study was rare, and of approximate equal frequency between
groups (3.57% for IIV-HD, 3.53% for IIV-SD). Study mean participant
follow-up time was 226 days for both groups.
There were a total of 3173 hospitalization events (all-cause),
1590 in Year 1 and 1583 in Year 2. The number and rate of occur-
rence of all SAEs reported in the study (selected and not selected
for this supplementary analysis) by treatment group and study year
are available at clinicaltrials.gov [16].
A total of 948 serious cardio-respiratory events adjudicated as
possibly related to influenza were reported in the study, 440 in Year
1 and 508 in Year 2. The vast majority of these cardio-respiratory
events resulted in hospitalization (94.8%) and a smaller proportion
were fatal (6.9%).
Rates of all-cause hospitalizations and serious cardio-
respiratory events possibly related to influenza (overall and
by category) for IIV-HD and IIV-SD are presented in Table 1.
Corresponding RRs and CIs are depicted graphically in Fig. 1.
Rates of all-cause hospitalization did not differ between groups
in Year 1, whereas they were significantly lower for the IIV-HD
group in Year 2; for both study years combined, the rate of all-cause
hospitalization was 6.9% (95% CI, 0.5–12.8%) lower in the IIV-HD
group.
4990 C.A. DiazGranados et al. / Vaccine 33 (2015) 4988–4993

Table 1
Rates of all-cause hospitalization and serious cardio-respiratory events possibly related to influenza (intent-to-treat analysis).

Year 1 Year 2 Combined

IIV-HD IIV-SD (N = 7244), IIV-HD IIV-SD (N = 8749), IIV-HD IIV-SD

(N = 7253), n (rate)a (N = 8737), n (rate)a (N = 15,990), (N = 15,993),
n (rate)a n (rate)a n (rate)a n (rate)a

All-cause hospitalization 797 (109.89) 793 (109.47) 733 (83.90) 850 (97.15) 1530 (95.68) 1643 (102.73)
Serious cardio-respiratory events 204 (28.13) 236 (32.58) 224 (25.64) 284 (32.46) 428 (26.77) 520 (32.51)
Pneumonia events 29 (4.00) 54 (7.45) 42 (4.81) 64 (7.32) 71 (4.44) 118 (7.38)
Asthma/COPD/bronchial events 40 (5.51) 21 (2.90) 34 (3.89) 54 (6.17) 74 (4.63) 75 (4.69)
Influenza eventsb 1 (0.14) 0 (0.00) 3 (0.34) 6 (0.69) 4 (0.25) 6 (0.38)
Coronary artery events 55 (7.58) 70 (9.66) 66 (7.55) 54 (6.17) 121 (7.57) 124 (7.75)
Congestive heart failure 24 (3.31) 28 (3.87) 33 (3.78) 47 (5.37) 57 (3.56) 75 (4.69)
Cerebrovascular events 43 (5.93) 39 (5.38) 29 (3.32) 38 (4.34) 72 (4.50) 77 (4.81)
Other respiratory events 13 (1.79) 24 (3.31) 18 (2.06) 23 (2.63) 31 (1.94) 47 (2.94)

Abbreviations: IIV-HD, high-dose inactivated influenza vaccine; IIV-SD, standard-dose inactivated influenza vaccine; COPD, chronic obstructive pulmonary disease
a
n = number of events; rate = events per 1000 participant-seasons.
b
Corresponding to serious laboratory-confirmed influenza diagnosed outside study procedures by a participant’s health-care provider.

Rate Ratio (95% CI)

YEAR 1

All-cause hospitalization 1.00 (0.91; 1.10)

Serious cardio-respiratory events 0.86 (0.72; 1.04)
Pneumonia events 0.54 (0.34; 0.84)
Asthma/COPD/bronchial events 1.90 (1.12; 3.22)
Influenza events NA
Coronary artery events 0.78 (0.55; 1.12)
Congestive heart failure 0.86 (0.50; 1.48)
Cerebrovascular events 1.10 (0.71; 1.70)
Other respiratory events 0.54 (0.28; 1.06)

YEAR 2

All-cause hospitalization 0.86 (0.79; 0.95)

Serious cardio-respiratory events 0.79 (0.66; 0.94)
Pneumonia events 0.66 (0.45; 0.97)
Asthma/COPD/bronchial events 0.63 (0.41; 0.97)
Influenza events 0.50 (0.13; 2.00)
Coronary artery events 1.22 (0.86; 1.75)
Congestive heart failure 0.70 (0.45; 1.10)
Cerebrovascular events 0.76 (0.47; 1.24)
Other respiratory events 0.78 (0.42; 1.45)

COMBINED (YEAR 1 AND YEAR 2)

All-cause hospitalization 0.93 (0.87; 1.00)

Serious cardio-respiratory events 0.82 (0.73; 0.93)
Pneumonia events 0.60 (0.45; 0.81)
Asthma/COPD/bronchial events 0.99 (0.72; 1.36)
Influenza events 0.67 (0.19; 2.36)
Coronary artery events 0.98 (0.76; 1.25)
Congestive heart failure 0.76 (0.54; 1.07)
Cerebrovascular events 0.94 (0.68; 1.29)
Other respiratory events 0.66 (0.42; 1.04)

.13 .25 .5 1 2 4
< < Favors IIV-HD Favors IIV-SD > >

Fig. 1. Rate ratios (IIV-HD/IIV-SD) for all-cause hospitalization and serious cardio-respiratory events possibly related to influenza (intent-to-treat analysis). Each horizontal
line represents the 95% confidence interval of the rate ratio for each comparison, with the center being the corresponding point estimate. The vertical line represents the null
value of 1. Horizontal lines that do not intersect with the vertical line are statistically significant. Point estimates to the left of vertical line favor IIV-HD, and those to the right
favor IIV-SD. “Influenza Events” refer to serious laboratory-confirmed influenza diagnosed outside study procedures by a participant’s health-care provider. Abbreviations:
IIV-HD, high-dose inactivated influenza vaccine; IIV-SD, standard-dose inactivated influenza vaccine; COPD: chronic obstructive pulmonary disease.

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 C.A. DiazGranados et al. / Vaccine 33 (2015) 4988–4993
Table 2
Effectiveness of IIV-HD relative to IIV-SD against all-cause hospitalization and serious cardio-respiratory events possibly related to influenza (intent-to-treat analysis).
Year 1
N = 14,497,
rVE% (95% CI)
All-cause hospitalization −0.4 (−10.1; 8.5)
Serious cardio-respiratory events 13.7 (−3.8; 28.2)
Pneumonia events 46.4 (15.9; 65.8)
Asthma/COPD/bronchial events −90.2 (−222.3; −12.3)
Influenza eventsa NE
Coronary artery events 21.5 (−11.5; 44.8)
Congestive heart failure 14.4 (−47.5; 50.3)
Cerebrovascular events −10.1 (−69.7; 28.5)
Other respiratory events 45.9 (−6.2; 72.4)
Abbreviations: rVE, relative vaccine effectiveness; CI, confidence interval; COPD, chronic obstructive pulmonary disease; NE, non-evaluable.
a
Corresponding to serious laboratory-confirmed influenza diagnosed outside study procedures by a participant’s health-care provider.
For the 2 study years combined, the aggregate rates of seri-
ous cardio-respiratory events possibly related to influenza were
lower in the IIV-HD group for any event overall and for each of the
seven pre-specified categories. For each of the 2 study years, con-
sistently lower rates in the IIV-HD group were observed for any
serious cardio-respiratory event possibly related to influenza over-
all, serious pneumonia, serious congestive heart failure, and other
serious respiratory events (i.e., selected respiratory diagnoses other
than pneumonia, asthma/COPD/bronchial events, or influenza; see
Supplementary appendix for details).
Significantly lower rates in the IIV-HD group were observed for:
any serious cardio-respiratory event possibly related to influenza
overall in Year 2 and both years combined; serious pneumo-
nia in each study year and the 2 years combined; and serious
asthma/COPD/bronchial events in Year 2. A significantly lower rate
for IIV-SD compared to IIV-HD was observed only for the occurrence
of serious asthma/COPD/bronchial events in Year 1.
Point estimates and 95% CIs for the effectiveness of IIV-HD com-
pared to IIV-SD for the prevention of all-cause hospitalization and
serious cardio-respiratory events possibly related to influenza are
presented in Table 2. The largest reduction in disease burden was
observed for serious pneumonia, which was reported 39.8% less
frequently among IIV-HD recipients than among IIV-SD recipients
overall (both years combined): 46.4% in Year 1 and 34.3% in Year 2.
All three measures of rate reduction for serious pneumonia were
statistically significant (p values 0.001, 0.006, and 0.040 for both
years combined, Year 1 and Year 2, respectively).
4. Discussion
Influenza is associated with high morbidity and mortality in
older adults [4]. Although vaccination currently represents the
most effective intervention in preventing influenza and its com-
plications [2,18], antibody responses and protection elicited by
standard-dose influenza vaccines are lower in persons 65 years
of age and older compared to younger adults [19–21]. Strategies
to improve immune responses to influenza vaccines in this pop-
ulation may have a favorable impact on morbidity and mortality
[22]. Several approaches have been developed to improve immune
responses to influenza in older adults, including the use of higher
doses of antigen, adjuvants [23–26], and alternative delivery sys-
tems [27]. One of such approaches is IIV-HD, which contains four
times the amount of hemagglutinin antigen per strain compared to
standard-dose intramuscular influenza vaccines.
Because of the recognized association of influenza with seri-
ous illness in older adults, we explored the impact of IIV-HD
beyond its demonstrated superior efficacy over IIV-SD in preven-
ting laboratory-confirmed influenza illness, by evaluating IIV-HD
effectiveness in preventing hospitalization and serious illness pos-
sibly related to influenza. To achieve this objective, we performed a
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4991
Year 2 Combined
N = 17,486, N = 31,983,
rVE% (95% CI) rVE% (95% CI)
13.6 (5.1; 21.4) 6.9 (0.5; 12.8)
21.0 (6.1; 33.5) 17.7 (6.6; 27.4)
34.3 (3.1; 55.4) 39.8 (19.3; 55.1)
37.0 (3.3; 58.9) 1.3 (−36.0; 28.4)
49.9 (−100.1; 87.5) 33.3 (−136.2; 81.2)
−22.4 (−75.1; 14.5) 2.4 (−25.3; 24.0)
29.7 (−9.6; 54.9) 24.0 (−7.2; 46.1)
23.6 (−23.8; 52.8) 6.5 (−28.9; 32.1)
21.6 (−45.1; 57.7) 34.0 (−3.8; 58.1)
supplementary analysis of data collected during the original large-
scale efficacy study.
We observed that IIV-HD was significantly more effective than
IIV-SD in preventing serious cardio-respiratory events possibly
related to influenza, most of which corresponded to hospitaliza-
tions, with an overall relative vaccine effectiveness of 17.7%. Two
recently published studies have evaluated the effect of IIV-HD
compared to IIV-SD on similar outcomes: consistent with our find-
ings, a large retrospective cohort study [28] reported an overall
relative effectiveness estimate of 20.6% against influenza hospital
admissions or emergency department visits, with similar estimates
observed for individuals 65–74 years, 75–84 years, and ≥85 years;
in contrast, another retrospective cohort study found evidence of
improved effectiveness of IIV-HD against influenza and pneumonia
hospitalizations only in individuals ≥85 years of age [29]. Com-
pared to previous reports, our results have the major strength of
resulting from a large double-blind, randomized, controlled trial,
which minimizes the likelihood of bias, including the so-called
healthy vaccinee bias [30,31]. Moreover, we observed a borderline
significant overall effectiveness of IIV-HD relative to IIV-SD for the
prevention of all-cause hospitalization.
As the original study was only powered to evaluate the pri-
mary endpoint of laboratory-confirmed influenza associated with a
protocol-defined influenza-like illness, the present supplementary
analysis cannot be expected to reveal all true effects with statisti-
cal significance. Therefore, an important aspect for the evaluation
of a possible causal association between IIV-HD and prevention
of serious cardio-respiratory events compared to IIV-SD is the
reproducibility of the results under independent observations. The
efficacy study was performed over 2 years characterized by dis-
tinct influenza seasons: the first had low influenza activity and was
characterized by moderate to good match between the vaccine and
circulating strains; the second had high influenza activity and was
characterized by mismatch between the predominant circulating
influenza virus strain and the vaccine strains. Because of the het-
erogeneity of the two influenza study seasons, the consistency of
the association between IIV-HD and prevention of serious events
could be evaluated based on these two independent sets of data.
Rates of serious events were consistently lower for IIV-HD than for
IIV-SD in both study years for three of the seven pre-selected seri-
ous cardio-respiratory event categories (pneumonia, other selected
respiratory events, and heart failure) and for the aggregate occur-
rence of any serious event possibly related to influenza. Moreover,
the various point estimates (Fig. 1) were nearly all arrayed in favor
of IIV-HD, demonstrating an important consistency of results.
It is well-established that influenza can cause primary viral
pneumonia and predispose infected individuals to secondary bac-
terial pneumonia [13,32]. Community-acquired pneumonia (CAP)
is a major cause of morbidity and mortality in older adults, with
915,900 episodes estimated to occur annually in the United States
4992 C.A. DiazGranados et al. / Vaccine 33 (2015) 4988–4993
in adults 65 years of age and older [33]. Pneumonia is the third
leading cause of hospitalization and sixth leading cause of death
in older adults [7,34]. Strategies to prevent CAP have targeted
Streptococcus pneumoniae, which is the major bacterial pathogen
associated with this illness. Two vaccines are currently licensed in
the United States for the prevention of pneumococcal disease in
older adults: 23-valent pneumococcal polysaccharide vaccine and
13-valent pneumococcal conjugate vaccine. Although the polysac-
charide vaccine is considered efficacious in preventing invasive
pneumococcal disease in older adults [35], its role in the preven-
tion of non-bacteremic CAP has been a matter of debate [36]. The
13-valent pneumococcal conjugate vaccine recently demonstrated
significant efficacy in the prevention of invasive pneumococcal dis-
ease and pneumococcal pneumonia due to included serotypes in a
randomized placebo-controlled trial conducted in the Netherlands
among approximately 85,000 adults aged ≥65 years [37]. The study
showed 45.6% efficacy against vaccine-type pneumococcal pneu-
monia. In this context, the observed 39.8% overall effectiveness of
IIV-HD compared to IIV-SD against serious pneumonia of any etiol-
ogy in our study is particularly noteworthy. Moreover, IIV-HD effec-
tiveness against serious pneumonia was consistent and statistically
significant in each of the two study years. Previous reports have also
signaled a favorable impact of influenza vaccines on CAP [25,38].
A recent meta-analysis of randomized controlled trials reported
that the use of influenza vaccines was associated with a lower risk of
major adverse cardiovascular events (cardiovascular death or hos-
pitalization associated with myocardial infarction, unstable angina,
stroke, heart failure, or urgent coronary revascularization) [39]. We
observed 24.0% overall effectiveness of IIV-HD over IIV-SD against
serious congestive heart failure. Of note, although not statistically
significant, positive relative effectiveness point estimates (favor-
ing IIV-HD) for preventing serious heart failure were consistently
observed in both years of the study. This was not the case for serious
coronary and cerebrovascular events, for which the relative effec-
tiveness estimates were imprecise and variable across study years.
The interpretation of the results for serious asthma/COPD/
bronchial events and all-cause hospitalization in our study is chal-
lenging: the rate of asthma/COPD/bronchial events for IIV-HD
recipients was significantly higher than the rate for IIV-SD recipi-
ents in Year 1 of the study, but significantly lower in Year 2; and the
rate of all-cause hospitalization events for IIV-HD recipients was
the same as the rate for IIV-SD recipients in Year 1 of the study,
significantly lower for the IIV-HD group in Year 2, and also lower
for the IIV-HD group with borderline statistical significance for both
years combined. The apparent disparate estimates from year to year
for these outcomes may be explained by the large differences in the
epidemiology of the two influenza seasons encompassing the study,
the role that influenza may have played in triggering new onset or
exacerbations of bronchial events and any hospitalization, and the
fact that evaluated outcomes in this supplementary analysis did not
require laboratory confirmation of influenza. Since the first year of
the study coincided with very low influenza activity [40], and the
second year of the study coincided with very high influenza activ-
ity [41], it is conceivable that the majority of bronchial events and
hospitalizations in Year 1 of the study may have been unrelated to
influenza and therefore unlikely to be affected by a more efficacious
influenza vaccine. Given the higher level of influenza activity dur-
ing the second year of the study, it is likely that the proportion of
influenza-related bronchial events and hospitalizations increased
meaningfully in Year 2, revealing a possible protective effect from
IIV-HD over IIV-SD. Therefore, while investigating influenza vac-
cine effects, the influenza specificity of the bronchial and all-cause
hospitalization events might have been higher in the second year of
the study than in the first year. It has been well established that the
use of non-specific outcomes can affect efficacy/effectiveness esti-
mates by biasing them towards the null [42]. While this can explain
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null estimates for hospitalization in Year 1, it may not completely
explain the observed significantly higher rate of bronchial events
in the IIV-HD arm in Year 1. In our view, the most likely explana-
tion for this observation is random error in the context of multiple
comparisons.
It is also interesting that while the analyses showed that IIV-HD
was not effective in preventing serious bronchial events in Year 1,
it showed strong effectiveness of the vaccine against serious pneu-
monia during the same period. This suggests that the observed
serious pneumonia events may have been more likely to be asso-
ciated with influenza than the observed serious bronchial events,
making the pneumonia outcomes more specific than the bronchial
outcomes and therefore less likely to be negatively biased. How-
ever, the fact that strong effectiveness against serious pneumonia
was observed in the context of a weak influenza season in Year
1 of the study suggests that IIV-HD may have ancillary effects on
the most common etiologies of serious pneumonia (beyond its pre-
vention or modulation of influenza), mediated directly through a
cross-pathogen immune response or indirectly through alterations
of the nasopharyngeal microbiome. These interpretations remain
speculative at this time and further research is required to test them
as formal hypotheses.
This supplementary analysis of the original study has several
limitations. As mentioned earlier, the original study was not pow-
ered to address the objectives of this analysis, and the outcomes
evaluated here were not necessarily influenza-specific. These two
factors likely affected both the magnitude and precision of the
observed effects. In addition, the study compared IIV-HD with IIV-
SD, an active control that likely provided some protective effects
against the evaluated outcomes. Accordingly, the supplementary
analysis may underestimate the effect that IIV-HD may have on
the prevention of serious cardio-respiratory events. Finally, this
analysis evaluated multiple associations without correcting for
multiplicity. Therefore, even statistically significant effects need to
be interpreted with caution.
In conclusion, this supplementary analysis suggests that
compared to IIV-SD, IIV-HD may better prevent serious cardio-
respiratory illnesses considered potential sequelae or complica-
tions of influenza infection. The observed effectiveness against
serious pneumonia is particularly noteworthy considering the dis-
proportionate burden of influenza and pneumonia in older adults.
Acknowledgements
The authors would like to thank the study participants, the
investigators from the 126 participating research sites, and the
Sponsor’s Study Team for their contributions to the original study.
Conflict of interest statement: The study was sponsored by Sanofi
Pasteur.
C.A.D., C.A.R., V.L., A.J.D., and D.P.G. are employees of Sanofi Pas-
teur.
H.K.T has received research funding from MedImmune, Sanofi
Pasteur, and Gilead.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.vaccine.2015.07.
006
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