Mortality risk is shown by the number of successive vaccinations, ie,
first, second, third, fourth, fifth, more than 6, interruption of vaccination
(stop), or restart. The hazard ratio indicates the mortality risk following
vaccination vs no previous vaccination.
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Voordouw ACG, Sturkenboom MCJM, Dieleman JP, et al. Annual Revaccination Against Influenza and Mortality Risk in Community-Dwelling Elderly Persons. JAMA. 2004;292(17):2089–2095. doi:10.1001/jama.292.17.2089
Author Affiliations: Pharmaco-epidemiology
Unit, Departments of Internal Medicine and Epidemiology & Biostatistics
(Drs Voordouw, Sturkenboom, Dieleman, Stijnen, and Stricker), Department of
Medical Informatics (Drs Sturkenboom, Dieleman, and van der Lei), and Department
of Virology (Dr Smith), Erasmus University Medical Center, Rotterdam, the
Netherlands; Medicines Evaluation Board (Dr Voordouw) and DrugSafety Unit,
Inspectorate for Health Care (Dr Stricker), the Hague, the Netherlands; and
Department of Zoology, University of Cambridge, Cambridge, England (Dr Smith).
Context Although large-scale observational studies have demonstrated the effectiveness
of influenza vaccination, no large studies have systematically addressed the
clinical benefit of annual revaccinations.
Objective To investigate the effect of annual influenza revaccination on mortality
in community-dwelling elderly persons.
Design, Setting, and Participants A population-based cohort study using the computerized Integrated Primary
Care Information (IPCI) database in the Netherlands including community-dwelling
individuals aged 65 years or older from 1996 through 2002. For each year,
we computed the individual cumulative exposure to influenza vaccination since
Main Outcome Measure Association between the number of consecutive influenza vaccinations
and all-cause mortality vs no vaccination after adjusting for age, sex, chronic
respiratory and cardiovascular disease, hypertension, diabetes mellitus, renal
failure, and cancer.
Results The study population included 26 071 individuals, of whom 3485
died during follow-up. Overall, a first vaccination was associated with a
nonsignificant annual reduction of mortality risk of 10% (hazard ratio [HR],
0.90; 95% confidence interval [CI], 0.78-1.03) while revaccination was associated
with a reduced mortality risk of 24% (HR, 0.76; 95% CI, 0.70-0.83). Compared
with a first vaccination, revaccination was associated with a reduced annual
mortality risk of 15% (HR, 0.85; 95% CI, 0.75-0.96). During the epidemic periods
this reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). Similar estimates were
obtained for persons with and without chronic comorbidity and those aged 70
years or older at baseline. Overall, influenza vaccination is estimated to
prevent 1 death for every 302 vaccinees at a vaccination coverage that varied
between 64% and 74%.
Conclusion Annual influenza vaccination is associated with a reduction in all-cause
mortality risk in a population of community-dwelling elderly persons, particularly
in older individuals.
Influenza-associated morbidity and mortality increase with age, especially
for individuals with high-risk conditions.1,2 The
estimated impact of annual influenza epidemics on morbidity and mortality
on elderly persons and the effectiveness of influenza vaccination have been
the basis for implementing nationwide influenza vaccination programs for elderly
The effectiveness of vaccination has been reported to decrease in high-risk
influenza revaccination has been proposed as a strategy to increase vaccination
clinical studies have not always shown a consistent benefit of annual revaccination.
In institutionalized elderly persons, annual revaccination resulted in improved
survival,12,13 whereas, in a placebo-controlled
trial among 1838 community-dwelling elderly persons, prior vaccination did
not further reduce the occurrence of clinical influenza.4 In
a trial of healthy adults (aged 30-60 years), annual influenza vaccination
had no additional effect on the risk of clinically diagnosed influenzalike
illness, although both first vaccination and repeat vaccination showed a greater
decrease in virus shedding and better annual protection against influenza
virus infection compared with placebo.14,15 In
a clinical trial among boarding school students, revaccination did not confer
any benefit with respect to serologically or virologically confirmed influenza.16 A recent meta-analysis comparing single and multiple
vaccinations showed that although 7 of 10 field trials supported sustained
protection against laboratory-confirmed influenzalike illness upon revaccination,
the pooled rate difference of 1.1% was not significant.17
Recommendations regarding annual vaccination are often based on the
reported influenza-attributed mortality and morbidity and effectiveness of
vaccination without systematic data on revaccination status.18-21 So
far, studies to establish the effectiveness of repeated influenza vaccinations
within the scope of national programs have not been performed in a population-based
Our objective was to investigate the relationship of influenza revaccination
status on mortality in community-dwelling persons aged 65 years or older during
the epidemic influenza seasons covering 1996-2002.
In the Netherlands, a nationwide influenza vaccination program has been
active since 1997. In the Dutch health care system, all persons are designated
to their own general practitioner (GP) who files all relevant medical details
on patients from primary care visits, hospital admissions, laboratory examinations,
and visits to outpatient clinics. The vaccination program is executed by GPs
during annual mass vaccination days in October and November, during which
all individuals aged 65 years and older and adults and children with predefined
risk factors are invited to participate in the vaccination campaign. General
Practitioners register the vaccination date in the electronic patient record.
Since 1994, the Integrated Primary Care Information (IPCI) Project at the
Department of Medical Informatics of the Erasmus Medical Center in Rotterdam,
the Netherlands, has assembled electronic patient records on a cumulative
population of approximately 500 000 patients from approximately 150 GPs.
The IPCI database is a general practice research database that contains information
on all medical data, including demographic information, patient complaints
and symptoms, diagnoses, results of laboratory tests, referral notes from
consultants, and hospital admissions. The International Classification for
Primary Care is used as the coding system for symptoms and diagnoses,22 but these can also be included as free text. All
prescriptions are recorded in the database, which includes drug name, Anatomical
Therapeutical Chemical (ATC) code, dosage form, dose, prescribed quantity,
and indication. The IPCI database is the sole repository of medical records,
and no additional paper records of the patients are kept by the GPs. Patients
and practice identifiers are altered to warrant anonymity. The system complies
with European Commission guidelines on the use of data for medical research
and has shown to be valid for pharmacoepidemiologic research.6,23 The
IPCI internal review board approved the project and patient consent was not
In the IPCI database 49 818 individuals were 65 years or older
at any time during the study period. First, we excluded all practices that
did not consistently register influenza vaccination over the study years.
Nonconsistent registration was defined as a difference between minimum and
maximum annual vaccination coverage of at least 50% and/or a minimum vaccination
coverage recording of less than 25%. After exclusion, 34 991 persons
remained. In this remaining study population, we conducted a cohort study
during the period between October 1, 1996, and September 30, 2002. We included
patients who were 65 years or older on January 1 of the year of study start,
who had a permanent status in 1 of the practices in the IPCI source population,
and who had at least 1 year of recorded database history prior to study start
to determine heath status and vaccination status. We excluded 8920 individuals
who did not have a recorded database history in the GP practice of 1 year
or more. The eligible population thus included 26 071 persons. Censoring
was performed at death, moving out of the GP practice, or at the end of the
study period, whichever came first.
The cumulative number of influenza vaccinations was determined between
October 1 and December 31 of each calendar and was assigned to each individual
on January 1 of the next year. This date was chosen to compensate for the
slight variability in vaccination dates, mostly between late October and early
December, and the lag time before vaccination becomes effective. (An additional
analysis using actual date of vaccination did not substantively affect the
results.) Exposure status was categorized into 9 mutually exclusive categories
including nonexposed, first vaccination, second, third, fourth, fifth, and
sixth (or seventh) vaccination, vaccination interruption, and restart. A first
vaccination status was assigned to individuals who received the first vaccination
after study entry with no recorded influenza vaccination prior to study entry.
If persons were vaccinated prior to study entry they started with the number
of previously recorded vaccinations. Upon each additional consecutive vaccination
during the study period, the cumulative number of influenza vaccinations increased
by one. When a vaccination series was interrupted, it was categorized as such.
Finally, restart after 1 or more years of interruption was also categorized
separately. Once in the interruption category, individuals remained in it
until vaccination restart and vice versa. Consequently, in this time-varying
approach of exposure analysis, individuals contributed information to different
exposure categories during follow-up.
The primary outcome in this study was all-cause mortality. Death was
identified from the demographic patient file and validated in the medical
chart. Deaths occurring during the period January 1 and December 31 were allocated
to the vaccination status defined in the period between October 1 and December
31 of the preceding year. In an extra analysis, we compared mortality during
the epidemic periods (defined as the first day of the first week of the recorded
epidemic until the last days of the last week of the recorded epidemic) with
a reference period during the summer months (July and August).
Selection of covariates was based on an earlier study from our group
in the same database.6 In addition to age,
sex, and epidemic year, we identified 6 disease clusters as potential confounders:
chronic respiratory tract disease (chronic obstructive pulmonary disease,
emphysema, chronic bronchitis, asthma); chronic cardiovascular disease (heart
failure, angina pectoris, history of myocardial infarction or cerebrovascular
accident, aortic aneurysm, chronic arterial dysfunction); hypertension; diabetes
mellitus; chronic renal insufficiency; and malignancies. The presence of these
conditions at study entry or their development at any time during follow-up
was retrieved from the medical charts through automatic screening and further
manual validation. Those who had no comorbidity at baseline and did not develop
any of the predefined conditions during follow-up were considered as the population
Information on the size of each influenza epidemic was obtained from
Jan C. de Jong, PhD, of the National Influenza Center, Erasmus MC Rotterdam
(written communication, August 21, 2003, and March 5, 2004).24
To estimate the univariate association between vaccination, covariates,
and death we used a Cox proportional hazards model. Multivariate time-varying
Cox proportional hazard models were developed to estimate the hazard ratios
(HRs)for different vaccination states while adjusting for all other risk factors.25 In most analyses the nonexposed category was used
as reference category. For the estimation of the HRs of revaccination vs first
vaccination, the first vaccination was used as reference category. To fully
adjust for the strong influence of age on death in this analysis, we used
age in days as time axis. The exposure status of an individual on the date
of death was compared with all individuals in the cohort on that moment during
follow-up on which they had exactly the same age as the individual who died.
We also adjusted for sex and for time since the beginning of the study to
adjust for epidemic year. To adjust for comorbidity that occurred during follow-up,
time-dependent covariates were used for the diseases defined above.
The association of vaccine exposure with mortality risk was evaluated
in 3 analyses: any vaccination vs no previous vaccination; a first vaccination,
revaccination, interruption, and restart vs no vaccination; and any revaccination
vs a first vaccination. Subsequently, revaccination was further analyzed by
second, third, fourth, fifth, and sixth or seventh vaccination.
Stratified analyses were conducted on the presence of comorbidity and
age at study entry (65-69, 70-79, or >79 years).
All results were expressed as HRs with 95% confidence intervals (CIs).
In the total population, numbers needed to vaccinate to save 1 death were
calculated as: 1/[(1−e-IRcontrol × follow-up time]–[1−e-IRindex×follow-up time]), where
IR is the incidence rate. All analyses were performed using SAS software,
version 8.2 using the procedure Proc Phreg. Statistical significance was set
Baseline characteristics of the population and univariate associations
of covariates with all-cause mortality are provided in Table 1. Of the 26 071 persons who were eligible for study
entry, 3485 died during follow-up. The mean duration of participation in the
study was 3 years. The mean (SD) age at study entry was 73.1 (7.4) years and
58% were women. At baseline 53.3% of the population had some form of comorbidity,
mostly hypertension (24.6%) and chronic cardiovascular diseases (23.4%). Mortality
was strongly associated with age, sex, and comorbidity. The mortality rate
was highest for individuals with chronic renal dysfunction or malignancies.
The vaccination coverage and vaccination status for each study year
are shown in Table 2. During the total
study period, the population studied received 62 476 influenza vaccinations.
Ninety-six percent of the vaccinations were given in October or November,
and 3.6% in December. The annual vaccination coverage ranged from 64% in 1996
to 74% in 1999. A total of 5095 eligible individuals (19.5%) never received
influenza vaccination during follow-up. Influenza epidemics during the study
period were of mild to moderate severity (Table
3); the 2000-2001 season showed no clear epidemic activity. Generally,
vaccine strains and the predominant circulating strain (mainly A[H3N2]) were
well matched except for the 1997-1998 season.24 The
peak activity of influenzalike illness ranged between 7 cases per 10 000
persons (2000-2001 season) and 32 cases per 10 000 persons per week (1999-2000
season) and was observed between weeks 2 and 13.
In the total population, any vaccination was associated with a 22% lower
risk of all-cause mortality (adjusted HR, 0.78; 95% CI, 0.72-0.85; Table 4). First vaccination was associated with
a nonsignificant reduction in mortality risk of 10% in the total population
(adjusted HR, 0.90; 95% CI, 0.78-1.03). Any revaccination was associated with
a risk reduction of approximately 24% (adjusted HR, 0.76; 95% CI, 0.70-0.83),
which was strongest during the epidemic period (adjusted HR, 0.72; 95% CI,
0.59-0.89) and was not significant during a reference summer period (July
and August; adjusted HR, 0.89; 95% CI, 0.70-1.12). Compared with a first vaccination,
revaccination was associated with a significantly reduced mortality risk of
15% (adjusted HR, 0.85; 95% CI, 0.75-0.96). During the epidemic period this
risk reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). When each individual
vaccination was modeled separately, the mortality risk showed a decreasing
trend with additional consecutive vaccinations (Figure). Interruption of the vaccination series was associated with
a strong and significant increase in mortality risk (adjusted HR, 1.25; 95%
CI, 1.10-1.42). When the vaccination series was interrupted for more than
1 year, this risk estimate increased further, although it was no longer significant
(adjusted HR, 1.83; 95% CI, 0.94-3.78). Restarting vaccination after an interruption
resulted in a mortality risk reduction similar to that observed following
revaccination. In the total population 1 death was prevented for every 302
vaccinations, or 1 for every 195 revaccinations.
Exclusion of the population with a history of vaccinations prior to
study entry did not change the effect estimates (data available on request).
Stratification for comorbidity showed that the largest effects following any
vaccination and revaccination were observed in the subpopulation without comorbidity
(Table 4). Revaccination was not associated
with a reduction in mortality risk in persons aged 65 through 69 years at
baseline (adjusted HR, 0.98; 95% CI, 0.78-1.23) but was significantly reduced
in persons aged 70 through 79 years at baseline (adjusted HR, 0.78; 95% CI,
0.68-0.91), and persons aged 80 years and older at baseline (adjusted HR,
0.69; 95% CI, 0.61-0.78). This age-related difference following revaccination
seemed to reflect age-related differences in causes of death. In the highest
age groups, relatively more individuals died from causes that may be more
likely to be influenced by influenza vaccination, such as infectious causes
(HR following vaccination, 0.58; 95% CI, 0.43-0.79) or old age or “frailty”
(HR following vaccination, 0.63; 95% CI, 0.55-0.73; Table 5).
We assessed the possibility of confounding by indication, ie, the possibility
that those who were not vaccinated were sicker than those who were. However,
in our population, the proportion of the population with comorbid illnesses
was 50.9% for those with no previous vaccination, 55.8% for those who refused
(34% of all those who were not vaccinated), 68.9% for those who had an interruption,
and 68.5% for those who had any vaccination in series, suggesting that those
who were not vaccinated were at least as healthy as those who were. Furthermore,
compared with nonusers who refused vaccination, the adjusted mortality risk
following the first vaccination was an HR of 1.09 (95% CI, 0.93-1.28) and
following revaccination, an HR of 0.93 (95% CI, 0.83-1.04). Compared with
those who were not vaccinated and did not refuse, the adjusted HR for mortality
following the first vaccination was 0.73 (95% CI, 0.63-0.85) and following
any revaccination, 0.62 (95% CI, 0.56-0.70).
In this study, we showed that influenza vaccination is associated with
a reduced risk of mortality in community dwelling elderly despite several
mild epidemic seasons, and that revaccination is an effective strategy to
further reduce or sustain reduced mortality risk in both healthy elderly individuals
and in those with underlying chronic disease. In our population, annual revaccination
was associated with a significant mortality reduction among those aged 70
years and older. This result may reflect differences in age-related causes
of death, which probably were less influenced by vaccination in those at a
younger age than those in the highest age groups. Additionally, the observed
lack of effect in the youngest age categories may be a result of a lower baseline
risk of death. Interruption of yearly influenza vaccination was associated
with a significantly increased mortality, but after restarting vaccination,
mortality risk reduced again to a revaccination status level. Absence of protection
from the vaccination may be an explanation for the observed risk increase,
since individuals who interrupted vaccination for 2 or more consecutive years
had a further increase in mortality risk.
Although a protective association between mortality and revaccination
status in elderly persons has been suggested previously, only 1 case-control
study has examined this association. In this study, a previous vaccination
significantly increased vaccine effectiveness in the next season.9 However, the study was not population-based; approximately
half of the individuals were institutionalized. Nichol et al7,19 and
Hak et al5 studied the effect of influenza
vaccination on long-term outcomes but did not take revaccination status into
account. Gross et al20 published a meta-analysis
on mortality risk in 20 cohort studies. Based on the current study, the large
variability in effects identified by Gross et al might be explained by different
revaccination states, variations in epidemic activity, and population characteristics.
It has also been proposed that variability of revaccination efficacy might
be due to antigenic differences among the vaccine and epidemic strains.26 Our study did not find an effect of first vaccination,
but past studies and our previous study in the same database found a significant
Our study has several strengths. We were able to assess the overall
annual and epidemic effectiveness of annual influenza vaccinations as well
as the effect of individual revaccinations. The study was population-based
and less subject to selection bias, information bias, and confounding. In
the Dutch health care system, all individuals are designated their own GP,
so selection bias is unlikely. Information bias may have occurred if the vaccination
was not recorded. However, such misclassification would likely be random because
exposure is prospectively recorded before death occurred. Such random misclassification
would tend to reduce the size of the estimate, suggesting that the real protective
effect could be even greater. All-cause mortality was chosen as an end point
because it is an important outcome, which cannot be misclassified. Deaths
were unlikely to have been missed since death rates in IPCI were similar to
national data on mortality. As discussed above, confounding by indication
is possible but in this study, comorbidity and a higher risk of mortality
would be an indication for vaccination, reducing the likelihood of confounding
as an explanation for the observed effect. Moreover, perceived good health
has, among others, been reported as a reason for noncompliance with the influenza
vaccination program.27 Indeed, compared with
those refusing vaccination, mortality risk was not reduced following a first
or revaccination. However, excluding those who refused vaccination from the
reference category resulted in a significant adjusted risk reduction following
a first and revaccination. In addition, we adjusted for chronic respiratory
tract disease, cardiovascular disease, hypertension, diabetes mellitus, malignancies,
and chronic renal insufficiency, either preexisting or having developed during
follow up, because they were both indications for vaccination and independent
risk factors for mortality. Even if some residual confounding by indication
cannot be excluded, a poorer prognosis in individuals who were vaccinated
would mean that our results would tend to underestimate the protective effect
of annual revaccination.25
In summary, our study shows that annual revaccination against influenza
in a population of community-dwelling elderly persons is associated with a
reduction of mortality risk. This study supports the recommendation for yearly
influenza vaccination for elderly individuals, not only for those with comorbid
illness but also in those without comorbidity and in patients 80 years or
older. Because influenza vaccination is inexpensive and safe, clinicians should
recommend annual influenza revaccination for such patients.
Corresponding Author: Bruno H. Ch. Stricker,
MB, PhD, Department of Epidemiology & Biostatistics, Erasmus Medical Center,
PO Box 1738, 3000 DR Rotterdam, the Netherlands (firstname.lastname@example.org).
Author Contributions: Drs Voordouw, Sturkenboom,
Dieleman, van der Lei, and Stricker had full access to the IPCI database.
All coauthors had full access to the data set for this study.
Study concept and design: Stricker, Voordouw,
Acquisition of data: Voordouw, van der Lei.
Analysis and interpretation of data: Stricker,
Voordouw, Sturkenboom, Dieleman, Stijnen, Smith.
Drafting of the manuscript: Stricker, Voordouw,
Critical revision of the manuscript for important
intellectual content: Stricker, Voordouw, Sturkenboom, Dieleman, Stijnen,
Smith, van der Lei.
Statistical analysis: Stricker, Voordouw, Sturkenboom,
Obtained funding: Stricker.
Study supervision: Stricker, Sturkenboom, Dieleman,
van der Lei.
Funding/Support: This study was supported by
an unconditional grant from the Netherlands Organisation for Health Research
and Development (ZonMw), project number 2200.0090. The grant was obtained
following review of a submitted protocol to evaluate the effectiveness of
the influenza vaccination program in Dutch elderly citizens. Dr D. J. Smith
was supported by European Union grant QLRT-2001-01034.
Role of the Sponsor: The sponsor had other
no influence on the design or conduct of the study.
Acknowledgment: We kindly thank Jan C. De Jong,
PhD, from the department of Virology, National Influenza Centre, Erasmus Medical
Center, for the use of the data for Table 2. We also kindly thank S. Salmaso,
MD, PhD, Instituto Superiore di Sanità, Rome, Italy, and I. S. M. Uhnoo,
MD, PhD, Medical Products Agency, Uppsala, Sweden, for their advice in preparing