I-MOVE multi-centre case control study 2010-11: overall and stratified estimates of influenza vaccine effectiveness in Europe.

Abstract

In the third season of I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe), we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in eight European Union (EU) member states to estimate 2010/11 influenza vaccine effectiveness (VE) against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza.
Using systematic sampling, practitioners swabbed ILI/ARI patients within seven days of symptom onset. We compared influenza-positive to influenza laboratory-negative patients among those meeting the EU ILI case definition. A valid vaccination corresponded to > 14 days between receiving a dose of vaccine and symptom onset. We used multiple imputation with chained equations to estimate missing values. Using logistic regression with study as fixed effect we calculated influenza VE adjusting for potential confounders. We estimated influenza VE overall, by influenza type, age group and among the target group for vaccination.
We included 2019 cases and 2391 controls in the analysis. Adjusted VE was 52% (95% CI 30-67) overall (N = 4410), 55% (95% CI 29-72) against A(H1N1) and 50% (95% CI 14-71) against influenza B. Adjusted VE against all influenza subtypes was 66% (95% CI 15-86), 41% (95% CI -3-66) and 60% (95% CI 17-81) among those aged 0-14, 15-59 and ≥60 respectively. Among target groups for vaccination (N = 1004), VE was 56% (95% CI 34-71) overall, 59% (95% CI 32-75) against A(H1N1) and 63% (95% CI 31-81) against influenza B.
Results suggest moderate protection from 2010-11 trivalent influenza vaccines against medically-attended ILI laboratory-confirmed as influenza across Europe. Adjusted and stratified influenza VE estimates are possible with the large sample size of this multi-centre case-control. I-MOVE shows how a network can provide precise summary VE measures across Europe.

Full text

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I-MOVE Multi-Centre Case Control Study 2010-11: Overall
and Stratified Estimates of Influenza Vaccine
Effectiveness in Europe
Esther Kissling1*, Marta Valenciano1, Jean Marie Cohen2, Beatrix Oroszi3, Anne-Sophie Barret4,5,
Caterina Rizzo6, Pawel Stefanoff7, Baltazar Nunes8, Daniela Pitigoi9,10, Amparo Larrauri11, Isabelle
Daviaud2, Judit Krisztina Horvath12, Joan O’Donnell4, Thomas Seyler1,6, Iwona Anna Paradowska-
Stankiewicz7, Pedro Pechirra8, Alina Elena Ivanciuc9, Silvia Jime ´nez-Jorge11, Camelia Savulescu1, Bruno
Christian Ciancio13, Alain Moren1
1EpiConcept, Paris, France, 2GROG/Open Rome, Paris, France, 3Office of the Chief Medical Officer, Budapest, Hungary, 4Health Protection Surveillance Centre, Dublin,
Ireland, 5European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control, Stockholm, Sweden, 6National
Centre for Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanita `, Roma, Italy, 7National Institute of Public Health, Warsaw, Poland, 8Instituto
Nacional de Sau ´de Dr Ricardo Jorge, Lisbon, Portugal, 9National Institute of Research - Development for Microbiology and Immunology, Cantacuzino, Bucharest,
Romania, 10University of Medicine and Pharmacy, Carol Davila, Bucharest, Romania, 11National Centre for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain,
12National Center for Epidemiology, Budapest, Hungary, 13European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden
Abstract
Background: In the third season of I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe), we undertook a
multicentre case-control study based on sentinel practitioner surveillance networks in eight European Union (EU) member
states to estimate 2010/11 influenza vaccine effectiveness (VE) against medically-attended influenza-like illness (ILI)
laboratory-confirmed as influenza.
Methods: Using systematic sampling, practitioners swabbed ILI/ARI patients within seven days of symptom onset. We
compared influenza-positive to influenza laboratory-negative patients among those meeting the EU ILI case definition. A
valid vaccination corresponded to . 14 days between receiving a dose of vaccine and symptom onset. We used multiple
imputation with chained equations to estimate missing values. Using logistic regression with study as fixed effect we
calculated influenza VE adjusting for potential confounders. We estimated influenza VE overall, by influenza type, age group
and among the target group for vaccination.
Results: We included 2019 cases and 2391 controls in the analysis. Adjusted VE was 52% (95% CI 30-67) overall (N=4410),
55% (95% CI 29-72) against A(H1N1) and 50% (95% CI 14-71) against influenza B. Adjusted VE against all influenza subtypes
was 66% (95% CI 15-86), 41% (95% CI -3-66) and 60% (95% CI 17-81) among those aged 0-14, 15-59 and $60 respectively.
Among target groups for vaccination (N=1004), VE was 56% (95% CI 34-71) overall, 59% (95% CI 32-75) against A(H1N1)
and 63% (95% CI 31-81) against influenza B.
Conclusions: Results suggest moderate protection from 2010-11 trivalent influenza vaccines against medically-attended ILI
laboratory-confirmed as influenza across Europe. Adjusted and stratified influenza VE estimates are possible with the large sample
size of this multi-centre case-control. I-MOVE shows how a network can provide precise summary VE measures across Europe.
Citation: Kissling E, Valenciano M, Cohen JM, Oroszi B, Barret A-S, et al. (2011) I-MOVE Multi-Centre Case Control Study 2010-11: Overall and Stratified Estimates of
Influenza Vaccine Effectiveness in Europe. PLoS ONE 6(11): e27622. doi:10.1371/journal.pone.0027622
Editor: Suryaprakash Sambhara, Centers for Disease Control and Prevention, United States of America
Received September 9, 2011; Accepted October 20, 2011; Published November 15, 2011
Copyright: ? 2011 Kissling et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have the following competing interest: E. Kissling, M. Valenciano, T. Seyler, C. Savulescu and A. Moren are employees of
EpiConcept, Paris. J.M. Cohen and I. Daviaud are employees of GROG/Open Rome, Paris. As Head of Open Rome, J.M. Cohen is involved in several epidemiological
studies that are partially or fully funded by pharmaceutical companies (Sanofi-Pasteur, GSK, Roche), nonprofit organizations (Mutuelles, Re ´saeu DES France) or
public institutions (ECDC, CU Strasbourg). He is a member of Association Mieux Prescrire and the advisory boards of Novartis, Roche, and Wyeth (free
participation, no compensation). During the past five years, he has received travel grants from Sanofi-Pasteur and Roche. I. Daviaud is involved, through the other
institution with which she is affiliated and salaried (Open Rome research department), in the coordination or analysis of epidemiological studies partially or fully
funded by Roche and GSK. EpiConcept conducted for the Mexican Social Security and GSK an evaluation of the Mexican hospital based surveillance system for
intussusceptions (2008). EpiConcept coordinated studies for measuring influenza vaccine effectiveness funded by EVM, the association of the European Vaccine
Manufacturers. None of the current authors were involved in these studies (2009). EpiConcept conducts for SP-MSD the data analysis of a study conducted in
Finland to measure the impact of rotavirus vaccination on hospitalisation for acute gastroenteritis due to rotavirus infection (2009-10). There are no patents,
products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.
All other authors have declared that no competing interests exist.
* E-mail: e.kissling@epiconcept.fr
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Figure 1. Influenza-like illness/Acute Respiratory Infection rates by week as reported by the National Sentinel systems, I-MOVE
multi-centre case control study, influenza season 2010-11.
doi:10.1371/journal.pone.0027622.g001
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Introduction
Influenza is a constantly evolving virus and the antigenic
composition of vaccines requires annual formulation. Therefore,
vaccine effectiveness (VE) estimates from previous years cannot be
used to measure the performance of the current year’s vaccine.
In Europe, influenza vaccine composition is reviewed every year.
The available vaccine brands, the target groups for vaccination and
thevaccinationcoverage varyacrosscountries.In 2009the European
Council of Ministers recommended European Union (EU) Member
States (MS) to reach an influenza vaccination coverage of 75% in all
riskgroupsbythewinterseasonof2014-15.Riskgroupsweredefined
asindividuals65yearsand older,andpeoplewithunderlyingmedical
conditions in the following categories: chronic respiratory and
cardiovascular diseases; chronic metabolic disorders; chronic renal
and hepatic diseases; immune system dysfunctions (congenital or
acquired)[1]. A survey conducted in 2009 among 27 EU MS,
Norway and Iceland indicated that all the 27 responding countries
recommended seasonal vaccination to the older adultpopulation and
to individuals with underlying chronic disease. Six countries
recommended vaccination of children aged between six months
and , 18 years and ten to pregnant women. Twenty three countries
recommended vaccination to health careworkers (HCW)in hospitals
and long-term facilities and 22 to HCW in out-patient clinics [2].
Taking into account the differences between EU MS, monitoring
influenza VE at European level is a major challenge. In 2007, the I-
MOVE (Influenza Monitoring Vaccine Effectiveness in Europe)
network was established to monitor influenza vaccine effectiveness
within and across the seasons in the EU and the European
Economic Area (EEA) [3]. The network is funded by the European
Centrefor Disease Preventionand Control(ECDC)and includes19
public health institutes from the EU and EEA.
In 2008-9, the pilot season for I-MOVE, we conducted a multi-
centre case control study among study sites in five EU MS to
provide a pooled estimate of influenza VE among elderly (age $
65 years) across Europe [4]. During the pandemic season in 2009-
10, the multi-centre case control study was expanded to study sites
in seven countries and the study population included all age
groups. During this season the adjusted pandemic VE was 71.9%
(95% CI 45.6-85.5) overall, 78.4% (95% CI 54.4 – 89.8) in the ,
65 years and 72.9 (95% CI 39.8-87.8) in those without chronic
disease [5].
In the 2010-11 season, study sites from eight EU MS
participated in the I-MOVE multi-centre case control study.
The objectives were to measure the effectiveness of the 2010-11
trivalent seasonal influenza vaccine to prevent medically-attended
influenza-like illness (ILI) confirmed as influenza, by influenza
virus type, among all the population and among the target
population for the influenza vaccine.
Table 1. Seasonal 2010-11 vaccines used by study site, I-MOVE multi-centre case control study, influenza season 2010-11.
VaccinesAdjuvant
Countries
FranceHungary IrelandItaly PolandPortugal RomaniaSpain
Fluval AB Aluminium
phosphate
x
FLUADM59C.1 x*x*
ChiromasM59C.1x
GRIPGUARDM59C.1 x *
ISIFLU V Virosomesx
InflexalVirosomesx
ID flu (intradermal)x x**x
ISTIVACx
ISTIVAC infantil (6-35 months)x
FLUARIXxxxxxx
Chirofluxx
INTANZA 15 (. . 60 years)x
Inactivated Split Virionx
INFLUVACxxxx
AGRIPALxxx
IMMUGRIPx
VAXIGRIPxx
MUTAGRIPxx
BERNAx
Estevex
Letix
Gripavac x
Cantacuzino (split)x
*For individuals . 64 years.
**For individuals . 18 years.
doi:10.1371/journal.pone.0027622.t001
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Methods
The eight study sites included in the multi-centre case control
study were settings in France, Hungary, Ireland, Italy, Poland,
Portugal, Romania and Spain. In six study sites, primary care
practitioners belonging to the national influenza sentinel networks
were invited to participate in the study. In Portugal and Italy,
practitioners other than those participating in the national
influenza sentinel networks were also invited to participate.
The study population consisted of non-institutionalised patients
consulting a participating practitioner for ILI or acute respira-
tory illness (ARI) (France only) who had a nasal or throat
swab taken less than eight days after symptom onset and with no
contra-indication for influenza vaccination. In Hungary the study
population was restricted to those 18 years or older. We defined
the start of the study period in each of the study sites as more than
14 days after the start of the 2010-11 influenza vaccination
campaign.
Practitioners in Ireland, Poland Portugal, Spain and France
swabbed all ILI/ARI patients aged 65 and over, in Hungary they
swabbed all ILI patients 60 and over and in Italy they
systematically swabbed one ILI/ARI patient aged 65 and over
per week. In all study sites practitioners systematically sampled
ILI/ARI patients to swab among the other age groups, apart from
Romania where practitioners swabbed all ILI patients in all age
groups.
In all study sites, practitioners interviewed the ILI patients
using country-specific questionnaires. The common variables
collected in the the eight study sites included ILI signs and
symptoms, age, sex, pregnancy, presence of chronic conditions,
severity of the chronic disease measured as the number of
hospitalisations for the chronic disease in the previous 12 months,
smoking history (none, past, current smoker), number of
practitioner visits in the previous 12 months, 2009-10 pandemic
vaccination status, seasonal influenza vaccination in the 2009-10
and in the 2010-11 season.
A case was defined as a patient with signs and symptoms
adhering to the EU ILI case definition (sudden onset of symptoms
and at least one of the following four systemic symptoms: fever or
feverishness, malaise, headache, myalgia and at least one of the
following three respiratory symptoms cough, sore throat, shortness
of breath), who was swabbed and tested positive for influenza using
real-time polymerase chain reaction (RT-PCR) or culture.
Controls were EU ILI patients who were swabbed and tested
negative for influenza.
An individual was considered vaccinated if he/she received at
least one dose of the 2010-11 seasonal vaccine more than 14 days
before the date of onset of ILI symptoms. Swabs were tested for
influenza at the respective countries’ National Influenza Reference
Laboratory (in Spain, the laboratories of the regional sentinel
networks integrated in the Spanish Influenza Sentinel Surveillance
System). In each country, all or a subset of influenza isolates were
antigenically characterised. Laboratory viral detection, typing,
subtyping and variant analysis performed in each of the National
Reference Laboratories are described elsewhere [6].
According to country specific requirements for ethical approval,
all participants provided oral or written consent for recruitment to
the study. The eight study teams sent their anonymised dataset to
EpiConcept, the I-MOVE coordination focal point where a
common dataset was created.
We excluded ILI patients if they presented ILI symptoms before
the week of onset of the first recruited influenza case. For each
study site, we excluded ILI patients presenting either after the
onset week of the last recruited influenza case or after the onset
week of the case prior to two consecutive weeks of no positive case
recruited. To estimate VE against A(H1N1)2009 and against
influenza B virus, we based the exclusion criteria on the week of
onset of the first and last A(H1N1)2009 and influenza B case
respectively. We compared the characteristics of cases and controls
using Chi square tests, T-tests, Fisher’s exact test or the Mann-
Whitney test depending on the nature of the variable.
Table 2. Practitioner participation, Influenza-like illness (ILI) patients recruited by case control status, vaccination status, and study
site, I-MOVE multi-centre case control study, influenza season 2010-11.
Study site
Number of
practitioners
in the National
sentinel system
Number of
practitioners
accepting to
participate in
the study
Number of
practitioners
recruiting at
least one ILI*
Number of
ILI patients*
recruited by
practitioners
Inclusion period for
the study{
Number of ILI
patients included
in the study positive
for influenza{
Number of ILI patients
included in the study
negativeforinfluenza{
TotalVaccinatedTotalVaccinated
France 571 425 3171186 wk 51, 2010 –wk 11, 2011597 15 58939
Hungary140098 78727wk 50, 2010 –wk 13, 2011 1194 60852
Ireland135
1009+
48 17190 wk 48, 2010 –wk 9, 2011 1060 846
Italy
3827 415wk 46, 2010 –wk 13, 2011 11617 29964
Poland 971 33 29180wk 48, 2010 –wk 14, 2011 986 8110
Portugal1445834 253 wk 45, 2010 –wk 11, 2011 1446 10919
Romania27089 66255 wk 52, 2010 –wk 15, 20111547 10113
Spain 8482461971205wk 49, 2010 –wk 12, 2011 68526 52053
Total534810357654410 201981 2391256
*ILI patients meeting the EU case definition, swabbed , 8 days after onset of symptoms within the study period.
{For each study site, from 15 days after the start of the vaccination campaign up to the week that preceded two consecutive weeks in which none of the ILI patients
recruited tested positive for influenza. Week number as defined by the International Standards Organization to ensure consistency across study sites (ISO weeks used).
{ILI patients in the study after applying exclusion criteria (contraindications for vaccine, antiviral use before swabbing, missing lab results) and excluding those not
adhering to the EU ILI case definition, having a delay between symptom onset and swabbing of less than 8 days and presenting outside the study period.
+Mean number of participating GPs.
doi:10.1371/journal.pone.0027622.t002
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We used chained equations to impute missing values; we used
missing at random assumptions and independently analysed 20
copies of the data using 30 cycles of regression [7]. The variables
included in the imputation model were the outcome and the
vaccination status for the 2010-11 season as well as covariates: age
group, sex, presence of chronic conditions, at least one hospitalisa-
tion in the previous 12 months for chronic disease, smoking history,
number of practitioner visits in the previous 12 months (0–1, 2–4,
5+), 2009-10 pandemic vaccination status, seasonal influenza
vaccination in the 2009-10, belonging to a target group for
vaccination, week of symptom onset and study site.
We estimated the pooled VE as 1- the odds ratio (OR) using a
one-stage method with study as fixed effect in the model. We
estimated VE against all influenza, influenza A(H1N1)2009 and
influenza B.
To estimate confounder adjusted VE, we used a logistic
regression model including the potential confounding factors:
age (ten year age bands), sex, presence of chronic conditions, at
least one hospitalisation in the previous 12 months for chronic
disease, current smoking, number of practitioner visits in the
previous 12 months, 2009-10 pandemic vaccination status, seasonal
influenza vaccination in the 2009-10, week of symptom onset.
We stratified VE into three age groups (0–14, 15–59 and 60
years and above). Analyses were further restricted to the target
group for vaccination. Five study sites included the variable
‘‘belongs to the target group for vaccination’’ in their question-
naire. For the other three study sites, we defined it based on the
variables (e.g. age group, chronic diseases, pregnancy, profession)
included in the study site questionnaires that allowed target groups
to be identified.
We used Cochran’s Q-test and the I2index to test the
heterogeneity between study sites [8] and as a sensitivity analysis
we carried out a two-stage pooled analysis [9] to compare against
the one-stage pooled results. In the two-stage pooled analysis
adjusted influenza VE estimates are calculated by study site and a
pooled average of those results is computed. Due to limitations in
sample size we only included the potential most important
confounders age groups (0-14, 15-59 and 60+ years), time (month
of symptom onset), and chronic disease in the models as stable
models could be fitted for each study site with these covariates.
The Irish study site was excluded from this analysis, due to sparse
data (no vaccinated cases).
We conducted all statistical analysis using Stata version 11
(StataCorp. 2007. Stata Statistical Software: Release 11. College
Station, TX: StataCorp LP).
Results
In the countries of the eight study sites, influenza activity peaked
between week 52 2010 (Portugal) and week 8 2011 (Romania)
(Figure 1). A total of 23 vaccines were used in the eight countries;
six of them were adjuvanted (Table 1).
A total of 1035 practitioners agreed to participate in the study;
765 of them (74.0%) recruited at least one ILI patient meeting the
EU case definition and swabbed , 8 days after onset of symptoms
within the study period (Table 2). We excluded two individuals with
contraindications for vaccination, two individuals who had received
antivirals prior to swabbing, 58 individuals without information on
lab results, 12 individuals who received vaccination prior to begin of
the country’s national vaccination campaign, 660 individuals who
did not adhere to the EU ILI case definition, 26 individuals who
were swabbed more than seven days after symptom onset and 163
individualsthatpresented outside oftheonset weekofthefirstorlast
case (Figure 2). We included 4410 ILI patients in the analysis: 2019
cases and 2391 controls. Among the cases, 1179 (58.4%) were
positive for influenza A(H1N1)2009 virus, 40 (2.0%) for influenza
A(H3N2) virus, 37 (1.8%) were positive for influenza A virus that
could not be subtyped and 765 (37.9%) were positive for influenzaB
virus(Figure 3).Twoofthecasespresentedaco-infection,onepositive
for influenza A(H1N1)2009 and for influenza B virus and one positive
for influenza A(H3N2) and influenza B virus.
Among 4390 individuals with information on vaccination status
and vaccination date for seasonal vaccination in 2010-11, 337 (7.7%)
were vaccinated (ranging from 3.2% in Ireland to 19.5% in Italy).
The median age was lower in cases (23 years, standard deviation
(SD): 19.4 years) than in controls (32 years, SD: 22.7 years)
(Table 3). The delay between onset of symptoms and swabbing
was slightly shorter in cases (mean: 1.7 days, range: 0–7 days) than
in controls (mean: 1.8 days, range: 0–7 days). The proportion of
individuals presenting with fever, headache, myalgia or cough was
higher among cases than among controls, while the proportion of
those presenting with shortness of breath or sore throat was higher
Figure 2. Flowchart of data exclusion for pooled analysis, I-
MOVE multi-centre case control study, influenza season 2010-
11.
doi:10.1371/journal.pone.0027622.g002
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among controls than among cases. Compared with cases, a higher
proportion of controls had diabetes, heart disease, any chronic
disease or were hospitalised at least once for their chronic disease
in the previous 12 months. A higher proportion of controls were
current or past smokers, vaccinated with the 2009-10 seasonal
influenza vaccine, vaccinated with the 2009-10 pandemic
influenza vaccine and belonged to the target group for
vaccination. The proportion of individuals visiting their practi-
tioner more than once in the previous 12 months, was higher
among controls (68.6%) than among cases (56.9%).
In the complete case dataset, the Q test (p=0.337) and the I2
index (12.1%) testing for heterogeneity between the individual VE
estimates of seven study sites (Ireland excluded as no vaccinated
cases) using models adjusted for age group, onset month and
chronic disease suggested no statistical heterogeneity.
In the complete case analysis we included 3254 ILI patients,
giving 73.8% of complete data. Two variables contained 1271 of
the 1540 missing values (82.5%): practitioner visits in the previous
year, missing values in 789 records (17.9%), and smoking, missing
values in 482 records (10.9%). Excluding these variables, the data
were 95.4% complete. Crude VE against all influenza was 65.5%
(95% CI 53.2-74.6) and adjusted VE was 50.9% (95% CI 25.2-
67.7)(Table S1).
In the imputed analysis we included 4410 individuals. Crude
imputed VE against any influenza was 64.2% (95% CI 53.2-72.6)
and the adjusted 51.9% (95% CI 30.0-66.9) (Table 4). The
adjusted VE against all influenza by age group was 65.7% (95%
CI 15.4-86.1), 41.3% (95% CI -2.6-66.4) and 59.9% (95% CI
16.7-80.7) among those aged 0-14, 15-59 and 60 and above years
respectively (Table 4).
Adjusted VE against A(H1N1)2009 was 55.5% (95% CI 28.7-
72.2) and against influenza B 49.8% (95% CI 13.8-70.8). Adjusted
VE against A(H1N1)2009 was 77.2% (95% CI 16.0-93.8), 27.2%
(95% CI -37.1-61.4) and 72.3 (95% CI 26.5-89.6) in the 0-14, 15-
59 and 60+ year old age groups. Adjusted VE estimates against
influenza B virus in these age groups ranged between 55.5% and
63.7% (Table 4).
The two-stage random effects pooled analysis VE estimate
against all influenza was similar to the one-stage complete case
fixed effects analysis adjusted for the same covariates (47.7% and
48.7%; Table S2).
Analysis restricted to the groups targeted for the
seasonal 2010-11 vaccine
Of the 4410 ILI patients included in the study 1012 (23.0%)
belonged to a group targeted for the seasonal 2010-11 vaccination:
381 influenza cases and 631 controls. Among the cases, 227
(59.6%) were positive for influenza A(H1N1)2009 virus, nine
(2.4%) for influenza A(H3N2) virus, 11 (2.9%) were positive for
influenza A virus that could not be subtyped and 134 (35.2%) were
positive for influenza B virus.
Among 1002 individuals with information on vaccination status
and vaccination date for seasonal vaccination in 2010-11, 281
(28.0%) were vaccinated (ranging from 11% in Poland to 43% in
Italy).
The characteristics for which cases and controls differed were
the same among the target group for vaccination as among all the
ILI patients included in the study. The only exceptions were that
in the target group there were no differences in the proportion of
cases and controls presenting with myalgia or sore throat (Table 5).
In the complete case database (Ireland excluded as no
vaccinated cases), the Q test (p=0.045) and the I2index (53.4%)
testing for heterogeneity between the individual VE estimates of
the seven study sites (Ireland excluded as no vaccinated cases)
using models adjusted for age, onset month and chronic disease
suggested medium statistical heterogeneity.
The adjusted imputed VE against all influenza was 56.2% (95%
CI 34.3-70.7) overall and 54.0% (95% CI 6.6-77.3) in the 15-59
year age group (Table 6). The overall adjusted VE against
A(H1N1)2009 was 58.9% and 63.4% against influenza B.
The two-staged random effects pooled analysis VE estimate against
all influenza was 57.1% and the one-stage complete case fixed effects
analysis adjusted for the same covariates was 52.8% (Table S2).
Figure 3. ILI patients influenza positive (N=2019), A(H1N1)2009 positive (N=1179), B positive (N=765) and influenza negative
(N=2391) by week of symptom onset, I-MOVE multi-centre case control study, influenza season 2010-11.
doi:10.1371/journal.pone.0027622.g003
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Discussion
The 2010-11 I-MOVE multi-centre case control study based on
sentinel primary health practitioner networks from eight countries
in the EU provided overall and stratified VE estimates. All the
overall and stratified pooled estimates (range from 27.2% to
77.2%) suggested a moderate adjusted VE against medically
attended influenza. The overall adjusted VE against A(H1N1)2009
and influenza B virus did not differ substantially from the VE
estimate against all influenza.
Table 3. Characteristics of influenza cases and test-negative controls included in the study by characteristics, I-MOVE multi-centre
case control study, influenza season 2010-11.
Cases
N=2019
Test-negative controls
N=2391P value
Median age2332
,0.001*
Age group - n6/total n6. (%)
0-4269/2019 (13.3) 372/2391 (15.6)
,0.001**
5-14 503/2019 (24.9)286/2391 (12.0)
15-59 1117/2019 (55.3)1394/2391 (58.3)
60+ +
130/2019 (6.4)339/2391 (14.2)
Female sex - n6/total n6. (%)
1046/2012 (52.1)1241/2383 (52.1)1.000**
Symptoms - n6/total n6. (%)
Fever1964/2016 (97.5) 2246/2381 (94.3)
,0.001**
Headache1446/1995 (72.5) 1562/2361 (66.2)
,0.001**
Myalgia 1487/1990 (74.7) 1659/2361 (70.3)0.001**
Cough1891/2018 (93.7) 2049/2382 (86.0)
,0.001**
Sore throat 1361/1993 (68.3)1766/2376 (74.3)
,0.001**
Shortness of breath208/1959 (10.6) 327/2349 (13.9)0.001**
Days between onset of symptoms and swabbing – n6/total n6. (%)
0 138/2019 (6.8) 170/2391 (7.1) 0.002**
1 944/2019 (46.8)1033/2391 (43.2)
2 587/2019 (29.1)650/2391 (27.2)
3 219/2019 (10.8)303/2391 (12.7)
4 74/2019 (3.7)116/2391 (4.9)
5 39/2019 (2.0)62/2391 (2.7)
69/2019 (0.4) 32/2391 (1.3)
7 9/2019 (0.4)25/2391 (1.0)
Mean swab delay 1.71.8
,0.001***
Diabetes - n6/total n6. (%)
30/1296 (2.3)90/1715 (5.2)
,0.001**
Heart disease62/1296 (4.8) 201/1715 (11.7)
,0.001**
Any reported chronic disease 219/1990 (11.0)428/2356 (18.2)
,0.001**
Any hospitalisation in the previous 12 months for
chronic diseases - n6/total n6. (%)
25/2012 (1.2)56/2371 (2.4) 0.007**
Smoker - n6/total n6. (%)
Current 165/1791 (9.2)319/2137 (14.9)
,0.001**
Former93/1791 (5.2)201/2137 (9.4)
Never1534/1791 (85.6)1617/2137 (75.7)
Pandemic vaccination 2009-10 - n6/total n6. (%)
148/1994 (7.4)300/2348 (12.8)
,0.001**
Seasonal vaccination, 2009-10 - n6/total n6. (%)
134/1990 (6.7) 341/2349 (14.5)
,0.001**
Number of practitioner visits in previous 12 months
0-1 695/1611 (43.1)631/2010 (31.4)
,0.001**
2-4482/1611 (29.9) 657/2010 (32.7)
5+ +
434/1611 (27.0) 722/2010 (35.9)
Belongs to target group for vaccination
n6/total n6. (%)
381/2017 (18.9)631/2380 (26.5)
,0.001**
*Non parametric test of the median.
**Two-sided Fisher’s exact test *** T-test.
doi:10.1371/journal.pone.0027622.t003
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According to data reported by the Community Network of
Reference Laboratories (CNRL) for Human Influenza in Europe,
in 2010-11 there was a good match between the vaccine and
circulating A and B influenza virus strains [10]. The adjusted point
VE estimates against all influenza and against A(H1N1)2009 virus,
were lower in the 15–59 year olds than in the 0-14 and 60 and
above age groups. Age-specific VE estimates against influenza B
virus did not vary substantially.
Our results suggest that the effectiveness of the seasonal 2010-11
influenza vaccine against medically attended ILI confirmed as
A(H1N1)2009 virus was lower than the effectiveness of the 2009-
10 season monovalent pandemic vaccine[5,11,12]. This could be
explained by last season’s perfect match between the circulating
and the vaccine virus strain, by last season’s use of adjuvanted
influenza vaccines, by the amount of A(H1N1)2009 antigen that
was higher in the monovalent than in the trivalent vaccine or by
an overestimation of the VE in 2009-10. In the pandemic season,
vaccination campaigns started during the pandemic wave or after
the peak of the pandemic once part of the population had acquired
natural immunity. If vaccinated persons had had a higher risk of
infection before vaccination (e.g. children) the VE could have been
overestimated [5].
While some studies carried out in the 2010-11 season suggested
a higher effect of the combined use of 2010-11 seasonal and
2009-10 pandemic vaccine, this was not seen in our study [13–
15]. Adjusted VE against all influenza was around 12% for the
2009-10 pandemic vaccine, around 59% for the 2010-11
seasonal influenza vaccine and 44% for both vaccines together
(data not shown).
The majority of countries participating in this study used
both adjuvanted and non-adjuvanted influenza vaccines
(Table 1). The different vaccine types were used in different
subpopulations. With the data collected for this study, it was not
possible to identify the target groups to enable an estimate by
vaccine type.
For both analyses done (all ILI patients and those targeted for
vaccination) our study is limited by the small sample size for
subgroup analysis and the low vaccination coverage. Precise
estimates were not always possible, particularly in children 0-14
years usually not targeted for vaccination.
As any observational study, the I-MOVE multi-centre case
control study is subject to selection bias. However systematic
sampling of ILI/ARI patients in all study sites and the blinding of
participating practitioners to the case/control status of ILI cases
should minimise this bias.
We applied the test-negative design, which has been suggested
to adjust for health seeking behaviour amongst study participants
[16,17]. In the analysis of the 2009-10 season multi-centre case
control study, the number of practitioner visits in the previous year
was a strong confounder [5]. In 2010-11 controls had a poorer
health status than cases. However for all outcomes used, in the
multivariable analysis the only covariates that changed the OR by
more than 5% when omitted from the model were age group
(-10.7%) and onset week (7.1%) (Figure S1). In the target group for
vaccination this was similar (age group: -11.5%; onset week: 8.0%)
(Figure S2).
When comparing crude and adjusted VE estimates, negative
confounding was predominant among the youngest and oldest
age groups, whereas for the 15-59 year age group there was
positive confounding. This differential confounding may be due
to the small sample size and highlights the need for adequate
sample size for age-stratified estimates to investigate this
further.
We adjusted by age using ten-year age bands to minimize
residual confounding by age, however we cannot exclude there
was further residual confounding in this variable or from
unmeasured confounders.
Comparison of one-stage and two-stage results showed similar
results (Table S2), indicating the appropriateness of the one-
stage model. While analyses using the whole population showed
no significant heterogeneity, the results suggested medium
heterogeneity between study sites when restricting the analysis
to the target group for vaccination. While all study sites used the
same protocol, there were differences in influenza incidence,
Table 4. Pooled crude and adjusted seasonal vaccine
effectiveness against all influenza, A(H1N1)2009 and influenza
B, overall and by age group, imputed data, I-MOVE multi-
centre case control study, influenza season 2010-11.
OutcomeN VE % 95% CI
All influenzaAll agesCrude{
Adjusted model#
441064.253.2-72.6
441051.930.0-66.9
0-14 years1
Crude{
Adjusted model#
142250.5-4.2-76.5
142265.715.4-86.1
15-59 years2Crude{
250956.531.2-72.6
Adjusted model#
250941.3-2.6-66.4
60+ years3
Crude{
Adjusted model#
464 55.229.0-71.7
464 59.916.7-80.7
A(H1N1)2009All ages Crude{
Adjusted model#
3344 67.9 54.6-77.3
334455.528.7-72.2
0-14 years4
Crude{
Adjusted model#
910 63.1-10.6-87.7
91077.216.0-93.8
15-59 years5Crude{
205141.4 1.7-65.1
Adjusted model#
205127.2 -37.1-61.4
60+ years6
Crude{
Adjusted model#
35072.5 47.7-85.5
35072.3 26.5-89.6
Influenza BAll ages Crude{
Adjusted model#
294465.849.4-76.9
294449.813.8-70.8
0-14 years7
Crude{
Adjusted model#
106745.5 -30.1-77.2
106762.9-6.4-87.1
15-59 years8Crude{
1502 74.638.4-89.6
Adjusted model#
150263.7-3.9-87.4
60+ years9
Crude{
Adjusted model#
345 47.6-1.6-72.9
34555.5 -37.9-85.6
{Study site included in the model as fixed effect.
#Model adjusted for 2009-10 seasonal and pandemic influenza vaccination,
presence of at least one chronic disease, sex, at least one hospitalisation for
chronic disease in the previous 12 months, current smoker, age group (10 year
bands), practitioner visits in previous 12 months (0-1, 2-4 and 5+ visits), week of
symptom onset.
NB: For influenza B imputed analysis, we are obliged to drop week 14 (1 record)
in order to do computation.
For the certain analyses, weeks of onset had to be dropped due to only positive
or negative outcomes during this week.
1Weeks 13 and 14 dropped (8 records dropped).
2Week 14 dropped (2 records dropped).
3Weeks 46 and 14 dropped (5 records dropped).
4Weeks 12, 13 and 14 dropped (8 records dropped).
5Week 14 dropped (1 record dropped).
6Weeks 48,49 and 10-14 dropped (28 records dropped).
7Week 13 dropped (4 records dropped).
8Week 49 dropped (14 records dropped).
9Weeks 46 and 50 dropped (14 records dropped).
doi:10.1371/journal.pone.0027622.t004
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Page 9

vaccines used, health seeking behaviour and target groups for
vaccination. In the next season a higher sample size will be
sought among the target group for vaccination in order to carry
out a two-stage random effects pooled analysis adjusted for more
covariates.
The Italian VE point estimate appeared to deviate in the
distribution of VE per country (Figure S3 and S4). Upon exclusion
of Italy, heterogeneity was neither present overall nor in any
subgroups and all VE estimates were higher. Detailed investigation
into information or selection bias or into differences in missing
data between Italy and other study sites yielded no differences.
Therefore we assumed that a one-stage model was still appropriate
and included Italy in the pooled VE estimates.
Overall VE estimates from the target population were similar to
the estimates from the whole population. One limitation of the
analysis restricted to the target population for vaccination is that
the variable ‘‘belonging to the target population’’ was not collected
homogeneously between study sites. In some sites not all
information on target group for vaccination was available (mainly
lack of information on people with professions that are targeted for
Table 5. Characteristics of influenza cases and test-negative controls among the target group for vaccination, I-MOVE multi-centre
case control study, influenza season 2010-11.
Cases
N=381
Test-negative controls
N=631P value
Median age39 58
,0.001*
Age group - n6/total n6. (%)
0-415/381 (3.9) 23/631 (3.6)
,0.001**
5-14 72/381 (18.9)39/631 (6.2)
15-59 181/381 (47.5)266/631 (42.2)
60+ +
113/381 (29.7) 303/631 (48.0)
Female sex - n6/total n6. (%)
200/381 (52.5) 338/631 (53.6) 0.845**
Symptoms - n6/total n6. (%)
Fever 362/380 (95.3) 565/628 (90.0)0.003**
Headache 298/380 (78.4) 436/624 (69.9)0.003**
Cough 356/381 (93.4)544/628 (86.6) 0.001**
Shortness of breath69/372 (18.5) 151/621 (24.3)0.040**
Days between onset of symptoms and swabbing – n6/total n6.
(%)
028/381 (7.3)28/631 (4.4) 0.007**
1 160/381 (42.0)256/631 (40.6)
2 127/381 (33.3)173/631 (27.4)
3 35/381 (9.2) 86/631 (13.6)
4 10/381 (2.6)40/631 (6.3)
5 16/381 (4.3)27/631 (4.5)
6 2/381 (0.5)11/631 (1.7)
7 3/381 (0.8)10/631 (1.6)
Mean swab delay1.820.001***
Diabetes - n6/total n6. (%)
29/338 (8.6)90/575 (15.7) 0.002**
Heart disease58/338 (17.2) 196/575 (34.1)
,0.001**
Any reported chronic disease 209/352 (59.4) 423/604 (70.0)0.001**
Smoker - n6/total n6. (%)
Current40/357 (11.2)78/590 (13.2)0.002**
Former37/357 (10.4) 107/590 (18.1)
Never280/357 (78.4) 405/590 (68.6)
Pandemic vaccination 2009-10 n6/total n6. (%)
55/379 (14.5) 148/615 (24.1)
,0.001**
Seasonal vaccination, 2009-10 - n6/total n6. (%)
77/372 (20.7)247/619 (39.9)
,0.001**
Number of practitioner visits in previous 12 months
0-1118/364 (32.4)100/608 (16.4)
,0.001**
2-4 96/364 (26.4) 189/608 (31.1)
5+ +
150/364 (41.2)319/608 (52.5)
*Non parametric test of the median.
**Two-sided Fisher’s exact test.
***T-test.
doi:10.1371/journal.pone.0027622.t005
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Page 10

vaccination). This may have resulted in excluding some of the
target population from the analysis.
The strengths of this study lie in the sample size due to the
multi-centre case control study design. Early adjusted estimates
were possible in February 2011 [18] as well as estimates by
influenza type, age group and target group for vaccination.
Countries share the same protocol, which includes systematic
sampling and documentation of many covariates to adjust for
positive and negative confounding [17].
In conclusion, the I-MOVE multi-centre case control study
provided summary influenza VE estimates across Europe and
showed a moderate VE against medically attended ILI laboratory-
confirmed influenza in a season of good match between the
circulating influenza strains and the strains included in the 2010-11
trivalent vaccine. Next season further study sites may be included in
the pooled analysis and current study sites will focus on increasing
sample size through recruitment of more GPs in order to obtain
more precise estimates, to carry out an adjusted two-stage pooled
analysisandtoobtainage-specificestimates byinfluenzatype among
the target group for vaccination. Even if the trivalent inactivated
influenza vaccines may only provide a moderate protection against
medically-attended ILI laboratory confirmed as influenza, they
remain, until more efficient vaccines are available, the most effective
measure to prevent influenza infection and its consequences.
Supporting Information
Figure S1
covariates from imputed adjusted model, total population,
Percentage difference in OR when omitting
by influenza type, I-MOVE multi-centre case control study,
influenza season 2010-11
(DOC)
Figure S2
covariates from imputed adjusted model, target popu-
lation for vaccination, by influenza type, I-MOVE multi-
centre case control study, influenza season 2010-11
(DOC)
Percentage difference in OR when omitting
Figure S3
adjusted for age group, chronic conditions and onset
month and pooled estimate using random effects, multi-
centre case control study, influenza season 2010-11.
(DOC)
Overall VE against all influenza by study
Figure S4
target group for vaccination adjusted for age group,
chronic conditions and onset month and pooled estimate
using random effects, multi-centre case control study,
influenza season 2010-11.
(DOC)
VE against all influenza by study site among
Table S1
effectiveness against all influenza, A(H1N1)2009 and
influenza B virus, for all ages, complete case analysis, I-
MOVE multi-centre case control study, influenza season
2010-11.
(DOC)
Pooled crude and adjusted seasonal vaccine
Table S2
1-stage and 2-stage pooled models, I-MOVE multi-
centre case control study, influenza season 2010-11.
(DOC)
Comparison of VE against all influenza using
Acknowledgments
All participating GPs and paediatricians in France (Re ´seau des GROG),
Hungary, Ireland, Italy, Poland, Portugal (‘‘Me ´dicos-Sentinela’’ and GPs
participating in EUROEVA project), Romania, Spain (cycEVA).
France: I Grog (Re ´seau des GROG), A Mosnier, TT Bui (Open Rome),
V Enouf (National Reference Centre for Influenza virus France North and
South), M Valette, A Vabret, P Pothier, G Agius, F Stoll-Keller, S Rogez,
JM Mansuy, G Giraudeau, H Fleury, N Leveque (associated hospital
laboratories).
Hungary: M Melles, A Csoha ´n, Z Molna ´r, K Kasza ´s, O Budavari, E
Kozma (National Centre for Epidemiology, Department of Epidemiology),
S Caini (National Centre for Epidemiology, Department of Epidemiology;
EPIET, European Centre for Disease Prevention and Control (ECDC),
Sweden), M Ro ´zsa, E´ Hercegh (National Centre for Epidemiology,
Influenza Reference Laboratory), local study coordinators from the
National Public Health and Medical Officers’ Service.
Ireland: A O’Malley, D O’Flanagan, A O’Hora, O Bannon, S Cotter, L
Domegan, S Gee, D Igoe, J Mereckiene, P O’Lorcain (Health Protection
Surveillance Centre); C Collins, O Levis, M Joyce (Irish College of General
Practitioners), S Coughlan, J Moran, A Waters (National Virus Reference
Laboratory).
Italy: MC Rota, A Bella, F D’Ancona, S Giannitelli, S Declich, S Puzelli,
and I Donatelli (ISS), A Azzi (Regional Reference Laboratory Toscana), G
Delogu (Catholic University of the Sacred Heart, Department of
Microbiology).
Poland: M Głuchowska (National Institute of Public Health, Department
of Epidemiology), M Romanowska, L Brydak (National Institute of Public
Health, National Influenza Centre).
Portugal: A Machado, CM Dias, JM Falca ´o (Instituto Nacional de
Sau ´de Dr. Ricardo Jorge, Department of Epidemiology) I Falca ´o (Direcc ¸a ˜o
Geral da Sau ´de, Unidade de Emerge ˆncia em Sau ´de Pu ´blica), R Guiomar,
P Conde, P Gonc ¸alves (Instituto Nacional de Sau ´de Dr. Ricardo Jorge,
Department of Infectious Diseases).
Table 6. Pooled crude and adjusted seasonal vaccine
effectiveness overall and by influenza type and age group
among the target group for vaccination, imputed data, I-
MOVE multi-centre case control study, influenza season 2010-
11.
OutcomeN VE%95% CI
All influenzaAll agesCrude{
Adjusted model#
100463.248.4-73.7
100456.234.3-70.7
15-59 years ˆ Crude{
Adjusted model#
44767.637.9-83.1
44754.06.6-77.3
60+ years ˆ,*Crude{
Adjusted model#
41352.723.3-70.9
41362.832.8-79.4
A(H1N1) All ages ˆ,$
Crude{
Adjusted model#
78071.155.4-81.3
780 58.932.0-75.1
Influenza BAll ages Crude{
Adjusted model#
70562.2 37.4-77.2
70563.4 31.0-80.6
{Study site included in the model as fixed effect.
#Model adjusted for 2009-10 pandemic influenza vaccination, presence of at
least one chronic disease, sex, at least one hospitalisation for chronic disease in
the previous 12 months, current smoker, age group (10 year bands),
practitioner visits in previous 12 months (0–1, 2–4 and 5+ visits), week of
symptom onset.
For the certain analyses, weeks or months of onset had to be dropped due to
only positive or negative outcomes during this week or month.
*April dropped (3 records dropped).
+ Week 13, 14 and 45 dropped (8 records dropped)
ˆOnset month used for adjusting instead of onset week.
$ November and April dropped (5 records dropped).
, Weeks 45 and 13 dropped (7 records dropped).
doi:10.1371/journal.pone.0027622.t006
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Page 11

Romania: E Lupulescu (INCDMI Cantacuzino, Laboratory for Viral
Respiratory Infections), V Alexandrescu, G Ionescu (INCDMI Cantacu-
zino, Pharmacovigilence and clinical study), A Pistol, R Popescu (National
Institute for Public Health), E Duca (Public Health Directorate Iasi), S
Ibram (Public Health Directorate Constanta), D Dan (Public Health
Directorate Prahova), C Truica (Public Health Directorate Calarsi), CM
Sima (Public Health Directorate Maramures), E Marialaki (Public Health
Directorate Mures).
Spain: S de Mateo (National Centre of Epidemiology), F Pozo, I Casas, J
Ledesma (National Influenza Centre), J Gime ´nez, JM Vanrell (Baleares); C
Rodrı ´guez, T Vega (Castilla y Leo ´n); A Martinez, N Torner (Catalun ˜a);
JM Ramos, MC Serraro (Extremadura), M Garcı ´a Cenoz, J Castilla
(Navarra); JM Altzibar, JM Arteagoitia (Paı ´s Vasco); C Quin ˜ones, M
Perucha (La Rioja); D Castrillejo (Melilla).
Author Contributions
Conceived and designed the experiments: MV JMC CR BN DP AL JOD
CS BCC AM. Performed the experiments: JMC BO ASB CR PS BN DP
AL ID JKH JOD TS IAP-S PP AEI CS. Analyzed the data: EK MV AM.
Participated in protocol writing: MV AM EK. Adapted GROG network
database to I-MOVE design: JMC. Conceived the idea of a European
network for monitoring influenza vaccine effectiveness: BCC. Wrote the
first draft of the paper: EK MV. Contributed to the writing of the paper:
EK MV JMC BO ASB CR PS BN DP AL ID JKH JOD TS IAP-S PP AEI
SJ-J CS BCC AM.
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IMOVE: Influenza Vaccine Effectiveness in Europe
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