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 respiratory 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 
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.
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 
. 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 hospitalisation 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 questionnaire. 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 I2
index to test the heterogeneity between study sites 
and as a sensitivity analysis we carried out a two-stage pooled analysis 
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).