aa Beran 2009a.

Methods	Randomised, double‐blind, placebo‐controlled study conducted in the Czech Republic during the 2005 to 2006 influenza season. This was defined retrospectively as starting the first week with 2 culture‐confirmed cases in the study area and ending the last week with 1 culture‐confirmed case in the study area. Randomisation was generated by GSK (sponsor) using the SAS program, in a 2:1 blocking scheme using a minimisation procedure (with no explanation of why such a method or the ratio was used). The allocation concealment method was not explicitly mentioned. However, the authors mentioned that placebo and vaccine treatments were indistinguishable in appearance and that blinding to treatment assignment was maintained until study analysis.
Participants	Self referred healthy adults (n = 6203), predominately Caucasian (understood to be white) (99.8%), aged between 18 and 64 years (mean 35 + 13 years) of both genders (TIV group: female 55.3%, placebo group: female 54.2%) and with no history of influenza vaccination within the last 3 influenza seasons. A subset of participants who were randomly selected for vaccine safety and reactogenicity were given a calibrated thermometer and a diary card to record symptoms. The method of selection of this subset was not explained. Use of antimicrobial/influenza antiviral therapy seemed to be allowed but was not quantified.
Interventions	TIV vaccine: 0.5 mL single dose by IM injection or placebo (normal saline). Use of more than 1 lot was not reported. TIV contained haemagglutinin antigens of: A/New Caledonia/20/99 (H1N1) IVR‐116 virus as an A/New Caledonia/20/99‐like strain; A/New York/55/2004 (H3N2) X‐157 virus as an A/California/7/2004‐like strain; B/Jiangsu/10/2003 virus as a B/Shanghai/361/2002‐like strain. 2 modes of surveillance were used. Passive: started on the day of vaccination, participants self report of ILI symptoms through a toll‐free number. Active: started 2 weeks after vaccination day: a biweekly telephone contact of the participants by someone (not clear who) for ILI symptoms. It is not clear if the surveillance included the entire cohort or just a subset, or why the authors carried out harms surveillance using the 2 surveillance methods already in place.
Outcomes	Serological Blood samples were collected for the specified subset and were tested/analysed at GSK Biologicals SSW Dresden, Germany. Blood sample obtained prior to vaccination and at 21 days following vaccination. Serum samples were stored at ‐20 °C until blinded analyses were conducted. A haemagglutination‐inhibition test was done using chicken red blood cells with the 3 virus strains present in the TIV used as antigens. The serum titre was expressed as the reciprocal of the highest dilution that showed complete inhibition of haemagglutination. Serology was not a primary outcome in this study. Effectiveness Incidence of culture‐confirmed ILI (primary outcome, reported as the attack rate in the efficacy cohort) Nasal and throat swab collected by a nurse on the same day. Swab samples were stored at 28 °C and transferred within 5 days of the onset of ILI symptoms. Sample sent to the National Reference Laboratory for Influenza (NRL, Prague, Czech Republic) for conventional influenza virus culture using MDCK cells. Confirmation of influenza A or B was determined using the following: haemagglutination assay with turkey and guinea pig erythrocytes; haemagglutination inhibition to identify virus type, subtype, and drift variant; direct immunoperoxidase assay using anti‐influenza A and anti‐influenza B nucleoprotein antibodies. There were 814 reported ILI episodes, only 46 gave positive culture.  Clinical Incidence of ILI symptoms (secondary outcome, reported as attack rate in the ATP cohort) Influenza‐like illness was defined as fever (oral temperature greater or equal to 37.8 °C) plus cough and/or sore throat. An ILI episode was defined as the period from the first day of ILI symptoms until the last day of ILI symptoms. A new episode was taken into account only after the complete resolution of the previous one. To count as a separate episode at least 7 days free of any symptoms should pass. Number of events was 370 reported events (254 in TIV and 120 in placebo). Number of participants reporting at least 1 event (240 in TIV and 113 in placebo) was used to calculate the attack rate. Reasons to exclude from the ATP cohort included: protocol violation (inclusion/exclusion criteria): seems that the selected subset have certain criteria but not mentioned by the authors; underlying medical condition: not specified what? Or why not excluded from the efficacy cohort as well since participants are reported to be healthy; forbidden by the protocol: protocol not clear; participants not exposed during the influenza season: unclear what this means (did the participant travel after getting the study treatment?). Immunogenicity Blood sample obtained prior to vaccination and at 21 days following vaccination. Performed only for a subset of participants, not all efficacy cohort. Safety Data on SAEs began at the receipt of vaccine/placebo and continued until the end of the study. However, safety was solicited from a subset of participants (no mention of method used to randomly select them, no justification for not collecting SAEs from all participants, especially with the presence of 2 surveillance methods). Reactogenicity Defined as the presence and intensity of the following symptoms within 4 days of vaccination: pain, redness, and swelling (found to occur more in the TIV group), other general symptoms of fatigue, fever, headache, muscle aches, shivering, and joint pain (found to occur more in the TIV group). The intensities of adverse events were recorded according to a standard 0 to 3 grade scale: "absent", "easily tolerated", "interferes with normal activity", and "prevents normal activity".
Notes	The authors report that due to the atypical nature of the influenza season during this study they were unable to assess TIV efficacy. Industry funded
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A randomisation list was generated by the sponsor by SAS program and used to number the vaccine and placebo treatments"; "A randomization blocking scheme (2:1) was employed to ensure that balance between treatments was maintained."
Allocation concealment (selection bias)	Unclear risk	No explicit description of the method of concealment, authors only mentioned that treatments were numbered and that they were indistinguishable in appearance.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Authors reported that the blinding assignment was maintained until study analysis. Authors mentioned that the treatments were indistinguishable in appearance.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Exclusion of allocated participants from the analysis of the trial: a) did the report mention explicitly the exclusion of allocated participants from the analysis of trial results? Yes; b) if so did the report mention the reason(s) for exclusion? Yes. Details were reported in the study flow chart.
Summary assessment	Unclear risk	Unclear risk of bias