aa Jackson 2010a.

Methods	Randomised, multicentre, double‐blind, placebo‐controlled trial assessing the effectiveness and safety of a trivalent inactivated vaccine in preventing confirmed influenza. The study was performed during 2 influenza seasons (2005 to 2006 and 2006 to 2007) in the USA.
Participants	Healthy adults aged between 18 and 49 years without significant acute or chronic medical or psychiatric illness. Individuals with cancer; systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg; belonging to a risk group for which routine influenza vaccination is recommended (chronic pulmonary, cardiovascular, renal, hepatic, haematological, or metabolic disorders; immunosuppressive illness, recent/ongoing receipt of immunosuppressive therapy, immunoglobulin, other vaccines, or with HIV infection were excluded. Participants enrolled for the first season were not included in the second season. In season I (2005 to 2006), 3514 participants were recruited at 37 centres from 17 September 2005 onwards. In season II (2006 to 2007), 4144 participants were recruited at 44 centres from 16 October 2006 onwards.
Interventions	Recruited participants were randomised at the beginning of each season to receive 1 dose of trivalent inactivated split influenza vaccine (FluLaval, a trademark of the GlaxoSmithKline group of companies; manufactured by ID Biomedical Corporation of Quebec, Canada) or saline placebo injection. Each 0.5 mL dose of TIV contained 15 μg of HA antigen of each recommended influenza strain. For season I (2005 to 2006) antigens were: A/New Caledonia/20/1999 (H1N1) A/New York/55/2004 (H3N2, A/California/7/2004‐like) B/Jiangsu/10/2003 (B/Shanghai/361/2002‐like)
Outcomes	Effectiveness During the influenza seasons, participants were instructed to report symptoms meeting the ILI definition by using a toll‐free, study‐specific phone number within 48 hours from their onset and to record them together with temperature. Influenza‐like illness symptoms were moreover solicited by weekly outbound phone contact. Visits from nurses were dispatched to participants who filled ILI definition within 24 hours after symptoms onset, and nasopharyngeal and oropharyngeal swabs for viral culture were drawn. During season I surveillance for influenza was conducted between 14 November 2005 and 30 April 2006; during season II between 13 November and 30 April. Primary effectiveness study endpoint was: VMCCI (vaccine‐matched, culture‐confirmed influenza). The case definition required the presence of ILI, defined as symptoms that interfered with normal daily activities and that included cough and at least 1 additional symptom from among fever (oral temperature > 37.7 °C/99.9 °F), headache, myalgia and/or arthralgia, chills, rhinorrhoea/nasal congestion, and sore throat. Participants meeting the definition for ILI and with concurrent isolation from a nasopharyngeal swab of an influenza A and/or B virus isolate antigenically matching a vaccine strain for the relevant year were considered to be cases of VMCCI. Secondary effectiveness endpoints were: CCI (culture‐confirmed influenza illness). ILI with any influenza A or B virus isolate by culture. LCI (laboratory‐confirmed influenza illness). 1 or both of CCI or ILI with a 4‐fold increase in HI serum antibody titres to a circulating influenza virus strain between day 21 (±4 days) postvaccination and final visit specimens obtained after the end of the influenza season. Immunogenicity Serum samples were collected from study participants at day 0, 21, and about 4 weeks after the end of the surveillance period. Immunogenicity was assessed determining GMT, seroconversion and seroprotection rate between samples collected at day 21 and at day 0 on a randomly selected subset of participants. Safety Local and systemic reactions (events) occurred within 3 days after immunisation. Participants were observed for the first 30 minutes following immunisation. Participants recorded further reactions occurring no later than 8 days following vaccination by means of an interactive voice response system. The following symptoms were reported (3 days). Fever (at least 37.5 °C) Injection site pain/soreness Injection site redness Injection site swelling Myalgia or arthralgia, or both Headache Tiredness Chills Malaise Red eyes Swelling of the face Cough Chest tightness or difficulty in breathing Sore throat, hoarseness, or pain on swallowing Participants with at least 1 vaccine reactogenicity event Data were provided pooled for the 2 study seasons. Unsolicited spontaneous adverse events, for which follow‐up was extended for at least 135 days following immunisation. Pregnancy outcomes Pregnancies Spontaneous abortion Full‐term birth
Notes	Per‐protocol: participants who received the treatment to which they were randomised, responded to ≥ 1 postvaccination active surveillance telephone calls, and had no major protocol deviations considered to affect the efficacy or immunogenicity data (determined before unblinding) (for effectiveness estimates). Intention‐to‐immunise: the per‐protocol set plus participants with protocol deviations and treatment errors and analysed as randomised. The safety set included participants who received any study treatment and had any postvaccination safety data. If an incorrect treatment was conclusively documented, participants in the safety set were analysed based on the treatment they had actually received. Funding source was pharmaceutical. "GSK Biologicals was the funding source and was involved in all stages of the study conduct and analysis. GSK Biologicals also took in charge all costs associated with the development and the publishing of this manuscript. The corresponding author had full access to the data, and final responsibility for submission of the manuscript for publication"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Treatment allocation was determined by blocked, stratified randomization with a 1:1 distribution to TIV or placebo; randomization was stratified by study center, age (18‐34 and 35‐49 years), and the subject's report of previous recent receipt (within ≤ 2 years) of TIV.”
Allocation concealment (selection bias)	Unclear risk	Insufficient description of allocation concealment: “Each study center had a pre‐determined sequence of randomization numbers which were allocated sequentially to eligible participants. Participants were allocated equally among 3 different vaccine lots”
Blinding (performance bias and detection bias) All outcomes	Low risk	“Clinic staff (excluding the nurse giving the vaccine), were blinded to the treatment group until the study was complete.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Participant flow
Summary assessment	Unclear risk	Unclear