aa Barrett 2011.

Methods	Double‐blind, placebo‐controlled, multicentric RCT performed at 36 centres in the USA assessing effectiveness, reactogenicity, and antibodies responses of a Vero cell‐derived, trivalent, split influenza vaccine
Participants	Healthy adults aged 18 to 48 years recruited at 36 centres throughout the USA. Individuals were excluded if they belonged to a CDC risk category for complications of influenza illness, had a history of surgical or functional asplenia, had been treated with any blood product or immune globulin in the previous 90 days, had a history of allergy to vaccine components, had received a live vaccine within 4 weeks or an inactivated vaccine within 2 weeks of study entry, or had dermatological disorders or tattoos that would obscure the assessment of injection‐site reactions. Individuals were not specifically excluded because of egg allergy. Immunisation in previous seasons was not judged to be an exclusion criterion.
Interventions	Inactivated, Vero cell‐derived, trivalent split influenza vaccine containing 15 µg haemagglutinin of the following strains, which were recommended by WHO for the season 2008 to 2009 in the Northern Hemisphere: A‐H1N1: A/Brisbane/59/2007 A‐H3N2: A/Uruguay/716/2007 (A/Brisbane/10/2007‐like) (A/H3N2) B: B/Florida/4/2006 The vaccine was manufactured by Baxter AG, Vienna. Vaccine strains were egg‐derived wild type strains provided by the National Institute for Biological Standard and Control. Placebo consisted of phosphate‐buffered saline. Participants were randomly allocated to receive one 0.5 mL dose of either vaccine or placebo into the deltoid muscle. Vaccinations were performed between 1 and 15 December 2008.
Outcomes	Safety: participants were provided with a diary card, on which they had to record their temperature daily for the first 7 days following immunisation and to report fever and other adverse events for 21 days after immunisation. Participants returned for a final study visit 166 to 194 days after vaccination for a physical examination and final assessment of adverse events. Serological: the first serum samples were presumably collected before vaccine administration (this is not well described in any of the 3 reports), and the second 18 to 24 days later. Haemagglutination‐inhibiting titres and GMT against vaccine strains were assessed by Focus Diagnostics (Cypress, CA, USA). Haemagglutination‐inhibiting assays were done in triplicate with egg‐derived antigen. Titres of less than 1:10 were expressed as 1:5 and judged to be negative. Effectiveness: during the visit at days 18 to 24 after immunisation, participants were instructed to return to the clinic within 48 hours after the onset of symptoms of an influenza‐like illness, should they have fever with cough, sore throat, muscle ache, headache, fatigue, nausea, or bloodshot eyes, or any 2 of these symptoms without fever. At every visit for an influenza‐like illness until 15 May 2009, nasopharyngeal swabs were obtained for culturing and typing viruses. Nasopharyngeal swab specimens were sent to BioAnalytical Research (Lake Success, NY, USA), for culture using Rapid R‐Mix (Diagnostic Hybrids, Athens, OH, USA) and traditional culture methods, and for virus typing with RT‐PCR analyses. Influenza type A/H1N1 or A/H3N2 isolates were sent to the laboratory of the Influenza Division, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, GA, USA, for analyses of HI using ferret antiserum to assess the antigenic relatedness of the isolate to the vaccine strains.
Notes	Industry funded
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Individuals were randomly assigned by use of a centralised telephone system" "Randomisation was done in blocks, with block sizes greater than two"
Allocation concealment (selection bias)	Low risk	"The allocation sequence was generated by Baxter, using an interactive voice response system with the random number generator algorithm of Wichmann and Hill, as modified by Mcleod"
Blinding (performance bias and detection bias) All outcomes	Low risk	"At each study site, an investigator, subinvestigator, or study nurse who was masked to treatment allocation was designated to vaccinate participants, and was then prohibited from participation in data collection or the study. To ensure masking, the participants were enrolled by investigators who were not involved in the randomisation process. Because the syringes containing the test and the control products were different in appearance both studies employed an observational blinding procedure such that study personnel who administered vaccinations were not involved in recording or reviewing study data"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Both efficacy and safety estimates were calculated on ITT study population. We know that all treated participants (3623 to influenza vaccine and 3620 to placebo) had been included in the safety analysis, whereas 3619 and 3617 had been considered for the effectiveness estimate calculation (i.e. those vaccinated and with at least 21 days' follow‐up after immunisation). Participants in the per‐protocol population (those who completed the study without major protocol deviations) were 3316 and 3318 in the vaccine and placebo arms, respectively. Reasons for non‐inclusion in the per‐protocol population were not specified for 150 vaccine and 135 placebo recipients.
Summary assessment	Low risk	Low risk of bias