aa Vesikari 2006a

Methods	Double‐blind RCT assessing efficacy and safety of CAIV‐Trivalent in children. The trial was multicentre conducted in Belgium, Finland, UK, Israel, Spain during the period 2 Oct 2000 to 31 May 2002. Follow‐up for each year lasted until 31 May and was a composite of phone calls, home and visit clinics. Coding was carried out centrally as well as randomisation and assigned by a blind investigator on the basis of a pre‐printed randomisation schedule. Both ITT and PP populations were defined. Analyses were carried out only for outcomes occurring in periods of viral circulation in the different centre areas
Participants	1616 healthy children aged 6 to 35 months attending daycare (at least 12 hours weekly) in 1 of the centres who continued to be healthy during year 2 were included in the primary analysis (951 vaccine and 665 placebo recipients). Originally 1784 participants were randomised on 3:2 basis. There was considerable attrition between the year 1 ITT population (1059 in the active arm and 725 in the placebo arm) and the year 2 PP population (640 and 450 respectively), with 65 dropouts in the placebo arm and 132 in the intervention arm (calculated from the flow diagram of population which does not add up). Table 1 reports 174 of the 1616 PP population being aged 6 to 12 months, 598 12 to 23 months and 844 aged 24 months or more
Interventions	CAIV‐T (Wyeth) containing A/New Caledonia/20/99 (H1N1), A/Sydney/05/97 (H3N2) and B/Yamanashi/166/98 in year 1 and A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) and B/Victoria/504/2000 or sterile physiological solution placebo. For technical reasons, antigens in year 1 were similar to those recommended and in year 2 they were those recommend by WHO. Dose was 0.2 ml in each nostril twice in year 1 (approximately 35 days apart) and once in year 1. Spray applicators were preloaded centrally and all identical. In year 1 the match was good, in Year 2 the match was not so good because of drifted variants and the appearance of 2 different strains of influenza B vaccine
Outcomes	Serological Children with fever (rectal 38°C or more and oral 37.5°C or more), wheezing shortness of breath, pulmonary congestion, pneumonia or ear infection got a nasal swab and those with 2 or more of the following: runny nose, nasal congestion, sore throat, cough, muscle aches, chills, irritability, decreased activity or vomiting Effectiveness Influenza caused by subtypes antigenically similar to those contained in the vaccine (primary endpoint) and by those drifted from the recommended ones (secondary endpoint) AOM (visually abnormal tympanic membrane (for colour, position and or mobility) with 1 or more of the following: fever (rectal 38°C or more and oral 37.5°C or more), earache, irritability, diarrhoea, vomiting, otorrhoea or any URI symptom. Febrile OM (with fever rectal 38°C or more and oral 37.5°C or more). Influenza associated AOM if it occurred in a child with a positive culture for influenza. Data were included only for those episodes occurring 15 days or more since vaccination or placebo administration and during a period of influenza virus isolation in each country. An episode of AOM had to take place at least 30 days since the previous one Time off work of parent or guardian to care for the child with ILI (at least once during the study period) Days off paid work. Days of daycare missed by ill children At least 1 visit to ER/outpatients department because of ILI At least 1 prescription for antibiotics because of ILI Days of antibiotic treatment because of ILI Safety Parents/guardians kept diary card to record axillary or rectal temperature, runny nose or nasal congestion, sore throat, cough, vomiting, activity level, appetite, irritability, headache, chills, muscle pain and antipyretic medication use, unscheduled physician contacts for 11 consecutive days from vaccination and throughout the study any unscheduled event that required healthcare contact or study termination. Fevers were classified as mild, moderate or severe (equal to or more than 37.5°C, 38.6°C and 40°C axillary respectively or 38°C, 39.1°C and 40°C rectally). AEs are reported in a mixture of table and text format. We have extracted the AEs for up to 11 days post‐vaccination but the text reports no significant difference between those occurring within 11 days of vaccination and those occurring throughout the surveillance period. These are classed as possible, probable or definitely caused by vaccination but the definition of the association is unclear: "Lower respiratory tract illnesses reported as serious AEs from receipt of the first dose of study medication through the end of the first influenza surveillance period were also similar between treatment groups (pneumonia: 11 CAIV‐T recipients and 9 placebo recipients; bronchitis: 3 CAIV‐T recipients and 1 placebo recipient; bronchospasm: 2 CAIV‐T recipients and 2 placebo recipients; bronchiolitis: 1 CAIV‐T recipient and 2 placebo recipients) In participants 6 to 12 months of age, lower respiratory tract infections reported as serious AEs were pneumonia (2 CAIV‐T recipients and 1 placebo recipient), bronchitis (2 CAIV‐T recipients and 0 placebo recipients) and bronchospasm (1 CAIV‐T recipient and 0 placebo recipients). Serious AEs judged to be possibly, probably, or definitely related to study vaccination were reported for 9 CAIV‐T recipients (pneumonia and AOM, 2 recipients; bronchopneumonia, 2 recipients; pneumonia, 1 recipient; bronchiolitis, 1 recipient; bronchitis and AOM, 1 recipient; idiopathic thrombocytopenic purpura, 1 recipient; and fever, acute respiratory tract infection, dehydration and AOM, 1 recipient) and 5 placebo recipients (1 each for pneumonia and constipation; cough, wheeze and lung consolidation; pneumonia; idiopathic thrombocytopenic purpura; and hypersensitivity, erythema and periorbital edema). There were no statistically significant differences in serious AEs between treatment groups during the second influenza surveillance period. Six lower respiratory tract illnesses were reported, all among CAIV‐T recipients (5 cases of pneumonia and 1 of bronchospasm). 2 cases of pneumonia were judged to be possibly, probably, or definitely related to study vaccination. A total of 4 participants (2 CAIV‐T recipients and 2 placebo recipients) were withdrawn from the study because of AEs. No deaths occurred during the study period"
Funding Source	Industry
Notes	The authors conclude that "cold‐adapted influenza vaccine‐trivalent was well tolerated and effective in preventing culture‐confirmed influenza illness in children as young as 6 months of age who attended day care". Formally this is a very well reported study following CONSORT guidelines. There are however numerous discrepancies in the text. Vaccine was not available until the end of Nov in year 2 and it is unclear what effect this had (immunisation was completed on 21 December, in the case of Israel this was after the beginning of viral circulation). In addition the centres went from 70 in year 1 to 62 in year 2 for unexplained reasons. A major unexplained problem is seen in table 7 (harm events reporting). 2 figures are shown for the six columns (vaccine and placebo by dose by year of the trial) representing "the number of subjects with known values" and then presumably the randomised denominator (which does not fit with either ITT or PP numbers). The figures show runny nose as significantly higher in dose 1 year 1 recipients and this may explain the high attrition between dose 1 year 1 and single dose year 2 (from 1021 to 631 !!!!!!!)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Adequate
Allocation concealment (selection bias)	Low risk	Adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	Adequate
Incomplete outcome data (attrition bias) All outcomes	Low risk	The proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate
Summary assessments	Low risk	Plausible bias unlikely to seriously alter the results