aa Tam 2007a

Methods	Multicentre (8 centres in Southeast Asia: China, Hong Kong, India, Malaysia, the Philippines, Singapore, Taiwan and Thailand) RCT carried out over three seasons (enrolment and follow‐up was carried out between 30 September 2000 and 31 May 2003) to assess efficacy, immunogenicity and safety of live recombinant vaccine in small children. The randomisation schedule for each year was generated by Wyeth. In year 1, vaccine and placebo were labelled with 1 of 5 treatment codes, 3 of which corresponded to CAIV‐T treatment and 2 to placebo, to ensure blinding with a 3:2 ratio. At enrolment, each subject was assigned the next sequential subject number and received study product of the treatment code assigned to that subject number according to a preprinted randomisation allocation list In year 2, randomisation at each site was accomplished using an interactive voice response system. Trial personnel telephoned the interactive voice response system to obtain a 6‐digit vaccine identification number corresponding to nasal sprays mailed to that site and numbered according to a predetermined randomisation list. The per‐protocol (PP) population in year 1 included all randomised participants who received all doses of assigned treatment and who remained in the study for at least 15 days after receiving the second dose of CAIV‐T or placebo The PP population in year 2 included all re‐randomised participants who received their assigned treatment and remained in the study for at least 15 days after vaccination in year 2 The intent‐to‐treat population in year 1 included all participants who were enrolled in the study and received at least 1 dose of study treatment. The year 2 intent‐to‐treat population included all participants re‐randomised in year 2
Participants	Starting from 30 September 2000, 3174 children aged 12 to 36 months were enrolled and allocated either to CAIV (1900) or to placebo (1274). Each year the participants were re‐randomised to either placebo or vaccine at a ratio of 2:3 The year 1 PP efficacy population was 2764 participants (1653 CAIV‐T and 1111 placebo) In year 2, 2947 participants were re‐randomised either to a single dose of CAIV‐T or placebo from 9 November 2001 The year 2 PP efficacy population was 2527 participants. 69 participants from year 1 were not randomised in year 2 but were followed up for safety and influenza surveillance throughout year 2. Detailed participant flow with reasons for exclusion from PP analysis is reported in Web‐only supplementary materials. Participating children had evenly mixed genders (46% vs 53%) and were mainly of Chinese (36.1%), Filipino (26.5%) or Thai (29.4%) ethnicity Mean age at first vaccination is reported as 23.5 (SD 7.4) months which is strange, as if the enrollees are always the same, most of them should have been out of age by the second season. In year 1, participants were randomised 3:2 (CAIV‐T: placebo) to receive 2 doses of CAIV‐T or 2 doses of placebo at least 28 days apart using a randomisation schedule generated by Wyeth In year 2, participants were re‐randomised in a 1:1 ratio to receive a single dose of CAIV‐T or placebo without consideration of their group assignment in the first year. Although there is a very detailed figure (2) representing viral isolates in the 2 seasons in countries in which the study took place and comparison with study isolates, it is unclear how country‐surveillance was carried out and how these relate to study isolated strain. The matching of the vaccines for both seasons is described as not matching for strain B and only partial for A viruses Figure 1 is not fully explained in the text. It shows four groups at year 2 with differing sequences of allocation to CAIV‐T and placebo. The initial trial description is that of a crossover but that is not fully explained in the text as well as the 3rd year of the study which disappears in the folds of the text
Interventions	Intranasal CAIV‐T (MedImmune) containing A/New Caledonia/20/99 (H1N1), A/Sydney/05/97 (H3N2) and B/Yamanashi/166/98 (year 1) and A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) and B/Yamanashi/166/98 influenza strains (year 2). The vaccines used were refrigerated formulations of CAIV‐T vaccine made Wyeth. The vaccine contained no preservatives Placebo was sterile physiological saline (Wyeth) Both CAIV‐T and placebo were supplied in identically packaged sprayers; study participants, their parents or guardians and the clinical personnel were blinded. Although vaccine content was planned to be antigenically representative of the WHO recommendations for the Northern Hemisphere for each year. "However, in year 1, because of industry‐wide technical problems in the production of the A/H3N2/Moscow/10/99‐like virus, A/H3N2/Panama/2007/99 vaccine virus, the recommended strain was replaced with A/H3N2/Sydney/05/97.25 This decision was based on the antigenic similarity of the hemagglutinin (HA) antigens, a WHO report indicating that A/H3N2/Sydney/05/97‐like viruses were circulating before the 2000 to 2001 season, 26 and previous clinical trials with the frozen formulation of LAIV that had demonstrated efficacy against mismatched influenza A/H3N2 virus. In year 2, because of delays in manufacture, the recommended B vaccine component, B/Victoria/504/2000 (B/Sichuan/379/99‐like), was replaced with B/Yamanashi/166/98. Therefore, the B component of the second‐year vaccine formulation was not antigenically representative of the B/Victoria/504/2000 (B/Sichuan/379/99‐like) virus recommended by the WHO for the upcoming influenza season" In summary the vaccines in both years were not well matched
Outcomes	Serological Paired sera were taken from 111 participants at 5 sites. However "the same participants did not necessarily participate in the cohort in both years". Blood samples were obtained before and after the second vaccination in year 1 and before and after vaccination in year 2. In summary it is unclear what the relationship of these participants is with the rest of the study population. Nasal swabs were taken from symptomatic ILI cases Effectiveness The primary efficacy end point was the first episode of culture‐confirmed influenza illness caused by a subtype antigenically similar to that in the vaccine after receipt of the second dose of study vaccine or placebo during year 1 in the PP population. Secondary efficacy end points included the first episode of culture‐confirmed influenza illness caused by any influenza virus subtype after receipt of the second dose of study vaccine or placebo during year 1 and the first episode of culture‐confirmed influenza caused by subtypes. It is unclear whether follow‐up included all participants with ILI symptoms. The text reports follow‐up was carried out by phone and clinic visits Safety Parent or legal guardians recorded daily symptom information for 11 consecutive days including the day of administration. AEs were defined as any clinically significant event, including but not limited to (1) events requiring prescription or nonprescription medication within 11 days of vaccination, (2) any event requiring an unscheduled healthcare provider visit and/or consultation within 11 days of vaccination, (3) events resulting in study termination and (4) any other clinically significant event occurring at any time during the course of the study. SAEs, including hospitalisations, were monitored from enrolment until the end of the study. Fever, runny nose, decreased activity or appetite and use of increased fever medications. Other outcomes reported were bronchospasm (7 CAIV‐T, 3 placebo), bronchitis (3 CAIV‐T, 2 placebo) and rhinitis (3 CAIV‐T, 0 placebo) in year 1. In year 2 a child was hospitalised with pneumonia 6 days after receiving CAIV‐T. There was 1 dropout (20‐month‐old female developed fever that persisted for 3 days) after receiving the first dose of CAIV‐T in year 1. There were 2 deaths unrelated to vaccine. Perusal of reported safety denominators in Table 6 show the usual discrepancies in trials of these CAIV‐T vaccines‐ denominators that are reported as ranges with the usual (see Vesikari) caption "†n represents the number of participants with known values". According to Table 6, 1345 received CAIV‐T in season 2 but according to Figure 1 the total should be 1757. There is no mention of the fate of the other children
Funding Source	Industry
Notes	The authors conclude that "In year 1, efficacy of CAIV‐T compared with placebo was 72.9% [95% confidence interval (CI): 62.8 to 80.5%] against antigenically similar influenza subtypes and 70.1% (95% CI: 60.9 to 77.3%) against any strain. In year 2, revaccination with CAIV‐T demonstrated significant efficacy against antigenically similar ( 84.3%; 95% CI: 70.1 to 92.4%) and any (64.2%; 95% CI: 54.2 to 77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite and use of fever medication were more frequent with CAIV‐T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV‐T recipients. CAIV‐T was well tolerated and effective in preventing culture‐confirmed influenza illness over multiple and complex influenza seasons in young children in Asia. Randomisation and allocation concealment are described very well but inconsistencies in the text (a vanished season), unclear denominators and a real possibility of biased follow‐up and reporting bias of safety outcomes make this study at high risk of bias. Safety remains a concern in these studies with bronchospasm a possible AE
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number
Allocation concealment (selection bias)	Low risk	"At enrolment, each subject was assigned the next sequential subject number and received study product of the treatment code assigned to that subject number according to a preprinted randomisation allocation list"
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Possibility of biased follow‐up and reporting bias
Summary assessments	Low risk	Plausible bias unlikely to seriously alter the results