aa Bracco Neto 2009a.

Methods	Placebo‐controlled (year 1 = 2001) Multicentre study conducted during the 2001 and 2002 influenza seasons at 35 sites in South Africa, Brazil, and Argentina (Southern Hemisphere)
Participants	3200 children 6 to 36 months of age in good health were enrolled. Exclusion criteria in year 1 included any serious chronic disease, immunosuppression or presence of an immunocompromised household member, receipt of any commercial or investigational influenza vaccine before enrolment, a documented history of hypersensitivity to any component of LAIV or placebo.
Interventions	LAIV versus 2 placebos: excipient or saline placebo. Saline placebo (Salplacebo) consisted of physiologic saline; excipient placebo (Eccplacebo) was the vaccine excipient alone (sucrose‐phosphate‐glutamate buffer, arginine, acid hydrolysed porcine gelatin, and normal allantoic fluid), in the same concentration as in LAIV. There were 4 arms in year 1: LAIV 2 doses, Eccplacebo, Salplacebo, and LAIV 1 dose plus Salplacebo 1 dose each. Vaccine content and degree of vaccine matching were unclear.
Outcomes	Laboratory Culture “standard techniques by laboratories in Argentina, Brazil and South Africa” Effectiveness Cultured‐confirmed influenza illness and all episodes of AOM and any LRTI, hospitalisation Safety Reactogenicity events and AEs
Funding Source	Industry
Notes	The authors conclude “that a single dose of LAIV provided clinically significant protection against influenza in young children previously UV against influenza and 2 doses provided persistent protection through a second season without revaccination. These benefits, together with the vaccine’s safety profile in children 2 years of age and older, provide support for increased use of LAIV in children < 2 years of age. LAIV was well tolerated; no significant differences in solicited reactogenicity events were seen between treatment groups. LAIV was not associated with an increased rate of AEs through day 11 postvaccination. When AEs were assessed through day 28 postvaccination in year 2, the rate of bronchitis was significantly increased in LAIV recipients, although rates of bronchospasm and any respiratory AEs were similar between groups. Additionally, no differences in solicited reactogenicity events or other AEs were seen after either saline or excipient placebo. This suggests that the excipients in LAIV, which include egg protein and acid‐hydrolyzed gelatin, do not contribute to reactogenicity in vaccine recipients”. The description of trial methods and results is unclear. The rationale for the use of 2 placebos is unclear. An allocation mistake was made in year 2 of the study with a swap of a group from active to placebo and vice versa. It is unclear whether blinding was maintained throughout or not, but attrition appears to have gone up to 58% (Figure 1 is very difficult to interpret). In addition, numerators are not reported, and there is no mention of attempts at standardisation of laboratory procedures across 2 continents and 3 countries.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random lists
Allocation concealment (selection bias)	Low risk	Centralised randomisation scheme
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few losses to follow‐up
Summary assessments	Low risk	Plausible bias unlikely to seriously alter the results.