aa Hoberman 2003a

Methods	RCT to assess effectiveness of inactivated influenza vaccine against OM and influenza. 2 groups in 2 following years were randomised before beginning of the respiratory season (December 1st to March 31 of each year) to receive 2 doses of vaccine or placebo
Participants	Children aged 6 to 24 months enrolled at Children Hospital of Pittsburgh. In the first study year 417 children were enrolled and randomised between October 4th and November 30th, 1999) to receive 2 doses of vaccine or placebo. In the second study year 376 children were randomised between September 5th and December 8th, 2000)
Interventions	Participants were stratified according to whether they were prone to OM (at least 3 episodes occurred in the last 6 months or 4 in the last year) In the second study year participants were also stratified depending if they received at least 1 dose of pneumococcal conjugate vaccine Within each stratum children were randomised in blocks of 9 by means of a computer‐generated list to receive 2 doses of vaccine or placebo in ratio 2:1. The 2 doses were intramuscularly administered approximately 4 weeks apart First study year: Inactivated trivalent subvirion influenza vaccine (Fluzone, Aventis Pasteur, Swiftwater, Pa) containing strains A/Beijing/262/95 (H1N1) , A/Sydney/15/97 (H3N2), B/Yamanashi/166/98 versus Placebo consisting of a standard diluent and supplied also by Aventis In both years 2 doses were administered 4 weeks apart Of the 417 initial participants, 278 were randomised to receive placebo and 139 to placebo. Five participants in the vaccine and 1 in the placebo group were discarded because of failure to meet eligibility criteria. The first dose was administered to 273 (vaccine) and 138 (placebo) children. The second dose was administered to 267 and 134 participants respectively Second study year: Inactivated trivalent subvirion influenza vaccine (Fluzone, Aventis Pasteur, Swiftwater, Pa) containing strains A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Yamanashi/166/98 versus Placebo (standard diluent, Aventis) 1 subject from the placebo group was excluded for failure to reach eligibility. 252 children were administered vaccine, 123 placebo. The second dose was administered to 246 and 118 participants respectively
Outcomes	Serological Seroconversion. 4‐fold increase in antibody titres or post‐immunisation titre > 1:40 (before immunisation/4 weeks second dose) Effectiveness "First study year: Biweekly visit carried out after the second dose of vaccine up to 31 March 2000 (4 months); Monthly visits up to November 15th, 2000 Second study year: Biweekly visits from after second dose was administered (December 2000) up to March 31st, 2001 (4 months). Parents were instructed to contact staff for cases of upper respiratory tract infection or otitis. In these cases an interim visit was conducted Acute care visits: visits resulted from fever (38°C) within 72 hours or occurrence of otalgia or illness‐related visit to the primary care clinicians Middle ear effusion: decreased or absent tympanic membrane mobility; yellow or white discolouration of the tympanic membrane; opacification of tympanic membrane not due to scarring; visible bubbles or air‐fluid levels. Outcome is defined as presence of at least 2 symptoms Acute otitis media: presence of purulent otorrhoea of recent onset not due to otitis externa or middle ear effusion accompanied by 1 or more symptoms: ear pain, marked redness of the tympanic membrane, bulging of the tympanic membrane Influenza: positive culture obtained from throat swab during visits at which study participants had upper respiratory tract infection accompanied by fever (38°C) or acute otitis media or both (during flu seasons: first year Jan 3rd–Feb 15th, 2000; second year Jan 4th‐March 30th, 2001) In the first study year 25 cases occurred during the epidemic and a further 12 in the following 25 weeks of surveillance. In the second study year the corresponding values were 11 and 2 (sixteen weeks surveillance)" Safety "Minor systemic or local adverse events were not systematically recorded (1 child had 2 brief episodes of unexplained staring on the day of the first vaccination; 1 had mild intercostals reactions and wheezing 1 day after the second vaccination; 1 child developed acute gastroenteritis 3 days after first vaccination) Other possible adverse were monitored during the care visits"
Funding Source	Industry
Notes	The authors conclude that the vaccine was well tolerated but had no effect on OM, resource consumption, or any of the other indicators
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number, computer‐generated list, block randomisation (block of 9)
Allocation concealment (selection bias)	Low risk	"randomisation lists were kept in locked files not accessible to blinded personnel"
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	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