aa Belshe 1998

Methods	Multicentre, prospective, randomised, double‐blind, placebo‐controlled trial to assess efficacy and safety of a cold‐adapted influenza vaccine in single‐ and 2‐dose regime versus placebo. Vaccine and placebo were randomly assigned sequential vaccination numbers. Randomisation sequence was incorporated in the preparation and labelling of materials. Each eligible child received the next available study number at a site, ensuring proper randomisation. Placebo was indistinguishable from the vaccine in appearance and smell
Participants	"Healthy children aged between 15 and 71 months at the time of their enrolment (August ’96). A total of 1314 children were enrolled in the 2‐dose group and 288 for the 1‐dose. No statistical differences in age, sex, race, daycare and household makeup were observed between vaccine and placebo groups Subjects scheduled to receive 2 doses of vaccine; received the first between August 21, 1996 and October 23, 1996; the second dose between October 15, 1996 and January 11, 1997. Subjects in the 1‐dose cohort were vaccinated between September 30, 1996 and December 5, 1996"
Interventions	Cold‐adapted, trivalent influenza vaccine (supplied by Aviron, Mountain View, California). Vaccine reassortants contained the strains A/Texas/36/91‐like (H1N1), A/Wuhan/359/95‐like (H3N2), B/Harbin/7/94‐like in egg allantoic fluid with sucrose, phosphate and glutamate. The mean dose of each attenuated strains was 106.7. These matched the antigens recommended for that year by the Food and Drug Administration (1996 to 1997) Placebo consisted only of egg allantoic fluid with sucrose, phosphate and glutamate Both were intranasal administered through a spray applicator (0.25 ml of placebo or vaccine per nostril) In the 1‐dose group 189 participants were vaccinated and 89 received placebo; in the 2‐dose group 881 participants were randomised to receive vaccine and 433 to receive placebo. From this group 42 participants didn't receive the second dose for the following reasons: 2 withheld because they had adverse reactions after the first dose 18 withdrawal of consent 7 intercurrent illness 12 violation of protocol or withdrawal by an investigator 3 loss to follow‐up or departure from the area and 13 were excluded from the efficacy analysis (only for the 2 doses alone) because: 5 had received influenza vaccine outside of the study 8 were infected by influenza virus A (H3N2) before receiving the second dose 1 case was in the vaccine recipients and seven among the placebos All these 55 (and the eight cases of influenza A) were included in the efficacy analysis considering the 2 groups together
Outcomes	Serological Hemagglutination Inhibiting Antibody Responses After 1 or 2 doses of vaccine or placebo were evaluated. Data for 136/849 (2 doses recipients) vaccinated only reported ‐ likely SELECTION BIAS Effectiveness Influenza defined as any illness detected by active surveillance associated with positive culture for wild type influenza virus 28 days after the first dose and any time after the second dose during the influenza A H3N2 and B epidemic, that lasted up to April 1997. After the outbreak of influenza in the community (end November 1996) parents were contacted and reminded to notify if the subject had symptoms suspected to be caused by influenza: fever, runny nose, nasal congestion, sore throat, cough, headache, muscle aches, chills, vomiting, suspected or confirmed OM, decreased activity, irritability, wheezing, shortness of breath and pulmonary congestion. It was attempted to collect viral culture specimens within four days after the onset of any illnesses Safety The parent or guardian of each subject was given a digital thermometer and asked to record on a diary card temperature (fever was defined as an axillary temperature above 37.6°C or oral temperature above 37.7°C or rectal temperature above 38.1°C) and occurrence of specific symptoms including decreasing activity, irritability, runny nose or nasal congestion, sore throat, cough, headache, muscle aches, chills and vomiting, daily for 10 days after each vaccination
Funding Source	Government/Industry
Notes	The authors conclude that live attenuated, cold adapted influenza vaccine is safe, immunogenic and effective against influenza A and B in healthy children. Vaccine efficacy is equally high for older and younger children
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisations (block size of six)
Allocation concealment (selection bias)	Low risk	"The randomisation sequence was incorporated in to the preparation and labelling of materials, and each eligible child received the next available study number at a site"
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few losses of follow‐up
Summary assessments	Low risk	Plausible bias unlikely to seriously alter the results