aa Clover 1991

Methods	Multicentre, cluster‐randomised, placebo‐controlled clinical trial in which the efficacy of bivalent cold adapted and trivalent inactivated influenza vaccines were compared. Seventy per cent of the study population had already been immunised in the previous “Gruber 90”, whose participants were enrolled at the same centres and that was carried out during the previous year. Design and methods of enrolment are similar to those adopted in that study (see linked studies list)
Participants	103 families were enrolled from Houston Family Study, Baylor Family Practice Clinic (Houston) and Family Medicine Clinic (University of Oklahoma). They were randomly assigned to receive placebo (40%) or 1 of the 2 vaccines (each 30%). About 70% of the families were enrolled and randomised the previous year and received the same preparation. The entire study population consisted of 166 adults and 225 children. Ninety‐eight families with 157 adults and 192 children aged almost 3 years and 20 children younger than 3 years completed the study
Interventions	Bivalent cold recombinant influenza A vaccine containing 107 TCID50 of CR – 90 (A/Bethesda/1/85 H3N2) and 10 7 TCID 50 of CR – 98 (A/Texas/1/85 H1N1) in 0.5 ml. 1 dose intranasally administered Trivalent, inactivated influenza vaccine (standard licensed Fluogen, Parke Davis, Detroit) containing 15 μg of each A/Chile/83 H1N1, A/Missisipi/85 (H3N2) and B/Ann Arbor/86 hemagglutinin antigen in 0.5 ml. 1 dose intramuscularly administered Placebo consisted of buffered or sterile saline, which were administered respectively intranasally or intramuscularly. Subjects in the placebo arm were randomised to receive one or the other preparation
Outcomes	Serological Children receiving vaccine or placebo, were brought in 3–4 weeks after vaccination to obtain a second blood specimen to determine antibody responses to vaccine antigens. However, paired sera were taken from 112 children with no explanation as to why Effectiveness "Influenza A infection Febrile illnesses (with temperature >38°C) : including upper or lower respiratory tract illness, otitis media, influenza‐like illness Afebrile illnesses When ongoing community surveillance at the Influenza Research Center indicated that influenza virus was spreading in the community (influenza A/Taiwan/86), weekly telephone contacts to families were made to evaluate respiratory illnesses. Home or clinic visits were scheduled for physical examination and collection of nasal washes or swab specimens for viral isolation. An illness was attributed to influenza A infection if influenza virus was isolated during the illness or , for a person with a postseason antibody rise only, if no other virus was detected in the illness specimen and if the illness occurred within 10 days of an isolate in household contact or during the period of most intense influenza activity in the community. Illnesses were characterised by review of records which included date of onset, symptoms, physical signs diagnosis of each contact." Safety N/A
Funding Source	Unclear
Notes	The authors conclude that TIV gave a better protection against detectable infection in older children (P > 0.1 TIV vs placebo) than CR vaccine, who instead were more protective in younger children (based however on a denominator of 27, 35 and 51 CR, TIV and placebo recipients). There were no statistical differences in infection rates for family contacts of children receiving TI or CR or placebo Analysis seems to have been done at individual level, whereas randomisation was at cluster level. The authors report that the vaccines were ineffective at preventing transmission
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No description
Allocation concealment (selection bias)	Unclear risk	Not used
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, unlikely to be related to true outcome
Summary assessments	Unclear risk	Plausible bias that raises some doubt about the results