aa Gruber 1990.

Methods	Multicentre, randomised, placebo‐controlled clinical trial to determine effectiveness and safety of cold bivalent cold recombinant (CR) and trivalent inactivated (TIV) influenza vaccines. Randomisation and allocation procedures were not described.
Participants	"One hundred ninety one (191) healthy children aged 3 to 18 years from 92 families recruited from HFS, Oklahoma Family Practice Center (Oklahoma City), Baylor College of Medicine Family Practice Clinic (Houston, Texas) were enrolled. Recruited families were independently randomised at each participating institution to form 1 of three immunisation groups: 30% were assigned to each vaccine group and 40% to the placebo group. Placebo recipients were randomly assigned to receive intranasal buffered saline or intramuscular sterile saline. No significant differences were noted in socioeconomic status, average size of the family, age distribution of the vaccine recipients. Thirty families were assigned to the TIV group (54 children), 25 to the CR group (58 children) and 37 to the placebo (77). UV family contacts were also followed up during the epidemic of B/Ann Arbor/86 (TIV = 56; CR = 47; placebo = 72)"
Interventions	Bivalent CR influenza A vaccine composed of 2 vaccine strains, each of which contains the 6 genes coding for the cold‐adapted parent influenza strain A/Ann Arbor/6/60. CR – 59 (H3N2, lot E‐204, containing 107.3 TCID50 per mL) were diluted 1:10 with CR – 64 (H1N1, lot E – 221, containing 106.3 TCID50 per mL). CR – 64 and CR – 59 contain the haemagglutinin and neuraminidase of A/Dunedin/6/83 (H1N1) and A/Korea/1/82 (H3N2). 1 dose of 0.5 mL intranasally administered. Trivalent inactivated influenza vaccine (Fluogen, subvirion; Parke Davis, Morris Plains, NJ, USA) containing 15 mg of each A/Chile/83 (H1N1), A/Philippines/82 (H3N2), B/USSR/83 haemagglutinin antigens in 0.5 mL. 1 dose of 0.5 mL intramuscularly administered. Placebo consisting of either 0.5 mL of buffered saline (intranasally) or 0.5 mL of sterile saline (intramuscularly).
Outcomes	Serological Antibody titres Effectiveness Febrile illness (including upper respiratory tract illnesses with fever, otitis media, influenza‐like illnesses with fever, lower respiratory tract illnesses with fever) Afebrile illnesses (no definition given) Influenza B infection "When ongoing community surveillance at the Influenza Research Center (Baylor College of Medicine) indicated that influenza virus was present in the community, weekly telephone contacts to families were initiated to evaluate all respiratory illnesses. Home or clinic visits were scheduled for physical examination and collection of nasal washes and throat swab specimens for virus isolation. Children and their families were followed up during the influenza B/Ann Arbor/86 epidemic (winter 85 – 86). An illness was attributed to influenza B infection if an isolate was obtained during the illness or, in a person with a postseason antibody rise only, if the illness occurred within 10 days of an isolate in household contact or during the period of most intensive viral activity in the community" Safety Families were contacted by telephone to record local, systemic, respiratory symptoms occurring within 2 weeks after vaccination.
Funding Source	Government
Notes	The authors conclude that TIV is highly effective but that serological responses to CR vaccine depended on previous exposure and immunological memory. No precise information concerning the time the study was conducted. Efficacy data for the CR group are not in the table. Number of virus positive is not utilisable for the analysis. It is not possible to determine how many participants received placebo intranasally and how many received it intramuscularly, which prevents an analysis of the safety outcomes. There appears to be a major problem with this study. Randomisation and allocation are not described in detail, so the success of randomisation is unclear. In addition, there is a very long and detailed discussion on differences in susceptibility, exposure, and immunological memory between arms of the trial, where CR recipients had lower serological responses to the circulating B/Ann Arbor strain. If this trial was randomised there should be no significant differences in immunological memory between participants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Insufficient description
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient description
Summary assessments	Unclear risk	Randomisation and allocation are not described in detail, so the success of randomisation is unclear.