aa Rudenko 1996a

Methods	Cluster randomised controlled trial(s) to determine efficacy and safety of cold adapted flu vaccines prepared with different virus strains. The study was carried out in four steps in USSR (Kalinigrad), Kazakhstan (Alma Ata) and Cuba (Havana). St Petersburg is also mentioned but no results are reported. Neither randomisation nor allocation concealment are mentioned
Participants	Children aged between 3 and 14 years enrolled from schools and kindergartens in St Petersburg, Kalinigrad, Alma Ata and Havana. About 131,930 children were involved in the study
Interventions	Children were randomly divided into groups to receive either live cold adapted influenza vaccine or placebo (2 doses of 0.5 ml, administered 21 to 28 days apart) Kalinigrad 1986: Intranasal live cold adapted A H1N1 (Virology Department of the Institute of Experimental Medicine, St. Petersburg) 2 0.5 ml doses Alma Ata 1986 to 87: Intranasal live cold adapted flu A H1N1 A/Brazil/1/79 and H3N2 A/Philippines/1/82; (Virology Department of the Institute of Experimental Medicine, St. Petersburg) 2 0.5 ml doses Alma Ata 1988 to 89 Intranasal live cold adapted flu A H1N1 A/Brazil/1/79 and H3N2 A/Philippines/1/82; (Virology Department of the Institute of Experimental Medicine, St. Petersburg) 2 0.5 ml doses Havana 1990 Intranasal live cold adapted flu A H1N1 A/Taiwan/1/86 and B B/Victoria/3/87; (Virology Department of the Institute of Experimental Medicine, St. Petersburg) 2 0.5 ml doses. Havana 1991 Intranasal live cold adapted flu A H1N1 A/Taiwan/1/86, H3N2 A/Zakarpatie/354/89 and B B/Victoria/3/87; (Virology Department of the Institute of Experimental Medicine, St. Petersburg) 2 0.5 ml doses
Outcomes	Serological "Paired sera tested for seroconversion in subgroups of children and nasal swabs were taken from 22 vaccinated and 18 placebo recipient children to assess spread of vaccination strains (nil result). Haematological and biochemical full blood analysis and urine analysis were carried out on 20 children belonging to each group before vaccination, 3 days after the first dose, 1 month after the first dose, 3 days after the second dose and 1 month after the second dose) IGE determination and lymphocyte functional action assessments were also carried out." Effectiveness "A nurse in each participating school or kindergarten recorded details of acute respiratory diseases on (from) medical certificates starting in October of each year. A series of specific diagnoses were used. When acute respiratory diseases increased, virological surveillance (blood and nasal swabs) was started to identify influenza viruses. Effectiveness data are reported only for the trials conducted in Alma Ata (1986 to 87 and 1988 to 89) and Havana (1990 and 1991) The first epidemic season in Alma Ata was due to the strain A/Taiwan/1/86 (H1N1) and lasted between November 17th and December 21st. Considering that the epidemic began earlier than expected, it is possible that at this time not all study participants had received the second dose of vaccine or placebo respectively. In the second study year (1988 to 89), the epidemic was caused by the strains A/Taiwan/1/86 and B/Victoria/1/87 and lasted from March 26th 1989 for 9 weeks. In Havana clinical cases of influenza and acute respiratory diseases were registered from December 1st 1990 to December 31st 1991 Efficacy data from Kalinigrad are not reported The only effectiveness outcome reported is ILI" Safety Table 5 reports a long list of common non‐ILI ailments which appear to be related to safety for 2 years. These are labelled infectious and somatic diseases up to 6 months after vaccination but are not tied to any specific vaccine or study centre. Similarly Table 3 reports the incidence of febrile reactions by degree of fever and by age for three years without relation to years or vaccine composition. Children were examined for 7 days after vaccination by paediatricians for AEs. Temperature was registered. Data about children, who were immunised for three successive years are reported but have not been extracted as it is unclear which year, which vaccine and most of all how to reconcile massive differences in denominators (for example for year 1, data for a total of 262 children only are reported)
Funding Source	Unclear
Notes	The authors conclude that "the CA vaccines are effective against influenza B and against influenza in general" Febrile reactions and somatic and infectious diseases: To what group or groups belong the children? It is not possible to take back these data with the vaccination plan in table 1 Influenza and acute respiratory diseases in Havana: Arms in table 8 do not conform to the original randomised arms. Of how many arms consist the Havana trial? Were vaccination carried out in 2 years or were all participants immunised in November 1990? Efficacy data consider a study population aged between 5 and 14. Individuals aged 3 or 4 were apparently not included. Number of children, who received placebo and poli vaccine in table 8 coincide with those showed in the trial Havana 1991 in table 1 but the other are inconsistent Influenza–like diseases in Alma Ata: Follow‐up was probably carried out during the epidemics. Alma Ata 1986 – 87: From table 1 the number of placebo recipients aged 7 to 14 is 18,164. From table 7 results show that 22,963 recipients received vaccine. Could these 2 numbers be erroneously inverted? (and 4799 of the original 22,963 vaccinated excluded) Any subject excluded from the safety analysis of 1988 to 89? What about effectiveness of influenza immunisation in Kalinigrad? Chaotic inconsistent reporting. No attempt at reconciling viral circulation and seroconversion rates with clinical symptoms so it is impossible to assess how many of the ILI episodes are in fact influenza
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient descriptions
Allocation concealment (selection bias)	High risk	Not used
Blinding (performance bias and detection bias) All outcomes	Unclear risk	No blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No description
Summary assessments	High risk	Non‐sufficient information to assess study design