aa Rudenko 1996a.

Methods	Cluster‐RCT(s) to determine the efficacy and safety of cold‐adapted flu vaccines prepared with different virus strains. The study was carried out in 4 sites (USSR (Kalinigrad, St Petersburg), Kazakhstan (Alma Ata), and Cuba (Havana). However no results are reported from St Petersburg. Neither randomisation nor allocation concealment is 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 1986‐87: 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 1988‐89: 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 (1986‐87 and 1988‐89) 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 17 November and 21 December. 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 (1988‐89), the epidemic was caused by the strains A/Taiwan/1/86 and B/Victoria/1/87 and lasted from 26 March 1989 for 9 weeks. In Havana clinical cases of influenza and acute respiratory diseases were registered from 1 December 1990 to 31 December 1991. Efficacy data from Kalinigrad are not reported. Influenza‐like illness is the only reported effectiveness outcome. Safety Table 5 reports a long list of common non‐ILI ailments that 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 3 years without relation to years or vaccine composition. Children were examined for 7 days after vaccination by paediatricians for AEs. Temperature was registered. Data for children who were immunised for 3 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 (e.g. for year 1, data for a total of 262 children only are reported).
Funding Source	Unclear
Notes	The authors conclude that "the CA (cold‐adapted) vaccines are effective against influenza B and against influenza in general". Febrile reactions and somatic and infectious diseases: to what group or groups do the children belong? 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 does the Havana trial consist? Was 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. Children aged 3 or 4 were apparently not included. Number of children who received placebo vaccine in Table 8 coincide with those shown in the trial Havana 1991 in Table 1, but the others are inconsistent. Influenza–like diseases in Alma Ata: Follow‐up was probably carried out during the epidemics. Alma Ata 1986–87: in Table 1, the number of placebo recipients aged 7 to 14 is 18,164. In 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 child excluded from the safety analysis of 1988‐89? 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 description
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	Insufficient information to assess study design