aa Rudenko 1993a

Methods	2 years single‐blind placebo cluster RCT to assess efficacy of both live cold‐adapted and inactivated influenza vaccine
Participants	Children aged 7 to 14 years from 34 schools of Novgorod (USSR). School lists were randomly assigned as whole to one of the vaccine or placebo preparations. The assignment procedure was structured so that different regions of the city would be represented in each immunisation group. The assignment remained the same throughout the study but in the second year new schools were introduced. In the first year a total of 30 schools participated in the study, of which 10 were in the live attenuated group, 9 in the inactivated group and 11 in the placebo group. In the second year of the study the number were respectively 14, 9 and 11. Six of these schools comprised students , who had not participated in the previous year and 1 each of the inactivated vaccine and placebo schools had dropped out. Children aged 7 to 10 in the inactivated group received a more highly purified preparation than those aged 11 to 14. Placebo groups were also divided into 2 subgroups: 1 half was administered placebo intranasally, the other half intramuscularly. In the second year only intranasal placebo was administered
Interventions	The live attenuated vaccines were reassortant derived from A/Leningrad/134/47/57 (H2N2) and B/USSR/60/69 cold adapted donor strains. For the 1989 to 1990 season the wild type parents of the type A vaccine were A/Sichuan/2/87 (H3N2) and A/Taiwan/1/86 (H1N1) like viruses. For the 1990 to 1991 season wild type A/Shanghai/11/87 (H3N2), A/Taiwan/1/86 (H1N1), B/Victoria/2/87 like were employed. These contained almost 6.25 log10 median EID50 per 0.2 ml. Live vaccine was administered by intranasal spray in 2 doses 3 weeks apart The inactivated vaccine consisted of undisrupted whole virus inactivated with formalin. Bivalent vaccines were used in the first year and trivalent for the second year of the study. The strains contained in these preparations was antigenically similar to those present in the live attenuated preparations. For the 7 to 10 years old group a chromatographically purified preparation was employed, while the older subgroup were immunised with the whole virus preparation. In the first year the haemagglutinin content was 3 to 8 g of each component, in the second year 7 to 10 g. Inactivated vaccine was administered subcutaneously in the first year and intramuscularly in the second Placebo consisted of allantoic fluid handled in the same way as vaccines and packaged similarly. To ensure blinding, placebo group was divided in the first year so that children in about half of the schools received intranasal placebo twice, while half received injected placebo once. For the second year it was not possible to obtain approval for an injected placebo and it was all administered intranasally
Outcomes	Serological Paired sera were taken from approximately 100 children during the period preceding the immunisation campaign to test seroconversion Effectiveness "Starting mid‐October the nurse in each participating school began to monitor illnesses recorded as acute respiratory disease on medical certificate (required by Russian Schools after an absence). A series of specific respiratory diagnoses was used. Any illness with diagnosis termed as “respiratory illness” or “influenza” was considered a case. Investigation by the polyclinic was conduct if any certificate was provided after an absence from school. When acute respiratory disease increased, virologic surveillance was started to identify influenza viruses To avoid the lack of independence associated with counting multiple illnesses separately, the presence of 1 or more respiratory illnesses in the epidemic period was counted as 1 outcome, whereas the absence of respiratory illnesses during this period was the other outcome. A child receiving vaccine or placebo was included for analysis only if he or she received the full schedule of doses. The 1989 – 90 outbreak of influenza in Novgorod was exclusively A H3N2. the first isolate was made on 15.1.1990 and isolation continued through 22.2.1990. The period used to determine frequency of influenza associated illnesses was 1.1. – 4.3.1990. 12,837 children received full immunisation in the first year. In the school year 1990 – 1991 the influenza outbreak was caused by both types A (A/Taiwan//86 H1N1)and B (B/Yagamata/16/88 or B/Victoria/11/87 like) strains. For the efficacy analysis was considered for the period 14.1 – 24.3.1991 (11 weeks)" Safety "Reactogenicity was assessed 4 days post‐inoculation in approximately 100 children during the period preceding the immunisation campaign to test seroconversion Fever During the first year of the study, 1 child out of 162 in the live vaccine group had low‐grade fever (< 38.5°C). Any case of fever was observed in the controls and inactivated vaccine group but it was not reported how many participants composed these 2 subgroups. In the second year low‐grade fever was observed in 2 of 323 attenuated vaccine recipients and 2 of 278 placebo recipients and 5 of 271 inactivated vaccine group (age 7 to 10). 8 of the 435 children aged 11 to 14 years (inactivated vaccine, second study year) had also low‐grade fever. 3 children of this group had also fever > 38.5°C Induration In the second study year 3 of 271 participants, who received inactivated vaccine (group aged 7 to 10) developed induration as did 17 of 435 in the group aged 11 to 14 These data are not extracted as it is unclear how the children were selected"
Funding Source	Unclear
Notes	The authors conclude that CA live vaccine was more protective than TIV and possibly reduced transmission Randomisation units were schools and results were presented both at cluster (which is right) and individual (which is wrong) levels. How this affects results is impossible to say as no cluster coefficients are reported. Second year study had no intramuscular placebo. This unblinding could have had some effect if different schools were in communication. Data from the pilot reactogenicity cohort (?) study not extracted as provenance and allocation of participants is not clear. Second season inactivated vaccine has no placebo arm and data have not been extracted. No separate reporting of spray and subcutaneous placebo for first year
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No description
Allocation concealment (selection bias)	High risk	Not used
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not used
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No description
Summary assessments	High risk	Insufficient information