aa Alexandrova 1986

Methods	C‐RCT possibly followed by 2 cohort studies
Participants	Nearly 30,000 school children (aged 7 to 15) and preschool children (aged 3 to 6). The units sampled were schools and kindergartens. The samples were performed using random sampling numbers and stratified sampling in schools with different numbers of children. Initially reactogenicity of the vaccine was studied on a limited group of school children (190) and children between 3 and 6 years (267). After the low reactogenicity of the vaccine was assessed, vaccination of large groups of children was undertaken. The trial was extended to 45 schools (in 26 the bivaccine was administered, in 19 placebo) and to 142 community preschools (the children of 76 received vaccine, those from the other 66 received placebo). For each child a special form was completed in which data about immunisation and diseases were registered. No influenza was registered before the vaccination was carried out
Interventions	On a limited study population, (those vaccinated in October 1982), a reactogenicity study was separately carried out. This group consisted of 457 pupils and children, who were divided into 2 groups. One group was given vaccine, the other received placebo. Cases of mild, moderate or febrile reaction within 5 days of administration of vaccine or placebo were reported in consideration of the initial anti‐HA antibody level. These data were not considered because it is most probable that the treatments were not assigned randomly
Outcomes	Incidence of influenza and acute respiratory disease during influenza epidemic 15 March to end April, 1983 Serological Antibody titres carried out on a non‐random section of the study population Effectiveness The prophylactic effectiveness of the bivaccine was estimated during an influenza epidemic caused by viruses A/Brazil/11/78 H1N1 and A/Bangkok/1/79 H3N2 (similar to the strains employed in the vaccine), that started in the middle of March 1983 and lasted for 6 weeks. The comparison of the influenza morbidity rates among vaccines and control groups of children were based on clinical diagnosis during the epidemic period Safety A) The data on morbidity from acute respiratory diseases and tonsillitis within 5 days after first immunisation were analysed for 15,727 vaccinees and for 14,228 placebo recipients: 1) influenza and acute respiratory diseases, 2) bronchitis, 3) tonsillitis B) For the more susceptible age group of 3 to 6 years data were recorded for 6 months after the first dose of vaccine, with the exception of the 6‐week period of influenza epidemic: 1) influenza and acute respiratory diseases, 2) pharyngitis, laryngitis, tracheitis, bronchitis, 3) pneumonia, 4) allergy, 5) otitis, 6) tonsillitis
Funding Source	Government
Notes	"There are three studies reported in this paper. The first is a phase 2, 5‐day reactogenicity and safety trial carried out in 284 placebo recipients and 173 vaccine recipients. Although it claims randomisation, it is unclear why the imbalance in numbers and because of the unclear text describing what went on we classified it as a C‐RCT. There appears to be an extension of the safety data to 14,228 placebo and 15,727 vaccine recipients The second study (1 October 1982 to 14 march 1983) appears to be an extension of the first study assessing effectiveness in 3538 bivalent vaccine recipients and 3271 placebo recipients. However, in the absence of influenza viral circulation the vaccine appears to be highly effective against ILI, bronchitis, pneumonia, OM and tonsillitis A third study is the extension by 6 weeks (from 14 March 1983 of the second study) during the influenza epidemic. As the denominators are different in all three studies and there is no way to understand what went on, it is very difficult to classify study design."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Cluster‐randomisation: random sampling numbers and stratified sampling were used
Allocation concealment (selection bias)	Low risk	Both vaccine and placebo batches were coded
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Number lost to follow‐up is unknown
Summary assessments	Low risk	Plausible bias unlikely to seriously alter the results