aa Khan 1996

Methods	Single‐blind, placebo‐controlled randomised trial to compare the efficacy of trivalent cold adapted and trivalent inactivated split‐virus influenza vaccine. During the period 1 Jan to 2 Feb, 1992 there was a local epidemic of A/H3N2 (no better defined)
Participants	Children aged 9 to 12 years from 2 schools of Vologda (USSR). Participants were excluded if they had an acute illness, oral herpetic lesions, temperature > 37.0°C on the day of inoculation or a history of egg allergy or severe reaction to previous influenza vaccination. A total of 555 children were enrolled between 21 October and 1 November, 1991. 245 were enrolled from the school 1 and 310 from the other school
Interventions	After a physical examination participants were randomly assigned to receive vaccine or placebo, using the route of administration previously chosen by parents or guardians. For this purpose a blocked randomisation scheme was used with a vaccine to placebo ratio of 2:1 Vaccines Trivalent, live attenuated, cold adapted influenza vaccine (produced by Odessa Production Company for Biological Products, Odessa, Ukraine), was made using the donor strains A/Leningrad/134/17/57 H2N2 and B/Leningrad/14/55. The wild type viruses used were A/Leningrad/92/89 H1N1, A/Zakarpatje/354/89 H3N2 and B/Yagamata/16/88. Live vaccine contained 7.0 to 7.5 log10 EID50 of each virus per 0.5 ml dose (200). A single 0.5 ml dose was administered intranasally. Egg allantoic fluid as placebo (100) Commercial trivalent inactivated split‐virus influenza vaccine (Wyeth‐Ayerst, Philadelphia) containing 15 μg of haemagglutinin of A/Taiwan/1/86 H1N1, A/Shanghai/16/89 H3N2 and B/Yamagata/16/88 1990 to 91 formulation). (168) The vaccine was administered as a single 0.5 ml dose injected into the deltoid muscle with disposable, unit dose syringe and needle Saline solution as placebo (87) The vaccine groups do not differ significantly by age, sex, school, grade attended, or seronegativity for the 3 strains. Blood specimens were collected by fingerstick on the day of inoculation and again 28 days and 5 months after inoculation
Outcomes	Serological Three sera samples over the period of 5 months were taken from about half the children Effectiveness Schoolchildren absent for medical reasons were examined from physician who was not affiliated with the study and re‐examined before they return to school. A letter stating the medical condition causing their absence was filled out. These data were recorded onto the child’s school medical card and covered the period 10 November 1991 to 17 March 1992, were transcribed from the medical card at the time of serum collection 5 months after vaccination. Absenteeism due to ILI was defined as the first school absence with physician’s diagnosis of either acute respiratory disease or influenza. The epidemic lasted from 1.1. to 2.2.1992. (Specific diagnosis of influenza refers to an acute respiratory illness occurring during the official influenza season and is a clinical diagnosis, moreover the employed criteria were not uniform and these outcomes were not used). Vaccine efficacy was also estimated by using 4‐fold serum antibody increase to A H3N2 (circulating virus) Safety Children enrolled during the first week were monitored daily for 4 days after inoculation. Those enrolled during the second week were monitored on the day after inoculation. Children with reaction after inoculation were monitored by paediatricians who were unaware of the child’s vaccine group until the symptoms resolved. Data on low grade axillary fever and other local reactions were reported. Some harms are reported with insufficient information for extraction (coryza and sore throat)
Funding Source	Government
Notes	The authors conclude that there is no significant difference between live attenuated and inactivated vaccine in preventing school absence due to ILI but both are significantly more effective than placebo. The authors report ILI and assume it to be influenza because of the background rate. The text is also contradictory because half the participants are supposed to have had serology carried out on a non‐random basis but the middle line of Table 2 (reporting more than 4‐fold titre rise) appears to indicate that school absentees had titres done and lumps absences with titre rises under "both" with a calculation of vaccine efficacy. The 2 placebos are not reported separately, so it is impossible to assess safety apart from what is in the text at page 173 right hand column. Denominators do not match between tables and text and the only mention of attrition is the statement that medical card for 5 of the 555 participants were not received
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient descriptions
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Single
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few losses to follow‐up
Summary assessments	Unclear risk	Possible confounding by indication