ab Mallory 2010.

Methods	Randomised, placebo‐controlled trial carried out on children aged between 2 and 17 years in order to assess safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 LAIV (MedImmune)
Participants	Inclusion criteria Male or female, aged 2 to 17 years Healthy by medical history and physical exam Written informed consent and any locally required authorisation (e.g. HIPAA in the USA, EU Data Privacy Directive in the EU, and written informed assent) obtained from the participant or their legal representative before performing any protocol‐related procedures, including screening evaluations Participant or their legal representative available by telephone Participant or participant’s legal representative is able to understand and comply with the requirements of the protocol, as judged by the investigator Ability to complete follow‐up period of 180 days after dose 2 as required by the protocol  Exclusion criteria History of hypersensitivity to any component of the investigational product including egg or egg protein, gelatin, or arginine, or serious, life‐threatening, or severe reactions to previous influenza vaccinations History of hypersensitivity to gentamicin Any condition for which the inactivated influenza vaccine is indicated, including chronic disorders of the pulmonary or cardiovascular systems (e.g. asthma), chronic metabolic diseases (e.g. diabetes mellitus), renal dysfunction, or haemoglobinopathies that required regular medical follow‐up or hospitalisation during the preceding year Acute febrile (> 100.0 °F oral or equivalent) or clinically significant respiratory illness (e.g. cough or sore throat), or both within 14 days before randomisation History of asthma, or history of recurrent wheezing in children aged < 5 years Any known immunosuppressive condition or immune deficiency disease, including HIV infection, or ongoing immunosuppressive therapy History of Guillain‐Barré syndrome A household contact who is severely immunocompromised (e.g. haematopoietic stem cell transplant recipient, during those periods in which the immunocompromised individual requires care in a protective environment); participant should additionally avoid close contact with severely immunocompromised individuals for at least 21 days after receipt of investigational product Receipt of any investigational agent within 30 days before randomisation, or expected receipt through 30 days after the second dose of investigational product (use of licenced agents for indications not listed in the package insert is permitted) Use of aspirin or salicylate‐containing products in children within 30 days before randomisation or expected receipt through 30 days after final vaccination Expected receipt of antipyretic or analgesic medication (non‐salicylate‐containing) on a daily or every‐other‐day basis from randomisation through 14 days after receipt of each dose of investigational product Administration of intranasal medications within 14 days before randomisation, or expected receipt through 14 days after administration of each dose of investigational product Receipt of any non‐study vaccine within 30 days before or after dose 1 or expected receipt of any non‐study vaccine within 30 days before or after dose 2 Known or suspected mitochondrial encephalomyopathy Any condition (e.g. chronic cough, allergic rhinitis) that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of participant safety or study results Participant, legal representative, or immediate family member of participant is an employee of the clinical study site or is otherwise involved with the conduct of the study
Interventions	H1N1 LAIV (2009 formulation) by MedImmune was derived by genetic reassortment of the haemagglutinin and neuraminidase genes from the wild‐type A/California/7/2009 virus and the remaining 6 gene segments from an attenuated master donor virus. The resulting 6:2 reassortant vaccine virus is grown in chicken eggs employing the same manufacturing process used to produce MedImmune’s seasonal trivalent LAIV. Monovalent vaccine was supplied in intranasal spray applicators containing approximately 107 fluorescent focus units of the reassortant influenza virus in a total volume of 0.5 mL of sucrose‐phosphate buffer and egg allantoic fluid (0.25 mL administered into each nostril). Placebo (0.5 mL of sucrose‐phosphate buffer) was supplied and administered using identical intranasal applicators. Eligible participants were randomly assigned using an interactive voice response system in a 4:1 ratio to receive 2 doses of live monovalent H1N1 LAIV or placebo by intranasal spray 28 days apart. Randomisation was stratified by age (2 to 8 years and 9 to 17 years).   Initially 326 children were enrolled and 261 (133 between 2 and 8 years and 128 between 9 and 17 years) were allocated to vaccine group, whereas 65 (29 between 2 and 8 years and 36 between 9 and 17 years) were allocated to control placebo.   Children  were further randomised (1:1) to provide a blood sample on either day 15 or day 29 after their first vaccination. A final immunogenicity blood sample was collected on day 57, approximately 28 days after the second vaccination. After conclusion of the blinded portion of the study, children randomised to receive placebo in the studies were offered optional H1N1 vaccination after collection of their day 57 blood sample.
Outcomes	Laboratory Serum antibody titres were measured at baseline and on day 15 or 29 after dose 1 and on day 57 (28 days after dose 2) using a standardised HAI assay against antigenically matched influenza A/H1N1 6:2 virus reassortants. Safety A) The primary safety analysis compared the rates of fever (defined as a temperature of at least 38.3 °C) during days 1 to 8 after dose 1.   B) Additional safety endpoints (from day 1 through day 8 and from day 1 through day 15 after each vaccination) included the following.   Solicited symptoms: fever (temperature was recorded daily), runny/stuffy nose, sore throat, cough, muscle aches, decreased activity, decreased appetite, and headache Adverse events: blood and lymphatic system disorders, ear and labyrinth disorders, eye disorders, gastrointestinal disorders, general disorders and administration site conditions, immune system disorders, infections and infestations, injury poisoning and procedural complications, musculoskeletal and connective tissue disorders, nervous system disorders, respiratory thoracic and mediastinal disorders, skin and subcutaneous tissue disorders Antipyretic and analgesic use. In any case their use was discouraged during the 14 days' postvaccination to avoid masking the primary safety endpoint of fever Memory aid worksheets were provided to record solicited symptoms, AEs, and concomitant medication use for 14 days after dosing.   C) Serious adverse events and new‐onset chronic diseases were collected through 180 days after the final dose.   Children who experienced a febrile illness within 7 days after dose 1 were instructed to return to the study site for evaluation.
Funding Source	Industry (MedImmune)
Notes	The authors conclude that “This study demonstrates that 2 doses of 2009 H1N1 LAIV are safe in healthy children. Overall, the frequency of solicited symptoms and AEs were similar between H1N1 LAIV and placebo recipients, and most were mild to moderate in severity”.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random list
Allocation concealment (selection bias)	Low risk	Centralised
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few losses to follow‐up
Summary assessments	Low risk