ab Plennevaux 2011.

Methods	Randomised, placebo‐controlled trial assessing reactogenicity and immunogenicity of a split‐virion monovalent vaccine administered in children aged between 6 months and 9 years
Participants	A total of 474 children were enrolled in the study; 229 of them were aged 6 to 35 months, 245 between 3 and 9 years. Exclusion criteria Known or suspected influenza infection since March 2009; any vaccination in the previous 4 weeks or planned within 6 weeks following the first trial vaccination; hypersensitivity to any vaccine component or life‐threatening reaction to a vaccine containing the same substances; known or suspected immunodeficiency; recent history (< 6 months) of immunosuppressive therapy or long‐term systemic corticosteroid therapy; known HIV, hepatitis B or C infection; receipt of blood or blood‐derived products in the previous 3 months; and febrile or acute illness on the day of enrolment
Interventions	Used vaccine was an inactivated split‐virion preparation of the New York Medical College (NYMC) X‐179A reassortant of the A/California/07/2009 (H1N1) strain and the PR8/8/34 strain, distributed by the US Centers for Disease Control and Prevention (CDC). Seed virus was propagated in embryonated chicken eggs, inactivated and split according to the process used to produce a seasonal influenza vaccine licensed in the US for people aged > 6 months (Fluzone, Sanofi Pasteur, Swiftwater, PA, USA). 2 different antigenic concentrations were tested: 7.5 mcg or 15 mcg HA per dose. Vaccine was supplied as single‐dose vials without preservative for 6‐ to 35‐month‐olds and multidose vials containing 0.01% thiomersal preservative for 3‐ to 9‐year‐olds. Children were randomly assigned to 1 of 3 study groups (7.5 mcg HA, 15 mcg HA, placebo) using randomisation lists with stratification by age group (6 to 35 months and 3 to 9 years). 2 doses were administered 21 days apart.
Outcomes	HI antibody titration against the vaccine strain using the standard HI assay with turkey erythrocytes had been performed on serum samples collected at baseline and 21 days after each inoculation. Immunogenicity data were summarised using geometric mean titre, geometric mean titre ratio, seroprotection rate (defined as % of participants with titres ≥ 1: 40), seroconversion rate (defined as % of participants with a prevaccination titre < 1:10 and a postvaccination titre ≥ 1:40, or with a prevaccination titre ≥ 1:10 and ≥ 4‐fold increase after vaccination). Parents or legal guardians noted the following solicited site reactions on safety diaries every day for 7 days after each injection, together with body temperature. Local reactions: pain (children ≥ 2 years) or tenderness (children < 2 years), erythema, swelling, induration, or ecchymosis Systemic reactions: fever, headache, malaise, myalgia, and shivering (children ≥ 2 years) or fever, vomiting, abnormal crying, drowsiness, loss of appetite, and irritability (children < 2 years) Grade 3 reactions were defined as: pain: incapacitating, preventing usual activities; tenderness: infant cries when injected limb is moved/reduced limb movement, erythema; swelling, induration, or ecchymosis ≥ 5 cm; fever > 39.5 °C/103.1 °F for infants aged 6 to 23 months, or > 39.0 °C/102.1 °F for children aged 2 to 9 years; vomiting ≥ 6 episodes/24 hours or parenteral hydration required; abnormal crying > 3 hours; drowsiness: sleeping most of the time/difficult to wake up; loss of appetite: refused ≥ 3 meals or refused most meals; irritability: infant inconsolable; headache, malaise, myalgia, or shivering: significant, prevents daily activities. Unsolicited AEs occurring within 21 days after each vaccination were also recorded in the participant diaries and were judged by the investigator to be either related or unrelated to vaccination. Adverse events judged by the investigator to be a new onset of a chronic illness were to be reported separately. Serious adverse events, including AEs of special interest (i.e. anaphylaxis, Guillain–Barré syndrome, Bell’s palsy, optic neuritis, convulsions, or syncope) were reported throughout the study (until day 20 after first vaccination) using the standard procedure of immediate initial notification and follow‐up reporting.
Funding Source	Industry
Notes	The authors conclude that the safety and reactogenicity of the pandemic (H1N1) 2009 vaccine, at either dose, were acceptable and similar to placebo after both the first and second vaccinations. The safety results observed were similar to those seen historically with seasonal inactivated trivalent influenza vaccines.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Adequate
Allocation concealment (selection bias)	Low risk	Adequate
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