ab Plennevaux 2011

Methods	Randomised, placebo controlled trial assessing reactogenicity and immunogenicity of a split virion monovalent administered in children aged between 6 months and 9 years of age
Participants	A total of 474 children were enrolled in the study, 229 of them were aged 6 to 35 months, and 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 persons aged > 6 months (Fluzone®, sanofi pasteur, Swiftwater, PA). 2 different antigenic concentrations were tested: 7.5 mcg or 15 mcg hemagglutinin (HA) per dose. Vaccine was supplied as single‐dose vials without preservative for 6 to 35 month‐olds and multi‐dose vials containing 0.01% thimerosal preservative for 3 to 9 year‐olds. Children were randomly assigned to 1 of three 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 21 days apart were administered
Outcomes	On serum samples collected at baseline and 21 days after each inoculation, hemagglutination inhibition (HI) antibody titration against the vaccine strain using the standard HI assay with turkey erythrocytes had been performed. Immunogenicity data were summarised using geometric mean titre (GMT), geometric mean titre ratio (GMTR), seroprotection rate (defined as % of subjects with titers ≥ 1: 40), seroconversion rate (defined as % of subjects with a pre‐vaccination titre < 1:10 and a post‐vaccination titre ≥ 1:40, or with a pre‐vaccination titre ≥ 1:10 and ≥ 4‐fold increase after vaccination) The following solicited site reactions were noted by parents or legal guardians 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 subject diaries and were judged to be either related or unrelated to vaccination by the investigator AEs judged by the investigator to be a new onset of a chronic illness (NOCI) were to be reported separately. SAE, 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 2011 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
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few losses to follow‐up
Summary assessments	Low risk