Jansen 2008.

Study characteristics
Methods	Randomised: yes, at individual level Design: standard parallel‐group design Intention‐to‐treat: yes Follow‐up: follow‐up started 14 days after the second set of vaccinations and continued for 6 to 18 months, depending on the year of inclusion
Participants	N: 597 children with a previously diagnosed RTI Age: 18 to 72 months Setting: GPs in the centre of the Netherlands selected children Inclusion criteria: children aged 18 to 72 months with a previously diagnosed RTI registered according to the ICPC, i.e. AOM; cough (with fever); acute upper RTI; acute laryngitis/tracheitis; acute bronchitis/bronchiolitis; influenza; pneumonia; pleurisy/pleural effusion Exclusion criteria: children with chronic asthma or recurrent wheezing (for longer than 3 months) treated with corticosteroids; craniofacial abnormalities; clinically significant hypersensitivity to eggs; previous serious adverse reactions to vaccines; previous influenza, pneumococcal, or hepatitis B vaccinations and those with conditions for which these vaccinations are already recommended, such as chronic cardiac and respiratory conditions Baseline characteristics: described and balanced (Table 1 of trial publication)
Interventions	Children were randomly allocated to either TIV/PCV7, TIV/placebo (TIV plus standard diluent (0.9% phosphate buffered NaCl)), or HBV/placebo (recombinant HBV vaccine‐Engerix B Junior plus placebo vaccine). Strains in the TIV 2003‐2004 formulation were H1N1, H3N2, and B/HongKong/330/01; strains in the TIV 2004‐2005 formulation were H1N1, H3N2, and B/Shanghai/361/2002; strains in the TIV 2005‐2006 formulation included H1N1, H3N2, and B/Shanghai/361/2002. Children received 2 vaccinations 4 to 8 weeks apart in the first year of inclusion; the first 2 cohorts of children received a subsequent vaccination in the subsequent year. Tx: TIV/CRM197‐PCV7; N = 197 (N = 163 completed; 67,867 person‐days analysed, 14% missing) C1: TIV/placebo; N = 187 (N = 148 completed; 60,515 person‐days analysed, 20% missing) C2: HBV/placebo; N = 195 (N = 160 completed; 67,679 person‐days analysed, 15% missing) Additional vaccines: not described
Outcomes	Primary outcome: febrile RTI, defined as fever (tympanic temperature 38.0 °C) for at least 2 consecutive days accompanied by 1 or more of the aforementioned signs or symptoms of RTI with a moderate or severe severity score Secondary outcomes: febrile RTI–related PCR‐confirmed influenza, GP visits, antibiotic prescriptions, or a physician‐diagnosed episode of AOM, tolerability and safety. Each parent was instructed to keep a daily diary in which they recorded any clinical signs or symptoms associated with RTI and characterised their severity on a scale of 1 (mild) to 3 (severe). The parent was also instructed to measure the child's body temperature using a validated electronic tympanic thermometer, and was asked to record all GP visits due to their child's RTI‐related complaints. For each such visit, the GP was instructed to complete a form including information on the diagnosis and possible antibiotic prescriptions. During influenza seasons, the parent was instructed to contact the trial centre for evaluation for influenza if the child had fever (tympanic temperature 38.0 °C) for more than 1 day accompanied by at least 1 RTI‐associated sign or symptom of severity score 2. A trained research assistant obtained a nasopharyngeal swab for viral determination within 4 days of onset of fever and symptoms. Each sample was analysed by real‐time PCR for the presence of influenza A and B viruses.
Funding sources	The study was funded by the Netherlands Organisation for Health Research and Development (ZonMw). The funding agency played no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Influenza vaccines were provided by Solvay, Weesp, the Netherlands. Pneumococcal vaccines were provided by Wyeth Vaccines Research, Berkshire, UK. Hepatitis B vaccines were provided by GlaxoSmithKline BV, Rixensart, Belgium.
Declarations of interest	The authors declared no conflicts of interest.
Notes	Participants lost to follow‐up:total: 108/579 (18.7%) completely (N = 41) or partially (N = 67) lost to follow‐up Participants lost to follow‐up:Tx: 34/197 (17.3%) completely (N = 8) or partially (N = 26) lost to follow‐up; 67,867 person‐days analysed, 14% missing Participants lost to follow‐up:C1: 39/187 (20.8%) completely (N = 19) or partially (N = 20) lost to follow‐up; 60,515 person‐days analysed, 20% missing Participants lost to follow‐up:C2: 35/195 (17.9%) completely (N = 14) or partially (N = 21) lost to follow‐up; 67,679 person‐days analysed, 15% missing 2 of the 3 treatment arms received an additional vaccination in the second year of the study. To evaluate blinding, parents of these cohorts of children were asked which vaccinations they thought their child had received just after the vaccinations were given and at the end of the study. Just after the vaccination, 87% of the parents either did not know or identified the wrong set of vaccinations; at the end of the study, this percentage was 80%, indicating successful blinding.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not described; children were randomly assigned in blocks of 3 in a 1:1:1 ratio.
Allocation concealment (selection bias)	Unclear risk	No method of allocation concealment was described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The injections were administered by non‐blinded research nurses who were not involved in subsequent follow‐up and who were instructed not to reveal the intervention allocation. The treatment group assignments were not revealed to parents, investigators, research personnel conducting the follow‐up, or healthcare providers, all of whom remained blinded throughout the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The parents were asked to record all GP visits due to their child's RTI‐related complaints. For each such visit, the GP was instructed to complete a form including information on the diagnosis and possible antibiotic prescriptions. The treatment group assignments were not revealed to parents, investigators, and research personnel conducting the follow‐up, or healthcare providers, all of whom remained blinded throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Substantial loss to follow‐up (< 14% in both groups)
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (primary and secondary) are listed in ClinicalTrials.gov.
Other bias	Low risk	No other sources of bias identified.