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Review
, 2 (2), CD004879

Vaccines for Preventing Influenza in Healthy Children

Affiliations
Review

Vaccines for Preventing Influenza in Healthy Children

Tom Jefferson et al. Cochrane Database Syst Rev.

Abstract

Background: The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age. This is an update of a review published in 2011. Future updates of this review will be made only when new trials or vaccines become available. Observational data included in previous versions of the review have been retained for historical reasons but have not been updated because of their lack of influence on the review conclusions.

Objectives: To assess the effects (efficacy, effectiveness, and harm) of vaccines against influenza in healthy children.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 12), which includes the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE (1966 to 31 December 2016), Embase (1974 to 31 December 2016), WHO International Clinical Trials Registry Platform (ICTRP; 1 July 2017), and ClinicalTrials.gov (1 July 2017).

Selection criteria: Randomised controlled trials comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy children under 16 years. Previous versions of this review included 19 cohort and 11 case-control studies. We are no longer updating the searches for these study designs but have retained the observational studies for historical purposes.

Data collection and analysis: Review authors independently assessed risk of bias and extracted data. We used GRADE to rate the certainty of evidence for the key outcomes of influenza, influenza-like illness (ILI), complications (hospitalisation, ear infection), and adverse events. Due to variation in control group risks for influenza and ILI, absolute effects are reported as the median control group risk, and numbers needed to vaccinate (NNVs) are reported accordingly. For other outcomes aggregate control group risks are used.

Main results: We included 41 clinical trials (> 200,000 children). Most of the studies were conducted in children over the age of two and compared live attenuated or inactivated vaccines with placebo or no vaccine. Studies were conducted over single influenza seasons in the USA, Western Europe, Russia, and Bangladesh between 1984 and 2013. Restricting analyses to studies at low risk of bias showed that influenza and otitis media were the only outcomes where the impact of bias was negligible. Variability in study design and reporting impeded meta-analysis of harms outcomes.Live attenuated vaccinesCompared with placebo or do nothing, live attenuated influenza vaccines probably reduce the risk of influenza infection in children aged 3 to 16 years from 18% to 4% (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.41; 7718 children; moderate-certainty evidence), and they may reduce ILI by a smaller degree, from 17% to 12% (RR 0.69, 95% CI 0.60 to 0.80; 124,606 children; low-certainty evidence). Seven children would need to be vaccinated to prevent one case of influenza, and 20 children would need to be vaccinated to prevent one child experiencing an ILI. Acute otitis media is probably similar following vaccine or placebo during seasonal influenza, but this result comes from a single study with particularly high rates of acute otitis media (RR 0.98, 95% CI 0.95 to 1.01; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. Vaccinating children may lead to fewer parents taking time off work, although the CI includes no effect (RR 0.69, 95% CI 0.46 to 1.03; low-certainty evidence). Data on the most serious consequences of influenza complications leading to hospitalisation were not available. Data from four studies measuring fever following vaccination varied considerably, from 0.16% to 15% in children who had live vaccines, while in the placebo groups the proportions ranged from 0.71% to 22% (very low-certainty evidence). Data on nausea were not reported.Inactivated vaccinesCompared with placebo or no vaccination, inactivated vaccines reduce the risk of influenza in children aged 2 to 16 years from 30% to 11% (RR 0.36, 95% CI 0.28 to 0.48; 1628 children; high-certainty evidence), and they probably reduce ILI from 28% to 20% (RR 0.72, 95% CI 0.65 to 0.79; 19,044 children; moderate-certainty evidence). Five children would need to be vaccinated to prevent one case of influenza, and 12 children would need to be vaccinated to avoid one case of ILI. The risk of otitis media is probably similar between vaccinated children and unvaccinated children (31% versus 27%), although the CI does not exclude a meaningful increase in otitis media following vaccination (RR 1.15, 95% CI 0.95 to 1.40; 884 participants; moderate-certainty evidence). There was insufficient information available to determine the effect of vaccines on school absenteeism due to very low-certainty evidence from one study. We identified no data on parental working time lost, hospitalisation, fever, or nausea.We found limited evidence on secondary cases, requirement for treatment of lower respiratory tract disease, and drug prescriptions. One brand of monovalent pandemic vaccine was associated with a sudden loss of muscle tone triggered by the experience of an intense emotion (cataplexy) and a sleep disorder (narcolepsy) in children. Evidence of serious harms (such as febrile fits) was sparse.

Authors' conclusions: In children aged between 3 and 16 years, live influenza vaccines probably reduce influenza (moderate-certainty evidence) and may reduce ILI (low-certainty evidence) over a single influenza season. In this population inactivated vaccines also reduce influenza (high-certainty evidence) and may reduce ILI (low-certainty evidence). For both vaccine types, the absolute reduction in influenza and ILI varied considerably across the study populations, making it difficult to predict how these findings translate to different settings. We found very few randomised controlled trials in children under two years of age. Adverse event data were not well described in the available studies. Standardised approaches to the definition, ascertainment, and reporting of adverse events are needed. Identification of all global cases of potential harms is beyond the scope of this review.

Conflict of interest statement

Tom Jefferson (TJ) was a recipient of a UK National Institute for Health Research grant for a Cochrane Review of neuraminidase inhibitors for influenza. In addition, TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011‐13, TJ acted as an expert witness in litigation related to the antiviral oseltamivir, in two litigation cases on potential vaccine‐related damage, and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997‐99), GSK (2001‐2), Sanofi‐Synthelabo (2003), and IMS Health (2013). In 2014 he was retained as a scientific adviser to a legal team acting on oseltamivir. TJ has a potential financial conflict of interest in the drug oseltamivir. In 2014‐16, TJ was a member of three advisory boards for Boerhinger Ingelheim. He is holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane Reviews. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. Between 1994 and 2013, TJ was the co‐ordinator of the Cochrane Vaccines Field. TJ is a cosignatory of the Nordic Cochrane Centre Complaint to the European Medicines Agency (EMA) over maladministration at the EMA in relation to the investigation of alleged harms of human papillomavirus vaccines and consequent complaints to the European Ombudsman.

Alessandro Rivetti: none known.

Carlo Di Pietrantonj: none known.

Vittorio Demicheli: none known.

Eliana Ferroni: none known.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Analysis 1.1
Analysis 1.1
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 1 Influenza.
Analysis 1.2
Analysis 1.2
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 2 Influenza‐like illness.
Analysis 1.3
Analysis 1.3
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 3 Otitis media (all episodes).
Analysis 1.4
Analysis 1.4
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 4 School absenteeism.
Analysis 1.5
Analysis 1.5
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 5 Working days lost (number of events, parents).
Analysis 1.6
Analysis 1.6
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 6 Drug prescriptions (number of events).
Analysis 1.7
Analysis 1.7
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 7 Outpatients attendance for pneumonia and influenza.
Analysis 1.8
Analysis 1.8
Comparison 1 Live vaccine versus placebo (RCTs), Outcome 8 Influenza‐like illness (clustering sensitivity analysis).
Analysis 2.1
Analysis 2.1
Comparison 2 Inactivated vaccine versus placebo (RCTs), Outcome 1 Influenza.
Analysis 2.2
Analysis 2.2
Comparison 2 Inactivated vaccine versus placebo (RCTs), Outcome 2 Influenza‐like illness.
Analysis 2.3
Analysis 2.3
Comparison 2 Inactivated vaccine versus placebo (RCTs), Outcome 3 Acute otitis media.
Analysis 2.4
Analysis 2.4
Comparison 2 Inactivated vaccine versus placebo (RCTs), Outcome 4 School absenteeism.
Analysis 2.5
Analysis 2.5
Comparison 2 Inactivated vaccine versus placebo (RCTs), Outcome 5 Influenza‐like illness (clustering sensitivity analysis).
Analysis 3.1
Analysis 3.1
Comparison 3 Live vaccine versus placebo or no intervention (RCTs by age group), Outcome 1 Influenza.
Analysis 3.2
Analysis 3.2
Comparison 3 Live vaccine versus placebo or no intervention (RCTs by age group), Outcome 2 Influenza‐like illness.
Analysis 4.1
Analysis 4.1
Comparison 4 Inactivated vaccine versus placebo or no intervention (RCTs by age group), Outcome 1 Influenza.
Analysis 4.2
Analysis 4.2
Comparison 4 Inactivated vaccine versus placebo or no intervention (RCTs by age group), Outcome 2 Influenza‐like illness.
Analysis 5.1
Analysis 5.1
Comparison 5 All vaccine types versus placebo, Outcome 1 Influenza.
Analysis 5.2
Analysis 5.2
Comparison 5 All vaccine types versus placebo, Outcome 2 Influenza‐like illness.
Analysis 5.3
Analysis 5.3
Comparison 5 All vaccine types versus placebo, Outcome 3 Secondary cases.
Analysis 5.4
Analysis 5.4
Comparison 5 All vaccine types versus placebo, Outcome 4 School absenteeism.
Analysis 5.5
Analysis 5.5
Comparison 5 All vaccine types versus placebo, Outcome 5 Lower respiratory tract disease.
Analysis 5.6
Analysis 5.6
Comparison 5 All vaccine types versus placebo, Outcome 6 Acute otitis media.
Analysis 5.7
Analysis 5.7
Comparison 5 All vaccine types versus placebo, Outcome 7 Hospitalisation due to acute otitis media.
Analysis 5.8
Analysis 5.8
Comparison 5 All vaccine types versus placebo, Outcome 8 Consequences of acute otitis media.
Analysis 5.9
Analysis 5.9
Comparison 5 All vaccine types versus placebo, Outcome 9 Outpatients attendance for pneumonia and influenza.
Analysis 5.10
Analysis 5.10
Comparison 5 All vaccine types versus placebo, Outcome 10 Working days lost (number of events, parents of children 6 to 36 months of age).
Analysis 5.11
Analysis 5.11
Comparison 5 All vaccine types versus placebo, Outcome 11 Drug prescriptions (number of events, 6 to 36 months of age).
Analysis 6.1
Analysis 6.1
Comparison 6 Case‐control studies, Outcome 1 Influenza vs influenza‐like illness (crude data).
Analysis 6.2
Analysis 6.2
Comparison 6 Case‐control studies, Outcome 2 Influenza vs influenza‐like illness (adj. estimates).
Analysis 6.3
Analysis 6.3
Comparison 6 Case‐control studies, Outcome 3 Influenza‐like illness vs no symptoms.
Analysis 7.1
Analysis 7.1
Comparison 7 Live attenuated vaccines (cohort studies by age group), Outcome 1 Influenza.
Analysis 7.2
Analysis 7.2
Comparison 7 Live attenuated vaccines (cohort studies by age group), Outcome 2 Influenza‐like illness.
Analysis 8.1
Analysis 8.1
Comparison 8 Inactivated vaccines (cohort studies by age group), Outcome 1 Influenza.
Analysis 8.2
Analysis 8.2
Comparison 8 Inactivated vaccines (cohort studies by age group), Outcome 2 Influenza‐like illness.
Analysis 8.3
Analysis 8.3
Comparison 8 Inactivated vaccines (cohort studies by age group), Outcome 3 Otitis media.

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