Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children

Abstract

In 2010, increased febrile convulsions (FC) occurred after administration of inactivated trivalent influenza vaccine (TIV) in Australia. We systematically reviewed the rates of fever, FC and serious adverse events (SAEs) after TIV, focussing on published and unpublished clinical trial data from 2005 to 2012, and performed meta-analysis of fever rates. From 4,372 records in electronic databases, 18 randomised controlled trials (RCTs), 14 non-randomised clinical trials, six observational studies and 12 registered trials (five RCTs and seven non-randomised) were identified. In published RCTs, fever ≥ 38 °C rates after first dose of non-adjuvanted TIV were 6.7% and 6.9% for children aged 6-35 months and ≥ 3 years, respectively. Analysis of RCTs by vaccine manufacturer showed pooled fever estimates up to 5.1% with Sanofi or GlaxoSmithKline vaccines; bioCSL vaccines were used in two non-randomised clinical trials and one unpublished RCT and were associated with fever in 22.5-37.1% for children aged 6-35 months. In RCTs, FCs occurred at a rate of 1.1 per 1,000 vaccinated children. While most TIVs induced acceptably low fever rates, bioCSL influenza vaccines were associated with much higher rates of fever in young children. Future standardised study methodology and access to individual level data would be illuminating.

Influenza vaccine efficacy in young children attending childcare: A randomised controlled trial

“…We found TIV to be well tolerated by young children with adverse events experienced being predominantly mild or moderate in severity. Rates of fever after TIV were consistent with recent observational studies and systematic reviews of fever after inactivated influenza vaccination . No febrile seizures or SAEs were reported.…”

Real-time safety surveillance of seasonal influenza vaccines in children, Australia, 2015

“…Adverse event rates reported by parents/carers remained low and within expected ranges throughout the surveillance period. The fever rate was lower than the pooled estimate (6.7%) in a recent systematic review of randomised control trials of children aged six to 35 months receiving the first dose of a trivalent influenza [12]. Active, prospective vaccine safety surveillance is superior to traditional post-marketing vaccine safety surveillance which typically relies on passive reporting.…”

“…Expected and threshold rates were set according to previous surveillance results and published studies. For fever, the expected rate was 6% and the threshold rate for triggering a signal was 13% [5,[10][11][12].…”

Timeliness of signal detection for adverse events following influenza vaccination in young children: a simulation case study

“…FIR CUSUM control charts track the log-likelihood ratios of an observed cumulative event rate at a maximum acceptable level versus an expected level 14. Expected and maximum acceptable rates are set at the start of each influenza vaccination season based on a synthesis of clinical trial data and surveillance data from previous influenza seasons 12 13 15. For children aged 6 months to <5 years the expected MA rate in 2018 was set at 1%, while the expected fever rate was set at 3%.…”