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Impact of Fever and Antipyretic Use on Influenza Vaccine Immune Reponses in Children

Li-Kim-Moy, Jean MBBS*,†,‡; Wood, Nicholas PhD*,†,‡; Jones, Cheryl PhD§,¶,‖; Macartney, Kristine MD*,†,‡; Booy, Robert MD*,†,‡

The Pediatric Infectious Disease Journal: October 2018 - Volume 37 - Issue 10 - p 971–975
doi: 10.1097/INF.0000000000001949
Original Studies

Background: Comparing postvaccination fever rates in pediatric influenza vaccine clinical trials is difficult due to variability in how fever is reported. The impact of vaccine-related fever and antipyretic use on trivalent influenza vaccine immunogenicity in children is also unclear.

Methods: In this pilot study, we used individual-level data provided by GlaxoSmithKline from 3 pediatric clinical trials of GlaxoSmithKline versus comparator trivalent influenza vaccine. We explored a primary study (NCT00764790), the largest trial involving young children (6–35 months, n = 3317), and further explored key findings in the 2 other trials (3–17 years, NCT00980005; 6 months to 17 years, NCT00383123). We analyzed postvaccination fever and antipyretic use, and their association with immunogenicity through use of multivariable regression.

Results: Postvaccination fever data were reanalyzed from the primary study using the Brighton Collaboration standardized definition (vaccine-related fever ≥38°C, measured by any route, reported after each dose). Rates were substantially lower after first (2.7%–3.4%) and second doses (3.3%–4.1%), than those published (6.2%–6.6%; combined dose data, any causality). A pooled immunogenicity analysis combining the 3 studies (n = 5902) revealed children with postvaccination fever had significantly higher adjusted geometric mean titers than those without fever (ratio, 1.21–1.39; P ≤ 0.01). Conversely those with antipyretic use had significantly lower adjusted geometric mean titers (ratio, 0.80–0.87; P < 0.0006), dependent on virus strain.

Conclusions: Varying analyses and reporting methods can result in substantially different reported fever rates in studies. Standardized reporting of fever is needed to facilitate comparison between studies. Fever and antipyretic use may have important associations with influenza vaccine immunogenicity in children and need further prospective investigation.

From the *The Children’s Hospital at Westmead

National Centre for Immunisation Research and Surveillance

University of Sydney, Sydney, New South Wales, Australia

§Royal Children’s Hospital

University of Melbourne

Murdoch Children’s Research Institute, Melbourne, Victoria, Australia.

Accepted for publication February 12, 2018.

N.W. is supported by a National Health and Medical Research Council (NHMRC) Career Development fellowship (APP1063629). N.W. has been an investigator on industry supported (GlaxoSmithKline) investigator initiated trials. No personal funds were received during the conduct of these studies. R.B. has worked with several manufacturers of influenza vaccines in an advisory capacity, as a researcher on vaccines and as presenter of academic information at conferences and occasionally as an Advisory Board member. He has received support to travel and attend such conferences and meetings from BioCSL/Seqirus, GlaxoSmithKline, Sanofi, Novartis and Medimmune/Astra Zeneca. Funding and honoraria are paid directly to a research account at The Children’s Hospital at Westmead and are not personally accepted by R.B. The other authors have no conflicts of interest to disclose.

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Address for correspondence: Jean Li-Kim-Moy, National Centre for Immunisation Research & Surveillance (NCIRS), The Children’s Hospital at Westmead, Corner Hawkesbury Road and Hainsworth Street, Westmead NSW 2145, Australia. E-mail:

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