Fever After Influenza, Diphtheria-Tetanus-Acellular Pertussis, and Pneumococcal Vaccinations

Pediatrics. 2020 Mar;145(3):e20191909. doi: 10.1542/peds.2019-1909. Epub 2020 Feb 6.


Background: Administering inactivated influenza vaccine (IIV), 13-valent pneumococcal conjugate vaccine (PCV13), and diphtheria-tetanus-acellular pertussis (DTaP) vaccine together has been associated with increased risk for febrile seizure after vaccination. We assessed the effect of administering IIV at a separate visit from PCV13 and DTaP on postvaccination fever.

Methods: In 2017-2018, children aged 12 to 16 months were randomly assigned to receive study vaccines simultaneously or sequentially. They had 2 study visits 2 weeks apart; nonstudy vaccines were permitted at visit 1. The simultaneous group received PCV13, DTaP, and quadrivalent IIV (IIV4) at visit 1 and no vaccines at visit 2. The sequential group received PCV13 and DTaP at visit 1 and IIV4 at visit 2. Participants were monitored for fever (≥38°C) and antipyretic use during the 8 days after visits.

Results: There were 110 children randomly assigned to the simultaneous group and 111 children to the sequential group; 90% received ≥1 nonstudy vaccine at visit 1. Similar proportions of children experienced fever on days 1 to 2 after visits 1 and 2 combined (simultaneous [8.1%] versus sequential [9.3%]; adjusted relative risk = 0.87 [95% confidence interval 0.36-2.10]). During days 1 to 2 after visit 1, more children in the simultaneous group received antipyretics (37.4% vs 22.4%; P = .020).

Conclusions: In our study, delaying IIV4 administration by 2 weeks in children receiving DTaP and PCV13 did not reduce fever occurrence after vaccination. Reevaluating this strategy to prevent fever using an IIV4 with a different composition in a future influenza season may be considered.

Trial registration: ClinicalTrials.gov NCT03165981.

Publication types

  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Diphtheria-Tetanus-acellular Pertussis Vaccines / administration & dosage
  • Diphtheria-Tetanus-acellular Pertussis Vaccines / adverse effects*
  • Female
  • Fever / etiology*
  • Humans
  • Infant
  • Influenza Vaccines / administration & dosage
  • Influenza Vaccines / adverse effects*
  • Male
  • Pneumococcal Vaccines / administration & dosage
  • Pneumococcal Vaccines / adverse effects*


  • 13-valent pneumococcal vaccine
  • Diphtheria-Tetanus-acellular Pertussis Vaccines
  • Influenza Vaccines
  • Pneumococcal Vaccines

Associated data

  • ClinicalTrials.gov/NCT03165981