Elsevier

The Lancet

Volume 374, Issue 9698, 17–23 October 2009, Pages 1339-1350
The Lancet

Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials

https://doi.org/10.1016/S0140-6736(09)61208-3Get rights and content

Summary

Background

Although fever is part of the normal inflammatory process after immunisation, prophylactic antipyretic drugs are sometimes recommended to allay concerns of high fever and febrile convulsion. We assessed the effect of prophylactic administration of paracetamol at vaccination on infant febrile reaction rates and vaccine responses.

Methods

In two consecutive (primary and booster) randomised, controlled, open-label vaccination studies, 459 healthy infants were enrolled from ten centres in the Czech Republic. Infants were randomly assigned with a computer-generated randomisation list to receive three prophylactic paracetamol doses every 6–8 h in the first 24 h (n=226) or no prophylactic paracetamol (n=233) after each vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccines. The primary objective in both studies was the reduction in febrile reactions of 38·0°C or greater in the total vaccinated cohort. The second objective was assessment of immunogenicity in the according-to-protocol cohort. These studies are registered with ClinicalTrials.gov, numbers NCT00370318 and NCT00496015.

Findings

Fever greater than 39·5°C was uncommon in both groups (after primary: one of 226 participants [<1%] in prophylactic paracetamol group vs three of 233 [1%] in no prophylactic paracetamol group; after booster: three of 178 [2%] vs two of 172 [1%]). The percentage of children with temperature of 38°C or greater after at least one dose was significantly lower in the prophylactic paracetamol group (94/226 [42%] after primary vaccination and 64/178 [36%] after booster vaccination) than in the no prophylactic paracetamol group (154/233 [66%] after primary vaccination and 100/172 [58%] after booster vaccination). Antibody geometric mean concentrations (GMCs) were significantly lower in the prophylactic paracetamol group than in the no prophylactic paracetamol group after primary vaccination for all ten pneumococcal vaccine serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria, antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in the prophylactic paracetamol group for antitetanus, protein D, and all pneumococcal serotypes apart from 19F.

Interpretation

Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced.

Funding

GlaxoSmithKline Biologicals (Belgium).

Introduction

Fever is part of the normal inflammatory response and frequently occurs in response to infection. This host-defence mechanism has a beneficial effect on many infections and can enhance survival. Fever is also a well described event after vaccination.1, 2, 3, 4 It is produced by endogenous pyrogens, mainly interleukin 1 and tumour necrosis factor α, and is associated with heightened T-cell activity, enhanced antigen recognition, and immune responses.5 Although generally benign and self-limiting,6 fever after vaccination is frequently a concern for parents and health-care professionals, driven by fears of febrile convulsion and by beliefs that it represents a serious pathological change.7, 8 These notions can result in medical visits, unnecessary laboratory investigations, and avoidance or deferral of subsequent vaccinations.

The prophylactic administration of antipyretic drugs has thus become routine practice and is even recommended in some countries for vaccination against diphtheria, tetanus, and whole-cell pertussis (DTPw), combination vaccinations,9, 10 or for children with a history of febrile convulsion.11 Evidence lending support to this approach is scarce; the level of fever is unrelated to the onset of convulsion,12, 13 and antipyretic drugs are ineffective in prevention of benign febrile convulsion in children who are at risk.14

We assessed the effect of the prophylactic administration of paracetamol at the time of vaccination and within the next 24 h on the rate of febrile reactions and vaccine responses in infants after primary vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b vaccine (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccine (HRV), followed by a booster dose of PHiD-CV plus DTPa-HBV-IPV/Hib.

Section snippets

Study design and participants

Two consecutive (primary and booster vaccination) phase 3, randomised, controlled, open-label studies were undertaken in ten centres in the Czech Republic from Sept 18, 2006, to April 10, 2007 (primary vaccination study), and from July 2, 2007, to April 1, 2008 (data lockpoint for reported analysis, while the study continued for nasopharyngeal carriage endpoints, booster vaccination study).

Study participants were healthy infants aged 9–16 weeks at time of enrolment and 12–15 months at time of

Results

459 participants were enrolled and vaccinated in the primary vaccination study and 414 in the booster study (figure 1). Results from 37 participants from the group not receiving prophylactic paracetamol and who were boosted after the protocol amendment were not included in the reported analyses. One child (no prophylactic paracetamol group) withdrew due to a serious adverse event, encephalitis 27 days after the second vaccine dose, which was not considered by the investigator to be causally

Discussion

This study shows how prophylactic paracetamol reduces febrile reactions after infant primary and booster vaccination. The percentage of children reporting fever of 38°C or greater after each vaccine dose was 40–50% lower when prophylactic paracetamol was administered at the time of vaccination and for the next 24 h. The effect ceased once paracetamol administration ended. However, febrile episodes greater than 39·5°C were uncommon even in the group without prophylactic paracetamol; medical

References (40)

  • AS El-Radhi

    Why is the evidence not affecting the practice of fever management?

    Arch Dis Child

    (2008)
  • M Crocetti et al.

    Fever phobia revisited: have parental misconceptions about fever changed in 20 years?

    Pediatrics

    (2001)
  • Wyeth Pharmaceuticals. Summary of product characteristics

  • Australian immunisation handbook

    (2008)
  • AT Kroger et al.

    General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP)

    MMWR Recomm Rep

    (2006)
  • A Fetveit

    Assessment of febrile seizures in children

    Eur J Pediatr

    (2008)
  • C Waruiru et al.

    Febrile seizures: an update

    Arch Dis Child

    (2004)
  • AS El-Radhi et al.

    Do antipyretics prevent febrile convulsions?

    Arch Dis Child

    (2003)
  • N Bermal et al.

    The 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with DTPw-HBV/Hib and poliovirus vaccines: assessment of immunogenicity

    Pediatr Infect Dis J

    (2009)
  • N Concepcion et al.

    Pneumococcal type 22F polysaccharide absorption improves the specificity of a pneumococcal-polysaccharide enzyme-linked immunosorbent assay

    Clin Diagn Lab Immunol

    (2001)
  • Cited by (0)

    View full text