Acetaminophen may decrease antibody response in infants being immunized
Article Outline
- Question
- Design
- Setting
- Participants
- Intervention
- Outcomes
- Main Results
- Conclusions
- Commentary
- References
- Copyright
Prymula R, Siegrist C, Chlibek R, Zemlickova H, Vackova M, Smetana J, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet 2009;374:1339-50.
Question
Among infants receiving vaccinations, does prophylactic acetaminophen (paracetamol) affect infant febrile reaction rates and antibody responses?
Design
Two consecutive (primary and booster vaccination) randomized, controlled, open-label trials.
Setting
Ten centers in the Czech Republic.
Participants
A total of 459 healthy infants, aged 9 to 16 weeks at time of enrollment and 12 to 15 months at time of boosting.
Intervention
Infants were randomly assigned to receive acetaminophen (n = 226) or no prophylactic acetaminophen (n = 233). The prophylactic antipyretic treatment consisted of 3 doses of acetaminophen given via suppositories within the first 24 hours after each vaccine dose. The primary vaccination was with a 10-valent pneumococcal nontypeable Haemophilus influenzae protein D–conjugate vaccine (PhiD-CV) co-administered with hexavalent diphtheria-tetanus –3-component acellular pertussis – hepatitis B- inactivated poliovirus types 1, 2, and 3-H influenzae type b vaccine (DPTa-HBV-IPV/Hib) and oral human rotavirus vaccine (HRV) followed by a booster dose of PhiD-CV and DTaP-HBV-IPV/Hib.
Outcomes
The first objective was the reduction in febrile reactions of 38.0°C or greater in the total vaccinated cohort. The parents or caregivers measured temperature rectally the evening of the day of vaccination, and the morning and the evening of the first day after vaccination in both groups. The second objective was assessment of immunogenicity in the according-to-protocol cohort. Sera were analyzed with validated methods to measure specific antibody concentrations for all vaccines antigens.
Main Results
The percentage of children with temperature of 38 °C or greater after at least 1 dose was significantly lower in the prophylactic acetaminophen group 94/226 (42%) after primary vaccination and 64/178 (36%) after booster vaccination than in the no prophylactic acetaminophen 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 acetaminophen group than in the no prophylactic acetaminophen group after primary vaccination for all 10 pneumococcal vaccine serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria, antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in the prophylactic acetaminophen group for antitetanus, protein D, and all pneumococcal serotypes apart from 19F.
Conclusions
Although febrile reactions decrease significantly, prophylactic administration of acetaminophen at time of vaccination should not be routinely recommended because antibody responses to several vaccine antigens were reduced.
Commentary
The administration of acetaminophen to infants who receive vaccines is widespread in clinical practice, specifically in children with clinically relevant injection site reactions, irritability, or fever, in addition to discomfort. The interesting work of Prymula et al demonstrates a possible effect of acetaminophen on diminishing the immune response after vaccination, as Lewis et al1 had suggested in 1988. This finding has potentially important clinical and public health implications, and thus it should be taken into careful consideration. Despite the biologic plausibility of Prymula's findings, no investigations are found in animal models to prove this hypothesis. In previous human investigations, no clinical effects were noted on immunogenicity with acetaminophen prophylaxis and diphtheria-tetanus whole cell pertussis vaccine.1, 2 Moreover, a similar trial of elderly patients vaccinated with the influenza vaccine did not demonstrate biologic differences in specific antibody titers between groups with and without acetaminophen prophylaxis.3 This study has some methodologic weak points that require debating: the sample is of a relatively small size to be able to demonstrate a very little effect size (∼1.5%); there is no demonstration of equal basal conditions between the patients of the 10 centers where the study was performed; it is an open unmasked trial, no placebo control was done to ensure equal intervention circumstances in both groups; there is a possibility of inadvertent cointervention of parents or caregivers, because they were in charge of administering the treatment; and the hypothesis was reached post hoc, after an unexpected discovery, rather than following a planned experiment. The validity of the results in terms of absolute risk increase and number needed to harm are not conclusive, with the only exception of the antipneumococcus serotype 6B concentrations. The findings of this article should be confirmed in other independent, randomized, blind, placebo controlled trials. Because conclusive results will be obtained in clinical practice, the parsimonious use of acetaminophen should not be discontinued.
References
- The effect of prophylactic acetaminophen administration on reactions to DTP vaccination. Am J Dis Child. 1988;142:62–65
- Acetaminophen prophylaxis of adverse reactions following vaccination of infants with diphtheria-pertussis-tetanus toxoids-polio vaccine. Pediatr Infect Dis J. 1987;6:721–725
- Immunogenicity and adverse reactions of influenza vaccination in elderly patients given acetaminophen or placebo. Clin Diagn Virol. 1993;1:129–136
PII: S0022-3476(10)00198-8
doi:10.1016/j.jpeds.2010.02.054
© 2010 Mosby, Inc. All rights reserved.
