Objective: to determine whether the use of paracetamol or ibuprofen in vaccination interferes with the immune response to the pneumococcal conjugate vaccine (PCV13) given concomitantly with the hexavalent vaccine (HV).
Design: open-label randomised controlled clinical trial with four treatment arms.
Setting: 14 sites in Poland, between August 2011 and January 2013.
Study sample: the study included 908 infants aged 2 months. Infants were excluded in case of contraindication to vaccination, a history of anaphylactic reaction to any vaccine component, allergy or contraindication to the antipyretic agents or chronic use of medications with known interactions with the antipyretic agents.
Intervention: patients were randomised to 5 groups using an interactive voice response system, with administration of vaccines at 2, 3 and 4 months (primary series) and 12 months (booster dose).
Groups 1 and 2 received paracetamol at 15 mg/kg/dose or ibuprofen at 10 mg/kg/dose, respectively, starting 6-8 hours after vaccination (delayed administration) and at 6-8 hours from the first dose.
Groups 3 and 4 received paracetamol and ibuprofen, respectively, at the same doses, but starting at the time of vaccination (coadministration).
The control group (group 5) did not receive prophylactic antipyretics. Use of antipyretics was permitted for all groups for treatment of fever or other symptoms.
Outcome measurement: the immune response was measured at 5 and 13 months, and results of the treatment groups and the control group were compared.
The primary endpoint was the immunogenicity of the PCV13 assessed by means of the geometric mean concentrations (GMCs) of each serotype-specific IgG.
The secondary endpoint was the measurement of the levels of specific IgG against PCV13 serotypes following the booster dose, and the immunogenicity of the components of the HV (diphtheria, tetatus, pertussis, hepatitis B, inactivated poliovirus and H. influenzae type B) after primary vaccination and the booster dose.
The authors used the Bonferroni correction to control for potential false positives in the multiple-group analysis, with a p-value of less than 0.0125. The Benjamini-Hochberg procedure, which controls false negative comparisons, was used in the analysis of the 13 PCV13 serotypes in the different groups.
Main results: Nine hundred children (99%) completed vaccination at 4 months and 892 at 12 months. Fewer than 10% of children in each group did not receive antipyretics as specified by the protocol.
Following primary vaccination, the pneumococcal IgG levels in groups 1 and 3 (paracetamol) were lower than those in group 5 for all serotypes. The reduction in group 3 (coadministration of paracetamol) was statistically significant for 5 out of the 13 serotypes (3, 4, 5, 6B and 23F) (P < .0125). In groups 2 and 4 (ibuprofen) there were no significant differences compared to group 5. There were no differences after the booster dose.
The immune response to the HV was lower in group 4 (coadministered ibuprofen) compared to group 5 (P < .0125) for tetanus and pertussis after primary vaccination, but not after the booster dose.
There were no statistically significant differences in the achievement of IgG levels considered to confer protection against PCV13 serotypes (> 0.35 µg/ml) or HV components.
In all groups, fever was mild and of short duration (< 1.5 days). Groups 2 and 4 (ibuprofen) reported more fever on day 2 (17.3-41%) compared to groups 1 and 3 (paracetamol) (11.8- 26.8%) and group 5 (13.2-21.9%).
Conclusion: the administration of prophylactic antipyretics affects the immune response to vaccination. These effects vary based on the vaccine, the antipyretic used and the timing of administration. In infants, paracetamol interferes with the immune response to pneumococcal antigens and ibuprofen may diminish the response against pertussis and tetanus.
Conflicts of interest: several researchers participated in clinical trials funded by GSK, Pfizer and Novartis (refer to original article).
Funding source: funded by Pfizer.