Effects of prophylactic ibuprofen and paracetamol administration on the immunogenicity and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine (PHiD-CV) co-administered with DTPa-combined vaccines in children: An open-label, randomized, controlled, non-inferiority trial

Abstract

Prophylactic paracetamol administration impacts vaccine immune response; this study ( www.clinicaltrials.gov : NCT01235949) is the first to assess PHiD-CV immunogenicity following prophylactic ibuprofen administration. In this phase IV, multicenter, open-label, randomized, controlled, non-inferiority study in Romania (November 2010-December 2012), healthy infants were randomized 3:3:3:1:1:1 to prophylactically receive immediate, delayed or no ibuprofen (IIBU, DIBU, NIBU) or paracetamol (IPARA, DPARA, NPARA) after each of 3 primary doses (PHiD-CV at age 3/4/5 months co-administered with DTPa-HBV-IPV/Hib at 3/5 and DTPa-IPV/Hib at 4 months) or booster dose (PHiD-CV and DTPa-HBV-IPV/Hib; 12-15 months). Non-inferiority of immune response one month post-primary vaccination in terms of percentage of infants with anti-pneumococcal antibody concentrations ≥0.2 µg/mL (primary objective) was demonstrated if the upper limit (UL) of the 98.25% confidence interval of difference between groups (NIBU vs IIBU, NIBU vs DIBU) was <10% for ≥7/10 serotypes. Immunogenicity and reactogenicity/safety were evaluated, including confirmatory analysis of difference in fever incidences post-primary vaccination in IBU or DIBU group compared to NIBU. Of 850 infants randomized, 812 were included in the total vaccinated cohort. Non-inferiority was demonstrated for both comparisons (UL was <10% for 9/10 vaccine serotypes; exceptions: 6B [NIBU], 23F [IIBU]). However, fever incidence post-primary vaccination in the IIBU and DIBU groups did not indicate a statistically significant reduction. Prophylactic administration (immediate or delayed) of paracetamol decreased fever incidence but seemed to reduce immune response to PHiD-CV, except when given only at booster. Twenty-seven serious adverse events were reported for 15 children; all resolved and were not vaccination-related.

Keywords: 10-valent pneumococcal conjugate; Ibuprofen; fever; paracetamol; prophylaxis; vaccine.

Figures

Figure 1.

Participant flow chart. Footnote: Primary vaccination: PHiD-CV and DTPa-(HBV)-IPV/Hib at 3, 4, and 5 months of age, with the following prophylactic antipyretic regimen: IIBU, immediate ibuprofen; DIBU, delayed ibuprofen; NIBU, no ibuprofen; IPARA, immediate paracetamol; DPARA, delayed paracetamol; NPARA, no paracetamol. Booster vaccination: PHiD-CV and DTPa-HBV-IPV/Hib at 12–15 months of age, with the following prophylactic antipyretic regimen: at primary vaccination: immediate ibuprofen, and at booster: immediate (IIBU-IIBU), delayed (IIBU-DIBU) or no ibuprofen (IIBU-NIBU); at primary vaccination: delayed ibuprofen, and at booster: immediate (DIBU-IIBU), delayed (DIBU-DIBU) or no ibuprofen (DIBU-NIBU); at primary vaccination: no ibuprofen, and at booster: immediate (NIBU-IIBU), delayed (NIBU-DIBU) or no ibuprofen (NIBU-NIBU); immediate paracetamol at primary vaccination and no paracetamol at booster (IPARA-NPARA); delayed paracetamol at primary vaccination and immediate paracetamol at booster (DPARA-IPARA); no paracetamol at primary vaccination, and immediate paracetamol at booster (NPARA-IPARA). ATP, according-to-protocol; N, number of participants.

Figure 2.

Incidence of fever post-primary (A) and post-booster (B) vaccination (TVC). Footnote: Primary vaccination: PHiD-CV and DTPa-(HBV)-IPV/Hib at 3, 4, and 5 months of age, with the following prophylactic antipyretic regimen: IIBU, immediate ibuprofen; DIBU, delayed ibuprofen; NIBU, no ibuprofen; IPARA, immediate paracetamol; DPARA, delayed paracetamol; NPARA, no paracetamol. Booster vaccination: PHiD-CV and DTPa-HBV-IPV/Hib at 12–15 months of age, with the following prophylactic antipyretic regimen: at primary vaccination: immediate ibuprofen, and at booster: immediate (IIBU-IIBU), delayed (IIBU-DIBU) or no ibuprofen (IIBU-NIBU); at primary vaccination: delayed ibuprofen, and at booster: immediate (DIBU-IIBU), delayed (DIBU-DIBU) or no ibuprofen (DIBU-NIBU); at primary vaccination: no ibuprofen, and at booster: immediate (NIBU-IIBU), delayed (NIBU-DIBU) or no ibuprofen (NIBU-NIBU); immediate paracetamol at primary vaccination and no paracetamol at booster (IPARA-NPARA); delayed paracetamol at primary vaccination and immediate paracetamol at booster (DPARA-IPARA); no paracetamol at primary vaccination, and immediate paracetamol at booster (NPARA-IPARA). Fever: rectal temperature ≥38.0°C; Grade 3 fever: rectal temperature >40°C or axillary/oral/tympanic temperature >39.5°C; TVC, total vaccinated cohort. Error bars indicate 95% confidence intervals.

Figure 3.

Study design. Footnote: Primary vaccination: PHiD-CV and DTPa-(HBV)-IPV/Hib at 3, 4, and 5 months of age, with the following prophylactic antipyretic regimen: IIBU, immediate ibuprofen; DIBU, delayed ibuprofen; NIBU, no ibuprofen; IPARA, immediate paracetamol; DPARA, delayed paracetamol; NPARA, no paracetamol. Booster vaccination: PHiD-CV and DTPa-HBV-IPV/Hib at 12–15 months of age, with the following prophylactic antipyretic regimen: at primary vaccination: immediate ibuprofen, and at booster: immediate (IIBU-IIBU), delayed (IIBU-DIBU) or no ibuprofen (IIBU-NIBU); at primary vaccination: delayed ibuprofen, and at booster: immediate (DIBU-IIBU), delayed (DIBU-DIBU) or no ibuprofen (DIBU-NIBU); at primary vaccination: no ibuprofen, and at booster: immediate (NIBU-IIBU), delayed (NIBU-DIBU) or no ibuprofen (NIBU-NIBU); immediate paracetamol at primary vaccination and no paracetamol at booster (IPARA-NPARA); delayed paracetamol at primary vaccination and immediate paracetamol at booster (DPARA-IPARA); no paracetamol at primary vaccination, and immediate paracetamol at booster (NPARA-IPARA). N, number of children per group; m, months; * DTPa-IPV/Hib instead of DTPa-HBV-IPV/Hib.