Food and Drug Administration Approval for Use of Hiberix as a 3-Dose Primary Haemophilus influenzae Type b (Hib) Vaccination Series

Immunogenicity and Safety

Immunogenicity and safety data for the use of Hiberix as a primary vaccination series in infants are from a phase three, single-blind, randomized, multicenter study conducted among 4,003 healthy infants treated at 67 sites in the United States (4). Noninferiority of Hiberix to ActHIB (U.S.-licensed monovalent Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate], manufactured by Sanofi Pasteur, Swiftwater, PA) was assessed 1 month after completion of the primary series (after dose 3) using anti-PRP antibody concentrations ≥0.15 μg/mL and ≥1.0 μg/mL. Based on animal and human studies, anti-PRP levels of ≥0.15 μg/mL and ≥1.0 μg/mL provide protection from invasive Hib disease in the short- and long-term, respectively.

For each study group, Hiberix was coadministered with recommended routine childhood vaccines (Pediarix [diphtheria and tetanus toxoids and acellular pertussis (DTaP)/hepatitis B (HepB)/inactivated poliovirus (IPV)]; Prevnar13 [Pneumococcal 13-valent Conjugate Vaccine], and Rotarix [Rotavirus Vaccine, Live, Oral Suspension]), and noninferiority of immune responses to antigens contained in the coadministered vaccines, with the exception of Rotarix, was assessed. Adverse events with onset <31 days after each vaccination were recorded and physician-verified serious adverse events were reported from time of vaccination through 6 months after vaccination.

Immunogenicity. Approximately 2,000 infants were included in the immunogenicity assessment. One month after dose 3, anti-PRP concentrations ≥0.15 μg/ml and ≥1.0 μg/ml were achieved in 96.6% and 81.2% of infants who received Hiberix, respectively, and in 96.7% and 89.8% of infants who received ActHIB, respectively. Noninferiority criteria were met for anti-PRP response ≥0.15 μg/ml, but were not met for anti-PRP response ≥1.0 g/ml. Noninferiority criteria were met for the following antigens contained in coadministered vaccines: 13 serotypes of Streptococcus pneumoniae; poliovirus types 1, 2, and 3; hepatitis B; pertussis toxin, filamentous hemagglutinin, and pertactin; diphtheria; and tetanus.

An open label study compared Pentacel (DTaP/IPV/Hib combination vaccine) and Hiberix at 1 month after dose 3; noninferiority was not assessed as a primary objective. The percentages of infants with titers ≥0.15 μg/ml and ≥1.0 μg/ml were higher after the 3rd dose of Hiberix (96.6% and 81.2%, respectively) than after the 3rd dose of Pentacel (92.5% and 78.3%, respectively).

Safety. Approximately 3,500 vaccinated infants were included in the safety assessment. Injection site pain, irritability, and drowsiness were the most frequently reported adverse events; rates were similar for Hiberix, ActHIB, and Pentacel. Fever >103.1°F (39.5°C) occurred in <1% of infants in all study groups. No deaths occurred. Nonfatal serious adverse events were reported for 3.6%, 4.6%, and 4.0% of infants receiving Hiberix, ActHIB, and Pentacel, respectively; one serious adverse event in the Hiberix group was considered related to vaccine administration (afebrile seizure 14 days after dose 1; the patient had no apparent seizure disorder at 1 month after dose 3).

Further information is available in the package insert (http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM179530.pdf).