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PEDIATRICS Vol. 109 No. 4 April 2002, pp. e58

ELECTRONIC ARTICLE

Safety and Reactogenicity of a Novel DTPa-HBV-IPV Combined Vaccine Given Along With Commercial Hib Vaccines inComparison With Separate Concomitant Administration ofDTPa, Hib, and OPV Vaccines in Infants

Fred Zepp, MD^*, Anne Schuind, MD^*, Claudius Meyer, PhD^*, Roland Sänger, MD, Achim Kaufhold, MD and Paul Willems, MD

^* Children’s Hospital, Pediatric Immunology and Infectious Diseases, Johannes Gutenberg University, Mainz, Germany
GlaxoSmithKline Biologicals S.A., Rixensart, Belgium

--> Objective. Combination vaccines simplify vaccine administration and have the potential to promote compliance and cost-effectiveness by decreasing the number of injections needed to immunize a child. The objective of this study was to assess the safety and reactogenicity of the diphtheria-tetanus toxoid-acellular pertussis-hepatitis B virus-inactivated polio virus (DTPa-HBV-IPV) vaccine when coadministered with different Haemophilus influenzae type B (Hib) vaccines in comparison with separate, commercially available, control vaccines in a 3-dose primary vaccination series.

Methods. An open-label, randomized, parallel-group study in 5318 infants who were 8 to 16 weeks of age at enrollment was conducted in 90 centers in Germany. The incidence of adverse events that occurred in infants who received the DTPa-HBV-IPV candidate vaccine coadministered with 1 of 4 different Hib vaccines (given in separate sites; groups 1–4) was compared with the incidence that occurred in infants who received commercially available control vaccines (DTPa, Hib, and oral polio virus [OPV] vaccine; group 5) administered separately. The vaccines were given as a 3-dose primary series at 3, 4, and 5 months of age. Infants were assessed for solicited local and general adverse events for 4 days and for unsolicited adverse events for 30 days after each vaccine dose. The primary endpoint was to rule out a 7.5% increase in infants who experienced grade 3 (defined as preventing normal everyday activities unless otherwise specified) solicited local and general adverse events over the 3-dose primary course after the combined DTPa-HBV-IPV vaccine coadministered with Hib as compared with commercially available vaccines.

Results. During the 3-dose primary course, 490 of 3029 infants (16.2%) in the pooled DTPa-HBV-IPV vaccine groups and 151 of 744 (20.3%) in the control vaccine group experienced a grade 3 adverse event (rate difference [control minus combination] 4.1%; 90% confidence interval, 1.41–7.13). The lower limit of the 90% confidence interval of the observed difference remained above the prespecified -7.5% limit for noninferiority, thereby meeting the primary endpoint. The incidences of local injection-site reactions were similar for the DTPa-HBV-IPV and DTPa injection sites. Significant differences in the incidence of both local and general adverse events were observed depending on which of the Hib vaccines was coadministered. Infants who received Hib N meningitidis outer-membrane complex protein conjugate vaccine had greater incidences of fever and, to a lesser extent, greater reactions at the Hib injection site than did infants who received other Hib vaccines.

Conclusions. The combination DTPa-HBV-IPV vaccine administered concomitantly with Hib vaccine at separate sites was at least as safe as coadministration of individual DTPa, Hib, and OPV vaccines in terms of the defined endpoints for safety.

Key Words: combination vaccine • diphtheria • pertussis • tetanus • hepatitis B virus • Haemophilus influenzae type b • polio

Abbreviations: DTPa, diphtheria-tetanus toxoid-acellular pertussis; HBV, hepatitis B virus • Hib, Haemophilus influenzae type b • IPV, inactivated polio virus • OPV, oral polio virus • ATP, according-to-protocol • ITT, intention-to-treat • CI, confidence interval • PRP-OMP, Haemophilus influenzae type b Neisseria meningitidis outer-membrane complex protein conjugate

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Received for publication Jul 11, 2001; Accepted Nov 28, 2001.

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