The reactogenicity and immunogenicity of commercial Haemophilus influenzae type b conjugate vaccines

Joseph F. Heyse Karen M. Kaplan The reactogenicity and immunogenicity of commercial Haemophilus in¯uenzae type b conjugate vaccines Received: 1 February 2000 and in revised form: 1 March 2000 Accepted: 26 March 2000 Sir: Multiple de®ciencies in the reported post-hoc analysis of the open-label study by Usonis and Bakasenas [1] make the authors' conclusions comparing Haemophilus in¯uenzae type b Hib) vaccines untenable. The paper purports to determine the eect of concomitant administration of a candidate diphtheria-tetanus-acellular pertussis- hepatitis B-inactivated poliovirus DTaP-HBV-IPV) vaccination on the reactogenicity and immunogenicity of each of four licensed Hib conjugate vaccines, The open, multicenter study was random- ized in a 2:1:1:1 split) to receive Hiberix n 219), ActHib n 110), HibTITER n 110), and PedvaxHIB n 110). PedvaxHIB has a two-dose regimen; the other vaccines require three doses. The authors conclude that there appears to be no interference with the immune response when Hib conjugate vaccines are concomitantly administered with DTaP- HBV-IPV vaccine as separate injections. No control group is included in which a Hib conjugate vaccine was administered at a time separate from administration of DTaP-HBV-IPV. No statistical criteria are provided to support the primary conclu- sion. Rather, the paper focuses on post-hoc comparisons among the four Hib vaccines. The authors report variations in injection site reactions and immunogenicity. The study design and statistical analysis appear to be seriously ¯awed and do not allow valid comparisons among the Hib vaccines. The study was not blinded, and follow-up was by parental diary card collected at least 1 month following vaccination. The statistical analysis was incorrectly based on diary cards rather than on individual subjects and is therefore severely biased. The observations for individuals contributing more than one diary card are not independent i.e. n 549 subjects contributed 1,525 dia- ries which were assumed to be independent observations). As a result, all reported P- values are greatly exaggerated. Clearly, the analysis does not account for the dierences in dosing regimens among the Hib vaccines, i.e. two doses for PedvaxHIB, and three doses for the others). The additional dose lowers the proportion of injection site reactions for the three-dose regimens, even if the absolute numbers of reactions are the same. Also, since later doses generally produce fewer injection site reactions, this analysis introduces a strong bias against PedvaxHIB. Furthermore, no discussion of the potential impact of concomitant administration of the candidate DTaP-HBV- IPV vaccine on the ®ndings is provided. Although multiplicity was identi®ed as fundamental in analyzing reactogenicity data, the statistical evaluation of immunogenicity did not adjust for multiple comparisons. None of the appropriately adjusted pair-wise comparisons of GMC between the Hib vaccines attains a level of statistical signi®cance. Given that the study was a non-blinded post-hoc analysis, the analysis was based on diary cards rather than individuals and did not account for dierences in dosing regimens, and multiplicity was not considered in the analysis of immunogenicity, the comparisons among Hib vaccines are not valid. Reference 1. Usonis V, Bakasenas V 1999) Does concomitant injection of a combined diphtheria-tetanus-acellular pertussis- hepatitis B- virus inactivated polio virus vaccine in¯uence the reactogenicity and immunogenicity of commercial Haemophilus in¯uenzae type b conjugate vaccines? Eur J Pediatr 158: 398±402 J. F. Heyse á K. M. Kaplan &) Merck Research Laboratories, Merck & Co. Inc., PO Box 4 BL 1-7, West Point, PA 19486, USA e-mail: [email protected] Tel.: +1-610-3973414; Fax: +1-610-3972992 932

The reactogenicity and immunogenicity of commercial Haemophilus influenzae type b conjugate vaccines

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