Haemophilus influenzae Type b Vaccine

Emmanuel Vidor, Agnes Hoffenbach, Mark A. Fletcher

Curr Med Res Opin. 2001;17(3) 

In This Article

Summary and Introduction

Immunogenicity data obtained after primary series immunisations against Haemophilus influenzae type b (Hib), using a vaccine prepared by conjugating the capsular polysaccharide of Hib to tetanus toxoid (ActHIB™), were compiled from 146 study groups comprising 85 clinical trials or vaccination programs conducted between 1987 and 1999. ActHIB™ was administered as a monovalent lyophilised vaccine, injected either in association with another paediatric vaccine (at separate administration sites) or in combination (where the different vaccines are mixed together in the same syringe before injection). Review of these data reveals two trends. First, PRP-T vaccine, given either alone or in combination with DTwcP, resulted in a stronger anti-PRP serum antibody response than when PRP-T was combined with DTacP vaccine. Second, an accelerated (i.e. one-month interval) immunisation schedule tended to induce a poorer anti-PRP antibody response than did the more widely spaced, standard inoculation schedules. Although an in-depth analysis of these over 11,000 study subjects on an individual basis with multivariate analysis or multifactorial statistical methods might eventually provide working hypotheses to fully understand these phenomenon, the various licensed, PRP-T-containing paediatric combination vaccines have proved to be clinically effective.

Haemophilus influenzae type b (Hib) is an important cause of meningitis and pneumonia in children. A widely used Hib vaccine is prepared by chemically conjugating the capsular polysaccharide of Hib to tetanus toxoid (PRP-T), with the final vaccine preparation often in a lyophilised form. The monovalent PRP-T vaccine is clinically effective after the primary series immunisation, and a challenge for vaccine producers has been to demonstrate that when this Hib vaccine component is included in a paediatric combination vaccine it continues to induce protective anti-PRP antibody titres. Consequently, a contentious point between vaccine producers, regulatory agencies and immunisation policy advisory committees has been to define the lowest acceptable serum antibody titres to the PRP antigen that are induced after the primary series immunisation. In other words, before any PRP-T-containing paediatric combination vaccine may be licensed, the following question must be confronted: What serum titre value threshold needs to be reached by a child receiving the PRP-T-containing paediatric combination vaccine to ensure subsequent clinical protection? For many authorities, serum antibody levels above the 0.15 mg/ml threshold are taken to reflect short-term persistence of clinical protection[1,2]; antibody levels above the 1.0 mg/ml threshold then represent long-term persistence of clinical protection. For other regulatory agencies, the maximum allowed difference in serum immune responses that is observed between a group that received monovalent PRP-T vaccine and a group that received a PRP-T-containing paediatric combination vaccine has been an issue during clinical trials that were designed to demonstrate equivalence (i.e. non-inferiority). With these perspectives, licensing criteria for the Hib component of paediatric combination vaccines have tended to be based either on achievement of established anti-PRP antibody titre thresholds or on fulfilling a criterion of non-inferiority[3,4].

Recently published papers have downplayed the clinical relevance of the observed interference of serum antibody responses to PRP from Hib-containing paediatric combination vaccines in the light of the effectiveness of routine Hib vaccination programs throughout the world[1,2].

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