Haemophilus influenzae type b (Hib) vaccine

General information

Haemophilus influenzae causes several infectious diseases in man, the most serious being meningitis. Most cases of Haemophilus influenzae infection are due to type b of the organism (Hib). Two types of Hib vaccines have been developed: Hib capsular polysaccharide (PRP) vaccines are first-generation Hib vaccines, while Hib conjugate vaccines are second-generation vaccines. The capsular polysaccharide vaccines do not protect infants and children under 18 months, whereas Hib conjugate vaccines have greater immunogenicity and induce a high rate of protection in children under 18 months. The latter have therefore completely replaced the first-generation polysaccharide vaccines.

Four different types of conjugated vaccines are commercially available:

• 1.

  PRP-D Hib vaccine (a mutant polypeptide of diphtheria toxin covalently linked to PRP), for example ProHIBit (produced by Connaught Laboratories, Philadelphia).

• 2.

  HbOC vaccine (Hib oligosaccharides linked to the non-toxic diphtheria toxin variant CRM197), for example HibTITER (produced by Lederle-Praxis Biologicals, Pearl River, NY).

• 3.

  PRP-OMC (PRP conjugated to outer membrane protein of Neisseria meningitidis group B), for example PedvaxHIB (produced by Merck Sharp & Dohme Research Laboratories).

• 4.

  PRP-T Hib vaccine (tetanus toxoid linked to PRP), for example ActHIB or OmniHIB (produced by Pasteur Merieux, Lyon, France) and PRP-T (produced by Pasteur Mérieux Connaught and Glaxo SmithKline).

PRP-D-Hib has been almost completely replaced by different conjugated Hib vaccines [ ]. The four types of conjugated Hib vaccines have been reviewed [ ]. More than 100 million doses of conjugated vaccines have now been administered worldwide, and no reports of deaths, anaphylaxis, or residual neurological damage have been causally connected with them.

Drug studies

Comparisons of adverse reactions to different vaccines are difficult, because vaccines are virtually always administered together with other vaccines. However, the general experience is that adverse reactions to Hib vaccine are mild. Most reactions develop when the vaccine is given simultaneously with DTP vaccine. There have been no deaths or permanent sequelae attributable to Hib immunization.

In a study of the tolerability and immunogenicity of Hib vaccines, 30 volunteers aged 69–84 years were immunized with either Pedvax-Hib (a conjugate of Hib polysaccharide and an outer membrane protein complex of Neisseria meningitidis -PRP-OMP) or Hib TITER (a conjugate of Hib oligosaccharide and a non-toxic mutant diphtheria toxin, CRM 197-HbOC) [ ]. The volunteers received a pediatric dose. Before immunization, 40% of the volunteers had serum anti-PRP antibody concentrations below 1.0 μg/ml. Four weeks after immunization, all the volunteers had concentrations over 1.0 μg/ml, which is generally considered to be protective. Adverse reactions to vaccination were mild, except in one volunteer given HbOC, who developed extensive erythema and swelling at the injection site.

Different vaccines and immunization strategies have been evaluated in Denmark, Finland, Iceland, Norway, and Sweden [ ]. Few places outside Scandinavia have collected data on Hib immunization programs for so long (more than a decade has elapsed since universal Hib immunization was initiated in Scandinavia) and with similar accuracy. Phase 3 studies with PRP-D-Hib vaccine were done in Finland in the late 1980s, and PRP-D-Hib vaccine has been the only vaccine used in Iceland. HbOC vaccine was first compared with PRP-D-Hib vaccine in Finland and then reintroduced to the primary health-care system as the only Hib vaccine used. Finally, PRP-T-Hib vaccine was first temporarily used in Finland, and then as almost the only vaccine in Denmark, Norway, and Sweden. Besides the different conjugate vaccines, the immunization programs have differed in other aspects, such as immunization schedule and administration of vaccines (separate versus simultaneous administration with other vaccines, such as DT, DTP, DTaP, IPV, or MMR).

Experience with PRP-D derives from Finland and Iceland. In Finland, 14.1 adverse reactions per 100 000 doses were reported in all, consisting respectively of 5.3, 6.3, 4.4, and 2.9 per 100 000 doses of local reactions, fever, rash, and irritability. These rates probably underestimate the true rate. In Iceland, adverse reactions have not been monitored, but no serious events have been reported. For PRP-CRM, there were 17.8 per 100 000 doses in all, of which 7.7 per 100 000 doses were due to local reactions, 8.9 to fever, and 8.3 to rash. PRP-T currently enjoys the largest use in Scandinavia, being the routine choice in three countries. Of 115 reactions reported in Denmark, none was of serious concern; most were local reactions, fever, or rash. In Norway, the incidence of systemic reactions was 1 in 550 doses; fever and other symptoms and signs similar to those after DTP vaccination were the most common complaints. However, two findings were characteristic of Norway, where local reactions were reported with an overall frequency of 1/1500 doses:

• immediate mild allergic reactions were more common than if DTP or IPV was given alone; their incidence was 1 in 3 000 doses of PRP-T;

• large swellings at the vaccination site, with edema and sometimes bluish or other discoloration of the legs, were reported in 18 children, suggesting an incidence of about 1 in 30 000 doses; this reaction developed within hours after vaccination and subsided within 24 hours; all the vaccinees recovered spontaneously without treatment or sequelae.

About 1.5 million doses of PRP-T have been used in Sweden. Similar concerns about adverse reactions have been raised as in Norway, and further elucidation has recently begun. In Finland (where PRP-T was used in 1990–93), there were 15.9 reports per 100 000 doses; 6.2 per 100 000 doses were local reactions, 5.9 fever, 2.8 rash, and 2.4 irritability [ ].

Notwithstanding the different approaches taken in the various Scandinavian countries, the results are similar: before vaccination against invasive Hib diseases, first introduced in Finland in 1986, the incidence of cases in the five Scandinavian countries was 49 per 100 000 per year in 0- to 4-year olds and 3.5 per 100 000 overall. During the next decade, Hib conjugates given to young children had about 95% effectiveness, regardless of which conjugate was used, whether two or three primary doses were used, and at no matter what age in early infancy the first vaccination was given. Invasive diseases due to Hib have thus been nearly eliminated.

On the request of the French Drug Agency, the Regional Pharmacovigilance Center of Tours has analysed the adverse events that occurred in 1986–90 with the use of three different tetravalent DTwP-IPV vaccines produced by French vaccine manufacturers [ ]. The most frequent adverse events were local reactions (43% of the 631 events reported). Serious adverse events represented 25% of all reported events, including 23 reports of persistent crying, 12 febrile seizures, 14 apyretic seizures, and 3 reports of shock-like events.

Immunological interference, particularly to the Hib response, has been assessed in 135 infants at 2, 4, 6, and 18 months of age in studies of two different types of administration of DTaP and Hib vaccines: combined administration of the two vaccines mixed in the same syringe and simultaneous administration of separate injections at different sites [ ]. The vaccines were well tolerated and there were no differences in the rates of local and systemic reactions. Immune responses were also comparable between the two groups.

In 57 volunteers, 32 of whom had recently undergone splenectomy, who received Hib conjugate vaccine, antibodies to Hib were measured at 2, 6, 12, 24, and 36 months after immunization [ ]. All tolerated the vaccine well and reached protective antibody titers. The authors concluded that the vaccine is safe and protective in patients with thalassemia.