Vaccine-Preventable Diseases

Haemophilus influenzae type b

Haemophilus influenzae type b (Hib) causes invasive infections mainly in young children. Other serotypes of H. influenzae are commonly associated with asymptomatic nasopharyngeal colonization and may cause otitis media, sinusitis, bronchitis, and other upper respiratory tract infections. Until the early 1990s, Hib was recognized as the most common cause of bacterial meningitis in Canada; Hib meningitis outnumbered all other reported bacterial causes combined. Hib infection also results in a number of clinical syndromes including epiglottitis, septicemia, cellulitis, pneumonia, septic arthritis, and pericarditis. Before immunization became routine, about two-thirds of Hib diseases occurred in children < 18 months of age and over 80% occurred in children < 5 years of age. Mortality associated with Hib disease is between 1% and 5%, and permanent neurologic sequelae occur in 20% to 30% of children who survive meningitis.

Very little was known about the frequency of Hib infections in Canada prior to 1979 when Hib meningitis became reportable nationally. Reporting improved gradually until 1988, which accounts for the change observed in Figure 5. Before the introduction of the first line of Hib vaccines in 1987, it was estimated that one in every 200 children developed invasive Hib disease by the age of 5 years. This represented about an estimated 2,000 cases in Canada annually; a little more than one-half were meningitis. After the introduction of the vaccine, the incidence fell rapidly by more than 50% in Canada; similar reductions were reported in the United States. Although vaccination was limited initially to children aged 15 to 18 months or older, a decline in incidence was also reported in children < 18 months of age, suggesting either a herd-immunity effect of vaccination or a reduced transmission of the bacteria.

Since the introduction of the newer conjugate vaccines in 1992 for use in infants (starting from 2 months of age), the incidence of Hib disease has decreased even further. Cases admitted to pediatric centres in the Immunization Monitoring Program, Active (IMPACT) surveillance network were reported to have decreased by more than 70% from 1991 (90 cases) to 1995 (24 cases) despite the expansion of the surveillance program from five to 10 centres. A decreasing trend is also supported by the number of cases of Hib disease reported to the LCDC notifiable disease reporting system, although the numbers reported are well below the estimated incidence and indicate gross underreporting.  From 1979 to 1992 more than 200 cases (and as many as 686 cases) were reported each year; however, only 117 cases were reported in 1993, the first year after introduction of the infant conjugate vaccines. In the last 5 years alone, the incidence has decreased from 1.4 per 100,000 population (370 cases) in 1991 to 0.2 per 100,000 (52 cases) in 1995; this represents an 86% reduction.

In 1994 and 1995, the percentage of reported cases < 5 years of age was approximately 41%, which is about one-half that estimated prior to infant vaccination. The majority of cases occur now in children too old to have received primary vaccination in infancy or any vaccination at all. The incidence of Hib invasive disease is expected to decrease further because more children receive immunization against Hib in infancy.

1998 Update:Since national reporting began for invasive Hib in 1986, the annual number of cases ranged from 100 to 650/annum. After 1993, when the infant conjugate vaccines were introduced into all routine immunization schedules, the number of cases decreased to less than 60 cases/year (Figure 2). The lowest recorded number was reported in 1998, with only 50 cases. In 1998, the highest incidence remained in the younger than one-year-old age group with 1.9/100,000 (seven cases). The next highest age-specific incidence was in the one- to four-year-old age group at 0.6/100,000 (10 cases).

Figure 2) Number of reported invasive Haemophilus influenzae type b cases in Canada, 1986 to 1998. PRP Polyribose ribitol phosphate; PRP-D PRP-Diphtheria toxoid conjugate

Hib Vaccine

All Canadian provinces and territories include Hib conjugate vaccine in their immunization program for children. Hib conjugate vaccines are the second generation of vaccines against Hib disease, having replaced an earlier polysaccharide product. Polysaccharide-protein conjugate antigens have the advantage of producing greater immune response in infants and young children than purified polysaccharide vaccine. The latter stimulates only B-cells, whereas the former activates macrophages, T-helper cells and B-cells, resulting in greatly enhanced antibody responses and establishment of immunologic memory.

As of 1997, there are three Hib conjugate vaccines licensed for use in Canada in infants >= 2 months of age: HbOC (HibTITERTM), PRP-OMP (PedvaxHIBTM) and PRP-T (Act-HIBTM). A fourth Hib conjugate vaccine, PRP-D (ProHIBITTM), is licensed for use only in children >= 18 months of age. PRP-D is currently not recommended in Canada because it induces antibody responses that are suboptimal compared with other Hib conjugate vaccines.

The Hib conjugate vaccines differ in a number of ways, including the protein carrier, polysaccharide size and types of diluent and preservative. As of 1997, all Canadian provinces and territories use the PRP-T vaccine because it is the only Hib conjugate vaccine currently licensed for use that is combined with acellular pertussis vaccine and diphtheria and tetanus toxoids, with or without inactivated polio vaccine. The protein carriers in Hib conjugate vaccines should not be considered as immunizing agents against diphtheria, tetanus or meningococcal disease.

Efficacy and Immunogenicity

Across Canada, the H. influenzae conjugate vaccine is now given in combination with diphtheria, tetanus, pertussis and polio as PentacelTM. Several studies have demonstrated reduced antibody response to the Hib component when it is given as a combination vaccine, although the Hib responses are not reduced with PentacelTM. As well, since the switch to PentacelTM there has only been one breakthrough case of invasive Hib disease in Canada after completion of the primary immunization series.

When given as a single dose to previously unimmunized children >= 15 months of age, HbOC, PRP-OMP and PRP-T stimulate excellent antibody responses (> 1 µg/mL) in 80% to 100% of children. The duration of immunity following completion of age-appropriate immunization is unknown and warrants ongoing study. Current data suggest that protection will be long lasting.

Capsular polysaccharide antigen can be detected in the urine of vaccinees for up to 2 weeks after immunization with conjugate vaccine. This phenomenon could be confused with antigenuria associated with invasive Hib infection.

Hib conjugate vaccine failure, defined as onset of confirmed invasive Hib infection more than 28 days after completion of the primary immunization series, can occur but is rare with the products in current use.

Recommended Usage

Children in whom invasive Hib disease develops before 24 months of age should still receive vaccine as recommended, since natural disease may not induce protection. Infections due to encapsulated bacteria, including H. influenzae, occur more commonly in those with primary and secondary disorders of the humoral immune system, including disorders of antibody production or function, lymphoreticular or hematopoietic malignancies, antibody dyscrasias, protein wasting syndromes, anatomic or functional asplenia, bone marrow transplantation and HIV infection. For previously unimmunized adults and children > 5 years who have these underlying conditions, the efficacy of Hib immunization is unknown. Despite limited efficacy data, Hib vaccine is commonly given to those with anatomic or functional asplenia and may be considered in other immunocompromised people at increased risk of invasive Hib infection. Consultation with an infectious disease expert may be helpful in these cases.

Schedule and Dosage

Previously unimmunized children 15 to 59 months of age should be given a single dose of PRP-T, HbOC or PRP-OMP.

Preparation and Route of Administration

Booster Doses and Re-immunization

For children who have conditions that predispose them to infection with encapsulated bacteria and who have already received the primary Hib immunization series plus booster, it is not known whether additional doses of Hib vaccine are beneficial.

Storage Requirements

Simultaneous Administration with Other Vaccines

Any of the four Hib conjugate vaccines may be given simultaneously with polio, measles, mumps, rubella, hepatitis B, pneumococcal and meningococcal vaccines, but at a different site. There are no data on administration of Hib conjugate vaccines at the same time as influenza vaccine.

Adverse Reactions

A temperature of > 38.3o C has been reported in a minority of infants given Hib conjugate vaccine either alone or in combination with other vaccines. A local reaction at the site of injection, including pain, redness and swelling, occurs in 25% of immunized children. These symptoms are mild and usually resolve within 24 hours. No severe adverse reactions have been noted in clinical trials, although a few temporally associated allergic reactions have been reported in older children receiving the vaccine as part of their routine immunization program.

Contraindications

Selected References

Committee on Infectious Diseases. Haemophilus influenzae infections. In: American Academy of Pediatrics. Report of the Committee of infectious Diseases (Red Book), 25th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2000:262-74.

Eskola J. Analysis of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis combination vaccines. Infect Dis 1996;174:S302-5.

Friede A, O'Carroll PW, Nicola RM et al, eds. Centers for Disease Control and Prevention. CDC prevention guidelines. A guide to action. Baltimore: William and Wilkins, 1997:394-492.

Immunization Monitoring Program, Active (IMPACT) of the Canadian Paediatric Society and the Laboratory Centre for Disease Control. Recent trends in pediatric Haemophilus influenzae type b infections in Canada. Can Med Assoc J 1996;154:1041-47. 

LCDC. Canadian national report on immunization, 1996. CCDR 1997;23S4:13-4. 

Scheifele D, Halperin S. Haemophilus influenzae type B disease control using PENTACELTM, Canada, 1998-1999. CCDR 2000;26(11):93-6. 

Heath PT, Booy R, Slack MPE et al. Are Hib booster vaccinations redundant? Lancet 1997;349(9060):1197-202.