Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Haemophilus Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Schedule and dosage Route of administration Booster doses and re-immunization

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Selected references

Haemophilus influenzae type b (Hib) was the most common cause of bacterial meningitis and a leading cause of other serious invasive infections in young children before the introduction of Hib vaccines. About 55% to 65% of affected children had meningitis, the remainder suffering from epiglottitis, bacteremia, cellulitis, pneumonia or septic arthritis. The case-fatality rate of meningitis is about 5%. Severe neurologic sequelae occur in 10% to 15% of survivors and deafness in 15% to 20% (severe in 3% to 7%). H. influenzae is also commonly associated with otitis media, sinusitis, bronchitis and other respiratory tract disorders. However, since type b organisms seldom cause these disorders, Hib vaccines have not affected their incidence.

Universal immunization against Hib has led to a significant reduction in the incidence of invasive Hib disease in Canada. The protection resulting from infant immunization appears to be long lasting, and no cases have been reported to date in fully immunized, healthy adolescents.

Since the publication of the 2002 Canadian Immunization Guide, the changes that have occurred have been in the preparations approved for use in Canada and recent studies suggesting that vaccine failures may be associated with underlying immune deficiency.

Epidemiology

Since the introduction of Hib vaccines in Canada in 1988, the overall incidence of reported disease has decreased from 2.6 per 100,000 (686 cases) in 1988 to 0.3 per 100,000 (81 cases) in 2004. During this period, the number of reported cases among children < 5 years of age has fallen by almost 97%, from 526 to 17 cases. In 2004, the incidence was 2.4 per 100,000 children < 1 year of age and 0.7 per 100,000 children between the ages of 1 and 5 years. The majority of pediatric cases occur in unimmunized children or in children too young to have received their primary series.

Between 2001 and 2003 only 29 Hib cases were reported in children < 16 years of age by the 12 centres involved in the Immunization Monitoring Program, ACTive (IMPACT) enhanced surveillance program across the country. Only two cases occurred in fully vaccinated, previously healthy children. Twenty of the 29 cases had received no or incomplete primary vaccination, of whom 11 were children < 6 months of age. In addition, eight cases were in children with either an immunodeficiency or other chronic illness.

Non-typeable H. influenzae as well as other non-b typeable H. influenzae can rarely cause invasive disease. In Canada, only invasive Hib disease is under national surveillance. Between 2000 and 2004, 51 cases of invasive H. influenzae were detected in northern Canadian regions participating in the International Circumpolar Surveillance (i.e., Yukon, Northwest Territories, Nunavut and northern regions of Quebec and Labrador). Of these, only five cases (11% of 47 with serotype information) were due to serotype b. Fifty-five percent of cases were caused by serotype a, and 28% of invasive disease involved non-typeable isolates. Serotypes c, d and e were isolated in one case each of invasive disease.

The risk of Hib meningitis is at least twice as high for children attending full-time day care as for children cared for at home. The risk is also increased among children with splenic dysfunction (e.g., sickle cell disease, asplenia) or antibody deficiency, and among Inuit children. In 2002, a possible association between receipt of a cochlear implant and development of bacterial meningitis was identified. Persons who have received a cochlear implant should also be considered at high risk of invasive Hib disease.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

The vast majority of the Hib conjugate vaccines currently used in Canada contain purified polyribosylribitol phosphate (PRP) capsular polysaccharide of Hib covalently bound to tetanus protein (PRP-T) and are available as part of combination vaccine products. PRP-T vaccines include the following:

• Act-HIB^® (Haemophilus b conjugate vaccine [tetanus protein conjugate]), Sanofi Pasteur Ltd.
• Pentacel^® (Act-HIB^® [Haemophilus b conjugate vaccine (tetanus protein conjugate)] reconstituted with Quadracel^® [component pertussis vaccine and diphtheria and tetanus toxoids adsorbed combined with inactivated poliomyelitis vaccine]), Sanofi Pasteur Ltd.

There is one PRP-outer membrane protein (OMP) conjugate vaccine available in Canada, purified PRP capsular polysaccharide of Hib covalently bound to an outer membrane protein complex of a strain of serogroup B Neisseria meningitidis. No reconstitution is necessary.

• Liquid PedvaxHIB^® (Haemophilus b conjugate vaccine [meningococcal protein conjugate]), Merck Frosst Canada Ltd.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

All Canadian provinces and territories include Hib conjugate vaccine in their immunization program for children. Hib polysaccharide-protein 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.

The Hib conjugate vaccines differ in a number of ways, including the protein carrier, polysaccharide size, and types of diluent and preservative. PRP-OMP is unique among the Hib conjugate vaccines in its ability to induce a strong antibody response in young infants with the first dose. A third dose of PRP-OMP at 6 months of age does not boost levels or the proportion of responders, and therefore only a two-dose primary series has been recommended for infants. However, as of 1997, all Canadian provinces and territories use the PRP-T vaccine, as it is the only currently approved Hib conjugate vaccine that is combined with acellular pertussis vaccine, diphtheria and tetanus toxoids, and inactivated polio vaccine.

The protein carriers used in Hib conjugate vaccines should not be considered as immunizing agents against diphtheria, tetanus or meningococcal disease.

Efficacy and immunogenicity

PRP-T and PRP-OMP stimulate good antibody responses after primary immunization in infants starting at 2 to 3 months of age and prime them for an excellent booster response at 15 to 18 months. The booster response can be elicited by any of the conjugate Hib vaccines.

Several studies have demonstrated a reduction in the antibody responses to the Hib component when it is given as a combination vaccine with pertussis. However, with each of the products currently available in Canada, the Hib antibody levels are all in the range of what is considered protective, the functional antibodies are not reduced, and the immunologic memory is unchanged.

When given as a single dose to previously unimmunized children ≥ 15 months of age, PRP-T and PRP-OMP 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 vaccination with conjugate vaccine. This phenomenon could be confused with antigenuria associated with invasive Hib infections, and therefore this method alone should not be used to diagnose invasive disease in a recently immunized child.

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. Recent studies suggest that vaccine failures may be associated with underlying immune deficiency. It is therefore recommended that children who have invasive Hib disease after completing the 2, 4 and 6 month immunization series be evaluated for evidence of an underlying immune deficiency, although it is expected that this would only be a rare finding.

Recommended usage

Routine immunization with Hib conjugate vaccine is recommended for all infants beginning at 2 months of age. It is preferable to use the same product for all doses in the primary series. However, available data suggest that a primary immunization series consisting of three doses of different Hib conjugate vaccine products results in adequate antibody responses.

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 of age who have these underlying conditions the efficacy of Hib immunization is unknown. Despite limited efficacy data, Hib vaccination is commonly given to those with anatomic or functional asplenia and may be considered in other immunocompromised persons at increased risk of invasive Hib infection. Please refer to the Immunization of Immunocompromised Persons chapter, for more information on the recommendations related to provision of this vaccine for stem cell and solid organ transplant recipients. Individuals with cochlear implants are also considered at high risk of invasive Hib disease and should be immunized. Consultation with an infectious disease expert may be helpful in these cases.

The role of chemoprophylaxis in the management of contacts is not discussed in detail here. Rifampin or other appropriate chemoprophylaxis is not required for household contacts of cases of invasive Hib infection when the contacts are completely immunized against Hib. Complete immunization is defined as receipt of the primary Hib vaccination series and booster dose as presented in Table 2. When contacts < 48 months of age are not completely immunized, consultation with the local public health unit is advised.

Schedule and dosage

The recommended Hib vaccination schedule is shown in Table 2. The dose of Hib conjugate vaccine is 0.5 mL. Infants and children starting a primary series of Hib vaccine after 2 months of age should be immunized as soon as possible according to the schedules shown in the Table.

Hib conjugate vaccines that are supplied as a lyophilized powder (e.g., Pentacel^®) should be reconstituted only with products supplied by the same manufacturer, as recommended in the package insert. Liquid PedvaxHIB^® does not require reconstitution.

Table 2. Detailed Vaccination Schedule for Haemophilus b Conjugate Vaccines*

Route of administration

Conjugate vaccines should be administered intramuscularly.

Booster doses and re-immunization

Protective serum antibody (anti-PRP) concentrations are achieved in 99% of children after completion of the primary PRP-T immunization series of three doses. Antibody levels subsequently decline, and a booster dose is recommended at 15 to 18 months of age with any of the Hib conjugate vaccines approved for use in infants.

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. For further information, please see chapter on Immunization of Immunocompromised Persons.

Serologic testing

There is no indication for pre- or post-immunization serology

Storage requirements

Hib conjugate vaccines should be stored between +2º and +8º C and should not be frozen. Following reconstitution, vaccine should be used immediately.

Simultaneous administration with other vaccines

In Canada, Hib vaccines are usually administered as components of combination products. Combined vaccine products allow the administration of multiple antigens with the use of a single needle and have safety profiles similar to those of separately administered vaccines.

Any of the Hib conjugate vaccines may be given simultaneously with polio, measles, mumps, rubella, hepatitis B, polysaccharide and conjugate pneumococcal and meningococcal vaccines, and varicella. There are no data on administration of Hib conjugate vaccines with influenza vaccine, but expert opinion recommends that the two may be given concomitantly. Concomitant vaccines must be administered at separate sites and with separate syringes.

Adverse reactions

Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.

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 5% to 30% of immunized children. These symptoms are mild and usually resolve within 24 hours. A meta-analysis, which included 257,000 infants, reported no serious adverse events following administration of Hib conjugate vaccine.

Contraindications and precautions

Vaccination is contraindicated in people who are allergic to any component of the vaccine.

Selected references

Anderson EL, Decker MD, Englund JA et al. Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants. Journal of the American Medical Association 1995;273(11):849-53.

Eskola J. Analysis of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis combination vaccines. Journal of Infectious Diseases 1996;174(Suppl 3):S302-305.

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

National Advisory Committee on Immunization. Interchangeability of diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae type b combination vaccines presently approved for use in Canada for children < 7 years of age. Canada Communicable Disease Report 2005;(ACS-1):1-10.

Scheifele DW. Recent trends in pediatric Haemophilus influenzae type b infections in Canada. Immunization Monitoring Program, ACTive (IMPACT) of the Canadian Paediatric Society and the Laboratory Centre for Disease Control. Canadian Medical Association Journal 1996;154(7):1041-47.

Scheifele D, Halperin S, Law B et al. Invasive Haemophilus influenzae type b infections in vaccinated and unvaccinated children in Canada, 2001-2003. Canadian Medical Association Journal 2005;172(1):53-56.

Swingler G, Fransman D, Hussey G. Conjugate vaccines for preventing Haemophilus influenzae type b infections. Cochrane Database Systematic Reviews 2003(4):CD001729.

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