Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Pneumococcal 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 Other considerations Selected references

Streptococcus pneumoniae (pneumococcus) is the leading cause of bacteremia, meningitis, bacterial pneumonia and acute otitis media (AOM) in children. Invasive pneumococcal disease (IPD) is most common in the very young, the elderly and certain specific groups at high risk, such as individuals with functional or anatomic asplenia and congenital or acquired immune deficiency, including those with acquired immune deficiency syndrome (AIDS).

Since the publication of the 2002 Canadian Immunization Guide, the pneumococcal conjugate vaccine has been incorporated into the publicly funded immunization programs of all provinces and territories in Canada, and information has become available about the effect of its use on the epidemiology of this infection. The chapter has been updated to reflect this. It also includes specific recommendations for children whose immunization schedule is interrupted and information concerning the utilization of a three-dose infant immunization schedule. Finally, recommendations for re-immunization have been clarified.

Epidemiology

IPD has been nationally notifiable since 2000. Age-specific incidence rates (per 100,000 population per year) during the period 2000 to 2004 were 39.8 among infants < 1 year of age, 24.6 among children 1 to 4 years, and 13.3 among adults ≥ 60 years. Children < 1 year of age accounted for 7% of cases (mean 130 cases per year), those aged 1 to 4 years accounted for 18% (mean 345 cases per year), and adults ≥ 60 years accounted for 37% (mean 711 cases per year) of Canadian IPD cases.

The serotypes contained in the 7-valent vaccine consist of serotypes circulating during the pre-vaccine era in Canada, as follows: > 80% of serotypes isolated from the blood or cerebrospinal fluid (CSF) of children, 95% of serotypes isolated with high level penicillin resistance, and 73% of those isolated with intermediate level resistance. There may be populations or communities, such as Aboriginal children in northern communities, with a different distribution of serotypes.

In northern Canadian regions participating in the International Circumpolar Surveillance project between 1999 and 2004 (i.e., Yukon, Northwest Territories, Nunavut and northern regions of Quebec and Labrador), 62.5% of IPD isolates from children < 2 years of age were serotypes contained in the 7-valent vaccine. Among persons ≥ 65 years of age, 86.4% of isolates obtained were serotypes contained in the 23-valent vaccine. In Nunavut and Northern Quebec, the two regions with universal conjugate programs in place during 2002, there were 19 cases of preventable IPD (i.e., caused by the seven serotypes in the vaccine) among children < 2 years before program implementation (1999-2002) and none after (2003-2004).

The introduction of universal pneumococcal conjugate immunization for infants in the Calgary region of Alberta, in September 2002 led to a prompt and large decline in the incidence of IPD among children < 2 years of age (Figure 11). There has also been a decline in the incidence of IPD caused by the seven serotypes contained in the conjugate vaccine among adults ≥ 65 years (See Figure 12). As in the United States, the magnitude of the decline among older people is likely due to the indirect effect of conjugate vaccine rather than a direct effect of polysaccharide vaccine, because the reduction among adults ≥ 65 years was only for infections caused by serotypes contained in the conjugate vaccine and was larger than any reduction expected from the use of polysaccharide vaccine.

Preparations approved for use in Canada

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

Conjugate vaccine

• Prevnar^® (pneumococcal 7-valent conjugate vaccine), Wyeth Canada

This pneumococcal conjugate vaccine is approved for use in Canada for children from 6 weeks to 9 years of age and is composed of the purified polysaccharides of the capsular antigens of seven S. pneumoniae serotypes, individually conjugated to CRM197 (cross-reacting material 197), a purified non-toxic variant of diphtheria toxin. The vaccine is manufactured as a liquid suspension. Each 0.5 mL dose of vaccine is formulated to contain 2 µg of each polysaccharide for serotypes 4, 9V, 14, 18C, 19F and 23F, and 4 µg of serotype 6B per dose (16 µg total of polysaccharide); approximately 20 µg of CRM197 carrier protein; and 0.125 mg of aluminum as aluminum phosphate adjuvant. The vaccine contains no thimerosal or other preservatives.

Polysaccharide vaccine

• Pneumovax^® 23 (pneumococcal vaccine, 23-valent), Merck Frosst Canada Ltd.
• Pneumo 23^® (pneumococcal polysaccharide vaccine), Sanofi Pasteur Ltd.

Both of the two pneumococcal polysaccharide vaccines currently available in Canada contain 25 µg of capsular polysaccharide from each of 23 types of pneumococci: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F (Danish nomenclature). Approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 types. The six serotypes that are most often found to be resistant to one or more antibiotics are included in this vaccine.

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

Efficacy and immunogenicity

Conjugate vaccine

Infants immunized with a three-dose primary series beginning at 2 months of age, with doses separated by 4 to 8 weeks, develop a 3.4- to 20-fold increase in serum antibodies for the vaccine serotypes. The minimum serum antibody concentration necessary for protection against pneumococcal disease has not been determined for any serotype. Functional antibodies are induced in infants together with strong and rapid anamnestic responses upon boosting with either conjugate or polysaccharide vaccines in the 6 to 12 months after the primary series. The observed protective efficacy against invasive disease due to vaccine serotypes is 89% to 97%. Protection against development of AOM ranges from 6% against an episode from any cause to a 34% reduction in pneumococcal-associated AOM and a 54% reduction in AOM due to the serotypes included in the vaccine. A 20% reduction in tympanostomy tube placement has also been observed with the use of the vaccine. The immunogenicity of conjugate pneumococcal vaccine has been demonstrated in children with sickle cell disease and human immunodeficiency virus (HIV) infection.

The long-term efficacy of the conjugate pneumococcal vaccines is not known, but immunologic memory has been demonstrated 18 months after two to three doses in infancy and up to 20 months after one dose in children 2 to 3 years of age.

Polysaccharide vaccine

In healthy young adults, a single dose of polysaccharide vaccine stimulates an antibody response to each of the compound capsular polysaccharides. The immunity conferred is type specific. Efficacy, as measured by serotype-specific protection against IPD, can surpass 80% among healthy young adults. It is in the range of 50% to 80% among the elderly and in specific patient groups, such as those with diabetes mellitus, anatomic or physiologic asplenia, congestive heart failure or chronic pulmonary disease. Antibody response and clinical protection are decreased in certain groups at particularly high risk of pneumococcal infection. These include patients with renal failure, sickle-cell anemia or impaired immune responsiveness, including HIV infection. In general, children < 2 years of age respond poorly to polysaccharide vaccine; safety and effectiveness in children < 2 years have not been established. Following polysaccharide pneumococcal immunization, serotype-specific antibody levels decline after 5 to 10 years and decrease more rapidly in some groups than others. The duration of immunity is not precisely known.

Recommended usage

Conjugate pneumococcal vaccine is recommended for routine administration to all children ≤ 23 months of age. It is also recommended for children 24-59 months of age at higher risk of IPD. High-risk children include those who attend child care centres, are Aboriginal, have sickle cell disease and other sickle cell hemoglobinopathies, have other types of functional or anatomic asplenia, HIV infection, immunocompromising conditions (e.g., primary immunodeficiencies; malignancies; conditions resulting from immunosuppressive therapy, solid organ transplantation, or use of long-term systemic corticosteroids; nephrotic syndrome), chronic medical conditions (e.g., chronic cardiac and pulmonary disease such as bronchopulmonary dysplasia, diabetes mellitus, chronic renal disease or CSF leak) and children with cochlear implants or those receiving cochlear implants. The conjugate vaccine should be considered for all other children in this age group.

Polysaccharide vaccine is not recommended for children < 2 years of age, as it is relatively ineffective, and the conjugate vaccine is superior. Children aged 2 years to < 5 years of age who are at increased risk of IPD (defined earlier) should receive the conjugate vaccine, the polysaccharide vaccine being used as a booster dose in this age group to increase the serotype coverage (see Schedule and Dosage below).

Polysaccharide vaccine should be given to all individuals ≥ 5 years of age who have not received the vaccine previously and who are at higher risk of IPD. This includes the conditions defined earlier, as well as cirrhosis and alcoholism. Polysaccharide vaccine should also be given to those who smoke, since they are also at increased risk. When circumstances permit, some experts suggest that the conjugate vaccine may be given as the initial dose followed by the polysaccharide vaccine, as this may theoretically improve antibody response and immunologic memory. However, the polysaccharide vaccine is the vaccine of choice for these individuals, and if only one vaccine can be provided it should be the polysaccharide vaccine.

Polysaccharide pneumococcal vaccine is recommended for all individuals ≥ 65 years of age. Individuals with unknown immunization histories should receive the vaccine.

Immunologic abnormalities may decrease both the antibody response to and protection by either type of vaccine. When possible, vaccine should be given at least 2 weeks before splenectomy or initiation of immunosuppressive therapy and early in the course of HIV infection. Because of the variable vaccine efficacy in certain age groups, those at highest risk (and their families) should be counseled regarding the risk of fulminant pneumococcal sepsis, which may occur despite immunization.

Schedule and dosage

The dose of both the conjugate and the polysaccharide vaccine for all age groups is 0.5 mL.

The recommended optimal schedule for infants is four doses of the conjugate vaccine administered at 2, 4, 6, and 12-15 months of age (Table 11). Children ≤ 6 months should receive the first dose at 2 months of age (minimum age is 6 weeks) and at intervals of approximately 2 months (minimum interval 4 weeks). The fourth dose should be administered after 12 months of age and at least 2 months after the third dose. Infants of very low birth weight (< 1500 grams) should be given their first dose according to their chronological age and not their calculated gestational age. Children 7 to 11 months old who have not been previously immunized against IPD should receive two doses at least 4 weeks apart followed by a third dose after 12 months of age and at least 2 months after the second dose. Children 12 to 23 months of age not previously immunized should receive two doses at least 2 months apart. For children 2 to 5 years old, one dose is sufficient for healthy children, but two doses given 2 months apart is recommended for children with chronic conditions that place them at higher risk of IPD.

Children who present for pneumococcal conjugate immunization after an interruption of their schedule should be assessed to determine the number of doses required to complete the series. This is because the schedule varies by the age of the child. Children who are < 12 months of age when they represent should complete their immunization schedule as if no interruption had occurred. Children who present at 12 to 23 months of age who have not received a complete primary series (i.e., three doses) require two doses, 2 months apart. Children who present at 12 to 23 months of age who have received the complete primary series (i.e., three doses) only require one dose (i.e., the booster dose). Healthy children who present at ≥ 2 years of age require only one dose.

Table 11. Summary Schedule for Pneumococcal Conjugate Vaccine in Previously Unvaccinated Children

When used after administration of the conjugate vaccine, pneumococcal polysaccharide vaccine should be given only after a delay of at least 8 weeks. Polysaccharide vaccine should be administered as a single dose.

Some jurisdictions are considering or have already implemented a three-dose conjugate vaccine schedule at 2, 4 and 12-15 months of age. At this time, the available data do not allow for a direct comparison of the efficacy of the three-dose and the four-dose schedule. The available data indicate that the short-term efficacy of the three-dose schedule after the third dose is comparable. The long-term efficacy of a three-dose schedule has not been determined, but this is generally not known for most vaccines at the time of approval. As the studies evaluating a three-dose schedule were not conducted among children at high risk of IPD, the National Advisory Committee on Immunization (NACI) emphasizes that such children should continue to receive the recommended four-dose schedule in jurisdictions that have implemented a routine three-dose schedule.

Route of administration

The conjugate vaccine is given as an intramuscular injection. The polysaccharide vaccine may be given by either intramuscular or subcutaneous injection.

Booster doses and re-immunization

Conjugate vaccine

Data are not yet available on any decrease in immunity over time following the use of the conjugate vaccine in infancy and early childhood, and further booster doses are not thought to be necessary at this time.

Polysaccharide vaccine

Results from serologic and case studies indicate that immunity induced by polysaccharide vaccine decreases over time. At present, routine re-immunization for those who have been vaccinated with polysaccharide vaccine is not recommended. However re-immunization should be considered for those of any age at highest risk of invasive infection, including those with functional or anatomic asplenia or sickle cell disease; hepatic cirrhosis, chronic renal failure or nephrotic syndrome; HIV infection; and immunosuppression related to disease or therapy. Experience with re-immunization is limited. If re-immunization is carried out, only a single re-immunization is recommended after 5 years in those aged > 10 years at the time of initial immunization with polysaccharide vaccine and after 3 years for those who received the initial vaccine when they were ≤ 10 years of age. See chapter on Immunization of Immunocompromised Persons, for considerations for persons undergoing hematopoietic stem cell transplantation.

Serologic testing

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

Storage requirements

These vaccines should both be stored, refrigerated, at a temperature of +2° C to +8° C as per the manufacturers' package inserts. Freezing must be avoided.

Simultaneous administration with other vaccines

If necessary or convenient, pneumococcal conjugate vaccine may be administered at the same time as diphtheria, tetanus, acellular pertussis (DTaP), polio (IPV), Haemophilus influenzae type b (Hib), hepatitis B, measles, mumps and rubella (MMR), varicella or meningococcal conjugate vaccines, at separate sites and with separate syringes. The pneumococcal polysaccharide vaccine may also be given simultaneously with other vaccines (except the pneumococcal conjugate vaccine) at a separate location and using a separate needle and syringe. When used after administration of the pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine should be administered only after a delay of at least 8 weeks. Similarly, when used after administration of pneumococcal polysaccharide vaccine, pneumococcal conjugate vaccine should be delayed by at least 8 weeks. Providers should be aware that minimal safety or efficacy data are available regarding these sequences.

Adverse reactions

Conjugate vaccine

The pneumococcal conjugate vaccine is generally well tolerated when administered at the same time as other childhood vaccines. Fever has been reported more frequently among children receiving their primary immunization series when conjugate vaccine was included. Few serious side effects have been reported. Redness, swelling and tenderness at the injection site may occur; this might be more commonly reported in recipients of multiple injections. The severity or frequency of these reactions has not been found to increase with subsequent doses in the primary series or with booster doses.

Polysaccharide vaccine

Reactions to the pneumococcal polysaccharide vaccine are usually mild. Local soreness and erythema are quite common. Occasionally, slight fever may occur. Re-immunization of healthy adults < 2 years after the initial dose is associated with increased local and systemic reactions. Subsequent studies have suggested that revaccination after intervals of ≥ 4 years is not associated with an increased incidence of adverse side effects. Severe local reactions are rare.

Contraindications and precautions

Anaphylactic reaction to pneumococcal conjugate vaccine or pneumococcal polysaccharide vaccine is a contraindication to re-immunization with that product.

Neither pregnancy nor breast-feeding is a contraindication to pneumococcal polysaccharide vaccine.

Conjugate vaccines containing CRM197 should not be considered as immunizing agents against diphtheria, and no changes in the schedule for administering vaccines containing diphtheria toxoid are recommended.

Other considerations

Strategies to improve vaccine utilization

Immunization is a safe and effective means of preventing IPD among individuals at increased risk of serious illness or death. It offers a partial solution to the emerging problem of disease caused by strains resistant to antibiotics. In general, immunization recommendations for young children are well followed. However, surveys show that less than 5% of the population > 2 years of age at increased risk have received the polysaccharide vaccine. Several provinces and territories have initiated programs to make the polysaccharide pneumococcal vaccine more readily available to target populations.

Recommended strategies for delivering pneumococcal vaccine to individuals at higher risk of invasive disease include the following:

• Ensuring that all recipients of influenza vaccine are also immunized with pneumococcal vaccine, if appropriate. Providers should have both vaccines available to facilitate concurrent administration.
• Implementing standing orders for pneumococcal immunization of residents on admission to long-term care facilities, if indicated.
• Implementing standing orders in hospitals for pneumococcal immunization of patients in high-risk groups to be immunized on discharge or during ambulatory visits.
• Delivering pneumococcal vaccine in adult day care and community centres to people at risk.
• Promoting pneumococcal and influenza immunization programs concurrently to both consumers and providers.

Selected references

American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;106:362-66.

American Academy of Pediatrics. Committee on Infectious Diseases. Technical report: prevention of pneumococcal infections, including the use of pneumococcal conjugate and polysaccharide vaccines and antibiotic prophylaxis. Pediatrics 2000;106(2 Pt1):367-76.

Black S, Shinefield H, Fireman B et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infectious Disease Journal 2000;19(3):187-95.

Butler JC, Breiman RF, Campbell JF et al. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. Journal of the American Medical Association 1993;270(15):1826-31.

Centers for Disease Control and Prevention. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease - United States, 1998-2003. Morbidity and Mortality Weekly Report 2005;54(36):893-97.

Eskola J, Anttila M. Pneumococcal conjugate vaccines. Pediatric Infectious Disease Journal 1999;18(6):543-51.

Eskola J, Kilpi T, Palmu A et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. New England Journal of Medicine 2001;334(6):403-09.

Fine MJ, Smith MA, Carson CA et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis of randomized clinical trials. Archives of Internal Medicine 1994;154(23):2666-77.

Kellner JD, Church DL, MacDonald J et al. Progress in the prevention of pneumococcal infection. Canadian Medical Association Journal 2005;173(10):1149-51.

National Advisory Committee on Immunization. Statement on recommended use of pneumococcal conjugate vaccine. Canada Communicable Disease Report 2002;28(ACS-2):1-32.

National Advisory Committee on Immunization. Statement on the recommended use of pneumococcal conjugate vaccine: addendum. Canada Communicable Disease Report 2003; 29(ACS-8):14-5.

Rodriguez R, Dyer PD. Safety of pneumococcal revaccination. Journal of General Internal Medicine 1995;10(9):511-12.

Scheifele D, Halperin S, Pelletier L et al. Invasive pneumococcal infections in Canadian children 1991-1998: implications for new vaccination strategies. Clinical Infectious Diseases 2000;31(1):58-64.

Shapiro ED, Berg AT, Austrain R et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. New England Journal of Medicine 1991;325(21):1453-60.

Shinefield HR, Black S, Ray P et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatric Infectious Disease Journal 1999;18(9):757-63.

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