An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*†

STATEMENT ON RECOMMENDED USE OF PNEUMOCOCCAL CONJUGATE VACCINE

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Preamble

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. Persons administering or using the vaccine(s) should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

INTRODUCTION

Streptococcus pneumoniae (pneumococcus) is the leading cause of invasive bacterial infections, bacterial pneumonia and acute otitis media in young children. In Canada, there are an estimated 65 cases of meningitis, 700 cases of bacteremia, 2,200 cases of hospitalized pneumonia, 9,000 cases of non-hospitalized pneumonia and an average of 15 deaths per year due to S. pneumoniae in children < 5 years of age. NACI previously recommended 23-valent pneumococcal polysaccharide vaccines (PPV23) for use in persons >= 2 years of age who are at high risk of invasive pneumococcal disease (IPD), but these vaccines are poorly immunogenic in younger children. A newly licensed heptavalent pneumococcal conjugate vaccine (PCV7), demonstrated to be  safe and highly effective in preventing IPD when given to children < 2 years of age, presents new options for the control of invasive pneumococcal disease. The current NACI statement provides recommendations for the use of PCV7 in children < 5 years of age, including recommendations for an infant immunization schedule (at 2, 4, 6, and 12 to15 months of age) and for immunization of children 24 to 59 months of age with or without additional risk factors. For children 24 to 59 months of age who are at high risk of IPD, NACI recommends that sequential vaccination with PCV7 followed, at least 8 weeks later, by one dose of PPV23 be considered. Persons >= 5 years of age who are at increased risk of IPD should receive PPV23 as per previous NACI recommendations.

Epidemiology of childhood pneumococcal diseases in Canada

Invasive pneumococcal disease

S. pneumoniae is a leading cause of invasive bacterial infections in children, including meningitis, bacteremia, sepsis and pneumonia. Several Canadian population-based studies of IPD have been conducted since the mid-1990’s (Table 1). The annual incidence rate for IPD in all age groups is estimated to be 11.6 to 17.3 per 100,000 population^(1-4). Children < 5 years, especially those < 2 years, and the elderly have the highest incidences. The observed incidence rates of IPD for children < 5 years of age and < 2 years of age were 35.0 to 63.8 per 100,000 and 58.8 to 112.2 per 100,000 per year respectively⁽⁵⁾ (Table 1). Given that not every case of IPD would have had cultures taken before starting antibiotics, these estimates likely represent the minimum incidence rates. The Immunization Program ACTive (IMPACT) network of 11 tertiary care pediatric sentinel sites across Canada reported a male majority in IPD cases, with a male to female patient ratio of 1.4:1⁽⁶⁾. Differences in IPD incidence from the various Canadian study populations should be interpreted with caution; given that most of the studies involved short periods of surveillance, and there were no data on potentially confounding variables (such as the local clinical practice of taking blood cultures and care-seeking behaviours). The age-specific incidences of IPD in Canadian populations are generally comparable to those seen in the United States (U.S.) and northern European countries^(7-12). Although the incidence of IPD for children < 2 years of age in Canada is somewhat lower than that observed in the U.S., the incidence of pneumococcal meningitis is similar in the two countries. A higher blood culture sampling rate for young children with bacteremia in the U.S. is one possible explanation for the differences observed^(12,13).

 

A review of children <= 12 years of age presenting with IPD to the pediatric tertiary care centres across Canada during 1991-1998 showed that the overall case-fatality rate (CFR) was 2.0%⁽⁶⁾. CFR in those < 6 months of age was 4.3% compared to 1.7% for older children. CFR was 6.5% for those with meningitis and 44.0% for those presenting with septic shock. Among children > 6 months of age, the CFR was significantly higher in those with underlying disease than in those who had been previously healthy (3.8% compared to 0.9%; p < 0.001). In addition, the Toronto/Peel region study reported a similar CFR (1.6%) for children <= 16 years of age (Dr. A. McGeer, Mt. Sinai Hospital, Toronto: personal communication, 2000). Using the incidence rates for S. pneumoniae meningitis, hospitalized pneumonia and hospitalized bacteremia (Table 2), and the CFRs for hospitalized cases^(6,15), there are an estimated 15 deaths due to IPD each year in Canadian children < 5 years of age. Although few children die of IPD in Canada, the sequelae from meningitis and septic shock can be considerable^(6,16-18).

In the Toronto/Peel region there was a decrease in the incidence of IPD in high-risk populations eligible for the publicly-funded pneumococcal polysaccharide vaccine program, but the rate remained stable in the vaccine ineligible group⁽⁴⁾. From 1991 to 1998, no temporal trends in case prevalence was evident from Canadian pediatric hospitals⁽⁶⁾.

Non-invasive pneumococcal disease

S. pneumoniae is responsible for a considerable number of non-invasive respiratory infections, and is the most common bacterial cause of community-acquired pneumonia (CAP), acute otitis media (AOM) and sinusitis in children^(19-25). Two prospective population-based serologic studies conducted in the U.S. and Finland, showed that 17% to 28% of cases of CAP in children < 15 years of age were due to pneumococcus^(19,20). The true proportion of CAP due to S. pneumoniae is likely to be higher, given that the diagnostic tests used in these studies were not very sensitive. The age-specific incidences of hospitalized and non-hospitalized pneumonia in children have been estimated using Quebec hospital separation (MED-ECHO) and Manitoba Health physician claims databases respectively (Table 2). Using these incidence data, there are an estimated 41,000 Canadian children < 5 years of age (6 to 59 months of age) with non-hospitalized pneumonia per year, and a further 9,600 with hospitalized pneumonia. Assuming that 22% of CAP are due to S. pneumoniae, there are an estimated 9,000 and 2,118 cases of non-hospitalized and hospitalized pneumococcal pneumonia respectively in this population.

S. pneumoniae has been found in 28% to 55% of middle ear aspirates from young children AOM^(21-24). In an U.S. study, almost two-thirds of children have had at least one episode of AOM by 12 months of age and 17% had at least three episodes by that age; 83% had one or more episodes of AOM by 3 years of age. The peak incidence for AOM occurred during the second 6 months of life⁽²⁶⁾. In one Canadian study, 32% of children < 5 years of age paid one or more visits to a physician for AOM during a 1 year period, and 80% of these received an antibiotic prescription. AOM was the most frequent reason for which an antibiotic was prescribed⁽²⁷⁾. The age-specific incidence rates of otitis media episodes and of myringotomy and ventilation tube insertion (MVT) have been estimated using the Manitoba Health physician claims database and the Quebec hospital separation database respectively (Table 2). Using these incidence data, there are an estimated 1 million AOM episodes and 1.8 million physician visits for AOM, as well as 20,539 MVTs each year in Canadian children < 5 years of age. If it is assumed, as per the opinion of a recent U.S. expert panel⁽²⁸⁾, that 19% of AOM are due to S. pneumoniae, there are an estimated 200,000 episodes and 360,000 physician visits for S. pneumoniae otitis media per year in this population.

Children at increased risk for invasive pneumococcal infections

Aboriginal populations

In the U.S., African Americans, Alaska Natives and certain American Indian populations (Navajo and Apache) have higher incidence rates of IPD compared with Caucasians. Alaska Natives < 5 years of age have three to seven times greater risk of invasive disease compared to non-natives⁽¹²⁾. Data from 2 years of surveillance (1999-2000) in the northern regions of Canada (Yukon Territory; Northwest Territories; Nunavut; north coastal Labrador; Nunavik and the Cree Council of James Bay in northern Quebec) suggest that the rate of IPD there is at least three times higher in aboriginals than in non-aboriginals. The overall incidence in this population was 27 per 100,000, and the overall case fatality rate was 9%. Of the reported cases, 30% were children < 2 years of age; incidence in children < 2 years of age was 190 per 100,000. Given that in the remote northern regions very few blood cultures are taken before antibiotics are commenced, the observed incidence for invasive pneumococcal disease in this population is likely an underestimate. (Dr. A. Bell, International Circumpolar Surveillance, Arctic Investigations Program, Anchorage: personal communication, 2000).

Children with functional or anatomic asplenia

Children with sickle cell disease (SCD), other sickling hemoglobinopathies (e.g., hemoglobin S-C disease or S-ß-thalassemia) and other conditions resulting in functional or anatomic asplenia are at high risk for IPD^(29-34). The rates of IPD among children with hemoglobin S-C disease are lower than rates among persons with SCD but are still much greater than that for healthy children. Asplenic children < 2 years of age are assumed to have high risks similar to those with SCD who are functionally asplenic by 18 months of age. Persons with SCD have reduced ability to clear encapsulated bacteria, such as S. pneumoniae, from the bloodstream, which is thought to occur as a result of low levels of circulating antibodies, splenic dysfunction, and complement deficiency. The protective effect of pneumococcal polysaccharide vaccine among SCD patients has not been demonstrated consistently^(32,35,36). The use of prophylactic penicillin has reduced the risk for IPD; however, children < 5 years of age with SCD still have very high incidence rates (range: 1,230 to 1,500 per 100,000 population in the U.S.)⁽¹²⁾. The continued high risk of IPD in this population may be due to non-compliance with or failure of penicillin prophylaxis, together with suboptimal protection by pneumococcal polysaccharide vaccine^(31,32,36).
 

HIV-infected children

Children infected with HIV are at considerably increased risk for pneumococcal infection compared with those who are not HIV-infected^(37-39). In two prospective cohort studies, HIV-infected children had rates of IPD that were three and 13 times the rate among HIV-negative control subjects for children < 5 years of age and < 3 years of age, respectively^(40,41). Incidence of IPD is six cases per 100 patient-years among HIV-infected children <= 7 years of age⁽⁴²⁾. Although there is little data on the risk of IPD in HIV-infected children, with the advent of highly active antiretroviral therapy, it is likely that these children will become increasingly immunosuppressed with time.

Children with other underlying medical conditions

There is minimal data on the incidence of IPD in children with other underlying medical conditions. However, case series show that a high proportion of children with IPD have chronic medical conditions, including: cardiopulmonary disease; congenital immune deficiency; HIV/AIDS and other diseases associated with immunosuppression; immunosuppressive therapy; solid organ transplantation; nephrotic syndrome; hepatic cirrhosis; cerebrospinal fluid leaks, and diabetes mellitus⁽⁶⁾.

Children in day care

Group child care increases the risk for IPD and AOM among children^(43-45). In an U.S. study, attendance at a group day care centre during the preceding 3 months was associated with an approximately two-fold increase in IPD among children 12 to 23 months of age, and three-fold increased risk among children 24 to 59 months of age⁽⁴³⁾. Risk for AOM is higher among children who attend day care outside the home compared with family day care, and risk for middle ear effusions increases with exposure to larger numbers of children in day care settings^(46-48).

 Younger age when starting day care also increases risk for experiencing recurrent AOM⁽⁴⁷⁾.

Pneumococcal serotype epidemiology

In Canada, S. pneumoniae capsular typing, based on the Danish nomenclature system, is performed by Quellung reaction using pool, group, type and factor sera obtained from Statens Seruminstitut, Copenhagen, Denmark. Currently, 90 serotypes of S. pneumoniae have been identified on the basis of antigenic differences in their capsular polysaccharides.

Seven S. pneumoniae serotypes (14, 6B, 19F, 18C, 4, 23F, and 9V) account for > 80% of invasive isolates from children < 5 years of age in Canada, and are the serotypes included in the licensed PCV7^(2,6,49,50) (Table 3). In the IMPACT study, a review of > 1,500 children presenting to sentinel hospitals with IPD during 1991-1998 indicated that PCV7 serotypes matched nearly 86% of isolates from children 6 months to 5 years of age, but matched significantly fewer isolates from younger and older children⁽⁶⁾. Similar serotype distribution for invasive isolates were observed in population-based studies (Sentinel Health Unit Surveillance System, Health Canada, Ottawa: unpublished data, 1996; Dr. A. McGeer, Mt. Sinai Hospital, Toronto: personal communication, 2000) and in isolates submitted to the National Centre for Streptococcus and the Laboratoire de santé publique du Québec^(2,49). In the northern Canadian population, only an approximate 70% of invasive isolates from children < 2 years of age match PCV7 serotypes. The most common serotypes in this population, in descending order of frequency, were 1, 14, 9V and 4, representing 49% of all invasive cases during 1999-2000 (Dr. A. Bell, International Circumpolar Surveillance, Arctic Investigations Program, Anchorage: personal communication, 2000).

PCV7 may offer cross protection for other serotypes, primarily 6A and 19A⁽⁵³⁾. Assuming complete cross-protection for these serotypes, the proportion of preventable IPD cases in the IMPACT series would increase by 5%⁽⁶⁾. Vaccine efficacy data are not yet sufficient to clarify any actual cross protection rates.

Among children with AOM in rural Kentucky, the PCV7 serotypes accounted for approximately 70% of infections among children < 24 months of age⁽⁵⁴⁾. Of 414 S. pneumoniae isolates cultured from the middle ear fluid of Finnish children with AOM, 250 (60%) were caused by serotypes contained in PCV7⁽⁵⁵⁾.

Antibiotic resistance

The increasing prevalence of pneumococci with antibiotic resistance, especially in young children and the elderly, underscores the need to consider the prevention of pneumococcal infections through vaccination. Data from the Canadian Bacterial Surveillance Network show that penicillin non-susceptible pneumococci (PNSP) (i.e., intermediate susceptibility [minimum inhibitory  concentration (MIC) = 0.12 to 1.0 mg/mL] or resistant [MIC >= 2.0 mg/mL]) increased from 2% in 1988 to 15% in 1998⁽⁵⁶⁾. A similar increase in PNSP was found amongst invasive isolates from tertiary care children hospitals⁽⁵⁵⁾. In the Calgary region, nearly 16% of S. pneumoniae isolated in 1999 were PNSP, including 10% of invasive isolates. The prevalence of PNSP was elevated in young children and in the elderly; 13% of invasive isolates from children < 5 years of age were PNSP⁽³⁾. During 2000, sentinel hospitals in Quebec reported that close to 20% of isolates from children < 2 years of age were PNSP (compared to 8% in 1996), while close to 19% of isolates in persons >= 2 years of age were PNSP (compared to 10% in 1996)⁽²⁾. Amongst invasive isolates referred to the National Centre for Streptococcus, the proportion that are PNSP increased from just over 5% in 1992-1993 to15% in 1999-2000⁽⁴⁹⁾. Pneumococci that are resistant to penicillin are commonly resistant to other antibiotics^{(2,49,50,57,58)}.

The pneumococcal serotypes most commonly associated with antibiotic resistance are covered by PCV7^(2,6,50) Amongst invasive isolates from children presenting to tertiary care hospitals, PCV7 serotypes matched 95% of isolates with high level resistance, and 73% of isolates with intermediate resistance⁽⁶⁾. Amongst invasive isolates referred to the National Centre for Streptococcus during 1992 to 1995, PCV7 serotypes matched 100% of those with high level resistance to penicillin, 59% of those with intermediate resistance⁽⁵⁰⁾. Similarly 84% to 93% of invasive PNSP isolates from persons of all ages presenting to sentinel hospitals in Quebec from 1996 to 1999 are of PCV7 serotypes⁽²⁾.

Risk factors associated with infection with PNSP include younger age, attendance at a day care centre, higher socio-economic status, recent (i.e., < 3 months) antibiotic use, and recurrent AOM^(43,59-61). Recent day care attendance as well as recent antibiotic treatment are independently associated with invasive disease from PNSP⁽⁴³⁾.

Penicillin resistance has been associated with treatment failures in AOM and meningitis^(21,62-64). Due to the increase in PNSP the empirical treatment of bacterial meningitis has changed considerably in Canada during the past decade, with 80% of children receiving empiric vancomycin during 1997-1999, whereas no children received it in 1991-1993. Of children presenting to Canadian tertiary pediatric hospitals, there were no significant differences in mortality or neurologic sequelae (including hearing loss) between those infected with PNSP and penicillin sensitive pneumococci (Dr. J. Kellner, Alberta Children’s Hospital, Calgary: personal communication, 2000). A study in the U.S. also suggests that beta-lactam-resistance is not a risk factor for elevated mortality from pneumoccocal infection. Further studies are required to determine if there is any association between penicillin resistance and treatment failure in pneumococcal pneumonia or bacteremia among children^(21,65-67).

Pneumococcal vaccines

Pneumococcal polysaccharide vaccine

Immunity to S. pneumoniae results from the development of protective antibodies to type-specific capsular polysaccharides. The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for individuals >= 2 years of age who are at increased risk for IPD⁽⁶⁸⁾. PPV23 serotypes match 85% to 90% of invasive and respiratory infections in children in developed countries, including Canada^(2,50); however, many of the polysaccharides contained in the vaccine are not immunogenic in children < 2 years of age, and may not be immunogenic for all serotypes until children are >= 5 years of age⁽⁶⁹⁾. In addition PPV23 confers only limited protection to persons with certain underlying illnesses, including HIV and other immunodeficiencies^(70,71). The efficacies of pneumococcal polysaccharide vaccines in children have not been evaluated in clinical trials. A retrospective analysis of U.S. children 2 to 5 years of age with underlying chronic disease (the majority with Sickle Cell Disease) suggests that PPV23 is 63% (95% confidence interval [CI], 8% to 85%) effective against invasive disease by PPV23 serotypes and 95% effective against serotypes included in PPV23 but not in heptavalent conjugate vaccines⁽³⁶⁾. An earlier U.S. study of PPV23 against invasive disease did not demonstrate vaccine effectiveness in children 2 to 10 years of age⁽⁷²⁾. Polysaccharide vaccines have not been demonstrated to reduce mucosal carriage of S. pneumoniae, protect against mucosal infections and otitis media, or limit the spread of resistant strains.

Pneumococcal conjugate vaccines

The poor immunogenicity of polysaccharide vaccines in infants is related to the T cell-independent nature of polysaccharide antigens. Conversion of a polysaccharide to a T cell-dependent antigen by covalent coupling to an immunogenic protein carrier enhances the antibody response, elicits immune memory and elicits stronger booster responses on re-exposure in infants and young children⁽⁷³⁾. Carrier proteins that have been used in pneumococcal conjugate vaccines include CRM₁₉₇, a mutant non-toxic diphtheria toxin^(74-77), meningococcal outer membrane protein complex (OMP)^(78,79), tetanus toxoid and diphtheria toxoid⁽⁸⁰⁾. Current pneumococcal conjugate vaccine formulations under development include polysaccharides of seven common invasive pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), nine serotypes (with addition of serotypes 1 and 5) and 11 serotypes (further addition of serotypes 3 and 7F).

Preparation(s) used for immunization

The first penumococcal conjugate vaccine licensed in Canada, Prevnar™ (Wyeth-Ayerst Canada Inc.), is composed of the purified polysaccharides of the capsular antigens of seven S. pneumoniae serotypes, individually conjugated to CRM₁₉₇⁽⁸¹⁾. 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 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. NACI will publish information concerning other pneumococcal conjugate vaccines when they become available in Canada.

Storage and handling requirements

Prevnar™ should be stored refrigerated at 2° C to 8° C (36° F to 46° F) as per manufacturer’s package insert. Freezing must be avoided.

Immunogenicity

Healthy infants and children

Pneumococcal conjugate vaccines, containing one to 11 serotypes and various protein carriers are immunogenic in healthy infants^{(74-77,80-82)}. Infants vaccinated with a three-dose primary series beginning at 2 months of age, with doses separated by 4 to 8 weeks develop a three- to 20-fold increase in serum antibodies for vaccine serotypes. These vaccines induced functional antibodies in infants^(73,74,83), together with strong and rapid anamnestic responses upon boosting with conjugate or polysaccharide vaccine, in the 6 to 12 months following the primary series^{(74-77,80,81)}. Toddlers primed with three doses of heptavalent pneumococcal OMP conjugate vaccine (at 12, 15 and 18 months) had a booster response that is greater than those primed with PPV23⁽⁷⁹⁾.

Serum antibody responses to some conjugate vaccine serotypes are substantial after one to two doses while with others consistent responses require the completion of three doses^(75,78,84). The minimum titre of circulating antibody necessary for protection against invasive pneumococcal disease and otitis media has not been determined for any specific serotype. In the California efficacy trial, over 97% of PCV7 recipients achieved antibody levels of >= 0.15 mg/mL for all serotypes after the primary series (2, 4, 6 months) and this correlated with the observed protective efficacy against invasive disease of 97%⁽⁸⁵⁾.

During U.S. clinical studies, PCV7 was administered simultaneously with other routine childhood vaccines: diptheria-tetanus-whole cell pertussis and Haemophilus influenzae type b conjugate vaccine combined (DTP-HbOC) or diptheria-tetanus-acellular pertussis vaccine (DtaP) and H. influenzae type b conjugate vaccine (HbOC), oral polio vaccine (OPV) or inactivated polio vaccine (IPV), Hepatitis B vaccines, Measles, mumps and rubella vaccine (MMR), and varicella vaccine^(75,76,85). The safety experience and vaccine efficacy with PCV7 has led to its use as part of the routine immunization schedule^(12,85).

Children at high risk for invasive pneumococcal disease

Satisfactory safety and immunogenicity of various pneumococcal conjugate vaccines has been demonstrated in children with SCD^(86-89) and HIV infection^(90,91). In a study of 34 infants < 2 years of age with SCD who were vaccinated with PCV7 at 2, 4, and 6 months of age, GMCs of type-specific immunoglobulin G (IgG) antibodies measured by enzyme linked immunoabsorbent assay (ELISA) increased from < 0.1 mg/mL at baseline to > 2.0 mg/mL 1 month after the third dose for all seven vaccine serotypes^(87,88). After administration of PPV23 at 24 months of age, a substantial booster response occurred for all serotypes in the PCV7 vaccine. Serum opsonic activity showed substantial increases after the PPV23 booster for the two serotypes tested (6B and 14). Vernacchio et al, in a study of persons 4 to 30 years of age with sickle cell disease, showed that those who received two doses of PCV7 followed by one dose of PPV23 8 weeks later, developed higher IgG anticapsular polysaccharide antibody titres and functional antibodies for PCV7 serotypes than those who received PPV23 alone. PCV7 did not interfere with the immune response to serotypes present only in the PPV23 vaccine^(86,92).

Small studies by King and colleagues suggest that conjugate pneumococcal vaccines are safe, immunogenic and elicit a higher antibody titre than polysaccharide vaccines in infants and children with HIV. Children with more advanced HIV disease were less likely to respond than children with milder disease, but these differences were not observed after the third dose^(90,91).

Children with recurrent otitis media

Children with frequently recurring otitis media may have an inadequate IgG2 antibody response to S. pneumoniae^(93-97). Small studies have shown that otitis-prone children and those with recurrent respiratory infections develop a higher IgG response with one dose of conjugate pneumococcal vaccine than with polysaccharide vaccine^(96,98). Others have shown that otitis-prone children who mounted a poor IgG2 response after one dose of PCV7 developed good IgG2 titres upon boosting with PPV23⁽⁹⁷⁾.

Aboriginal populations

There are no data on the immunogenicity of PCV7 in Canadian aboriginal populations. A heptavalent pneumococcal conjugate vaccine linked with the OMP of Neisseria meningitidis was administered to Alaska Native, American Indian (i.e., Apache and Navajo), and non-Alaska Native/non-American Indian infants 2, 4, and 6 months of age, with a booster dose at 15 months of age⁽⁹⁹⁾. Response after three primary doses of vaccine was similar among all three groups of infants, except for serotypes 14 and 23F. However, 1 month after the booster dose, IgG antibodies to all seven serotypes increased significantly in all three groups. This study indicated that PCV7 immunogenicity among Alaska Natives and American Indians would likely be similar to the immunogenicity in non-Alaska Natives/non-American Indians. The efficacy of Prevnar™ among American Indians is currently under study⁽¹⁰⁰⁾.

Previously unvaccinated older infants and children

To determine an appropriate schedule for children >= 7 months of age at the time of the first immunization with PCV7, 483 children in four ancillary studies received PCV7 at various schedules⁽⁸¹⁾. Children 7 to 11 months of age at first vaccination received three doses, with the first two doses at least 4 weeks apart and the third dose after the 1-year birthday, separated from the second dose by at least 2 months. Children 12 to 23 months of age received two doses, at least 2 months apart. Children 24 months to 9 years of age received a single dose of PCV7. Geometric mean concentrations of antibodies attained using the various schedules among older infants and children were comparable to immune responses of children, who received three doses of PCV7 with concomitant DTaP in the U.S. efficacy study⁽⁸⁵⁾. A single dose of pneumococcal conjugate vaccine in toddlers 12 to 18 months of age appears to induce functional antibodies and prime for immunologic memory on subsequent boosting with either conjugate or polysaccharide vaccine^(89,101). Another study demonstrated that, in this age group,  two doses of pneumococcal conjugate vaccine induced antibody concentrations for serotypes 6b and 14 that were higher than either polysaccharide or a single dose of conjugate vaccine⁽¹⁰²⁾. These data support the schedule for previously unvaccinated older infants and children who are beyond the age of the infant schedule, but further studies are required to determine whether these schedules provide protection against disease.

Efficacy

The clinical efficacy of the PCV7 has been studied in two large scale double-blind randomized trials conducted in the U.S. and Finland^(55,85). In the California efficacy trial, 37,830 healthy children were randomly assigned to receive either PCV7 (conjugated to CRM₁₉₇) or a control meningococcal C conjugate vaccine at 2, 4, 6 and 12 to 15 months of age, concurrent with other routine childhood vaccines⁽⁸⁵⁾. Study participants were followed to 34 months of age. The efficacy of PCV7 against invasive disease caused by vaccine serotypes was 94% (95% CI, 80% to 99%; p < 0.001) among fully and partially vaccinated children. The efficacy against invasive pneumococcal disease due to any serotype was 89% (95% CI, 74% to 96%; p < 0.001). The efficacy was 73% (95% CI, 3% to 88%) for X-ray confirmed pneumonia with consolidation (>= 2.5 cm), 33% (95% CI, 7% to 52%) for clinical pneumonia with any X-ray evidence of pulmonary pathology and 11% (95% CI, 1% to 21%) for any clinically diagnosed pneumonia. The estimated reduction of all otitis media episodes in the PCV7 group was 7% (95% CI, 4% to 10%), and 20% (95% CI, 4% to 34%) for tympanostomy tube placement. The effectiveness of the vaccine against frequent otitis media, defined as three or more episodes within 6 months or four or more episodes within a year, increased from 9.3% to 22.8% as the frequency of episodes increased. In the analysis of spontaneously draining ears, serotype-specific effectiveness was 64.7% (p = 0.035). In the Finnish efficacy trial, 1,662 infants were randomized to receive either PCV7 (conjugated to CRM₁₉₇) or a control hepatitis B vaccine at 2, 4, 6, and 12 months of age, and tympanocentesis was performed when children presented with symptoms of AOM⁽⁵⁵⁾. Compared to controls, children vaccinated with PCV7 experienced a 6% reduction (95% CI, -4% to 16%) in AOM episodes due to any cause, a 25% reduction (95% CI, 11% to 37%) in all pneumococcal AOM episodes and a 56% reduction (95% CI, 44% to 66%) in AOM due to PCV7 serotypes. In a small subset of children who received PPV23 as the booster at 12 months of age, vaccine efficacy was similar to those who were boosted with PCV7. The efficacy of conjugate pneumococcal vaccines in high-risk populations remains to be determined.
 

Duration of protection

The long-term efficacy of the PCV7 vaccine is unknown, but given that the greatest disease incidence in children occurs in the earliest years of life, it is likely that vaccination during infancy will be effective in reducing the bulk of disease burden. Immunologic memory has been demonstrated 18 months following two or three doses of PCV7 in infants, and <= 20 months following one dose of bivalent pneumococcal conjugate vaccine in children 2 to  3 years of age. The benefits of sequential vaccination with conjugate vaccine followed by PPV23, in providing longer immunity to conjugate vaccine serotypes, needs further study.

Possible benefits to the population

The success of H. influenzae type b (Hib) conjugate vaccine programs is thought to be partly due to the herd immunity effect as a result of reduction in nasopharyngeal (NP) carriage of the organism by vaccinees. To date, studies of children vaccinated with PCVs have shown a reduction in NP carriage of vaccine serotypes; however, almost all studies also show an increase in the carriage of non-vaccine serotypes^(102-106). In the Finnish efficacy trial, there was a 33% increase in the number of AOM episodes due to non-vaccine serotypes⁽⁵⁵⁾. In the California efficacy trial, no evidence of increased risk of disease caused by non-vaccine serotypes was seen, although the effect on NP carriage was not determined⁽⁸⁵⁾. Dagan et al. showed that immunizing day care attendees with pneumococcal conjugate vaccine protected their younger siblings from acquiring vaccine-type pneumococci; especially, resistant pneumococci⁽¹⁰⁷⁾. These findings suggest that herd immunity can be achieved. The prevention of pneumococcal respiratory tract infections through childhood PCV programs may offer a partial solution to reducing antibiotic use and more effective control of antibiotic resistance. The serotypes most commonly associated with antibiotic resistance are covered by PCV7. Preliminary data showed that PCVs result in a reduction in NP carriage of resistant pneumococci in young children, with associated reduction in various respiratory infections and antibiotic use⁽¹⁰³⁾. Ongoing studies after the widespread use PCVs are required to determine the long term effects on colonization, herd immunity, and the effect on antibiotic resistance.

Recommended use of pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine in children

All children <= 23 months of age

PCV7 is recommended for routine administration to all children <= 23 months of age. The recommended schedule for newborns is four doses administered at 2, 4, 6, and 12 to 15 months of age. Children <= 6 months of age should receive the first three doses at intervals of approximately 8 weeks (minimum interval 4 weeks), followed by a fourth dose at 12 to15 months. The first dose should be given no earlier than 6 weeks of age. Children 7 to 11 months of age who have not previously received doses of PCV7 should receive two doses 8 weeks apart (minimum interval 4 weeks), followed by a third dose at 12 to 15 months of age, or at least 8 weeks after the second dose. Children 12 to 23 months old who were not previously immunized should receive two doses at least 8 weeks apart (Table 4).

Children 24 to 59 months of age at high risk for invasive pneumococcal disease

PCV7 is recommended for all children 24 to 59 months of age that are at high risk for invasive pneumococcal infection (Table 5). High-risk children include those with: SCD and other sickling hemoglobinopathies, other types of functional or anatomic asplenia and HIV infection. Although minimal incidence data are available, children with the following medical conditions are also considered to be at higher risk of IPD: conditions causing immunodepression (e.g., primary immunodeficiencies, malignancies, immunosuppressive therapy, solid organ transplant, long term systemic corticosteroids, nephrotic syndrome), and chronic medical conditions (e.g., chronic cardiac and pulmonary disease [such as bronchopulmonary dysplasia and cystic fibrosis, but excluding asthma not requiring systemic steroid therapy], poorly controlled diabetes mellitus, or cerebral spinal fluid leak).

Children with HIV infection should be vaccinated early in the course of illness where possible, to better enable an adequate immune response prior to the onset of immune suppression.

Immunogenicity and safety studies have been conducted using PCV7 among children with SCD^(86-88) and a pentavalent conjugate vaccine among children with HIV infection^(90,91). The efficacy and immunogenicity of PCV7 among children with chronic disease, or who are immunocompromised, has not been evaluated; but, effectiveness is anticipated on the basis of studies conducted in other groups. The recommendation for two PCV7 doses is based on results of an immunogenicity study conducted among SCD patients. The study reported that after one dose of PCV7 the antibody response to serotype 6B was not statistically significant; however, it increased to a statistically significant level after a second dose of PCV7⁽⁸⁶⁾.

There are minimal safety and immunogenicity data regarding the use of PCV7 and PPV23 vaccine in combination, but persons at high risk of invasive pneumococcal disease could potentially benefit from such regimens. Conjugate vaccines may induce improvement of antibody levels and immunologic memory, as well as reduce carriage of vaccine serotypes; whereas, PPV23 is immunogenic and moderately efficacious in persons > 2 years of age and offers better serotype coverage. Limited data suggest that PCV7 vaccinees show a boosting response to several serotypes when subsequently vaccinated with PPV23. The safety, immunogenicity, and efficacy of sequential administration of PPV23 followed by PCV7, and revaccination with PPV23 after immmunization with PCV7 needs further study.

Children with SCD and functional or anatomic asplenia should be given penicillin prophylaxis until they are at least 5 years of age, regardless of vaccination with PCV7. Protective efficacy of PCV7 for children with SCD has not been studied, and the vaccine does not protect against all serotypes causing disease. Peniccillin prophylaxis, however, substantially reduces the risk of invasive pneumococcal infections among SCD patients⁽¹⁰⁸⁾. Oral penicillin V potassium should begin as soon as the diagnosis is made, at a dosage of 125 mg twice a day until 3 years of age, and 250 mg twice a day after 3 years of age. Amoxicillin, bacampicillin or pivampicillin are acceptable alternatives. For children < 6 months of age with congenital asplenia, Escherichia coli is a concern; therefore, trimethoprim/sulfamethoxazole (5 mg TMP/25 mg SMX/kg once a day) is the preferred agent. The duration of prophylaxis is controversial. Most infectious disease experts agree that children diagnosed with SCD or who become asplenic at <= 5 years of age should continue penicillin prophylaxis until 5 years of age. In children who become asplenic at > 5 years of age, prophylactic antibiotics should be given for at least 1 year after splenectomy. Some experts recommend continued prophylaxis throughout childhood and into adulthood, regardless of when the child is diagnosed with the ondition⁽¹⁰⁹⁾.

Aboriginal children from northern communities 24 to 59 months of age

PCV7 should be considered for aboriginal children 24 to 59 months of age living in remote northern communities in Canada. Preliminary data suggest that aboriginals from northern communities (including Nunavut; the Northwest Territories; the Yukon Territory; north coastal Labrador, Nunavik and the Cree Council of James Bay in northern Quebec) have a moderate risk of invasive pneumococcal disease and have a higher risk as compared to non-aboriginals.

There is no specific PCV7 data on Canadian aboriginal populations; however, it was demonstrated that a heptavalent pneumococcal conjugate vaccine was immunogenic among Apache, Navajo, and Alaska Native children⁽⁹⁹⁾. A combined PCV7 and PPV23 regime has been suggested for Alaska Native and American Indian children because in these populations > 50% of invasive serotypes do not match PCV7 serotypes⁽¹²⁾. Further epidemiologic data is required in Canadian aboriginal populations, but preliminary data from northern communities suggest a sub-optimal match of invasive isolates to PCV7 serotypes. For aboriginal children from these populations, a subsequent dose of PPV23 given no earlier than 8 weeks after the last dose of PCV7 may be considered to provide broadened serotype coverage.
 

Healthy children 24 to 59 months of age

PCV7 should be considered for healthy children 24 to 59 months of age, especially children 24 to 35 months of age and those who attend group child care (> 4 hours/week with at least two unrelated children). This recommendation is made on the basis of the moderate risk for IPD among this age group.

PCV7 is safe and immunogenic for healthy children of this age group. Although efficacy data is unavailable, data for children <= 23 months of age are probably relevant. Conjugate pneumococcal vaccines are immunogenic in children >= 2 years of age with recurrent otitis media^(97,98).

If pneumococcal vaccine is to be used among healthy children 24 to 59 months of age, NACI recommends that PCV7 be used. PPV23 is licensed for use among children >= 2 years of age that are at high risk for IPD. A single dose of PPV23 vaccine may provide modest (67%) protection and has a wide spectrum of serotype coverage⁽³⁶⁾. However, the conjugate vaccine has advantages over PPV23, which include induction of immune system memory (possibly resulting in longer duration of protection), reduction in carriage, probable higher efficacy against the the most frequent serotypes that cause invasive disease, and probable effectiveness against non-invasive syndromes (e.g., non-bacteremic pneumonia and AOM). PPV23 vaccine is not recommended for the prevention of AOM given the lack of efficacy data.

Children >= 5 years of age at high risk of invasive pneumococcal disease

Children >= 5 years of age with high-risk conditions who have not previously received pneumococcal vaccines should be vaccinated with PPV23 as per previous NACI recommendations⁽⁶⁸⁾. PCV7 is not contraindicated in children >= 5 years of age with high-risk conditions. When circumstances permit, the conjugate vaccine may be given as the initial dose followed by the polysaccharide vaccine to provide additional serotype coverage and as a booster. If both PCV7 and PPV23 are used, the administration of each should be separated by at least 8 weeks. One revaccination should be considered 3 to 5 years after the first dose for children: a) that are immunocompromised, have SCD, or suffer from functional or anatomic asplenia; and who are also b) < 10 years of age at the time of the first PPV23 vaccination.

Further data are required regarding efficacy of PCV7 among children >= 5 years of age and adults. Limited studies amongst high-risk groups showed that PCV7 is safe and immunogenic among persons 4 to 30 years of age with SCD⁽⁸⁶⁾, and a pentavalent pneumococcal conjugate vaccine is immunogenic among HIV-infected children 2 to 9 years of age⁽⁹⁰⁾. PCV7 has also been shown to be immunogenic among children 2 to 13 years of age with recurrent respiratory infections⁽⁹⁶⁾.

Studies among healthy adults > 50 years of age⁽¹¹⁰⁾ and among HIV-infected adults 18 to 65 years of age⁽¹¹¹⁾ did not demonstrate substantially greater ELISA antibody concentrations after administration of pentavalent pneumococcal conjugate vaccine compared with PPV23. Also, the proportion of invasive pneumococcal isolates covered by PCV7 is only 50% to 60% among older children and adults, in contrast with 80% to 90% coverage by PPV23 among this older group. PCV7 is currently not recommended for use in adult populations and should not be used as a substitute for the PPV23 in older adult populations⁽⁶⁸⁾.

General recommendations for use of pneumococcal vaccines

Children who have experienced invasive pneumococcal disease should receive all recommended doses of pneumococcal vaccine (PCV7 or PPV23) appropriate for their age and underlying condition. The recommended immunization schedule should be completed even if the series is interrupted by an episode of invasive pneumococcal disease.

Contraindications

Hypersensitivity to any component of the vaccine, including diphtheria toxoid, is a contraindication to use of this vaccine.

Precautions

Minor illnesses such as the common cold, with or without fever, are not contraindications to immunization. Moderate to severe illness, with or without fever, is a reason to defer routine immunization with most vaccines; this is to avoid superimposing adverse effects from the vaccine on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of vaccine use. The decision to delay vaccination depends on the severity and etiology of the underlying disease.

Immunization with Prevnar™ does not substitute for routine diphtheria immunization.

Prevnar™ is not contraindicated in children with impaired immune responsiveness due to immunosuppressive therapy, a genetic defect, HIV infection, or other causes; however, such persons may have reduced antibody response to active immunization.

Adverse reactions and safety

PCV7 is generally well tolerated and safe when administered with other childhood vaccines. The majority of the safety experiences with PCV7 come from the California efficacy trial in which > 17,000 infants received > 55,300 doses of PCV7 (conjugated to CRM₁₉₇), along with other childhood vaccines⁽⁸⁵⁾. No serious side effects and, in general, only mild and transient local reactions have been reported in PCV7 recipients^(75,76). Mild injection site reactions were more frequent with PCV7 as compared to acellular pertussis vaccines (DTaP), or the control meningococcal group C conjugate vaccine (MnCC), but there was no significant difference in the rate of more severe local reactions. The incidence of PCV7 injection site reactions were: redness 10% to 14%, swelling 10% to 12%, tenderness 15% to 23%. There were no significant increases in the number or severity of local reactions with any subsequent dose in the series. Infants who received PCV7 were more likely than controls to develop fever >= 38° C (p < 0.04) during the primary series but not after the booster dose. Among PCV7 vaccinees who received concurrent DTaP: 15% to 24% had fever >= 38° C; 1% to 2.5% had fever > 39° C; 44% to 59% had irritability; 17% to 41% had drowsiness; 15% to 25% had restless sleep; 17% to 21% had decreased appetite; 5% to 17% had vomiting; 8% to 12% had diarrhea; and, 0.5% to 1.5% had rash or hives. In general, systemic reactions were greatest after the second or third dose^(81,85). One case of a hypotonic-hyporesponsive episode (HHE) was reported in the efficacy study following PCV7 and concurrent whole-cell pertussis vaccine (DTP). Two additional cases of HHE were reported in earlier studies, and these also occurred in children who received PCV7 concurrently with DTP^(75,76). Rennels reported prolonged and unusual crying in three children who received PCV7 and DTP, compared with one child who received the control vaccine and DTP⁽⁷⁵⁾.

In the California efficacy study there was no significant difference in overall number of emergency room visits, within 30 days of vaccination, by PCV7 recipients as compared to controls (1,188 vs. 1,169 visits, p = 0.679); although, visits for breath holding was significantly more common in PCV7 recipients (no controls vs. five PCV7 recipients, p = 0.031). Cellulitis was more common in controls (seven controls vs. one PCV7 recipient, p = 0.039). There were no significant differences between PCV7 recipients and controls for outpatient visits for allergic reactions/hives, asthma, wheezing, shortness breath, or breath holding within 3 days of any dose. PCV7 recipients were less likely to present to outpatient clinics with seizures (11 PCV7 recipients vs. 23 controls, p = 0.041)⁽⁸⁵⁾.

PCV7 recipients were less likely than controls to be hospitalized within 60 days of a vaccine dose (3.0% vs 3.4%, p = 0.047). In children who received concurrent DTP, hospitalizations for febrile seizures were more common in the pneumococcal vaccine group than in controls. In those who had received DTaP concomitantly, there was no such difference (four PCV7 recipients vs. five controls, p = 0.76). There was no clustering of febrile seizures within the 3-day period after receipt of vaccine in either group of children. Elective admissions (including ventilator tube placement) occurred more commonly in the control group (116 controls vs. 87 PCV7 recipients, p = 0.043).

There were 32 deaths observed in the California efficacy trial study population; of which, 11 occurred in PCV7 recipients (four sudden infant death syndrome [SIDS] and seven with clear alternative cause), and 21 occurred in the control group (eight SIDS, 12 with clear alternative cause and one SIDS-like death in an older child). The incidence of SIDS deaths in PCV7 vaccinees (0.2 case per 1,000 children) was actually lower than the age- and season-adjusted expected rate observed in the State of California during 1996 and 1997 (i.e., 0.5 per 1000 children )^(81,85).

Vaccine administration

Prevnar™ is administered intramuscularly as a 0.5 mL dose, according to the manufacturer’s instructions in the product monograph and the recommended schedules in Tables 4 and 6.

Based on expert opinion it is recommended that, if necessary or convenient, Prevnar™ may be safely given with PENTACEL™ (Aventis Pasteur) or QUADRACEL™ (Aventis Pasteur), hepatitis B, MMR vaccines, at separate sites and with separate syringes at a single visit. Although there are no safety, immunogenicity, or efficacy data on the concurrent administration of Prevnar™ with PENTACEL™ or QUADRACEL™, there are safety data regarding the interaction of Prevnar™ with other combinations of vaccines. During clinical trials, the concurrent administration of PCV7 with DTP-HbOC or DTaP and HbOC, OPV or IPV, and hepatitis B vaccines was found to be safe and has not been found to meaningfully impair the immune response to other vaccines or PCV7^{(75,76,81,85)}. Data on the immunogenicity of MMR and Varicella  when administered concurrently with PCV7 are not available, although live vaccines given concomitantly with inactivated vaccines generally show satisfactory immune response.

Public health issues, limitations of knowledge and areas for future studies

Close monitoring of disease trends and long-term vaccine safety will be high priorities for public health organizations and healthcare providers. Post-licensure surveillance will be necessary to detect: changes in disease trends and the epidemiologic impact of PCV7; changes in serotype distribution including any increase in disease caused by serotypes not contained in PCV7; changing trends in antimicrobial resistance and antibiotic use; and, potential effects of PCV7 on carriage and herd immunity. Surveillance of vaccine coverage and close monitoring of long-term vaccine safety will be critical to monitor the impact or success of any vaccination program.

The decision to include a new vaccine in the routine immunization schedule for infants is made by provincial/territorial health  authorities and a cost-effectiveness, or cost-utility, analysis is central to the decision making process. A cost-effectiveness analysis of pneumococcal vaccination was performed in the U.S.⁽²⁸⁾, while an economic analysis of the routine immunization of infants with PVC7 and catch-up program in Canada is ongoing. The acceptability of the vaccine by healthcare professionals and the public, and the feasibility of vaccine program delivery are factors that should also be determined prior to decisions on the introduction of a vaccine program.

To determine the most effective use of PCV7, further studies are required that include the following:

• the optimal infant schedule, including evaluations of the effectiveness of fewer doses;
• the safety and immunogenicity of pneumococcal conjugate vaccines given concurrently with PENTACEL™ or QUADRACEL™, the combination vaccines commonly used in Canada;
• the safety and effectiveness of new combination vaccines that include PCV7, and other routine vaccines for children in order to improve program delivery and increase acceptability;
• the optimal schedule among persons > 2 years of age at high risk for invasive disease and the benefits of combining pneumococcal conjugate vaccine and PPV23;
• the safety, immunogenicity, efficacy, and potential role of pneumococcal conjugate vaccines, alone or in combination with PPV23, among adults at high risk for pneumococcal infection;
• the duration of protection conferred by PCV7 and the potential need for revaccination with PCV7, or PPV23, after primary vaccination;
• the identification and definition of the immune system markers that correlate most with clinical protection, in order to facilitate evaluation and licensure of new vaccines against pneumococcal infection;
• the development of new pneumococcal vaccine technologies (e.g., using conserved pneumococcal proteins as antigens), and novel routes of vaccine delivery including intranasal and oral routes.

Acknowledgements

NACI gratefully acknowledges assistance in the preparation of this statement from: Dr. A. Bell, State of Alaska Health Department, Anchorage; Dr. P. De Wals, Université de Sherbrooke, Sherbrooke; Dr. L. Jetté, Laboratoire de santé publique du Québec, Ste-Anne-de-Bellevue; Dr. J. Kellner, Alberta Children’s Hospital, Calgary; Dr. A. McGeer, Mt. Sinai Hospital, Toronto; Dr. G. Petit, MSc Candidate, Université de Sherbrooke, Sherbrooke; Dr. D. Scheifele, University of British Columbia, Vancouver; M. Lovgren, National Centre for Streptococcus, Edmonton.

References
 

* Members: Dr. V. Marchessault (Chairperson), Dr. A. King (Executive Secretary), J. Rendall (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, A. Zierler.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. V. Lentini (DND),Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. R. Massé (CCMOH), K. Pielak (CNCI), Dr. J. Salzman (CATMAT), Dr. L. Samson, (CPS), Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC), Dr. A. McCarthy (CIDS).

Ex-Officio Representatives: Dr. L. Palkonyay (BGTD).

† This statement was prepared by Dr. Theresa W.S. Tam and approved by NACI.

[Canada Communicable Disease Report]