Expected benefits of pneumococcal vaccination in Canadian infants and children < 5 years old

1 March 2006

Volume 32

Number 05

Introduction

Streptococcus pneumoniae (pneumococcus) is an important cause of childhood disease in Canadian children. The bacteria commonly colonize the upper respiratory tract and occasionally spread into the blood or into neighbouring tissues, resulting in invasive pneumococcal disease (IPD), including bacteremia, meningitis, and bacteremic pneumonia, or non-invasive pneumococcal disease, including pneumonia, sinusitis, and otitis media. The groups most commonly affected are the elderly, the immunocompromised, specific ethnic groups, and young children, particularly those < 2 years of age 1,2. In Canada, it has been estimated that for a cohort of Canadian children followed from 6 months to 9 years of age, the cumulative risk of pneumococcal meningitis is 1 in 5,000, for pneumococcal bacteremia it is 1 in 500, and for pneumonia caused by pneumococcus it is 1 in 203. In June 2001, the first pneumococcal conjugate vaccine (PCV) was approved for use in children in Canada. In previous clinical trials, the heptavalent vaccine (PCV7; Prevnar®,Wyeth Canada, Inc.) demonstrated promising efficacy and safety for the prevention of IPD in children as young as 2 months4. In addition, the vaccine was beneficial in reducing the frequency of pneumonia, otitis media, and placement of ventilatory tubes4,5. In 2002 the National Advisory Committee on Immunization (NACI) made recommendations for the use of this vaccine in all children < 2 years of age as well as particular recommendations for children aged 2 to 5 years at moderate to high risk of IPD1. The recommended 4-dose schedule for vaccinating newborns is at 2, 4, 6, and 12 to 15 months of age. As of January 2006, all provinces and territories will have added this vaccine to their routine childhood vaccination programs. The objective of this report is to review the significance of S. pneumoniae-induced disease in Canadian infants and children < 5 years of age, with particular attention to the expected benefits of vaccination according to post-marketing data.

Methods

The databases Pubmed and Web of Science were searched, as were specific Canadian journals, including the Canadian Journal of Infectious Diseases and the Canadian Journal of Public Health, for relevant references published after 1995. For the search, pneumococc* and vaccine were used as keywords. The number of references was limited by the addition of specific terms (conjugate, infant, and Canadian) into the search.

Results and Discussion

Pneumococcal disease in Canadian children

Incidence

S. pneumoniae is a leading cause of bacterial disease in Canada. In a Canadian coast-to-coast retrospective study from 1991 to 1998, 2,040 records from cases of IPD in children ≤ 18 years of age from 11 pediatric centres were examined for epidemologic trends⁶. Male children were affected more often than female (1.4 to 1), and the overall risk of disease decreased with age. Children < 3 years accounted for 71% of the total cases (29% were children < 12 months old, 32% between 12 and 23 months, and 10% from 24 to 35 months). In a related study, the average cumulative risk of IPD in these same cities among children in the first 5 years of life was determined to be 1 in 460, with a range of 1 in 732 in Calgary to 1 in 271 in Vancouver⁷. The incidence rates of S. pneumoniae disease before PCV7 became available have been estimated for a cohort of 340,000 Canadian children followed from 6 months to 9 years of age using provincial databases, ad hoc surveys, and previously published data (Table 1)³. There are estimated to be over 1 million cases of acute otitis media (AOM) (approximately 200,000 caused by pneumococcus) and 1.8 million physician visits for AOM (approximately 360,000 for pneumococcus) for children < 5 years of age in Canada each year. In addition, there are over 20,000 myringotomies with insertion of ventilation tube (MVT) (not all attributed to pneumococcus) performed each year in these children^1,3.

Table 1. Incidence rates of Streptococcus pneumoniae-associated diseases for a cohort of Canadian children as estimated by Petit ³

High-risk groups and risk factors

Besides young age, there are additional risk factors that predispose children to IPD, which NACI has summarized in Table 2¹. Approximately 25% of children with IPD have an underlying illness. In addition to immunocompromised patients, other groups at increased risk of IPD include Aboriginals, children with cochlear implants, and children who attend day-care^8-11. Reasons for the increased risk among Aboriginals are likely multifactorial and may include crowded homes and the low rate of breastfeeding¹². Children who have received cochlear implants before 6 years of age are also at higher risk of meningitis⁹. Associated risk factors include a particular model of implant and inner ear malformations in conjunction with cerebrospinal fluid leaks. Children who attend group day-care have also been identified to be at increased risk of IPD and AOM^9,10. The higher risk may be associated with increased antibiotic usage, poor hygiene, crowding, and increased viral respiratory infections supporting a likely environment for S. pneumoniae promotion and transfer^13,14.

S. pneumoniae vaccines and post-licensure effectiveness

Pneumococcal vaccination in Canadian children

There are over 90 known serotypes of S. pneumoniae as decided by chemical and antigenic differences in the virulence determining polysaccharide capsule. The seven capsular serotypes that are contained in the vaccine are the most prevalent invasive serotypes in North American children and will provide the most protection against IPD in infants and young children15. PCV7 contains serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F16. These correspond with the most common serotypes isolated from IPD in children in Canada6,17. Because serotypes of the same serogroup may produce cross protection, immunization may result in broader protection than against the seven vaccine serotypes18. For example, serotype 6B in the vaccine may stimulate protection against serotype 6A as well as against 6B. In addition to complete four-dose PCV7 vaccination protocols, PPV23 boosters are still recommended in Canada for children at high risk, especially those with chronic illness, to increase the spectrum of serotypes and to increase the immune response(1;2). PPV23 booster is also recommended for Aboriginal children after full vaccination with PCV7, for similar reasons. The common serotypes isolated in IPD in Northern Canadian Aboriginals include serotype 119, which is not contained in PCV7. PPV23 is a fundamental component of pneumococcal vaccination in high-risk children and should not be overlooked in light of new provincial and territorial PCV7 programs.

Table 2. Children at high risk of invasive pneumococcal infection - Canada ¹

PCV7 post-marketing experience in the United States

In February 2000, PCV7 vaccine was licensed in the United States for routine immunization of infants and young children. Since the introduction of the vaccine, many state and multiregional studies have shown a dramatic decline in IPD among young children^20-25. Kaplan et al. reported that in eight children's hospitals the rate of IPD among children ≤ 24 months dropped by 58% in 2001 and 66% in 2002 when compared with the average rate from 1994 to 2000²⁴. Excluding non-vaccine serotypes (NVS), IPD dropped by 63% in 2001 and 77% in 2002. In a multistate study,Whitney et al. reported a 69% (p < 0.001) reduction in IPD and 78% (p < 0.001) reduction in VS-specific IPD in children < 2 years of age for the year 2001 compared with the mean rate for 1998 and 1999²⁵. In a recent Centers for Disease Control and Prevention (CDC) release, the authors report that the rate continues to decline, showing a 94% reduction in VS-specific IPD among children < 2 years of age for the year 2003 compared with 1998 and 1999 ²⁶. Reductions in AOM and MVT have also been found²⁷. Poehling and colleagues²⁰ reported a 6% incidence reduction in cases of AOM from all causes in Tennessee and a 20% decrease in AOM in upstate New York in 2001-2002 relative to the baseline established in the few years prior to routine administration of PCV7. In addition to the dramatic reduction in IPD, racial disparities in the risk of IPD among blacks and whites have declined considerably since the introduction of PCV7^28,29. Using data from the CDC's Active Bacterial Core Surveillance (ABCs), post-licensure incidence rates were compared with pre-licensure rates in five Tennessee counties²⁸. In 1999, the incidence among black children was significantly greater than among white children, at 340.2 versus 163.7 per 100,000 children-years (p < 0.001). By 2002, the rates had dropped to 57.4 and 39.6 per 100,000 children-years respectively and were no longer significantly different. Blacks had a lower vaccine coverage rate than whites (31.2% versus 47.6%). Analysis of ABCs data for seven states showed similar findings²⁹. Overall incidence rates for pre-vaccination years 1998 to 1999 were 439.5 and 133.0 per 100,000 children-years among black and white children of < 2 years of age respectively (black to white ratio of 3.3:1). Post-vaccination rates were 48.0 and 30.3 per 100,000 children-years among black and white children respectively (black to white ratio of 1.6:1).

Vaccine safety was evaluated from data collected by the Vaccine Adverse Event Reporting System, a passive surveillance database in the United States³⁰. From February 2000 through February 2002 (the first 2 years after licensure), descriptive reports about adverse effects after vaccination were collected. Minor symptoms and signs reported were fever, injection site reactions, fussiness, rashes, and urticaria. The proportion of reports describing serious events (death, immune-mediated events, and vaccine failure) was low and similar to that for other vaccines.

Outcomes of vaccination on herd effect

A potential indirect impact of vaccination is the reduction of disease in non-vaccinees or herd protection³¹. Evidence suggests that herd protection to pneumococcal disease occurs as a result of reduced nasal carriage of VS of S. pneumoniae following vaccination, resulting in reduced transmission and spread of the pathogen ³². Reduction in nasal carriage after vaccination has been seen in many pneumococcal conjugate vaccine studies, including those involving day-care attendees^33-36. In all studies, VS pneumococcal nasal carriage decreased in PCV vaccinees compared with controls. In the previously described multistate study by Whitney et al., comparable reductions in IPD were found among adults as in children, suggesting a reduction in S. pneumoniae transmission to unvaccinated people from vaccinated children²⁵. The rate of IPD in 2001 compared with 1998 and 1999 dropped significantly (p < 0.05) by 32% in adults 20 to 39 years of age, by 8% in adults 40 to 64 years, and by 18% in adults ≥ 65 years. Reductions in adult incidence rates were also seen among both blacks and whites in the ABCs Tennessee study²⁸.

An Israeli 9-valent PCV study demonstrated significant reductions in carriage rates for both the VS pneumococci and antibiotic-resistant pneumococci among children vaccinated between 12 and 35 months of age14,36,37. Compared with controls, the carriage rate for vaccine serotypes was reduced by 68%, 60%, 43%, and 29% for the age groups 15 to 23, 24 to 35, 36 to 47, and > 48 months respectively. Pneumococcal carriage rates of the non-enrolled younger siblings of the day-care attendees were also measured14. Nasopharyngeal cultures were performed monthly until the siblings turned 18 months or were enrolled into daycare. The proportion of cultures positive for VS S. pneumoniae among the siblings of the vaccinated attendees and the siblings of the control attendees (21% vs. 34%, respectively; p < 0.05) mirrored those of the day-care attendees (13% vs. 21% respectively; p < 0.05).

Effect of vaccination on antimicrobial resistance

Another potential effect of pneumococcal vaccination is reduction in antimicrobial-resistant S. pneumoniae. Long-term followup of the Northern California clinical trial has demonstrated a reduction in the proportion of isolates highly resistant to penicillin recovered from IPD in young children from 15% in 2000 (at the start of routine vaccination) to 5% in the first half of 2003³⁸. Although only a few years have passed since the introduction of routine vaccination, a multiregional study in the United States has shown a significant decrease in the proportion of IPD isolates that are penicillin resistant, from a peak of 44% in 2000 and 45% in 2001 down to 33% in 2002 (2001 vs. 2002, p = 0.018)²⁴.

It is believed that vaccination with multivalent PCV reduces the rate of antimicrobial-resistant isolates by two primary mechanisms. First, the vast majority of pneumococcal isolates resistant to penicillin, cefotaxime, trimethoprim-sulfamethoxazole, and multiple drugs are of the serotypes 6A, 6B, 9V, 14, 19F, 19A, and 23F^31,36,39. These are serotypes covered by PCV7, and therefore vaccination will lead to a reduction of the nasal carriage of these resistant isolates. Without colonization of the nasopharynx, these S. pneumoniae will not proliferate or spread to other individuals ³⁶. Second, vaccination decreases the frequency of pneumococcal disease, leading to reduced antibiotic usage and antibiotic pressure on the isolates⁴⁰.

Effect of vaccination on serotype replacement

One theoretical consequence of vaccination is the exchange of the target pathogen with replacement pathogens.With respect to S. pneumoniae, there is limited evidence to suggest that vaccination may result in increased nasal colonization by NVS^33,36,41. In a follow-up to the large-scale Northern California clinical trial, there was no significant increase in the rate of NVS IPD among children < 5 years old³⁸. In the Finnish AOM study, however, there was a 33% increase in the number of cases of AOM caused by NVS among children < 2 years of age who were vaccinated with PCV7 (125 NVS AOM cases out of 1,251 AOM cases from any cause) as compared with the controls (95 NVS AOM cases out of 1,345 AOM cases from any cause)⁵. Similarly, in Kaplan et al.'s study in children's hospitals, a small increase in IPD cases caused by NVS was identified, particularly serogroups 15 and 33, although the overall rate of IPD among children ≤ 24 months dropped substantially following PCV7 introduction in 2001²⁴.

The long-term impact of S. pneumoniae serotype replacement on S. pneumoniae epidemiology and subsequent vaccination strategy remains to be seen.

Hypothesized PCV7 effectiveness in Canada

To date, there have been several unpublished immunogenicity and safety studies on PCV7 performed in Canada. Preliminary results reveal that Prevnar® is safe and results in strong antibody responses to the pneumococcal antigens when given with the other routine vaccines that make up the provincial and territorial routine immunization schedules. The incidence of IPD among Canadian children < 2 years of age is slightly lower than in the United States, but this discrepancy may actually be due to fewer blood culture tests being carried out for febrile illness in Canada and therefore fewer cases of pneumococcal bacteremia being detected^3,7,42. Results from an ongoing surveillance study in Calgary (Calgary Area Streptococcus pneumoniae Epidemiology Research [CASPER], run by Dr. J. Kellner), which is tracking disease incidence and serotypes in Alberta before and after introduction of routine childhood vaccination in 2002, suggests that the vaccine should perform similarly in Canada as it has in the United States. These preliminary results have shown a 62% decrease in IPD incidence among children between 6 and 23 months of age in 2003 compared with the average incidence between 1998 and 2001 (personal communication: Dr. J. Kellner, Alberta Children's Hospital, Calgary, 2005). Although the overall incidence of disease is slightly lower in Canada than the United States, the reduction in incidence of IPD is similar to those reductions reported in the United States^20-25.

The proportion of Canadian S. pneumoniae isolates covered by PCV7 is similar to that of the US isolates⁴. Serotypes isolated from IPD cases in Canadian children during the 1990s were analyzed (6,17,43). In Quebec, 90% and 88% of IPD isolates in children < 2 and < 5 years of age respectively were contained in PCV7⁴³. One Canada-wide study found that 94% and 84% were included in PCV7 for the same age groups respectively⁶. A second Canada-wide study reporting on isolates from children ≤ 5 years found that the vaccine matched 95% of the isolates¹⁷. With regard to antibiotic-resistant pneumococcal isolates found in Canada, different studies have reported the proportions of penicillin- resistant isolates that would have been covered by the serotypes in PCV7^6,17,43,44. These proportions included 94% in children < 2 years, 95% in children ≤ 18 years, and 100% in the general population. The CASPER surveillance showed that in 2003 the proportion of penicillin-nonsusceptible pneumoccocus IPD isolates from children < 16 years of age decreased from previous years. Thus, it is expected that routine vaccination of Canadian children will have a significant impact on the rates of IPD and on antibiotic-resistant pneumococcal disease.

Conclusion

Pneumococcus is a leading cause of bacterial disease in Canadian children. In particular, children < 2 years of age are at highest risk of IPD. Additionally, there are an estimated 200,000 cases of AOM attributed to pneumococcus each year in Canadian children < 5 years of age^1,3. In June 2001, PCV7 was approved for use in children in Canada. With continued vaccination and surveillance, the impact of PCV7 on S. pneumoniae-associated diseases will become more apparent. In addition, further research is necessary to answer some important questions relating to optimal vaccination schedules, serotype replacement, antimicrobial resistance, herd protection, length of immunity, and associated cost-effectiveness.

As of January 2006, all provincial/territorial governments will provide for routine immunization of children with PCV7. Catch-up vaccinations are given by Alberta, Saskatchewan, Manitoba, and Ontario for children < 1 year of age and in Quebec, Yukon, and Nunavut for children < 5 years of age. The results of this review strongly suggest that PCV7 is currently benefiting Canadian children and society as a whole by lowering S. pneumoniae-associated disease. They also suggest that additional gains from herd effects and reduction in antimicrobial resistance will be achieved as more Canadian children aged < 5 years of age are routinely vaccinated with PCV7.

Acknowledgements

We thank Wyeth Canada, Inc. for its support of this project.We are also grateful to Dr. D. Scheifele, BC Children's Hospital, Vancouver, and Dr. S. Deeks, Public Health Agency of Canada, for their critical review of an earlier version of this manuscript and their suggestions.

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Source: CA McClure, PhD, MS, University of Prince Edward Island, Charlottetown, PEI; MW Ford, MSc, Wyeth Canada, Inc., Markham, Ont.; JBWilson, PhD, University of Guelph, Ont.; JJ Aramini, PhD, MSc, University of Guelph, Ontario.