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Invasive Pneumococcal Infections in Canadian Children, 1991–1998: Implications for New Vaccination Strategies

  1. David Scheifele1,
  2. Scott Halperin1,
  3. Louise Pelletier2,
  4. James Talbot3, and
  5. Members of the Canadian Paediatric Society/Laboratory Centre for Disease Control Immunization Monitoring Program, Active (IMPACT)a
  1. 1Canadian Paediatric Society, Health Canada, Ottawa, Ontario
  2. 2Laboratory Centre for Disease Control, Health Canada, Ottawa, Ontario
  3. 3National Centre for Streptococcus, Edmonton, Alberta, Canada
  1. Reprints or correspondence: Dr. David Scheifele, Room L427, British Columbia's Children's Hospital, 4500 Oak St., Vancouver, BC, Canada V6H 3N1 (dscheifele{at}cw.bc.ca).

  1. Presented in part: 2d Vaccine Research Conference, National Foundation for Infectious Diseases, Bethesda, Maryland, March 1999 (abstract P11).

 
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Abstract

We reviewed 2040 consecutive cases of invasive pneumococcal infection that were seen at 11 pediatric centers across Canada during 1991–1998 to determine if such infections could be prevented by new conjugate vaccines. Isolates from 1528 cases were serotyped. Most cases (61.5%) occurred in patients aged >2 years. Underlying medical conditions were present in 23.2% of case patients. Serotypes in the 7-valent conjugate vaccine matched isolates as follows: 85.8% of tested isolates from children aged 6 months to 5 years, but significantly fewer isolates in younger and older children; 72.9% of isolates from non-healthy children, but 83.9% of isolates from previously healthy children; and 95.4% of isolates with high-level penicillin resistance, but only 72.7% of those with intermediate-level resistance. Significant natural variation in the proportion of isolates matching 7-valent vaccines occurred from year to year and among centers. New conjugate vaccines have great potential but their effectiveness and limitations require ongoing study.

Infections with Streptococcus pneumoniae (pneumococcus) are an important cause of morbidity and death among children [1–3]. Manifestations range from focal infections of the respiratory tract to bloodstream-invasive infections. The latter most often affect young children [2, 3] and those with various chronic conditions [3, 4]. Recent emergence of resistance to penicillin and other antibiotics [5–10] adds to the challenge of treating pneumococcal infections.

Although prevention of pneumococcal infections is desirable, the 23-valent polysaccharide vaccine has limited potential because of poor immunogenicity in young children [11]. Its use is limited to children aged >24 months with conditions predisposing them to invasive infection [12–14]. New pneumococcal polysaccharide-protein conjugate vaccines [15, 16] can induce protective T lymphocyte-dependent antibody responses from children aged 2 months and are well-tolerated [15]. A vaccine containing protein-conjugated polysaccharides from 7 common serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) was 97% effective in protecting young children in California against invasive infections with these serotypes [17]. This study also demonstrated reductions in the frequency of pneumonia and otitis media in vaccine recipients in comparison with their frequency among children in a control group. To cope with differences in common serotypes between invasive and noninvasive infections and between countries, products with nine components (including types 1 and 5) or 11 components (also including types 3 and 7F) are being developed [15].

Since only a limited number of the 90 pneumococcal serotypes [18] can feasibly be included in a conjugate vaccine for children [15], vaccine formulations must be based on extensive epidemiological data for the target populations. In 1993 we undertook a nationwide epidemiological study of invasive pneumococcal infections in Canadian children. This article presents our findings that pertain to new vaccination strategies.

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Methods

The survey was conducted by the 11 pediatric centers of the Canadian Paediatric Society (CPS) / Laboratory Centre for Disease Control Immunization Monitoring Program, Active (IMPACT) [19]. These academic centers are located from coast to coast, account for ∼85% of the tertiary care pediatric beds in Canada, and manage >90,000 inpatient admissions annually. Surveillance commenced at 10 centers early in 1993 and extended retrospectively to 1 January 1991 (at 9 centers) and prospectively to 30 June 1998. Both phases were initiated simultaneously and used the same case-finding strategies, case definition, and report forms. The 11th center contributed cases from January 1995.

The case definition required isolation of S. pneumoniae from a normally sterile site by the laboratory of a reporting center. Outpatients, inpatients, and patients with hospital-acquired infections were eligible for inclusion.

To find cases, the IMPACT nurse monitor at each center regularly visited the wards and microbiology laboratory, conferred with infection control nurses, and searched hospital records for specified discharge diagnosis codes. Outpatient cases were identified from laboratory records. The ICD-9 [20] separation codes searched were the following: 038.2 (pneumococcal bacteremia), 320.1 (pneumococcal meningitis), 481 (pneumonia, pneumococcal), and 041.2 (pneumococcal, other).

Case summaries, abstracted from the hospital medical record, included the patient's age and sex; their prior health, including any underlying condition; the extent of the current infection; the sources of positive cultures; and the outcome. Case reports were scrutinized at the IMPACT data center in Vancouver. Dual data entry by different operators was performed, with preprogrammed consistency checks. One investigator (D.W.S.) reviewed all underlying conditions to ensure their consistent categorization in the database.

Bacterial isolates from 1991–1993 were available because all centers except 1 routinely stored sterile-site isolates. All centers did so during prospective surveillance. At intervals, centers forwarded isolates (1 per case) to the National Centre for Streptococcus in Edmonton, Alberta, where they were serogrouped and typed by Quellung reaction with use of the Danish nomenclature (antisera purchased from the Statens Seruminstitut, Copenhagen) [10]. All isolates were screened for nonsusceptibility to penicillin with use of a 1-µg oxacillin disk; those with zone diameters ≤19 mm were tested further by broth microdilution to determine the MIC of penicillin G [21]. Isolates were defined as having intermediate-level resistance with MIC of 0.1–1.0 µg/mL and high-level resistance with MIC ≥2.0 µg/mL. Susceptibility to other antibiotics was not assessed.

Case reports and reference laboratory data were collated at the data center. Cases were retained in the analysis if a stored isolate was unavailable or nonviable. Software used was dBase 3 (Ashton-Tate, Torrance, CA) and SAS/Stat (SAS Institute, Cary, NC). Proportions were compared with the Fisher's exact test (2-tailed).

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Results

During the 7.5 years surveyed, 2040 eligible cases were reported. Annual case totals ranged from 231–317. For the 9 centers that participated throughout the survey period, no temporal trend in case prevalence was evident.

Clinical data. Males outnumbered females 1.4 to 1. The male preponderance existed at all ages and centers and with all syndromes and major serogroups.

The age distribution among the cases is shown in figure 1: 61.5% of cases occurred before the patient's second birthday, 26.1% occurred in patients aged 2–5, and 12.3% occurred in patients aged 6–16 (16 is the upper age limit for admissions at most of the centers in the study). Of 195 cases recorded during the first 6 months of life, 99 (4.9% of all cases) occurred in patients aged 0–3 months.

Figure 1
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Figure 1

Age distribution among children aged ≤18 years with cases of invasive pneumococcal infection in Canada, January 1991 to June 1998. Inset shows additional data concerning patients aged <2 years.

Before developing pneumococcal infection, 76.7% of the children had been considered healthy, whereas the rest had a significant medical condition (table 1). Only 16 had received pneumococcal polysaccharide vaccine. The proportion of children with an underlying condition increased with age, from 15.9% of children aged <2 years, to 30.4% of children aged 2–5 years, and 44.5% of children aged >5 years (P < .001). Conditions known to predispose to invasive pneumococcal infection [12–14] were reported in 16.9% of case patients, and other underlying conditions were present in 6.4%.

Bacteremia occurred alone in 38.4% of cases and with otitis media or sinusitis in an additional 20%. Pneumonia with a positive culture of blood or pleural fluid was documented for 20.8% of children. Pneumonia accounted for a larger proportion of cases in children aged >2 years than in younger children (30.8% vs. 14.6%, respectively; P < .001) and was the only syndrome with a marked difference in importance by age. Meningitis was reported in 16.7% of cases and was confirmed by CSF culture in 14.1%. Hypotensive shock was noted at the time of admission in 54 children (2.6%), about half of whom had underlying illnesses.

In total, 71.2% of children were treated in the hospital and 28.8% were managed as outpatients. The proportion of children admitted to the hospital increased with age, from 66.7% of those aged <2 years to 70.5% of those aged 2–5 years and 87.3% of those aged 6–16 years (P < .01). Those with underlying conditions were more likely to be admitted to the hospital at any age. Admission rates were higher among children with underlying conditions than among healthy children: 26.8% higher among children aged 0–1 year, 20.1% higher among those aged 2–5 years, and 9.4% higher among those aged 6–16 years.

Of 1906 patients for whom the outcome was known, 39 (2.0%) died of the reported infection. The case-fatality rate was 6.5% for those with meningitis and 44% for those presenting with shock. Eleven patients who died (28.2%) were aged ≤6 months, reflecting a case-fatality rate for this age group of 4.3%, compared to 1.7% for older children (P = .014). For those aged >6 months, the case-fatality rate among previously healthy children was 0.9%, whereas for those with underlying illnesses it was 3.8% (P < .001). Twenty-one patients who died (53.8%) had an underlying illness, 17 of which were illnesses known to predispose to pneumococcal infection, including cardiopulmonary disease (10 patients) and sickle cell disease (2).

Microbiological data. Up to 30 June 1998, a total of 1538 isolates had been tested at the national reference center. The proportion of isolates forwarded for testing was similar for all centers. The reference center identified 78 isolates with intermediate resistance to penicillin (5.1% of tested isolates) and 26 with high-level resistance (1.7%), for an overall rate of penicillin-nonsusceptibility of 6.8%.

Serotype data were available for 1528 isolates, representing 74.9% of cases. In total, 38 serogroups or serotypes were encountered, the frequency distribution of which is presented in figure 2. Nine isolates were not typeable. No statistically significant differences in serotype distribution were observed between the sexes or racial groups. Children aged 6 months to 5 years had the highest proportion of serotypes matched by 7-valent vaccines (85.8%; table 2). The lower proportion of matches among children aged 0–5 months (65.7%) was mainly due to the recovery of fewer type-14 isolates, whereas the lower proportion of matches among children aged >5 years (63.6%) (table 2) was mainly due to the reduced prevalence of types 14 and 6B. Across all age groups, the match with 7-valent vaccine serotypes was better in previously healthy children than in those with underlying conditions (table 2). This rate difference was greatest among those aged 2–5 years (13.6%; P < .001) and nonsignificant in those aged 6–23 months.

Figure 2
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Figure 2

Serotype distribution of 1528 pneumococcal isolates recovered from children aged <16 years in Canada, January 1991 to June 1998.

The proportion of isolates belonging to 7-valent vaccine serotypes varied year to year, from 77.6% to 86.6% (P = .02), with no evident trend, and among centers, from 71.4% to 88.0% (P < .001). No differences were found over large geographic areas; e.g., in western Canada, 80.6% of isolates matched vaccine types, and in eastern Canada, 81.7% did.

The match between 7-valent vaccine serotypes and serotypes encountered with various infection syndromes varied. Proportions of matches were as follows: for patients with isolated bacteremia, 83.4%; for those with meningitis, 78.9%; and for those with pneumonia, 78.3%. Cases in which shock occurred matched least well (74.4%) but included only 43 typed isolates. Among 27 typed isolates from fatal cases with any syndrome, 20 (74.1%) matched the 7-valent vaccine.

As indicated in table 2, the proposed 9-valent formulation would improve coverage minimally over the 7-valent one in any age group, whereas the 11-valent formulation would provide a modest increase in coverage in children aged <6 months or 6–16 years, largely because of the greater prevalence of serotype 7F at these ages, but the overall increase is only 3.7%.

Of 55 serotyped isolates with intermediate penicillin resistance, 40 (72.7%) were types included in the new conjugate vaccines, with no difference between 7-, 9-, and 11-valent products. Of 22 typed isolates with high-level penicillin resistance, 21 (95.4%) were types included in all 3 formulations, the exception being serotype 19A.

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Discussion

This case series demonstrates that invasive pneumococcal infections cause significant morbidity in children in Canada. The series is noteworthy for its national scope, extended duration, comprehensiveness of case-finding, linkage of clinical and microbiological information, and reference laboratory characterization of all isolates available for testing. Participating centers have undefined referral populations and cannot calculate disease incidence rates. Both outpatient and inpatient cases were included for a more balanced perspective, but the hospital-based experience may not accurately reflect the pattern of invasive infection in communities because of referral biases. Nevertheless, the breadth and duration of this series permit some useful insights for new vaccination programs.

As in previous reports [22–24], the preponderance of cases in males was striking. Because sex is so consistently important in disease risk, it would be relevant to look for any sex-related effects on vaccine immunogenicity and, ultimately, on protection. In studies of conjugate vaccines to date, sex-specific immune responses were not mentioned.

The age distribution of invasive infections in our study is consistent with that of other reports [3, 22–26] and has several implications for vaccine programs. The prominent peak early in childhood (figure 1) means that infant-based programs could rapidly reduce case totals and care costs. However, ∼10% of cases occur in the first 6 months of life, and these will not all be preventable. Some cases occur before the vaccination series is scheduled to begin and could be prevented only through maternal immunization.

Isolates causing illness during the first 6 months are less well matched by 7-valent conjugate vaccines than in later months, limiting what is achievable by active immunization. Insight is still limited as to when, during the primary series of doses, protection becomes evident. Serum antibody responses to some conjugate vaccine serotypes are substantial after administration of 1–2 doses, but with others, consistent responses require completion of a 3-dose regimen [27–29].

In the California study [17] of protection after doses at ages 2, 4, and 6 months, no cases were caused by vaccine serotype pneumococci in partially vaccinated children, a finding that suggests an early effect of vaccination. The study did not include enough subjects to calculate vaccine-induced protection by month of age, nor could it predict the consequences of delayed completion of the 3-dose series, relatively common with other primary immunizations. However, if widespread infant vaccination reduces carriage of vaccine serotypes in populations, this could benefit nonprotected infants. Observations on the effects of vaccination on colonization rates with vaccine serotypes are limited but encouraging [30–32].

It is noteworthy that 23% of the case patients in this series, as in recent reports from the United States [3, 33] and Canada [34], had an underlying illness. Among these children, 75% had conditions known to predispose to invasive pneumococcal infection, and 25% had various other chronic medical conditions (table 1). The proportion of cases with an underlying illness increased with age, reaching nearly half among those aged >5 years. Such children were more likely to be admitted to the hospital, increasing care costs.

Table 1
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Table 1

Preexisting medical conditions in children with invasive pneumococcal infection.

The vulnerability of chronically ill children has important implications for new vaccination programs. Most immediate is that vaccine performance in such children is largely unknown. Prelicensure studies to date, including the California vaccine efficacy trial [17], have generally been limited to healthy children. Satisfactory immunogenicity of certain conjugates has been demonstrated in persons with sickle cell disease [35] or immune dysfunction of various types, including HIV infection [15]. A related consideration is that children with underlying conditions were less often infected with pneumococci of serotypes included in 7-valent vaccines than were healthy children (table 2). A similar effect of underlying illness on serotypes causing invasive infection was recently reported among Finnish children by Eskola et al. [25].

Table 2
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Table 2

Proportions of serotyped pneumococcal isolates matched by 7-, 9-, and 11-valent conjugate and 23-valent polysaccharide vaccines, by age group and prior health status of recipients.

The true potential of new vaccines in general populations will not be known until their effectiveness is measured in postmarketing studies. The information gap is sufficient to warrant planning such studies as a high priority.

The 7-valent vaccine formulation appropriately anticipates the pneumococcal types that cause most invasive disease in Canadian children aged 6 months to 5 years (table 2). No significant differences in common serotypes are evident between case isolates from Canada and from the United States [10, 36–38]. Within Canada, there were no regional differences in common serotypes. Over the 7.5 years of this study, no progressive changes in any of the common serotypes were evident. However, during a recent 16-year survey in the United States [37] of invasive isolates from children, the proportions of the total number of isolates that were common types 14 and 18C changed progressively, with the former increasing and the latter decreasing. Over longer periods, more substantial changes in serotype distribution can occur, such as the decline of types 1–3 from most common to infrequent in the United States between 1935 and 1974 [39].

Pneumococcal immunization programs beyond infancy will require careful reconsideration regarding scope and vaccine choice. Relatively few cases occur in children aged >5 years, when nearly half the cases involve patients with underlying conditions and the isolates recovered are less well matched by 7-valent vaccine than at younger ages. Better coverage is possible with 11- and 23-valent vaccines, but their protective efficacy rates await comparison. In our series and others [3], many patients had underlying conditions not recognized as predisposing to pneumococcal infection (table 1), including a range of neurological conditions. Additional information on the relative risk of infection with these and other conditions will be helpful in refining programs.

Part of the rationale for implementing new vaccination programs will be to curb infections caused by antibiotic-resistant strains. In this series the 7-valent formulation matched almost all isolates we encountered with high-level penicillin resistance but only three-quarters of isolates with intermediate-level resistance. Nine- and 11-valent vaccines offered no better coverage. Similar coverage matches have recently been reported for invasive isolates collected from across Canada [10] and from children in the United States [37, 38]. The limited match with isolates of intermediate penicillin resistance means that new vaccines can provide only a partial remedy to the problem of antibiotic resistance.

In the preceding discussion of serotype matches with 7-valent vaccines, we considered only the actual vaccine constituents, but the possibility of some cross-protection exists, primarily between 6B and 6A and between 19F and 19A [40, 41]. If cross-protection with these serotypes were 100%, the proportion of preventable cases in our series would increase by 2.6% for 6A and 2.7% for 19A. Vaccine efficacy data for humans are not yet sufficient to clarify any actual cross-protection rates.

As new vaccination programs are established, it will be important to determine if serotypes included in new vaccines are replaced by other serotypes as common causes of invasive infection. Our data support the need for such surveillance programs to be large-scale and long-term if such trends are to be accurately assessed, because significant natural variation in the proportion of isolates matching 7-valent vaccines occurred from year to year and among centers. The latter likely reflects differences in case mix, especially the proportion of patients having underlying conditions. Interannual variation has been reported in South Africa but not in the United States [42] and could reflect sample size effects.

In summary, the new 7-valent conjugate vaccine has considerable potential to reduce invasive pneumococcal infections in children, but important information gaps remain. Surveillance is complicated by natural variations in serotype prevalence with time, place, age group, and prior health status.

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IMPACT Participants

IMPACT investigators and participating centers included the following: Dr. Scott Halperin (IWK Grace Health Center, Halifax, Nova Scotia); Dr. Robert Morris (Dr. Charles A. Janeway Child Health Center, St. John's, Newfoundland); Dr. Pierre Déry (Centre Hospitalier Universitaire de Québec [Pavilion CHUL], Quebec); Dr. Marc Lebel (Hôpital Ste-Justine pour les enfants, Montréal, Quebec); Dr. Elaine Mills (Montreal Children's Hospital, Quebec); Dr. Noni MacDonald (Children's Hospital of Eastern Ontario, Ottawa, Ontario); Drs. Ron Gold and Elaine Wang (Hospital for Sick Children, Toronto, Ontario); Dr. Barbara Law (Manitoba Children's Hospital, Winnipeg, Manitoba); Drs. Taj Jadavji and James Kellner (Alberta Children's Hospital, Calgary, Alberta); Dr. Wendy Vaudry (Health Sciences Centre, Edmonton, Alberta); Dr. David Scheifele (British Columbia's Children's Hospital, Vancouver, British Columbia); Drs. Victor Marchessault and Gilles Delage (CPS Liaisons, Ottawa); Drs. Phillipe Duclos, Robert Pless and Daniel Kertesz (LCDC Liaisons, Ottawa); and Dr. John Waters (Alberta Health Liaison, Edmonton).

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Acknowledgments

We gratefully acknowledge the expert assistance provided by the IMPACT nurse monitors and staff of the IMPACT data center, CPS Secretariat, and the National Centre for Streptococcus. Dr. Dorothy Moore and Dr. James Kellner provided helpful editorial assistance.

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Footnotes

  • ↵a Participating members of IMPACT are listed at the end of the text.

  • Financial support: IMPACT is funded by the Laboratory Centre for Disease Control, Ottawa, and Alberta Health, Edmonton. Additional grants were provided by Wyeth Lederle Vaccines and Pediatrics, Rochester, New York; Pasteur Mérieux Connaught, Toronto, Ontario; and Merck Frosst Canada, Kirkland, Quebec.

    Approval for this study was obtained from the clinical research review board of each participating center.

  • Received September 7, 1999.
  • Revision received December 14, 1999.
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References

  1. ↵
    1. Musher DM
    . Infections caused by Streptococcus pneumoniae clinical spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis 1992;14:801-9.
    FREE Full Text
  2. ↵
    1. Jacobs NM,
    2. Lerdkachornsuk S,
    3. Metzger WI
    . Pneumococcal bacteremia in infants and children: a 10-year experience at the Cook County Hospital with special reference to the pneumococcal serotypes isolated. Pediatrics 1979;64:296-300.
    Abstract/FREE Full Text
  3. ↵
    1. Kaplan SL,
    2. Mason EO,
    3. Barson WJ,
    4. et al
    . Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 1998;102:538-45.
    Abstract/FREE Full Text
  4. ↵
    1. Wong WY,
    2. Overturf GD,
    3. Powers DR
    . Infection caused by Streptococcus pneumoniae in children with sickle cell disease: epidemiology, immunologic mechanisms, prophylaxis, and vaccination. Clin Infect Dis 1992;14:1124-36.
    Abstract/FREE Full Text
  5. ↵
    1. Scheifele D,
    2. Gold R,
    3. Marchessault V,
    4. Talbot J
    ; members of the LCDC/CPS IMPACT group. Penicillin resistance among invasive pneumococcal isolates at 10 children's hospitals, 1991–1994. Can Commun Dis Rep 1996;22:157-62.
    Medline
    1. Campbell GD,
    2. Silberman R
    . Drug-resistant Streptococcus pneumoniae. Clin Infect Dis 1998;26:1188-95.
    Abstract/FREE Full Text
    1. Butler JC,
    2. Hofmann,
    3. Cetron MS,
    4. et al
    . The continued emergence of drug-resistant Streptococcus pneumoniae in the US: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System. J Infect Dis 1996;174:986-93.
    Abstract/FREE Full Text
    1. Low D
    1. Simor AE,
    2. Louie M
    ; the Canadian Bacterial Surveillance Network, Low D. Canadian national survey of prevalence of antimicrobial resistance among clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 1996;40:2190-3.
    Abstract/FREE Full Text
    1. Doern GV,
    2. Pfaller MA,
    3. Kugler K,
    4. Freeman J,
    5. Jones RN
    . Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North America: 1997 results of the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis 1998;27:764-70.
    Abstract/FREE Full Text
  10. ↵
    1. Lovgren M,
    2. Spika JS,
    3. Talbot JA
    . Invasive Streptococcus pneumoniae infections: serotype distribution and antimicrobial resistance in Canada, 1992–1995. Can Med Assoc J 1998;158:327-31.
    Abstract/FREE Full Text
  11. ↵
    1. Douglas RM,
    2. Paton JC,
    3. Duncan SJ,
    4. Hansman DJ
    . Antibody response to pneumococcal vaccination in children younger than 5 years of age. J Infect Dis 1983;148:131-7.
    Abstract/FREE Full Text
  12. ↵
    Committee on Infectious Diseases, American Academy of Pediatrics. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove, IL: American Academy of Pediatrics; 1997. p. 417.
  13. National Advisory Committee on Immunization. Canadian immunization guide. 5th ed. Ottawa: Health Canada; 1998. p. 140-3.
  14. ↵
    Advisory Committee on Immunization Practices. Prevention of pneumococcal disease. MMWR Morb Mortal Wkly Rep 1997;46:1-24.
    Medline
  15. ↵
    1. Eskola J,
    2. Anttila M
    . Pneumococcal conjugate vaccines. Pediatr Infect Dis J 1999;18:543-51.
    CrossRefMedlineWeb of Science
  16. ↵
    1. Siber GR
    . Pneumococcal disease: prospects for a new generation of vaccines. Science 1994;265:1385-7.
    FREE Full Text
  17. ↵
    1. Black SB,
    2. Shinefield H,
    3. Ray P,
    4. et al
    . Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Francisco). Washington, DC: American Society for Microbiology; 1999. Efficacy of heptavalent conjugate pneumococcal vaccine (Wyeth Lederle) in 37,000 infants and children: impact on pneumonia, otitis media and an update on invasive disease—results of the Northern California Kaiser Permanente efficacy trial [abstract 1398].
  18. ↵
    1. Henrichsen J
    . Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol 1995;33:2759-62.
    Abstract/FREE Full Text
  19. ↵
    1. Morris R,
    2. Halperin S,
    3. Dery P,
    4. et al
    . IMPACT monitoring network: a better mousetrap. Can J Infect Dis 1993;4:194-5.
  20. ↵
    World Health Organization (WHO). Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death. 9th ed. Geneva: WHO; 1997.
  21. ↵
    National Committee for Clinical Laboratory Standards [NCCLS]. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 4th ed. Wayne, PA: NCCLS; 1997. Approved standard; NCCLS document M7-A4.
  22. ↵
    1. Davidson M,
    2. Parkinson AJ,
    3. Bulkow LR,
    4. Fitzgerald MA,
    5. Peters HV,
    6. Parks DJ
    . The epidemiology of invasive pneumococcal disease in Alaska, 1986–1990: ethnic differences and opportunities for prevention. J Infect Dis 1994;170:368-76.
    Abstract/FREE Full Text
    1. Dagan R,
    2. Englehard D,
    3. Piccard E
    ; the Israeli Pediatric Bacteremia and Meningitis Group. Epidemiology of invasive childhood pneumococcal infections in Israel. JAMA 1992;268:3328-32.
    Abstract/FREE Full Text
  24. ↵
    1. Kertesz D,
    2. DiFabio JL,
    3. Brandileone MCC,
    4. et al
    . Invasive Streptococcus pneumoniae infection in Latin American children: results of the Pan American Health Organization Surveillance Study. Clin Infect Dis 1998;26:1355-61.
    Abstract/FREE Full Text
  25. ↵
    1. Eskola J,
    2. Takala AK,
    3. Kela E,
    4. Pekkanen E,
    5. Kalliokroski R,
    6. Leinonen M
    . Epidemiology of invasive pneumococcal infections in children in Finland. JAMA 1992;268:3323-7.
    Abstract/FREE Full Text
  26. ↵
    1. Shapiro ED,
    2. Austrian R
    . Serotypes responsible for invasive Streptococcus pneumoniae infections among children in Connecticut. J Infect Dis 1994;169:212-4.
    Abstract/FREE Full Text
  27. ↵
    1. Rennels MB,
    2. Edwards KM,
    3. Keyserling HL,
    4. et al
    . Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in US infants. Pediatrics 1998;101:604-11.
    Abstract/FREE Full Text
    1. Kayhty H,
    2. Ahman H,
    3. Ronnberg PR,
    4. Tillikainen R,
    5. Eskola J
    . Pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. J Infect Dis 1995;172:1273-8.
    Abstract/FREE Full Text
  29. ↵
    1. Ahman H,
    2. Kayhty H,
    3. Tamminen P,
    4. Vuorela A,
    5. Malinoski F,
    6. Eskola J
    . Pentavalent pneumococcal oligosaccharide conjugate vaccine Pnc CRM is well-tolerated and able to induce an antibody response in infants. Pediatr Infect Dis J 1996;15:134-9.
    CrossRefMedlineWeb of Science
  30. ↵
    1. Dagan R,
    2. Muallem M,
    3. Melamed R,
    4. Leroy O,
    5. Yagupsky P
    . Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J 1997;16:1060-4.
    CrossRefMedlineWeb of Science
    1. Dagan R,
    2. Melamed R,
    3. Muallem M,
    4. et al
    . Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J Infect Dis 1996;174:1271-8.
    Abstract/FREE Full Text
  32. ↵
    1. Mbelle N,
    2. Heubner RE,
    3. Wasas AD,
    4. Kimura A,
    5. Chang I,
    6. Klugman KP
    . Immunogenicity and impact on nasopharyngeal carriage of a nonvalent pneumococcal conjugate vaccine. J Infect Dis 1999;180:1171-6.
    Abstract/FREE Full Text
  33. ↵
    1. Levine OS,
    2. Farley M,
    3. Harrison LH,
    4. et al.
    ; for the Active Bacterial Core Surveillance Team. Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America. Pediatrics 1999;103:e28.
    Abstract/FREE Full Text
  34. ↵
    1. McGeer A,
    2. Green K,
    3. Landry L,
    4. Talbot J,
    5. Goldenberg E
    ; the Toronto Invasive Bacterial Diseases Network. Assessing the potential impact of vaccination programs on invasive pneumococcal disease: data from population-based surveillance. Can J Infect Dis 1999;10 Suppl A:24-6.
  35. ↵
    1. Vernacchio L,
    2. Neufeld EJ,
    3. MacDonald K,
    4. et al
    . Combined schedule of 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal vaccine in children and young adults with sickle cell disease. J Pediatr 1998;133:275-8.
    CrossRefMedlineWeb of Science
  36. ↵
    1. Scott JAG,
    2. Hall AJ,
    3. Dagan R,
    4. et al
    . Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in 7000 episodes of invasive disease. Clin Infect Dis 1996;22:973-81.
    Abstract/FREE Full Text
  37. ↵
    1. Butler JC,
    2. Breiman RF,
    3. Lipman HB,
    4. Hofmann J,
    5. Facklam RR
    . Serotype distribution of Streptococcus pneumoniae infections among pre-school children in the US, 1978–1994: implications for development of a conjugate vaccine. J Infect Dis 1995;171:885-9.
    Abstract/FREE Full Text
  38. ↵
    1. Butler JC
    . Epidemiology of pneumococcal serotypes and conjugate vaccine formulations. Microb Drug Resist 1997;3:125-9.
    MedlineWeb of Science
  39. ↵
    1. Finland M,
    2. Barnes MW
    . Changes in occurrence of capsular serotypes of Streptococcus pneumoniae at Boston City Hospital during selected years between 1935 and 1974. J Clin Microbiol 1977;5:154-66.
    Abstract/FREE Full Text
  40. ↵
    1. Yu X,
    2. Gray B,
    3. Chang S,
    4. Ward JI,
    5. Edwards KM,
    6. Nahm MH
    . Immunity to cross-reactive serotypes induced by pneumococcal conjugate vaccines in infants. J Infect Dis 1999;180:1569-76.
    Abstract/FREE Full Text
  41. ↵
    1. Robbins JB,
    2. Austrian R,
    3. Lee C-J,
    4. et al
    . Considerations for formulating the 2d-generation pneumococcal capsular polysaccharide vaccine, with emphasis on the cross-reactive types within groups. J Infect Dis 1983;148:1136-59.
    FREE Full Text
  42. ↵
    1. Sniadack DH,
    2. Schwartz B,
    3. Lipman H,
    4. et al
    . Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children: implications for vaccine strategies. Pediatr Infect Dis J 1995;14:503-10.
    MedlineWeb of Science
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  1. Clin Infect Dis. (2000) 31 (1): 58-64. doi: 10.1086/313923
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