ARCHIVED - Canada Communicable Disease Report

 

Volume 36 • ACS-3
April 2010

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

For readers interested in the PDF version, the document is available for downloading or viewing:

Update on Pediatric Invasive Pneumococcal Disease and Recommended Use of Conjugate Pneumococcal Vaccines (PDF document 30 Pages - 368 kb)

Update on Pediatric Invasive Pneumococcal Disease and Recommended Use of Conjugate Pneumococcal Vaccines

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of 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. People administering the vaccine 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 manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Introduction:

This statement provides an update on the epidemiology of pneumococcal disease since the introduction of Prevnar® (Wyeth Pharmaceuticals), as well as information regarding a newly authorised conjugate vaccine against pneumococcal disease, Synflorix™ (GlaxoSmithKline Inc.). It is anticipated that both pediatric and adult pneumococcal immunization programs will be changing over the next few years, as other vaccines are in development. These new vaccines will be reviewed in one or more additional statements once they are authorised for use in Canada. The 23 valent polysaccharide vaccine will not be discussed in the current statement. Recommendations for its use remain unchanged.

This Statement will:

  • review existing National Advisory Committee on Immunization (NACI) recommendations on the use of conjugate pneumococcal vaccines;
  • update the epidemiology of pneumococcal disease in Canada relevant to the introduction of Synflorix™;
  • provide an update on the conjugate pneumococcal vaccination schedules used in Canada;
  • review information on correlates of protection against pneumococcal disease;
  • provide information on a newly authorised vaccine against pneumococcal disease – Synflorix™; and
  • provide recommendations for the use of Synflorix™

Recommendations:

  1. NACI recommends that Synflorix™ can be used for the prevention of invasive pneumococcal disease in children. (NACI recommendation grade A)
  2. At this time, NACI concludes there is insufficient epidemiologic evidence to make a recommendation for the preferential use of Synflorix™ over Prevnar® for the routine infant immunization program in Canada. (NACI recommendation grade I)
  3. NACI recommends that Synflorix™ can be used for the prevention of invasive pneumococcal disease in children who require protection during outbreaks of S. pneumoniae due to serotypes 1, 5, or 7F. (NACI recommendation grade B)

NACI recommends strengthening surveillance and applied public health research related to serotype-specific pneumococcal disease across Canada.

Methods

The NACI Pneumococcal Working Group reviewed such considerations as the burden of illness of the disease to be prevented and the target population(s), safety, immunogenicity, efficacy, effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall immunization strategy. Literature published since the NACI pneumococcal statement of 2006 was sought by searching PubMed using the terms pneumococcal infections, pneumococcal disease and pneumococcal vaccines. Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy (Tables 6 and 7) were prepared, and proposed recommendations for vaccine use developed. The Working Group chair and PHAC medical specialist presented the evidence and proposed recommendations to NACI. Following thorough review of the evidence and consultation at the NACI meeting in June 2009, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text. PHAC maintains documentation of these processes throughout knowledge synthesis and recommendation development.

Overview of past National Advisory Committee on Immunization recommendations for conjugate pneumococcal vaccine

NACI issued a statement in 2002(1) recommending the addition of the seven-valent conjugate vaccine Prevnar® (PCV-7) to the routine immunization schedule for infants. Addenda to this statement were published in 2003(2) and 2006(3). Currently, vaccination with pneumococcal conjugate vaccine is recommended for the following groups:

  • -all children ≤ 23 months of age
  • -children 24-59 months of age at high risk of invasive pneumococcal disease (IPD); including those who: -attend childcare centers -are of aboriginal origin -have sickle cell disease or other hemoglobinopathies -have functional or anatomic asplenia -have HIV infection or other immunocompromising conditions -have chronic medical conditions -have or are receiving cochlear implants

Epidemiology of Pneumococcal Disease in Canada

The epidemiology of invasive pneumococcal disease (IPD) in Canada before 2001 was summarized in a previous NACI statement(1) This statement will review more recent epidemiology relevant to the introduction of Synflorix™.

Literature review

A total of nine published studies related to the epidemiology of invasive pneumococcal disease in Canada were identified; of these, seven are reviewed below. Two describe outbreaks, and are reviewed in a subsequent section.

A population-based study conducted by the Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) team examined the impact of PCV-7 vaccine on the incidence of IPD using data from 1998 to 2004(4), and reviewed further data from 1998 to 2007(5). In children under 2 years of age, the implementation of routine childhood pneumococcal vaccination in 2002 was associated with an overall reduction in IPD of 79% when comparing pre-vaccine pneumococcal rates (1998-2001) to pneumococcal rates in 2007, and a reduction in IPD due to vaccine serotypes of 94%. In those aged 65 years and over, the rate of IPD due to vaccine serotypes decreased 63% from the pre-vaccine era as compared to data from 2002 to 2004.There was no significant change in the incidence of IPD due to non-vaccine serotypes in any age group.

A study of pneumococcal nasopharyngeal colonization of children in Calgary before and after the implementation of the pediatric vaccination program demonstrated no change in the overall colonization rate, but a shift from colonization due to PCV-7 serotypes to colonization with other serotypes after the implementation of the vaccination program.(6)

Tyrrell et al. (7) report rates of IPD between 2000 and 2006 in the province of Alberta which introduced PCV-7 into its routine childhood immunization schedule in 2002. The overall rate of IPD due to vaccine serotypes decreased by 61% over the 7 year period with the greatest decline being seen in children less than 4 years old. The rate of IPD due to any serotype in children under 2 years declined from 96.7 cases per 100 000 in 2000 to 25.8 cases per 100 000 in 2006.

Bjornson et al. (8) used a retrospective cross-sectional design to compare the incidence of IPD in children 6 to 23 months of age in the 24 months prior to PCV-7 implementation and in the 28 months after the implementation of the vaccine in the Greater Vancouver area. Over this time period, there was a 72.7% decrease (125.5 to 34.1 cases per 100 000 population) in the annual incidence of pediatric IPD in this age group.

Paulus et al. (9) examined IPD surveillance data from British Columbia from 2002 and 2005 as reported through the Integrated Public Health Information System (iPIHS). The overall incidence of reported IPD was 8.3 per 100 000 in 2002, prior to the introduction of PCV-7, compared to 7.8 per 100 000 in the years after introduction of routine pediatric vaccination. However, the overall rate of IPD in children under 5 years of age decreased from 54 per 100 000 per year to 16 per 100 000 per year.

Degani et al. (10) describe data from International Circumpolar Surveillance (ICS). ICS surveillance includes approximately 7% of Canada’s aboriginal population; with 59% of the population being Inuit, First Nations or Métis. Three Canadian regions included in ICS surveillance (Northern Quebec, Nunavut and Northern Labrador) introduced routine infant vaccination programs between 2002 and 2003. For the ICS region as a whole, the incidence of IPD in children under 2 years of age decreased from 38.4 cases per 100 000 in 2001, to 17.3 cases in 2000. The most common serotypes observed were serotypes 1 (30.4%), 8 (8.8%), 14 (7.9%), 4 (6.3%) and 6B (5.8%). No cases of vaccine failure were identified.

A recent publication by Langley et al. (11) highlights the contribution of S. pneumoniae in community-acquired pneumonia and empyema prior to the introduction of pediatric vaccination programs. This article reviewed a total of 251 cases of empyema at eight Canadian pediatric centers from 2000 to the end of 2003, which was prior to the introduction of PCV-7. Most children were previously well (78%) with Aboriginal children representing 18% of all cases. Among 32% of cases with microbiologic etiology determined, just under half (47%) were due to S. pneumoniae, 48% of which were PCV-7 serotypes. Additional serotypes detected include serotypes 1, 3, and 6A.

In summary, current published literature on IPD suggests that in Canadian populations where PCV-7 has been introduced, there has been a substantial decline in the incidence of IPD due to serotypes included in the vaccine. Despite this, there continues to be a significant burden of invasive disease attributable to S. pneumoniae. In order to further characterize this, surveillance data from non-published sources for 2007/2008 were reviewed.

Surveillance data, 2007-2008

In Canada, surveillance data regarding IPD are available from the National Notifiable Disease Reporting System (NDRS), National Centre for Streptococcus (NCS), Toronto Invasive Bacterial Diseases Network (TIBDN), Calgary Streptococcus pneumoniae Research Study (CASPER), Immunization Monitoring Program Active (IMPACT), Institut Nationale de Santé Publique de Québec (INSPQ) and International Circumpolar Surveillance (ICS) (Table 1). Serotyping occurs at one of three laboratories: the National Centre for Streptococcus (NCS) in Edmonton, the Laboratoire de Santé Publique de Québec in Sainte Anne de Bellevue and the TIBDN central study laboratory at the Mount Sinai Hospital in Toronto.


Table 1. Surveillance for invasive pneumococcal disease in Canada
Program Description Strengths Challenges
National Disease Reporting System (NDRS) (12) National passive surveillance system - all of Canada
- all ages
- passive surveillance
- no serotype data
International Circumpolar Surveillance (ICS) (13) Active, prospective, population-based surveillance - detailed epidemiologic data
- all isolates serotyped
- 59% of population is Inuit, First Nations or Metis
- small number of cases
Toronto Invasive Bacterial Diseases Network (TIBDN) (14) Active, prospective population-based surveillance - detailed epidemiologic data
- all isolates serotyped
- limited geographic area (Metropolitan Toronto and Peel region)
Calgary Area Streptococcus pneumoniae Research study (CASPER) (5) Active, prospective population-based surveillance - detailed epidemiologic data
- all isolates serotyped
- limited geographic area (metropolitan Calgary)
Immunization Monitoring Program Active (IMPACT) (15) Active surveillance in 12 tertiary care pediatric centers - 90% of pediatric tertiary care in Canada represented
- detailed epidemiologic data
- all isolates serotyped
- not population-based
Institut National de Santé Publique de Québec (INSPQ) (16) Enhanced, passive laboratory surveillance system; - largest population-based system
- some of isolates serotyped
- mixed active and passive surveillance
- limited epidemiologic data
- single province
National Centre for Streptococcus (NCS) (17) Canada wide reference laboratory for S. pneumoniae - Canada-wide
- population-based for Alberta, and British Columbia
- all isolates serotyped
- passive surveillance
- limited clinical data

Of the Canadian sources of pneumococcal surveillance data, five sources provide information on IPD incidence rates by serotype: NCS for Alberta and British Columbia, INSPQ, TIBDN and ICS. These data are presented in the following two tables. Table 2 outlines the number of cases, and incidence per 100 000 population for the years 2007 and 2008. It considers residual disease caused by the PCV7 serotypes, disease due to additional strains covered by PCV10 and disease caused by all other serotypes, for which there is no currently available conjugate vaccine. Among the five data sources, which together comprise 58% of the Canadian population, the incidence rate of IPD additionally covered by PCV10 ranges from 0 to 3.7 cases per 100 000 for a total of 34 cases in 2007 and 2008. Table 3 presents information regarding cases of IPD among children less than 6 months of age. Four of the 34 cases additionally covered by PCV10 are in this age group, and thus may not be expected to have been directly preventable by vaccination.

Table 2. Incidence (per 100 000) and number of cases of invasive pneumococcal disease by serotype categories among children aged less than 5 years, 2007-08
Region Serotypes in
PCV7
Additional in
PCV10
Other Serotypes
2007
rate n
2008
rate n
2007
rate n
2008
rate n
2007
rate n
2008
rate n
BC * 3.3 (7) 2.3 (5) 1.9 (4) 0.0 (0) 11.9 (25) 9.8 (21)
Quebec * 3.1 (12) 1.0 (4) 2.8 (11) 1.5 (6) 23.0 (89) 27.8 (111)
Toronto * 6.2 (13) 0.0 (0) 0.4 (1) 2.1 (4) 9.6 (20) 12.1 (23)
Alberta 1 1.8 (4) 2.6 (6) 3.7 (8) 0.0 (0) 13.7 (30) 15.8 (38)
ICS 2 * 7.8 (1) 7.8 (1) 0.0 (0) 0.0 (0) 15.6 (2) 85.7 (11)
1Based on number of case-isolates received at the NCS for typing 2 ICS region includes Nunavut, Yukon, North West Territories, Northern Quebec and Northern Labrador * Number of cases with unknown serotypes in children less than 5 years of age were: BC, 2 in 2007 and 4 in 2008; Quebec, 8 in 2007 and 7 in 2008; Toronto/Peel, 2 in 2007 and 5 in 2008; ICS, no cases.

Table 3. Cases of invasive pneumococcal disease by serotype categories among infants ages 0 to 5 months (2007-08)
Region 2007 -
Serotypes in PCV7
2008 -
Serotypes in PCV7
2007 -
Additional in PCV10
2008 -
Additional in PCV10
2007 -
Other Serotypes
2008 -
Other Serotypes
BC* 2 3 1 0 1 2
Quebec* 1 1 2 0 10 12
Toronto* 3 0 0 0 1 1
Alberta1 1 1 1 0 3 8
ICS2* 1 0 0 0 0 1
1 Based on number of case-isolates received at the NCS for typing 2 ICS region includes Nunavut, Yukon, North West Territories, Northern Quebec and Northern Labrador * Number of cases with unknown serotypes in children less than 6 months of age: BC, no cases; Quebec, 1 case; Toronto/Peel, 1 case; ICS, no cases.

Outbreaks

From 2005 to 2008, there was a large outbreak of S. pneumoniae serotype 5 (ST5) that affected British Columbia, Alberta, Saskatchewan and Manitoba(18,19), with 1002 cases reported as of December 31, 2008. The majority of cases were in the adult population; hence this outbreak will not be further described in this statement.

In 2000/2001, an outbreak of acute pneumonia was reported in Nunavut. A total of 84 cases of severe pneumonia were identified between August 2000 and December 2001. All age groups were affected, with the highest rates among children <1 year of age (23 per 1000 population) and those ≥65 years of age (31 per 1000 population). Among those with positive blood cultures, 10 of 11 yielded Streptococcus pneumoniae serotype 1(20,21). A mass immunization campaign for individuals aged >5 years of age was launched using the 23-valent polysaccharide vaccine. Although this intervention was helpful in curbing the outbreak, the outbreak highlighted a need for conjugate vaccines with coverage for serotype 1(22).

Pneumococcal conjugate immunization schedules used in Canada:

Between 2002 and 2006 all provinces and territories introduced the conjugate pneumococcal vaccine into their routine immunization schedules (Table 4).

Table 4. Pneumococcal conjugate immunization schedules by province/territory (January 2009)(23).
Province/Territory Routine Childhood Schedule Date of implementation of routine infant program Catch up programs
(Date of implementation)
British Columbia 2, 4, 12 mos* September 2003 N/A
Alberta 2, 4, 6, 18 mos September 2002 N/A
Saskatchewan 2, 4, 6, 18 mos April 2005 High risk children < age 2 years (Sept 2002), expanded to high risk children < 5 years (Oct 2003)
Manitoba 2, 4, 6, 18 mos October 2004 N/A
Ontario 2, 4, 6, 15 mos January 2005 N/A
Quebec 2, 4, 12 mos* December 2004 All children < 5 years of age (Dec 2004)
New Brunswick 2, 4, 6, 18 mos January 2005 N/A
Nova Scotia 2, 4, 6, 18 mos January 2005 N/A
Prince Edward Island 2, 4, 6, 18 mos July 2005 N/A
Newfoundland and Labrador 2, 4, 6, 18 mos January 2005 High risk children including aboriginal children under age 2 years living in isolated communities (Jan 2003)
Northwest Territories 2, 4, 6, 18 mos January 2006 N/A
Yukon 2, 4, 6, 18 mos June 2005 N/A
Nunavut 2, 4, 6, 15 mos September 2002 N/A
* From 2003 to December 21, 2006, a four dose schedule was used for all infants. From January 2007 on, the recommended schedule was a three dose schedule for healthy infants, and a four dose schedule for medically high risk infants.

National immunization coverage data for pneumococcal conjugate vaccine are limited. The National Immunization Coverage Survey (NICS) is a national survey done every two years to determine immunization coverage rates at 2 years of age, 7 years of age and at 17 years of age. The most recent cycle of the National Immunization Coverage Survey (NICS) occurred in 2006, thus including children born during 2004. At that time, only three of thirteen jurisdictions (British Columbia, Alberta and Nunavut) had implemented a routine pediatric conjugate pneumococcal vaccination program. Therefore, nationally representative coverage rates are not currently available. Reported coverage rates in specific areas range from 64% in the first cohort of children eligible for vaccine in British Columbia(24) to 92% in the Capital Health region of Alberta in 2002(25) and 95-99% in Calgary in 2004/5(6).

Correlates of Protection:

After the authorization of Prevnar®, it was recognized that, for serotypes included in both Prevnar® and new pneumococcal vaccines, the new vaccines would need to be licensed based on non-inferiority to Prevnar® or to existing vaccines. However, both the multiplicity of antigens and limitations in what is understood about serologic correlates of protection against pneumococcal disease make such assessments extremely difficult. The World Health Organization (WHO) has thus engaged in a long-term project to develop guidance on the serological criteria for authorization of new pneumococcal vaccines(26). Serologic responses can by measured either by ELISA (enzyme-linked immunosorbent assay) or by OPA (opsonophagocytic assay). It is generally believed that OPA titers are a better reflection of protection against pneumococcal disease; however, OPA assays are technically more complex, more expensive, and more difficult to standardize.

In 2000, a WHO consultation established a well-characterized ELISA protocol as a reference standard for laboratories evaluating serologic responses to pneumococcal vaccines. In 2003, as a result of two further consultations, and analyses of data from the three randomized controlled trials of pneumococcal conjugate vaccines(27), WHO recommended that(28):

  • the primary measure to compare serotype specific immune responses to pneumococcal vaccines should be the concentration of IgG, measured by the standard ELISA (without pre-adsorption with serotype 22F), in serum obtained 4 weeks after completion of a primary series;
  • the reference threshold for all serotypes should be 0.35 mcg/ml;
  • the percentage of responders (i.e. those with an antibody concentration above 0.35 mcg/ml) should be the criterion to determine non-inferiority;
  • non-inferiority for each of the serotypes in the registered vaccine is desirable, but not an absolute requirement for authorization; and
  • additional data supporting the induction of functional (opsonophagocytic) antibody, and the existence of immunologic memory should be required for registration.

The recommendations stressed that the defined threshold antibody concentration did not necessarily predict protection in an individual patient and that the threshold is defined for invasive disease and therefore may not be applicable to other diseases such as pneumonia and otitis media. The report also emphasized the limitations inherent in the assumptions behind this threshold definition. These assumptions are that protection:

  • relates directly to IgG as measured by ELISA;
  • is best measured by antibody in serum one month after the primary series;
  • protection increases in a stepwise fashion at the threshold, but the protection does not further increase as antibody concentration increase above the threshold; and
  • is similar across different serotypes and populations.

In 2007, a WHO workshop recommended a strategy for the development of a “gold standard” OPA assay which will require several years to establish.({World Health Organization, 2007 51 /id}) In 2008, a WHO/Health Canada consultation reviewed new data regarding serologic correlates of protection(29) , to determine whether and how information accrued since 2003 should be incorporated into authorization guidelines. One important change since 2003 is that manufacturers have continued to develop ELISA assays, so that all are now using modifications of the standard assay, and “bridging" results, by comparing their new assays results to standard assay results using reference sera. The most important difference is the addition of 22F pre-adsorption with 22F reference sera. Both Wyeth and GSK use this step to increase assay specificity; however, they report significantly different effects of this step on ELISA end-points. Because of these differences in results, GSK studies report percentage achieving an ELISA response of 0.20 mcg/ml as the correlate of protection used in studies of Synflorix™ where Wyeth uses a threshold of 0.35mcg/ml.(30) The 2008 consultation re-affirmed that the 2003 WHO recommendations provide a solid basis for evaluating pneumococcal conjugate vaccines, however, given the above, it is recommended that:

  • work should be continued on OPA assay standardization, and care should be taken that ongoing studies are available to validate the relationship and maintain a link between immunogenicity and efficacy against IPD for conjugate vaccines;
  • the reasons why the cut-off of 0.35mcg/ml should not be regarded as a definitive correlate of protection should be clarified.
  • in addition to ELISA thresholds, comparisons of new conjugate vaccines should take into account the OPA thresholds, geometric mean antibody measurements by both OPA and ELISA , and reverse cumulative distribution curves. All should be presented for review.
  • the limitations of the predictive capacity of pre-authorization immunogenicity data strongly support the need for post-marketing studies.

Synflorix™

Vaccine Composition:

Synflorix™ is a capsular polysaccharide conjugate vaccine against Streptococcus pneumoniae which contains 10 capsular antigen from serotypes; 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F. Eight of these are conjugated to protein D derived from non-typeable Haemophilus influenzae, while 18C and 19F use tetanus toxoid and diphtheria toxoid respectively as carriers. All conjugates are adsorbed to aluminum phosphate.

The vaccine is provided in prefilled single dose syringes with a LUER lock slip tip. Latex is contained within the syringe component.

Immunogenicity:

Clinical trials to assess the immunogenicity of a primary vaccination series include over 3300 infants(31). A randomized controlled trial done in Poland, Finland and France compared the immunogenicity of Synflorix™ and Prevnar® in a 2, 3 and 4 month primary immunization schedule. Using an ELISA assay bridged to the WHO standard, and measuring antibody 1 month after completion of the primary series, non-inferiority of Synflorix™ was demonstrated for 5 of 7 serotypes included in Prevnar® (Table 5). Serotypes 6B and 23F were shown to have an inferior response in children who received Synflorix ™ compared to infants who received Prevnar® (66% vs 79% and 81% vs 94% meeting the pre-defined EIA or ELISA threshold, respectively). For all serotypes included in both vaccines, geometric mean titers were significantly lower among infants who received Synflorix™. Among infants receiving Synflorix™, > 97% met the pre-defined threshold for antibody response to serotypes, 1, 5, and 7F the three serotypes included in the Synflorix ™ vaccine but not in Prevnar®.

Table 5. Immunogenicity trial comparing response to Synflorix™ with Prevnar®: Percentage of subjects achieving an ELISA = 0.2 mcg/ml
Antibody SYNFLORIX™ PREVNAR® Difference in %= 0.2mcg/ml
(PREVNAR® minus SYNFLORIX™)
N % N % % 96.5%CI
Anti-4 1106 97.1 373 100 2.89 1.71 4.16
Anti-6B 1100 65.9 372 79.0 13.12 7.53 18.28
Anti-9V 1103 98.1 374 99.5 1.37 -0.28 2.56
Anti-14 1100 99.5 374 99.5 -0.08 -1.66 0.71
Anti-18C 1102 96.0 374 98.9 2.92 0.88 4.57
Anti-19F 1104 95.4 375 99.2 3.83 1.87 5.50
Anti-23F 1102 81.4 374 94.1 12.72 8.89 16.13

Further immunogenicity data are available from 4 randomized controlled trials comparing Synflorix™ to Prevnar® (32-35) These studies confirm the results of the previous trial. Using the defined WHO criteria and ELISA assays, vaccine responses to Synflorix™ are non-inferior to Prevnar® for serotypes 4, 9V, 14, 18C and 23F, inferior to Prevnar® for serotypes 6B and 23F. Over 95% of subjects achieved the correlate of protection for serotypes 1,5, and 7F. Geometric mean antibody concentrations achieved for serotypes included in both vaccines are consistently higher for Prevnar® compared than Synflorix™ for serotypes other than 19F.

In a smaller sub-sample of children in which OPA responses were measured using the GSK OPA assay, the proportion of children achieving OPA titers of >1:8 was not significantly different for Synflorix™ and Prevnar®. In general, OPA titers achieved were higher for serogroup 19 following administration of Synflorix™, higher for serotypes 23F, 14 and 6B following Prevnar®. No difference was observed between the two vaccines for serotypes 18C, 9V and 4(32).

Two-dose schedule:

A single published study has compared antibody responses after two doses of either Synflorix™ or Prevnar®.(35) The number of infants who attained threshold ELISA antibody concentration of 0.2mcg/ml after a 2 dose schedule was within a similar range for the two vaccines. Statistical analysis was not done on these differences and the relevance to clinical protection is unknown.

Efficacy:

No efficacy data is currently available for Synflorix™ for its primary indications against invasive pneumococcal disease.

A randomized controlled trial was conducted in the Czech Republic and Slovakia to assess efficacy against acute otitis media of an 11-valent investigational vaccine similar to Synflorix™.(36) A total of 2489 infants were immunized using a 3, 4, 5, and 12-15 month schedule. The 11-valent vaccine used in this trial contained all of the serotypes in Synflorix™ as well as serotype 3 and had all serotypes conjugated onto carrier protein D (derived from non-typeable Haemophilus influenzae). Whereas Synflorix™ does not contain serotype 3 and has 8 of 10 serotypes conjugated to protein D carrier, with serotype 18C conjugated to tetanus toxoid and 19F conjugated to diphtheria toxoid. Serotype 3 was removed from Synflorix since it failed to provide protection against AOM; and because serotype 3 did not demonstrate a booster response. This study showed a 33% (95% CI, 20-45%) reduction in cases of clinically significant acute otitis media. Vaccine efficacy against first episodes of acute otitis media due to pneumococcal vaccine serotypes was 52.6% (95% CI 35-65.5%) with an additional reduction in infection due to non-typeable H. influenzae of 35.3% (95% CI 1.8 – 57.4%).

A single study has assessed the serologic correlates of protection against AOM.(37) This study calculated a predicted vaccine efficacy against AOM due to serotypes 6B, 6A, 19F, and 23F for generic populations with different antibody levels (measured by ELISA) based on data from the Finnish Otitis Media Vaccine Trial. There was a significant association between antibody concentration and protection against otitis media; however, different levels of antibody were associated with protection from different serotypes. All estimated protective levels were considerably higher than 0.35mcg/ml; there was significant predicted protection at 0.5mcg/ml only for serotype 6B. Two other assessments have suggested that antibody levels as measured by ELISA are inversely correlated with protection against nasopharyngeal colonization with S. pneumoniae: again, the concentrations predicted to provide protection were for all serotypes significant greater than the concentrations required for protection against invasive pneumococcal disease.((38),(39))

Vaccine Safety:

Vaccine safety has been assessed in 5 randomized controlled trials assessing the immunogenicity of Synflorix™ and Prevnar®, concomitantly administered with other routine childhood vaccines(40), serious adverse events were reported by 150 of 2996 subjects (5%) in the Synflorix™ groups compared with 44 of 1008 subjects (4.4%) in the Prevnar® groups (P=0.46). Of 194 subjects for whom serious adverse events after primary vaccination studies were reported, 6 were considered by the investigator to be related to vaccination. Four of these occurred after Synflorix™ one with pneumonia, gastroenteritis, and nephrotic syndrome 27 days after dose one; one with febrile convulsions on the day of vaccination with dose two, and two with crying postvaccination on the day of dose) and 2 occurred after Prevnar® (one with irritability and anorexia on the day of the first dose and one with fever of 39.4°C for 1 day after the second dose). Seizures occurred in 11 of 2996 Synflorix™ recipients and 2 of 1008 Prevnar® recipients (P=.54). One death occurred, due to sudden infant death syndrome 16 days after receipt of the second dose of Synflorix™.

In two of three studies, rates of irritability, drowsiness and loss of appetite of any severity in the first three days post-vaccination were 3-11% greater in the Synflorix™ group compared to the Prevnar® group; however, the increase in rate of events graded as severe was much smaller (0.1-4%). There was no difference in rates of any systemic adverse events in the third study, and no difference in rates of fever in any study. There were also no differences in rates of local adverse reactions reported after receipt of Synflorix™ or Prevnar® in any studies, and no differences in rates of local or systemic reactions after booster doses of the two vaccines.

Concomitant administration of vaccine:

Three published reports describe the randomized controlled trials involving co-administration of pneumococcal vaccine with other routine infant immunizations.

Knuf et al.(33) summarized data on responses to primary and booster doses of antigens expected to be given concomitantly with conjugate pneumococcal vaccines, comparing infants receiving vaccines concomitantly with either Synflorix™ or Prevnar®. Vaccines included in at least one study were: DTPa-HBV-IPV/Hib, DTPa-HBV-IPV, DTPw-HBV/Hib, HepB/Hib, Hib-MenC-TT, OPV, IPV, menC-TT and MenC-CRM. Co-administration of Synflorix™ with all vaccines resulted in high levels of seroprotection/seropositivity against all antigens, with no evidence of negative interference on the immune response to any of the co-administered vaccine antigens. Synflorix can also be co-administered with Rotavirus and MMR vaccines (Synflorix Product Monograph)

Wysocki et al.(35) and Bermal et al.(32) describe serotype-specific responses to S. pneumoniae for infants receiving either Synflorix™ or Prevnar® (primary or booster) concomitantly with the antigens contained in both conjugate pneumococcal vaccines. There is no evidence that any of the concomitantly administered antigens interfered with the immune response to Synflorix™.

Interchangeability:

There is currently no data available on the interchangeability of Synflorix™ and Prevnar® for a primary vaccine series.

The interchangeability of Synflorix™ and Prevnar® for the booster dose given between 12 and 15 months of age has been assessed by immunogenicity. Infants who received Prevnar® for their primary series were randomized to receive a booster dose of either Synflorix™ or Prevnar® between 12 and 18 months of age.(32,34,35) After booster doses, the percentage of infants achieving antibody levels of ≥ 0.2mcg/ml was similar between the two groups for serotypes included in both vaccines. However, for these serotypes, geometric mean antibody concentrations were consistently higher after a boost with Prevnar®.

Dose and Schedule:

Synflorix™ is administered as four separate intramuscular injections of 0.5ml. Immunization can be started after six weeks of age up to 2 years of age. The primary vaccine series would be given at 2, 4 and then 6 months of age, with a booster dose between 12 to 15 months of age. It is anticipated that provincial schedules would not differ depending on whether Synflorix™ or Prevnar® is used.

Recommendations:

1. NACI recommends that Synflorix™ can be used for the prevention of invasive pneumococcal disease in children. (NACI recommendation grade A).
- Based on available immunogenicity data showing that Synflorix™ meets established criteria, it is likely this vaccine will be effective in preventing invasive pneumococcal disease in children due to included serotypes.

2. At this time, NACI concludes there is insufficient epidemiologic evidence to make a recommendation for the preferential use of Synflorix™ over Prevnar®for the routine infant immunization program in Canada. (NACI recommendation grade I).
- At this time, the use of Prevnar® is supported by multiple randomized controlled trials of clinical efficacy, as well as more than a decade of experience establishing effectiveness both in individuals and populations. The same level of epidemiologic evidence is not yet available for Synflorix™.
- Synflorix™ meets established criteria but is less immunogenic than Prevnar® for some serotypes included in both vaccines. Specifically, Synflorix™ is inferior to Prevnar® in WHO defined primary immunogenicity outcomes for serotypes 6B and 23F. The clinical significance of these differences for individual protection against invasive pneumococcal disease or herd immunity is unknown.
- Synflorix™ includes additional antigens from serotypes 1, 5 and 7F that are not present in Prevnar®. Protection against infection due to these serotypes may be desirable but invasive disease due to these serotypes is currently uncommon in most jurisdictions in Canada due to these serotypes.
- Synflorix™ also includes antigens that stimulate antibody production against non-typeable Haemophilus influenzae but the clinical or epidemiologic benefit of that is as yet unknown.
- In the current Canadian context, the choice of Synflorix™ or Prevnar® for routine infant immunization will depend upon local epidemiology and other program considerations.

3. NACI recommends that Synflorix™ can be used for the prevention of invasive pneumococcal disease in children who require protection during outbreaks of S. pneumoniae due to serotypes 1, 5, or 7F. (NACI recommendation B)
- Although serotype data are not always routinely available in Canada, prolonged community outbreaks of specific pneumococcal serotypes have been reported in Canada, in which outbreak management teams have used pneumococcal vaccines as a control measure; in outbreaks due to serotypes 1, 5 or 7F, Synflorix™ is the only vaccine likely to be effective for children under the age of 2 years.
4. NACI recommends strengthening surveillance and applied public health research related to serotype-specific pneumococcal disease across Canada.
- The 2007 WHO consultation (26) noted that uncertainties associated with the licensing of conjugate pneumococcal vaccines based on immunogenicity data mandates on-going surveillance and research to monitor vaccine performance; to assess validity of currently recommended serologic correlates of protection; and to identify populations or serotypes for which currently recommended thresholds may not be optimal. - Decisions regarding the on-going use of pneumococcal vaccines in Canada will require detailed and frequently updated regional information regarding serotype specific incidence of invasive pneumococcal disease, both to provide evaluation of the effectiveness of programs, and to monitor natural changes in the epidemiology of invasive pneumococcal disease. Additional information regarding the incidence of other types of infection (empyema, pneumonia, acute otitis media) and vaccine protection against that will also be necessary.

Table 6. Levels of Evidence Based on Research Design

I

Evidence from randomized controlled trial(s).

II-1

Evidence from controlled trial(s) without randomization.

II-2


Evidence from cohort or case–control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.

II-3



Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.

III


Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.


Table 7. Quality (internal validity) Rating of Evidence

Good


A study (including meta-analyses or systematic reviews) that meets all design- specific criteria* well.

Fair


A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known "fatal flaw".

Poor



A study (including meta-analyses or systematic reviews) that has at least one design-specific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.

* General design specific criteria are outlined in Harris (41) .

Table 8. NACI Recommendation for Immunization - Grades

A

NACI concludes that there is good evidence to recommend immunization.

B

NACI concludes that there is fair evidence to recommend immunization.

C


NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization, however other factors may influence decision-making.

D

NACI concludes that there is fair evidence to recommend against immunization.

E

NACI concludes that there is good evidence to recommend against immunization.

I


NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making.


Table 9. Summary of Evidence for NACI Recommendation(s) for Synflorix™:
Evidence for Safety and Reactogenicity - Study Details Evidence for Safety and Reactogenicity - Summary
Study Vaccine Study Design Participants Outcomes Level of Evidence Quality
Chevallier et al 40 . Synflorix™ Combination of 5 randomized controlled trials
-3 primary vaccination studies
-2 booster studies
-N=4004
-Age at first vaccination 6 to 16 weeks of age
-Age at booster 11 and 18 months
Diary cards for specific AE for 4 days post dose
-all other AE for 31 days post dose
-serious adverse events were reported throughout study period
Level I Good

Combination of 5 studies could introduce some heterogeneity to study outcomes
Evidence for Immunogenicity - Study Details Evidence for Immunogenicity - Summary
Study Vaccine Study Design Number of Participants Outcomes Level of Evidence Quality
Vesikari et al. 34 Synflorix™ vs Prevnar,® concomitant with Infanrix-hexa, Infanrix IPV Randomized Controlled Trial
-in Finland, France and Poland
Primary series: -N=1650
- 6 to 12 wks Booster:
-N=1112
-age 12 to 18 mos
Pneumococcal specific antibodies (ELISA) with cut off of > 0.2mcg/ml OPA with cut off of 1:8 IgG antibodies for H. influenzae (ELISA) Level I Good

-used a number of vaccines not used in Canada ie OPV, hib-MenC-TT
Wysocki et al. 35 Synflorix ™or Prevnar®, co administered with Infanrix-hexa, or infanrix penta and one of Menitorix, Neis-Vac, Meningitec or Infanrix-IPVHib, MenC Open Randomized Controlled Trial
-in Germany, Poland and Spain
Primary series: -N=1548
-age 6 to 16 weeks Booster:
-N=1437
-age 11 to 18 mos
Serological f/u on 180 pts per group (total 720) -pneumococcal serotype specific IgG antibodies GSK's 22F-ELISA -OPA Level I Good
Bermal et al 32 . Synflorix™, Prevnar®, DTPw-HBV/Hib +IPV or OPV Double blind, Randomized controlled trial
-Poland, Philippines
Primary series: -N= 761
-age 6 to 12 wks
Serological analysis Serum anti-pneumococcal IgG using GSK 22F ELISA
-OPA on a subset of 200 IgG antibodies to NTHi protein D
Level I Good

-generalizability since whole cell pertussis not used in Canada, or OPV
Knuf et al. 33 Synflorix™, Prevnar®, Infanrix-hexa, Infanrix penta, Tritanrix, Menitorix, OPV, IPV, Neis-Vac, Meningitec -Poland, Spain, France, Germany, the Philippines Primary Series -N=4004
-age 6 to 16 weeks
Booster -N=2549
-age 11 to 18 mos
Randomly selected subset Before primary series, 1 mos after primary series, 1 mos after booster, one group had blood work done 2 mos after second dose and 1 mos after third dose Anti-HBs, (>10IU/ml) ELISA for diphtheria, tetanus, Hib, pertussis antigensSBA-MenC Level I Good

-used a number of vaccines not used in Canada ie OPV, DTPw-HBV/Hib, hib-MenC-TT



Members: Dr. J. Langley (Chair), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Dr. N. Crowcroft (Ontario Agency for Health Protection and Promotion), Ms. A. Hanrahan (Alberta Health Services), Dr. B. Henry (BC Centre for Disease Control) , Dr. D Kumar (University of Alberta), Dr. A. McGeer (Mount Sinai Hospital) , Dr. S. McNeil (Associate Professor of Medicine, University of Alberta), Dr. C. Quach-Thanh (Montreal Children’s Hospital), Dr. B. Seifert (Winnipeg Regional Health Authority), Dr. D. Skowronski (BC Centre for Disease Control), Dr. B. Tan (Associate Professor of Pediatrics, Royal University Hospital), Dr. P. Orr (Association of Medical Microbiology and Infectious Disease Canada),

Liaison Representatives: Dr. B. Bell (Center for Disease Control and Prevention), Dr. C. Cooper (Canadian Association for Immunization Research and Evaluation), Ms. K. Pielak (Canadian Nursing Coalition for Immunization), Dr. S. Rechner (College of Family Physicians of Canada), Dr. M. Salvadori (Canadian Paediatric Society), S. Pelletier (Community Hospital Infection Control Association), Dr. N. Sicard (Canadian Public Health Association), Dr. V. Senikas (Society of Obstetricians and Gynaecologists of Canada), Dr. P. Plourde (Committee to Advise on Tropical Medicine and Travel), Dr. P.Van Buynder (Council of Chief Medical Officers of Health)

Ex-Officio Representatives: Ms. M. FarhangMehr (Centre for Immunization and Respiratory Infectious Diseases), Dr. S. Desai (Centre for Immunization and Respiratory Infectious Diseases), Dr. B. Law (Centre for Immunization and Respiratory Infectious Diseases), LCol (Dr.) James Anderson (Department of National Defence), Dr. Ezzat Farzad (First Nations and Inuit Health Branch – Office of Community Medicine), Dr. F. Hindieh (Biologics and Genetic Therapies Directorate), Dr. D. Elliott (Centre for Immunization and Respiratory Infectious Diseases, Dr. P. Varughese (Centre for Immunization and Respiratory Infectious Diseases)

This statement was prepared by Dr. Allison McGeer and Shalini Desai and approved by NACI.

References

  1. An Advisory Committee Statement (ACS). National Advisory Committee on Immunization (NACI). Statement on recommended use of pneumococcal conjugate vaccine. Can Commun Dis Rep 2002 Jan;28(ACS-2):1-32.
  2. An Advisory Committee Statement (ACS). National Advisory Committee on Immunization (NACI). Statement on the recommended use of pneumococcal conjugate vaccine: addendum. Can Commun Dis Rep 2003 Sep;29(ACS-8):14-5.
  3. Update on the recommendations for the routine use of pneumococcal conjugate vaccine for infants. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2006 May;32(ACS-4):1-6.
  4. Kellner JD, Church DL, MacDonald J, et al. Progress in the prevention of pneumococcal infection. CMAJ 2005 Nov;173(10):1149-51.
  5. Kellner JD, Vanderkooi OG, MacDonald J, et al. Changing epidemiology of invasive pneumococcal disease in Canada, 1998-2007: update from the Calgary-area Streptococcus pneumoniae research (CASPER) study. Clin Infect Dis 2009 Jul;49(2):205-12.
  6. Kellner JD, Scheifele D, Vanderkooi OG, et al. Effects of routine infant vaccination with the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization with Streptococcus pneumoniae in children in Calgary, Canada. Pediatr Infect Dis J 2008 Jun;27(6):526-32.
  7. Tyrrell GJ, Lovgren M, Chui N, et al. Serotypes and antimicrobial susceptibilities of invasive Streptococcus pneumoniae pre- and post-seven valent pneumococcal conjugate vaccine introduction in Alberta, Canada, 2000-2006. Vaccine 2009 Jun;27(27):3553-60.
  8. Bjornson G, Scheifele DW, Bettinger J, et al. Effectiveness of pneumococcal conjugate vaccine in Greater Vancouver, Canada: 2004-2005. Pediatric Infectious Disease Journal 2007 Jun;26(6):540-2.
  9. Paulus S, David ST, Tang W, et al. Incidence of invasive pneumococcal disease after introduction of the Universal Infant Immunization Program, British Columbia (2002-2005). Canada Communicable Disease Report 2006 Jul;32(14):157-61.
  10. Degani N, Navarro C, Deeks SL, et al. Invasive bacterial diseases in northern Canada. Emerging Infectious Diseases 2008 Jan;14(2):34-40.
  11. Langley JM, Kellner JD, Solomon N, et al. Empyema associated with community-acquired pneumonia: a Pediatric Investigator's Collaborative Network on Infections in Canada (PICNIC) study. BMC Infect Dis 2008;8:129.
  12. Case definitions for diseases under national surveillance. Can Commun Dis Rep 2000 May;26 Suppl 3:i-iv.
  13. Bruce MG, Deeks SL, Zulz T, et al. International Circumpolar Surveillance System for invasive pneumococcal disease, 1999-2005. Emerg Infect Dis 2008 Jan;14(2):25-33.
  14. Daneman N, McGeer A, Green K, et al. Macrolide resistance in bacteremic pneumococcal disease: implications for patient management. Clin Infect Dis 2006 Aug;43(4):432-8.
  15. Scheifele DW, Halperin SA. Immunization Monitoring Program, Active: a model of active surveillance of vaccine safety. Semin Pediatr Infect Dis 2003 Jul;14(3):213-9.
  16. Jette L, Bourgault A. Programme de surveillance du pneumocoque, Rapport 2007. Laboratoire de Sante Public du Quebec; 2007. http://www.inspq.qc.ca/pdf/publications/796_Rapport_2007_Pneumocoque.pdf PDF (242 Kb, 19 pages) Accessed on 7-30-2009.
  17. National Centre for Streptococcus: April 2004-March 2005 Annual Report. Provincial Laboratory for Public Health, Edmonton, Alberta, Canada; 2005. http://www.provlab.ab.ca/ncs/NCS2004-05_AnnualReport.pdf PDF (403 Kb, 27 pages) Accessed on 7-30-2009.
  18. Statement on the recommended use of pneumococcal 23-valent polysaccharide vaccine in homeless persons and injection drug users. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2008 Sep;34(ACS-5):1-12.
  19. Dawar M, Russell B, McClean K, et al. A case of necrotizing fasciitis due to Streptococcus pneumoniae serotype 5 in Saskatchewan. Can J Infect Dis Med Microbiol 2008 Jan;19(2):69-71.
  20. Herva E. Features of epidemiology of Streptococccus pneumoniae (serotype I) in the Arctic. International Journal of Circumpolar Health 2006 Dec;65(5):379-81.
  21. Proulx JF, Dery S, Jette LP, et al. Pneumonia epidemic caused by a virulent strain of Streptococcus pneumoniae serotype 1 in Nunavik, Quebec. Canada Communicable Disease Report 2002 Aug;28(16):129-31.
  22. Ndiaye AA, De WP, Proulx JF, et al. Impact of a mass immunization campaign to control an outbreak of severe respiratory infections in Nunavik, northern Canada. International Journal of Circumpolar Health 2006 Sep;65(4):297-304.
  23. Publicly Funded Immunization Programs in Canada - Routine Schedule for Infants and Children (including special programs and catch-up programs). http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php Accessed on 5-13-2008.
  24. Paulus S, David ST, Tang W, et al. Incidence of invasive pneumococcal disease after introduction of the Universal Infant Immunization Program, British Columbia (2002-2005). Can Commun Dis Rep 2006 Jul;32(14):157-61.
  25. Golmohammadi K, Nguyen T-H, Hanrahan A, et al. Immunization coverage against invasive pneumococcal disease among children in the capital health region of Alberta. Canada Communicable Disease Report 2005;31.
  26. World Health Organization. Meeting Report: WHO Workshop on Standardization of Pneumococcal Opsonophagocytic Assay. 25 Jan 2007. 1 p. http://www.who.int/biologicals/publications/meetings/areas/vaccines/pneumococcal/OPA meeting report- FINAL_June07.pdf PDF (242 Kb, 19 pages) Accessed on 7-29-2009.
  27. Jodar L, Butler J, Carlone G, et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine 2003;21(23):3265-72.
  28. World Health Organization. Annex 2: Recommendations for the production and control of pneumococcal vaccines. 2005. Report nr 927. 66 p. Accessed on 7-29-2009. http://www.who.int/entity/biologicals/publications/trs/areas/vaccines/pneumo/ANNEX 2 PneumococcalP64-98.pdf PDF (264 Kb, 36 pages)
  29. Feavers I, Knezevic I, Powell M, et al. Challenges in the evaluation and licensing of new pneumococcal vaccines, 7-8 July 2008, Ottawa, Canada. Vaccine 2009 Jun;27(28):3681-8.
  30. Poolman J, Siber GR, Chang I, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007 May 10;25(19):3816-26
  31. GlaxoSmithKline Inc. Product Monograph: Synflorix™. GlaxoSmithKline Inc. May 2008.
  32. Bermal N, Szenborn L, Chrobot A, et al. The 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) coadministered with DTPw-HBV/Hib and poliovirus vaccines: assessment of immunogenicity. Pediatr Infect Dis J 2009 Apr;28(4 Suppl):S89-S96.
  33. Knuf M, Szenborn L, Moro M, et al. Immunogenicity of routinely used childhood vaccines when coadministered with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). Pediatr Infect Dis J 2009 Apr;28(4 Suppl):S97-S108.
  34. Vesikari T, Wysocki J, Chevallier B, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine. Pediatr Infect Dis J 2009 Apr;28(4 Suppl):S66-S76.
  35. Wysocki J, Tejedor JC, Grunert D, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with different neisseria meningitidis serogroup C conjugate vaccines. Pediatr Infect Dis J 2009 Apr;28(4 Suppl):S77-S88.
  36. Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet 2006 Mar;367(9512):740-8.
  37. Jokinen J, Ahman H, Kilpi T, et al. Concentration of Antipneumococcal Antibodies as a Serological Correlate of Protection: an Application to Acute Otitis Media. Journal of Infectious Diseases 2004;190:545-50.
  38. Dagan R, Givon-Lavi N, Fraser D, et al. Serum Serotype-Specific Pneumococcal Anticapsular Immunoglobulin G Concentrations after Immunization with a 9-valent Conjugate Pneumococcal Vaccine Correlate with Nasopharyngeal Acquistion of Pneumococcus. Journal of Infectious Diseases 2005;192:367-76.
  39. Millar E, O'Brien K, Bronsdon M, et al. Anticapsular Serum Antibody Concentration and Protection against Pneumococcal Colonization among Children Vaccinated with 7-Valent Pneumococcal Conjugate Vaccine. Clinical Infectious Diseases 2007;44:1173-9.
  40. Chevallier B, Vesikari T, Brzostek J, et al. Safety and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with routine childhood vaccines. Pediatr Infect Dis J 2009 Apr;28(4 Suppl):S109-S118.
  41. Harris R, Helfand M, Woolf S, et al. Current methods of the US Preventative Services Task Force: a review of the process. American Journal of Preventive Medicine 2001;20:21-35.

Page details

Date modified: