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The Impact of the Meningococcal Serogroup C Conjugate Vaccine in Canada Between 2002 and 2012 Sadarangani, Manish; Scheifele, David W.; Halperin, Scott A.; Vaudry, Wendy; Le Saux, Nicole; Tsang, Raymond; Bettinger, Julie A. 2014

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M A J O R A R T I C L EThe Impact of the Meningococcal Serogroup CConjugate Vaccine in Canada Between 2002 and2012Manish Sadarangani,1,2 David W. Scheifele,1 Scott A. Halperin,3 Wendy Vaudry,4 Nicole Le Saux,5 Raymond Tsang,6 andJulie A. Bettinger1; For the investigators of the Canadian Immunization Monitoring Program, ACTive (IMPACT)a1Vaccine Evaluation Center, Division of Infectious and Immunological Diseases, Department of Pediatrics, BC Children’s Hospital and the Universityof British Columbia, Vancouver, Canada; 2Department of Paediatrics, University of Oxford, United Kingdom; 3Canadian Center for Vaccinology, IWK HealthCentre and Dalhousie University, Halifax, Nova Scotia, 4Division of Infectious Diseases, Department of Pediatrics, Stollery Children’s Hospital andUniversity of Alberta, Edmonton, 5Division of Infectious Disease, Children’s Hospital of Eastern Ontario, Ottawa, and 6Vaccine Preventable BacterialDiseases, National Microbiology Laboratory, Winnipeg, Manitoba, Canada(See the Major Article by Bijlsma et al on pages 1216–21, and the Editorial Commentary by Maiden and MacLennan onpages 1222–4.)Background. Before 2001, the incidence of invasive meningococcal disease (IMD) in Canada was 1.0 per100 000 per year, with 40% of cases caused by serogroup C organisms. During 2001–2005 all provinces introducedthe meningococcal serogroup C conjugate vaccine (MCCV) into their routine infant immunization schedule.Methods. Active, prospective, population-based surveillance of IMD in children and adults was conducted bythe Canadian Immunization Monitoring Program, ACTive (IMPACT) during 2002–2012. Inclusion criteria wereadmission to hospital and identification of Neisseria meningitidis from a sterile site. Incidence was estimatedusing population census data from Statistics Canada.Results. Prior to MCCV introduction, serogroup C disease incidence was 0.07–0.25 per 100 000 per year de-pending on the province. Following vaccine introduction, serogroup C disease decreased to <0.05 per 100 000 peryear, with a reduction of 14% per year (P = .0014). A decrease occurred in all provinces, despite differing schedulesbeing implemented. The largest decrease of 83% (from 0.27 to 0.05 per 100 000 per year) occurred in the 15–24 yearage group (P = .0100) who were not vaccinated in all provinces. There was no impact on the incidence of nonser-ogroup C disease over the same period (P = .9811).Conclusions. MCCV dramatically reduced the incidence of serogroup C IMD in Canada through both direct andindirect effects. The observation that disease incidence decreased with different schedules suggests that the doses at 12months (common to all provinces) and adolescence (7 of 8 provinces studied) were critical in achieving disease control.Keywords. conjugate vaccines; herd immunity; meningitis; meningococcal disease; serogroup C.Neisseria meningitidis causes around 500 000 casesof meningitis and septicemia globally every year andhas a case-fatality rate of 10% in developed countries[1]. The organism is carried asymptomatically in thenasopharynx by approximately 10% of the population,with highest carriage rates of up to 25% in 15–25 year-olds [2, 3]. The peak incidence of invasive disease occursin children between 6 months and 2 years of age, with asecond smaller peak in adolescents and young adults. InCanada, the incidence of invasive meningococcal disease(IMD) has been <2.1 cases per 100 000 per year since the1950s, with the majority of disease being caused by se-rogroup B and C organisms [4]. Between 1995 and2001 the incidence was just below 1.0 per 100 000 peryear, with 40% of cases caused by serogroup C. ThereReceived 18 February 2014; accepted 18 June 2014; electronically published 28July 2014.aIMPACT network investigators members are given in Appendix Section.Correspondence: Manish Sadarangani, BM BCh, DPhil, Department of Paediatrics,University of Oxford, Level 2, Children’s Hospital, Oxford OX3 9DU, UK (manish.sadarangani@paediatrics.ox.ac.uk).Clinical Infectious Diseases® 2014;59(9):1208–15© The Author 2014. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:journals.permissions@oup.com.DOI: 10.1093/cid/ciu5971208 • CID 2014:59 (1 November) • Sadarangani et al at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from was a rapid increase in serogroup C incidence between 1998 and2001, when it reached almost 0.6 per 100 000 per year and causedover half of all cases [4]. In addition, there were 8 outbreaks ofserogroup C disease in Canada between 1999 and 2001 [5].In October 2001, the National Advisory Committee on Im-munization (NACI) recommended inclusion of the meningo-coccal C conjugate vaccine (MCCV) in the routine childhoodimmunization schedule in Canada [6].The initial recommenda-tion was for 3 doses at 2, 4, and 6 months of age, with a modifiedschedule for older children [6, 7]. Current schedules include 0–3doses in infants (<1 year of age), 1 dose at 12–23 months, and1 dose at 12–24 years. Between 2001 and 2005, all provinces andterritories except Nunavut introduced MCCV into the routineschedule. Differences in local disease epidemiology and pro-grammatic considerations led to a variety of schedules beingused in different regions of Canada.The primary objective of this study was to determine theincidence of serogroup C IMD before and after introduction ofMCCV across Canada. Secondary objectives were to assess theimpact on other serogroups, and in particular examine if therewere any evidence of serogroup replacement, as well as to usethe provincial variability in immunization schedules as an oppor-tunity to compare different dosing schedules, and to compare theimpact of the vaccine in different age groups, including any dif-ference between those who were targeted for vaccination (directeffects) and those who were not (indirect effects).PATIENTS AND METHODSStudy LocationsActive, prospective, population-based surveillance of IMDin children and adults across Canada has been conducted bythe Canadian Immunization Monitoring Program, ACTive(IMPACT) since 2002. Surveillance was coordinated by 12urban centers, which collected data from over 150 hospitals in8 provinces. The catchment area of these hospitals includedover 16 million individuals, around 50% of the Canadian pop-ulation, and approximately 90% of the pediatric tertiary carebeds in Canada. This study included patients admitted to hos-pital with IMD between 1 January 2002 and 31 December 2012.To enable incidence rate calculations, a defined study popula-tion area was created for each IMPACT center based on thecatchment areas of study hospitals.Provinces used different schedules when implementing theMCCV Program (Supplementary Table 1). In Quebec MCCVwas introduced in 2001 with a campaign to vaccinate all thosebetween 2 months and 20 years of age, followed by routine im-munization of 12-month old children and catch-up for olderchildren. Alberta introduced the vaccine with doses at 2, 4,and 6 months from 2002 (and modified to 2, 4, and 12 monthsin 2007) with the addition of an adolescent dose at 14–16 yearsin 2010. In British Columbia, the vaccine was introduced in2003 with doses at 12 months and 11–12 years. An additionaldose at 2 months was added in 2005 and a catch-up programwas offered to adolescents aged 14–18 years during 2004–2007. In 2004 Ontario and Saskatchewan introduced thevaccine, followed by Nova Scotia, Manitoba and Newfoundlandand Labrador in 2005. These 5 provinces all introduced a 2-doseschedule, with an initial dose at 12 months and a booster/catch-up dose between 10 and 16 years, depending on the province.Manitoba initially introduced the adolescent dose only, chang-ing to a 2-dose schedule in 2009. In some provinces the ado-lescent dose is now administered as a component of themeningococcal quadrivalent conjugate vaccine, which protectsagainst serogroups A, C, W, and Y.Study SubjectsPatients with N. meningitidis identified by culture or polymer-ase chain reaction from a normally sterile body fluid or tissue,most commonly blood and/or cerebrospinal fluid, were includ-ed. Cases were actively identified via microbiology laboratories,infection control practitioners, ward and intensive care unit staffand local public health units, and by interrogation of hospitaldatabases for relevant discharge codes based on InternationalClassification of Diseases (ICD)-9 and ICD-10, which includedterms for meningococcal disease.Data CollectionClinical data were collected from patient health records, andimmunization history was also collected from immunizationregistries and family doctors. All information was recordedinto a standard form, which was reviewed at the IMPACT datacenter before being entered into an electronic database. A dualdata entry process was used with separate operators and pre-programmed consistency checks.Characterization of Bacterial IsolatesAll isolates were characterized initially in the local and provin-cial laboratories according to standard procedures and then sentto the National Microbiology Laboratory where the serogroupwas confirmed and isolates were stored.Incidence Rate AnalysisAge-specific population estimates of the defined study popula-tion areas were obtained from the 2006 Census of Population[8]. Study subjects residing outside the defined study populationarea were excluded from the incidence analysis. Poisson regres-sion models were used to examine trends in the incidence ofIMD, categorized by serogroup, province, age, and immuniza-tion status, and the logarithm of the population was used as anoffset for the Poisson regression. The incidence rate ratio (IRR)was calculated for each model, to estimate the relative change inImpact of MenC Vaccine in Canada • CID 2014:59 (1 November) • 1209 at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from incidence per year and determine P-values. SAS (version 9.3,SAS Institute, Cary, NC) was used for all analyses.For each province the year of introduction of MCCV wasconsidered to be year 0 of the MCCV Program, with yearsprior to vaccine introduction designated −3 to −1 and years fol-lowing MCCV +1 to +11. Data from all IMPACT provincescontributed to years +1 to +7, whereas years −3 to −1 includeddata from all IMPACT provinces except Quebec and Albertaand data for years +8 to +11 were based on Quebec, Alberta,British Columbia, Ontario, and Saskatchewan (Table 1). Anal-ysis of serogroup-specific incidence rates was performed foryears −2 to +8 as these years included the majority of thestudy population. This avoided distortion of the data by localepidemiologic variations, such as an ongoing outbreak of se-rogroup B disease in Quebec [9]. Analysis for direct effect ofthe vaccine included all individuals within age groups whowere targeted for vaccination (Supplementary Table 1). Allother individuals were included in the analysis of indirect effectsof the vaccine. Alberta was excluded from the analysis of indi-rect effects as the adolescent dose was only introduced in 2010,and indirect effects are mediated via interruption of transmis-sion in this age group. For Manitoba, children aged 1–4 yearswere excluded from the analysis of direct and indirect effectsas this group would have been classified in the indirect groupinitially, and then the direct group from 2009 following intro-duction of the dose in early childhood.Ethical ConsiderationsAppropriate approvals for the study were obtained in allhospitals.RESULTSPopulation CharacteristicsThere were 943 cases of IMD in the study population between2002 and 2012 and 81 deaths, giving a case-fatality rate of 8.6%.For the 172 serogroup C disease cases (18% of the total), theaverage age was 33 years, and the case-fatality rate was 12.2%.Within the defined study population area there were 807cases, and these were included in further analyses. There werea total of 157 cases of serogroup C disease in the definedstudy population area (19% of the total), with a peak of 37cases in 2002 and fewer than 8 cases per year from 2009 onward(Table 1).Table 1. Number of Cases of Serogroup C and all IMD Each Year by Province During 2002–2012, by Year of Meningococcal Serogroup CConjugate Vaccine (MCCV) ProgramProvince PopulationaNumber of Cases of Serogroup C/Number of Cases of all IMD per Year of MCCV Programin Each Provinceb (Calendar Year)−3 −2 −1 Year 0 +1 +2 +3 +4 +5 +6 +7 +8 +9 +10 +11 TotalQC 2 512 669 . . . . . . . . . . . . 10/23 5/21 4/24 1/21 3/21 4/28 3/21 0/20 0/26 1/40 0/28 31/273(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)AB 2 280 379 . . . . . . . . . 14/19 4/10 4/11 1/5 0/5 0/11 1/9 0/6 0/5 1/10 5/8 . . . 30/99(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)BC 2 549 714 . . . . . . 6/21 2/13 10/16 6/15 2/12 6/22 4/9 1/14 1/5 0/8 0/5 . . . . . . 38/140(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)ON 7 156 082 . . . 5/19 5/23 2/20 5/14 8/26 7/30 1/24 6/23 2/11 1/8 1/6 . . . . . . . . . 43/204(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)SK 596 539 . . . 0/0 1/1 0/1 0/2 0/2 0/3 0/2 0/2 0/0 0/1 0/1 . . . . . . . . . 1/15(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)MB 654 953 2/7 1/3 0/4 0/0 0/1 0/3 1/5 0/0 2/6 0/2 0/1 . . . . . . . . . . . . 6/32(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)NS 404 746 0/3 1/1 1/6 1/1 0/0 0/1 4/7 0/2 0/1 0/2 0/1 . . . . . . . . . . . . 7/25(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)NL 297 026 0/3 1/2 0/0 0/0 0/3 0/3 0/3 0/3 0/2 0/0 0/0 . . . . . . . . . . . . 1/19(’02) (’03) (’04) (’05) (’06) (’07) (’08) (’09) (’10) (’11) (’12)Total 16 452 108 2/13 8/25 13/55 19/54 29/69 23/82 19/89 8/79 15/75 8/66 5/43 1/40 1/41 6/48 0/28 157/807Abbreviations: AB, Alberta; BC, British Columbia; IMD, invasive meningococcal disease; MB, Manitoba; MCCV, meningococcal serogroup C conjugate vaccine;NL, Newfoundland and Labrador; NS, Nova Scotia; ON, Ontario; QC, Quebec; SK, Saskatchewan.a Population figures represent the total population in the defined study population area in each province based on the 2006 Census of Population carried out byStatistics Canada (available at: http://www12.statcan.gc.ca/census-recensement/2006/index-eng.cfm).b Year of introduction of MCCV was considered to be ‘Year 0,’ with years prior to vaccine introduction designated −3 to −1 and years following MCCV +1 to +11,depending on the province (see Supplementary Table 1 for full details of vaccine introduction in each province).1210 • CID 2014:59 (1 November) • Sadarangani et al at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from Serogroup-Specific Incidence of IMD in CanadaBetween 2002 and 2005, during the introduction of MCCVacross Canada, the incidence of IMD was 0.14 per 100 000per year for serogroup C and 0.33 per 100 000 per year for allother serogroups combined. Between 2009 and 2012, when allvaccine programs had been established, the incidence had de-creased by 77% to 0.03 per 100 000 per year for serogroup C(P < .0001), with no significant change in non-C disease,which was 0.34 per 100 000 per year (P = .9811). Separate anal-yses for serogroups B and Y confirmed there was no significantchange in the incidence of these serogroups (P = .5676 andP = .1768, respectively). During this time serogroup C decreasedfrom 30% of all IMD in 2002–2005 to 8.5% in 2009–2012.In relation to year of MCCV introduction, the incidence ofserogroup C disease was 0.10 per 100 000 per year duringyears −2 to −1, with the highest rates in Nova Scotia and BritishColumbia (0.25 and 0.24 per 100 000 per year, respectively). Inthe 8 years following vaccine introduction, serogroup C diseasedecreased to <0.05 per 100 000 per year, declining at a rate of14% per year (P = .0014) (Figure 1).Incidence of Serogroup C IMD in Different ProvincesThere was a similar reduction of serogroup C disease in all prov-inces (Figure 2). In Quebec, there was a 98% reduction in se-rogroup C disease between year +1 and years +8 to +11(P < .0001). In Alberta, the incidence was 0.61 per 100 000 peryear in 2002 (year 0), and this decreased by 98% to 0.01 per100 000 between years +4 and +9 (P = .0051). However, therewere 5 serogroup C cases in 2012 (year +10) in unvaccinatedindividuals in Alberta, and when these were included in theanalysis, the overall decrease of 93% observed throughout thestudy period no longer achieved statistical significance(P = .1195). Four of these cases occurred in individuals aged be-tween 11 years and 23 years, with 1 additional case in a 40-yearold. British Columbia had a significant reduction of 92% in se-rogroup C disease (P = .0088), and in provinces using a 2-doseschedule there was a downward trend, with a decrease of 66%from years −3 to −1 until +4 to +8 (P = .0825).Age-Specific Incidence Rates of Serogroup C IMDThe highest incidence of serogroup C IMD occurred in the15–24 year age group (Figure 3) and declined by 83% from0.27 per 100 000 per year (years −3 to −1) to 0.05 per100 000 per year (years +4 to +11; P = .0100). Although theoverall incidence in adults aged over 24 years was lower, therewas a significant reduction in serogroup C disease of 41%(P = .0009). In children <15 years of age there was a downwardtrend in incidence, with a drop of 44% (P = .4284).Comparison of Direct and Indirect Effects of the VaccineThe incidence in those targeted for vaccination was 0.14 per100 000 per year prior to MCCV introduction, compared to alower incidence of 0.10 per 100 000 per year in populations whowere not included in the immunization schedule. A reduction inFigure 2. Poisson regression models of incidence rates of serogroup CIMD from year −3 to +11 of MCCV Program by province. Abbreviations:IMD, invasive meningococcal disease; MCCV, meningococcal serogroupC conjugate vaccine.Figure 1. A, Serogroup-specific incidence rates of IMD from year −2 to+8 of MCCV Program in all provinces. B, Poisson regression model of inci-dence of serogroup C IMD from year −2 to +8 of MCCV Program in allprovinces. Abbreviations: IMD, invasive meningococcal disease; MCCV,meningococcal serogroup C conjugate vaccine.Impact of MenC Vaccine in Canada • CID 2014:59 (1 November) • 1211 at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from serogroup C disease was seen in both vaccinated and unvaccinatedpopulations. In the vaccinated, directly protected population therewas an 87% reduction in incidence during the study period(P = .0049) and a decrease of 46% in the unvaccinated, indirectlyprotected population (P = .0107; Figure 4).Cases of Serogroup C Disease in Recipients of MCCVThere were a total of 9 cases of serogroup C IMD in individualswho had previously been vaccinated with MCCV (Table 2). Onechild received a dose of vaccine 4 days prior to admission sowould not be expected to be protected. Three children whowere approximately 3 years of age when they had IMD hadreceived 2 doses of vaccine in early infancy but missed the12-month dose. Two children (aged 2 years and 3 years) hadreceived a single dose of MCCV at 12 months. Three childrenhad received a single dose of vaccine between 3 years and 14years of age and developed disease just over 5 years post-vaccination.DISCUSSIONThis study has demonstrated that MCCV has resulted in a dra-matic and sustained reduction in serogroup C meningococcalFigure 3. A, Incidence rates of serogroup C IMD from year −3 to +11 ofMCCV Program in all provinces, by age group. B–D, Poisson regressionmodels of incidence of serogroup C IMD from year −3 to +11 of MCCVProgram in all provinces in children <15 years (B) adolescents and youngadults 15–24 years (C) and adults >24 years (D). Abbreviations: IMD, inva-sive meningococcal disease; MCCV, meningococcal serogroup C conjugatevaccine.Figure 4. A and B, Actual incidence rates and Poisson regression modelsof incidence of serogroup C IMD from year −3 to +11 of MCCV Program inall provinces in individuals who were in age groups targeted for vaccinationand benefited from direct protection from the vaccine (A) and in individualswho were not in age groups targeted for vaccination and benefited fromindirect protection from the vaccine (B). Abbreviations: IMD, invasive me-ningococcal disease; MCCV, meningococcal serogroup C conjugatevaccine.1212 • CID 2014:59 (1 November) • Sadarangani et al at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from disease across Canada. If this effect is representative of the entirecountry, 75–85 IMD cases and 10–12 deaths will have been pre-vented in Canada annually [10]. There has been no evidence ofserogroup replacement overall, and a reduction in disease in allprovinces irrespective of the schedule used, suggesting that thedoses at 12 months and in adolescence may be the most impor-tant (and perhaps sufficient) since these were almost universallyincluded in immunization schedules. This study has providedclear evidence that this vaccine likely induced herd immunityby reducing the transmission of N. meningitidis, protectingthose in the population who were not vaccinated and likely pro-vided longer lasting population protection by prevention of me-ningococcal carriage.The reduction following introduction of MCCV in Canada issimilar to other countries. In Europe there was a 10-fold drop inthe incidence of serogroup C IMD in the 4–7 years after vaccineintroduction in 6 countries [11].These countries used 2–3 dosesin infants or a single dose at 12 months, with a catch-up cam-paign and no routine adolescent dose. In the United Kingdomthere was a decrease of 99% in serogroup C disease from 1.85 to0.02 per 100 000 per year in the 10 years following vaccine in-troduction, initially using a schedule of 3 doses in early infancyand a mass immunization campaign of everyone up to 24 yearsof age [12]. This was subsequently changed to 2 infant dosesplus a 12-month dose, similar to the initial schedule used in Al-berta. The decrease in the United Kingdom is similar to Canadain provinces where such longer-term data are available. In theNetherlands, children receive a single dose of MCCV at 14months of age, although a catch-up campaign of all childrenup to 18 years was undertaken when MCCV was introduced—similar to the program in Quebec. In 8 years followingMCCV introduction, there was a decrease in serogroup Cincidence from 1.7 to 0.03–0.07 per 100 000 per year [13]. Sim-ilar successes have also been achieved in Spain and Australia,but neither of these countries use an adolescent dose [14].MCCV has been a highly successful vaccine globally, in largepart due to its ability to induce herd immunity by reducing na-sopharyngeal carriage of N. meningitidis and consequent inter-ruption of transmission, primarily in adolescents and youngadults [15]. Inclusion of an adolescent dose of vaccine to includethis age group has therefore been a critical strategic decisionduring vaccine implementation. Although the presence of aroutine adolescent dose should maintain population herd im-munity, the effect of a 1-off catch-up campaign has the potentialto diminish over time due to waning of immunity in those im-munized as young children [13]. The cases of disease in vacci-nated individuals in this study confirm what others havedemonstrated regarding persistence of immunity following vacci-nation with MCCV. Overall, 8/157 cases (5.1%) occurred in vac-cinated children (excluding the child who developed disease 4days post-vaccine). This is similar to data from the United King-dom, where there were 53 cases in vaccinated children [16] in thefirst 3 years after introduction of MCCV of a total of 1294 se-rogroup C cases (4.1%) [17]. In the majority of children, protec-tion following doses in early infancy does not persist beyond 12months of age [18], whereas immunity is maintained for 1–2years after a dose at 12 months of age [13], 2–5 years for thosevaccinated between 1 year and 9 years of age, and at least 5years if vaccinated when 10 years or older [19–22].All provinces and territories in Canada have had a routineadolescent meningococcal vaccine dose in place since 2007,with the exception of Alberta (introduced in 2010) and Quebec(2013). This should ensure the current low incidence of se-rogroup C disease in Canada persists, as long as the highTable 2. Cases of Serogroup C Invasive Meningococcal Disease (IMD) in Individuals Who Had Previously Received MeningococcalSerogroup C Conjugate Vaccine (MCCV)CaseNumberYear of MCCVProgramNumber of MCCVDoses ReceivedAge When DosesReceivedAge of Child WhenAdmitted With IMDInterval Between Last Dose ofMCCV and IMD1 +2 1 12 mos 12 mo 4 d2 +3 2 2, 4 mo 3 y 2 mo 2 y 10 mo3 +3 2 4, 6 mo 2 y 9 mo 2 y 3 mo4 +3 2 5, 6 mo 2 y 11 mo 2 y 5 mo5 +4 1 12 mo 2 y 12 mo6 +6 1 12 mo 3 y 3 mo 2 y 3 mo7 +7 1 3 y 6 mo 8 y 11 mo 5 y 5 mo8 +2 1 6 y 10 mo 11 y 11 mo 5 y 1 mo9 +5 1 14 y 4 mo 19 y 9 mo 5 y 5 moCase 1 cannot be considered a true vaccine failure due to the short interval between vaccination and disease. Cases 2–4 occurred in children who only received 2doses of MCCV in infancy and missed the 12-month booster, developing IMD 2–3 years after their last dose of vaccine. Cases 5 and 6 only received a single 12-month dose of vaccine and developed disease 1–2 years subsequent to that. Cases 7–9 received a single dose as older children and developed IMD 5–6 years later.Most cases occurred in the first 3–4 years after introduction of MCCV program into a province.Abbreviations: IMD, invasive meningococcal disease; MCCV, meningococcal serogroup C conjugate vaccine.Impact of MenC Vaccine in Canada • CID 2014:59 (1 November) • 1213 at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from coverage required to sustain herd immunity can be achieved.This appears particularly relevant to serogroup C because thehighest incidence rate was observed in the 15–24 year agegroup. In Europe only Austria, Switzerland, and the UnitedKingdom currently have a routine adolescent dose [23, 24].The importance of the adolescent booster is also suggested inthis study with 4 cases in Alberta in 2012 occurring in unvacci-nated individuals in this age group, where the adolescent dosewas introduced in 2010, 8 years after MCCV was introduced. Itwill be important to observe whether serogroup C IMD re-emerges in those countries where incidence was previouslyhigh and an adolescent dose is not used.The major strengths of this study are that it was based on ac-tive, population-based surveillance to maximize case ascertain-ment and provides accurate estimates of disease incidence.Inclusion of several provinces and various MCCV scheduleshas enabled comparison of the different strategies, which canbe used to inform future policy decisions in Canada and inter-nationally. The study also has some limitations. Some individ-uals with IMD residing within the defined study populationarea may have attended hospitals outside the IMPACT network,leading to an underestimate of disease incidence. If individualswere too sick to have appropriate samples taken early in theirillness or they died before samples could be obtained, the bac-terium would not be isolated, and such cases would be excluded.The study population areas are generally in urban areas, so datafrom cases in rural areas were limited. Although it is possiblethat epidemiology may be different in rural Canada, trendsare similar to data collected by the National Enhanced InvasiveMeningococcal Disease Surveillance System [10], suggestingthat these results are a true reflection of Canadian epidemiology.Systematically collected vaccine uptake data were not availableto include in the analyses to provide further support to the con-clusion that reduction in serogroup C disease was due to imple-mentation of MCCV. Available data from some provinces showthat uptake of MCCV has been high at 82%–96% [9, 25–29],suggesting that MCCV has led to the decreased disease inci-dence. The number of cases of serogroup C IMD is relativelysmall, particularly in the 6 month to 2 year age group. There-fore, analyses in some subgroups, including those aged <15years, did not achieve statistical significance although a down-ward trend was always observed. However, statistical signifi-cance was still achieved for most of the analyses, suggestingthat effects were large enough for robust conclusions to bedrawn.The reduction of serogroup C IMD has been a great successstory for immunization. The variable implementation of MCCVin different provinces has provided a unique opportunity tocompare different policies and as data have emerged aboutthis vaccine, so the vaccination strategies have evolved. Follow-ing the successful control of serogroup C IMD, future attentionwill focus on reduction of disease caused by other serogroups,primarily serogroup B, which is now the leading cause of IMDin Canada [30]. A new vaccine based on subcapsular proteinsfound within the bacterial outer membrane has recently beenlicensed in Europe [31] and Canada (www.hc-sc.gc.ca). Quad-rivalent meningococcal conjugate vaccines for serogroups A, C,Y, and W are currently used in several provinces and territoriesas the adolescent dose as an alternative to MCCV. Adequate in-dividual surveillance, particularly in childhood, is also neededto maintain the current low rates of serogroup C disease, to en-sure children receive all recommended doses.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases online(http://cid.oxfordjournals.org). Supplementary materials consist of data pro-vided by the author that are published to benefit the reader. The posted ma-terials are not copyedited. The contents of all supplementary data are thesole responsibility of the authors. Questions or messages regarding errorsshould be addressed to the author.NotesAcknowledgments. The authors gratefully acknowledge the expert as-sistance provided by the Monitor Liaison (Heather Samson), the IMPACTnurse monitors and staff of the data center (Kim Marty, Wenli Zhang, ShuYu Fan and Debbe Heayn), the National Microbiology Laboratory (JianweiZhou), and our public health and infectious disease colleagues. They thankthe Directors and staff of the provincial and territorial public health labora-tories for providing the isolates for this study.Financial support. The Canadian Immunization Monitoring Program,Active (IMPACT) is a national surveillance initiative managed by the Cana-dian Pediatric Society (CPS) and conducted by the IMPACT network of pe-diatric investigators. From 2002 to 2011 IMPACT meningococcalsurveillance was supported by a grant from Sanofi-Pasteur and from 2012to 2015 by a grant from Novartis Vaccines & Diagnostics Canada to theCPS. The funders had no role in study design, data collection and analysis,decision to publish, or preparation of the article.Potential conflicts of interest. J. A. B. is supported by a Career Investi-gator Award from the Michael Smith Foundation for Health Research, andhas received speaker honoraria from Novartis Vaccines and Baxter Inc.M. S. is a coinvestigator on investigator-initiated research grants from Pfizerrelating to meningitis. S. A. H. has undertaken clinical trials on meningococ-cal vaccines funded by Novartis and GlaxoSmithKline and has served on adhoc advisory boards for both companies. All other authors report noconflicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConflicts of Interest. Conflicts that the editors consider relevant to the con-tent of the manuscript have been disclosed.References1. World Health Organization. Control of epidemic meningococcal dis-ease: WHO practical guidelines. 2nd ed. Geneva, Switzerland: WorldHealth Organization, 1998.2. Cartwright KA, Stuart JM, Jones DM, Noah ND. The Stonehouse sur-vey: Nasopharyngeal carriage of meningococci and Neisseria lactamica.Epidemiol Infect 1987; 99:591–601.3. Caugant DA, Hoiby EA, Magnus P, et al. Asymptomatic carriage ofNeisseria meningitidis in a randomly sampled population. J Clin Micro-biol 1994; 32:323–30.1214 • CID 2014:59 (1 November) • Sadarangani et al at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from 4. An update on the invasive meningococcal disease and meningococcalvaccine conjugate recommendations. An Advisory Committee State-ment (ACS). Can Commun Dis Rep 2009; 35(ACS-3): 1–40.5. Squires SG, Deeks SL, Tsang RS. Enhanced surveillance of invasive me-ningococcal disease in Canada: 1 January, 1999, through 31 December,2001. Can Commun Dis Rep 2004; 30:17–28.6. An Advisory Committee Statement (ACS). Statement on recom-mended use of meningococcal vaccines. Can Commun Dis Rep 2001;27:2–36.7. Meningococcal vaccine for children. Paediatr Child Health 2002; 7:425–9.8. Statistics Canada. 2006 Census of Population. Available at:http://www12.statcan.gc.ca/census-recensement/2006/index-eng.cfm.Accessed 29 November 2013.9. Gilca R, Deceuninck G, Lefebvre B, et al. The changing epidemiology ofmeningococcal disease in Quebec, Canada, 1991–2011: Potential impli-cations of emergence of new strains. PLoS One 2012; 7:e50659.10. Public Health Agency of Canada. National Enhanced Invasive Menin-gococcal Disease Surveillance System. Available at: http://www.phac-aspc.gc.ca/im/vpd-mev/meningococcal-eng.php. Accessed 21 January2013.11. Ramsay M, Fox A. EU-IBIS Network. Invasive Neisseria meningitidis inEurope 2006. London: Health Protection Agency, 2007.12. Campbell H, Andrews N, Borrow R, Trotter C, Miller E. Updated post-licensure surveillance of the meningococcal C conjugate vaccine inEngland and Wales: Effectiveness, validation of serological correlatesof protection, and modeling predictions of the duration of herd immu-nity. Clin Vaccine Immunol 2010; 17:840–7.13. Kaaijk P, van der Ende A, Berbers G, van den Dobbelsteen GP, Rots NY.Is a single dose of meningococcal serogroup C conjugate vaccine suffi-cient for protection? Experience from the Netherlands. BMC Infect Dis2012; 12:35.14. Safadi MA, McIntosh ED. Epidemiology and prevention of meningo-coccal disease: A critical appraisal of vaccine policies. Expert Rev Vac-cines 2011; 10:1717–30.15. Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against in-vasive bacteria with protein-polysaccharide conjugate vaccines. Nat RevImmunol 2009; 9:213–20.16. Auckland C, Gray S, Borrow R, et al. Clinical and immunologic risk fac-tors for meningococcal C conjugate vaccine failure in the United King-dom. J Infect Dis 2006; 194:1745–52.17. Public Health England. Meningococcal Reference Unit Laboratory con-firmed reports. Available at: http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317136087786. Accessed 5 December 2013.18. Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effec-tiveness of meningococcal serogroup C conjugate vaccine 4 years afterintroduction. Lancet 2004; 364:365–7.19. Khatami A, Peters A, Robinson H, et al. Maintenance of immune re-sponse throughout childhood following serogroup C meningococcalconjugate vaccination in early childhood. Clin Vaccine Immunol2011; 18:2038–42.20. Perrett KP, Winter AP, Kibwana E, et al. Antibody persistence after se-rogroup C meningococcal conjugate immunization of United Kingdomprimary-school children in 1999–2000 and response to a booster: Aphase 4 clinical trial. Clin Infect Dis 2010; 50:1601–10.21. Sakou II, Tzanakaki G, Tsolia MN, et al. Investigation of serum bacter-icidal activity in childhood and adolescence 3–6 years after vaccinationwith a single dose of serogroup C meningococcal conjugate vaccine.Vaccine 2009; 27:4408–11.22. Snape MD, Kelly DF, Lewis S, et al. Seroprotection against serogroup Cmeningococcal disease in adolescents in the United Kingdom: Observa-tional study. BMJ 2008; 336:1487–91.23. European Centre for Disease Prevention and Control. Annual epidemi-ological report 2012: Reporting on 2010 surveillance data and 2011 ep-idemic intelligence data. Stockholm: ECDC, 2013.24. Pollard AJ, Green C, Sadarangani M, Snape MD. Adolescents need abooster of serogroup C meningococcal vaccine to protect them andmaintain population control of the disease. Arch Dis Child 2013;98:248–51.25. De Wals P, De Serres G, Niyonsenga T. Effectiveness of a mass immu-nization campaign against serogroup C meningococcal disease in Que-bec. JAMA 2001; 285:177–81.26. British Columbia Centre for Disease Control. Immunization Uptake inGrade 6 Students. Vancouver, BC, Canada, 2013.27. British Columbia Centre for Disease Control. Immunization Coverage:Kindergarten. Vancouver, BC, Canada, 2012.28. Sundquist S, Dunlop T, Wright J, Findlater R, Grauer K. ImmunizationReport 2010: Saskatoon Health Region 2011.29. Public Health Ontario. Monthly Infectious Diseases Surveillance Report2013.30. Update on the use of quadrivalent conjugate meningococcal vaccines.Can Commun Dis Rep 2013; 39(ACS-1): 1–40.31. Snape MD, Pollard AJ. The beginning of the end for serogroup Bmeningococcus? Lancet 2013; 381:785–7.APPENDIXIMPACT network investigators from 2002 to 2012 included thefollowing: N. Bridger and R. Morris, Janeway Children’s Healthand Rehabilitation Centre, St. John’s, Canada; S. Halperin andK. Top, IWK Health Center, Halifax, Canada; P. Déry, CentreMère-Enfant de Québec, Québec City, Canada; D. Moore, Mon-treal Children’s Hospital, Montreal, Canada; M. Lebel, HôpitalSte-Justine pour les enfants, Montreal, Canada; N. Le Saux,Children’s Hospital of Eastern Ontario, Ottawa, Canada;D. Tran and L. Ford-Jones, The Hospital for Sick Children,Toronto, Canada; J. Embree and B. Law, Winnipeg Children’sHospital, Winnipeg, Canada; R. Tsang, National MicrobiologyLaboratory, Winnipeg, Canada; B. Tan, Royal University Hos-pital, Saskatoon, Canada; W. Vaudry, Stollery Children’s Hos-pital, Edmonton, Canada; T. Jadavji and O. G. Vanderkooi,Alberta Children’s Hospital, Calgary, Canada; D. Scheifele,L. Sauvé, and J. Bettinger, BC Children’s Hospital, Vancouver,Canada.Impact of MenC Vaccine in Canada • CID 2014:59 (1 November) • 1215 at University of British Columbia on February 1, 2016http://cid.oxfordjournals.org/Downloaded from 

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