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Diversity of Canadian meningococcal serogroup B isolates and estimated coverage of an investigational… Bettinger, Julie A.; Scheifele, David W.; Halperin, Scott A.; Vaudry, Wendy; Findlow, Jamie; Borrow, Ray; Medini, Duccio; Tsang, Raymond 2014

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Vaccine 32 (2014) 124–130Contents lists available at ScienceDirectVaccinejourna l homepage: www.e lsev ier .comDiversity of Canadian meningococcal serogroup Bcoverage by an investigational meningococcal serJulie A. Bettingera,∗, David W. Scheifelea, Scott A. Halperinb, WRay Borrowd, Duccio Medinie, Raymond Tsangf, For the membImmunization Monitoring Program, Active (IMPACT)a Vaccine Evalu V5Z4Hb Canadian Cen adac Stollery Childd Vaccine Evalue Novartis Vaccf National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg R3E3R2, Canadaa r t i c l e i n f oArticle history:Received 18 DReceived in reAccepted 28 MAvailable onlinKeywords:Serogroup B v4CMenB coverMeningococcaInvasive meniMeningitisa b s t r a c t1. IntroduSerogrousive menin PortionsInternational Stle, USA and tVancouver, Ca∗ Correspon950 West 28thfax: +1 604 87E-mail add0264-410X ©http://dx.doi.oecember 2012vised form 26 February 2013arch 2013e 12 April 2013accinesagel Antigen Typing Systemngococcal diseaseBackground: In collaboration with the Canadian Immunization Monitoring Program Active (IMPACT), theNational Microbiology Laboratory, the UK Health Protection Agency and Novartis Vaccines, we testedthe potential of an investigational 4-component meningococcal B vaccine (4CMenB) to cover Canadianstrains circulating from 2006 to 2009.Methods: IMPACT meningococcal surveillance is population based and includes over 50% of Canadianadults and children. All isolateswere characterized byMeningococcal Antigen Typing System (MATS) andsequencing for factor H-binding protein (fHbp), Neisseria Heparin Binding Antigen (NHBA) and Neisserialadhesin A (NadA).Results: In total, 157 isolates were tested. Overall, 4CMenB MATS predicted strain coverage was 66% (95%CI: 46–78%),with26%, 29%and11%of strains coveredbyone, twoand threevaccineantigens, respectively.The coverage of each antigen was as follows: 13% PorA, 1% NadA, 52% fHbp and 51% NHBA. The majorityof strains for clonal complex (cc) 41/44 and cc60 were covered by NHBA; the majority of strains for cc269and cc32 were covered by fHbp and NHBA.Coverage for two prevalent strains (sequence type (ST)-269 and ST-154) was 95% and 100%, respec-tively.Conclusions: 4CMenB has the potential to protect against a significant proportion of Canadian invasiveMenB strains.© 2013 The Authors. Published by Elsevier Ltd.ctionp B meningococci (MenB) account for 50–80% of inva-gococcal disease (IMD) in Canada, with the highestof these data have been presented in posters at the 5th Vaccine andociety for Vaccines Annual Global Congress, October 2–4, 2011, Seat-he 10th Canadian Immunization Conference, December 2–5, 2012,nada.ding author at: Vaccine Evaluation Center, BC Children’s Hospital, A5-Street, Vancouver, BC V5Z4H4, Canada. Tel.: +1 604 875 2422;5 2635.ress: jbettinger@cfri.ca (J.A. Bettinger).incidence seen in children <5 years of age [1,2]. Despite the needfor prevention, efforts to develop a vaccine against MenB diseasehavebeenhamperedby the similarity of thepolysaccharide capsuleof the bacterium to human fetal neural tissue [3,4] and the inabil-ity to identify common protective surface antigens among MenBstrains. However, reverse vaccinology has enabled the identifica-tion of several conserved non-capsular protein surface antigens,overcoming limitations of past epidemic-specific outer-membranevesicle (OMV) MenB vaccines [5–7]. Three antigens (Neisserialadhesin A (NadA) allele 3, Neisseria Heparin Binding Antigen(NHBA), factor H-binding protein (fHbp) variant 1 along withOMV of the epidemic strain (PorA P1.4) from New Zealand havebeen combined into a recently approved vaccine against MenBdisease (4CMenB) [8,9]. Two variants of fHbp have also beenused to create an investigational bivalent MenB vaccine (rLP2086)[10].2013 The Authors. Published by Elsevier Ltd.rg/10.1016/j.vaccine.2013.03.063Open access under CC BY-NC-ND license.Open access under CC BY-NC-ND license.ation Center, BC Children’s Hospital and the University of British Columbia, Vancouverter for Vaccinology, IWK Health Centre and Dalhousie University, Halifax B3K6R8, Canren’s Hospital and University of Alberta, Edmonton T6G1C9, Canadaation Unit, Health Protection Agency, Manchester M13 9WZ, UKines, Siena 53100, Italy/ locate /vacc ineisolates and estimatedogroup B vaccine (4CMenB)endy Vaudryc, Jamie Findlowd,ers of the Canadian4, CanadaJ.A. Bettinger et al. / Vaccine 32 (2014) 124–130 125To date, three OMV-based vaccines against invasive MenBdisease have successfully contained clonal outbreaks in variouscountries [11–13].However, immunogenicity of thesevaccineswasprimarily based on the PorA outer membrane protein containedin the OMVing differenMenBvacciagainst Medicted protand will begensexpresand on thecorrespondcal Antigenindividual Mvaccine [15epidemioloantigens fouIn collabing ProgramMicrobiolog(HPA) and Ntial strain cstrains isolaincidence rbut a higheof clonal coin Canada.2. MateriaActive,adult and pNeisseria mIMPACT, inis a nationprovinces [tured all IMsurveillancethe populameningitidisfrom bloodmation wasdefined ascharge. The[19,20]. EthAll IMPACT2006 to 200NML desequencingby Multilocwere determria pubMLSscheme avatide subvarpeptide IDNovartis claNHBA andBambini etHPA stuNadA, fHbprelative potmum levelthat predicto killing inbodies induproportion of strains with RP above the PBT for at least one vac-cine antigen in the MATS ELISA or matched to the PorA subtypeP1.4 [15].To account for inter-laboratory differences in the MATS, the 95%enceccoruarence bed foultstal osnot. Noby agmoc41/4n=6)gned69oST)we co) andand 9le (ning 5-275varipredI: 46I: 47ver.0%d byfHbp% (9the fe coinTaof thredihat renB4) wtivelyreasr onst frevalefou), P1.of isinaP1.1de va4. Thf agembin1.4 a).ralldentilate.and did not provide protection against strains carry-t PorA subtypes [14]. Antigens included in the newerneshave thepotential toprovidebroadcross-protectionnB strains and potentially other serogroups. The pre-ection afforded by these newer vaccines is not knownhighly dependent on both the quantity of vaccine anti-sedby strains causingdisease inagivengeographic areaextent of their immunologic cross reactivity with theing antigen in the vaccine. To this end, the Meningococ-Typing System (MATS) was developed to predict whichenB strains are likely to be covered by the 4CMenB]. To understand the potential coverage, a detailedgic, microbiologic and genetic characterization of thend in MenB disease isolates is required.oration with the Canadian Immunization Monitor-Active (IMPACT) surveillance network, the Nationaly Laboratory (NML), the UK Health Protection Agencyovartis Vaccines & Diagnostics, we tested the poten-overage of the 4CMenB vaccine against invasive MenBted in Canada from 2006 to 2009. During this time theate of MenB infection was stable at 0.25 per 100,000,r rate occurred in Québec as a result of the circulationmplex (cc) 269, [2,16,17] one of two hyper-endemic ccsls and methodsmetropolitan area population-based surveillance forediatric hospital admissions related to infection witheningitidis was conducted by the 12 centers of thecollaboration with local public health officials. IMPACTal surveillance initiative with centers located in 818]. Each center defined a population area and cap-D cases in children and adults. IMPACT meningococcalincludes over 17 million Canadians, just over 50% oftion. Inclusion as a case required the isolation of N.from a normally sterile site or a positive PCR testor cerebrospinal fluid (CSF). Standardized case infor-abstracted from the hospital record. Sequelae werecomplications attributable to IMD still present at dis-surveillance methodology has been detailed elsewhereics approval was obtained at all participating hospitals.MenB cases with a viable isolate that occurred from9 and were identified as of August 2010 were included.termined serogroup, serotype, sub-serotype and PorAof case isolates. The clonal identity of isolates (definedus Sequence Typing (MLST) [21]) and PorA variantsined following the guidelines included in the Neisse-T website [22]. The classification of fHbp followed theilable in the public fHbp database which divides pep-iants among three major variants, 1, 2 and 3 [22]. Thisis similar to the Novartis classification, although in thessification it is preceded by the major variant number.NadA classification followed Lucidarme et al. [23] andal. [24].died the levels of expression and cross-reactivity of, and NHBA in the MenB isolates using the MATS ELISAency (RP) [15]. The MATS method established a mini-of RP, named the positive bactericidal threshold (PBT)ts whether a given MenB isolate would be susceptiblethe human serum bactericidal antibody assay by anti-ced by 4CMenB. Strain coverage was defined as theconfidlated aChi-sqdifferewas us3. ResA tolatewaby PCRfoundThewere ccc60 (unassiand cc2types (of thes(n=11cc269or singremain269 (STand STThe(95% C(95% C2008. Ogen, 29coverelows:NadA 1showsage. Thshownby anywere pcases t4CMcc41/4respecthis incered fothe mo3.1. PrThe(n=34or 67%predomcc269.in a wicc41/4years ogen coPorA P(n=16Ovewere ione isointervals (CI) for vaccine strain coverage were calcu-ding to an inter-laboratory standardization study [25].and Fisher’s exact tests were used to test for significantetween groups. SAS version 9.3 (SAS Institute, Cary NC)r all analyses.f 157/200 (78.5%) MenB cases were tested. A viable iso-available for2 cases and41caseswere confirmedsolelysignificant differences in PCR confirmation rates weree or center (data not shown).st frequent ccs among the 68 different STs identified4 (n=51), cc269 (n=51), cc35 (n=11), cc32 (n=8) andcc213 (n=2). Of the remaining 28 isolates, 21 wereand 7 were singularly occurring ccs. Although cc41/44ccurredwith the same frequency, 25different sequenceere identified among isolates in cc41/44 and only threentained multiple isolates (ST-154 (n=15) and ST-571ST-340 (n=3). In contrast, only 9 STs were found in0.1% of these isolates belonged to either ST-269 (n=37),= 6) or double locus variants (n=3) of ST-269 and theisolates showed three allelic differences from the ST-and ST-1161). The distribution of the most frequent cced by province (Table 1).icted strain coverage of the 4CMenB vaccine was 66%–78%); ranging, non-significantly, from a high of 72%–84%) in 2006 to a low of 58% (95% CI: 33–70%) inall, 26.1% of strains were covered by one vaccine anti-by two antigens and 11.5% by three. No isolates wereall four antigens. Coverage by each antigen was as fol-52% (95% CI: 40–59%); NHBA 51% (95% CI: 21–71%);5% CI: 0.6–3%); and PorA 13% (95% CI: 8–18%). Table 2requency of antigen combinations sufficient for cover-verage by age group, gender, ethnicity and province isble3.Vaccine strain coveragedidnotdiffer significantlyese factors. Of the 6 isolates from fatal cases, 4 (67%)cted covered, as were 23 of the 34 (68%) isolates fromesulted in sequelae.coverage within the two most prevalent cc (cc269 andas 82% (95% CI: 47–90%) and 65% (95% CI: 55–80%),. For the two most common STs (ST-269 and ST-154)ed to 95% and100%, respectively,while ST-571was cov-ly 1 isolate (9%). The occurrence of vaccine antigens inequent cc is shown in Fig. 1.nce and diversity of PorA, fHbp, NadA and NHBAr most frequently detected PorA serosubtypes (P1.1914 (n=28), P1.9 (n=22), P1.4 (n=21))were found in 105olates. Strains containing serosubtype P1.19 occurredntly in Québec (n=30/34) and all strains were from4 occurred primarily in Ontario (n=16) and was foundriety of cc. PorA P1.4 was present in 21 strains all frome majority of strains with P1.4 occurred in children 0–4(n=14) and were distributed across Canada. Two anti-ationsoccurred frequently among thePorAP1.4 strains:nd NHBA peptide 2 (n=19) and PorA P1.4 and fHbp 1.444 different PorA variable region (VR) genosubtypesfied, but only 12 genosubtypes occurred in more thanThe seven most common PorA genosubtypes included126 J.A. Bettinger et al. / Vaccine 32 (2014) 124–130Table 1Most frequent clonal complex and sequence type by province, 2006–2009 (IMPACT surveillance).Clonal complex ProvinceAtlantic Quebec Ontario Central Alberta British Columbia Totalcc41/44 (n=51)ST154 5 0 7 0 3 0 15ST571 0 10 1 0 0 0 11ST340 2 0 0 0 0 1 3Othera 1 8 5 3 2 3 22cc269 (n=51)ST269 0 33 2 0 1 1 37ST1986 0 3 0 0 0 0 3ST275 0 1 0 0 1 0 2ST1161 2 0 0 0 0 0 2ST13 0 0 2 0 0 0 2Otherb 0 2 0 1 0 2 5cc35 (n=11)ST35 0 2 1 0 0 0 3ST570 0 1 2 1 0 0 4ST790 0 0 0 0 2 0 2Otherc 0 1 1 0 0 0 2cc32 (n=8)ST32 0 1 2 0 0 1 4Otherd 1 2 0 0 0 1 4cc60 (n=6)ST60 0 3 0 0 0 0 3Othere 1 1 0 0 1 0 3a Other cc41/44 sequence types occurring once included the following: ST1433, ST146, ST1475, ST157ST6473, ST6541, ST6551, ST6591, ST6623, ST7702, ST7746, ST839, ST944.b Other cc269 sequence types occurring once included the following: ST1284, ST283, ST6107, ST7812c Other cc35 sequence types occurring once included the following: ST278 and ST6472.d Other cc32 sequence types occurring once included the following: ST2017, ST2726, ST33, ST7814.e Other cc60 sequence types occurring once included the following: ST1754, ST6546 and ST7877.Table 2Percentages of strains covereda by specific antigen combinations in Canada,2006–2009 (IMPACT surveillance) (N=157).Vaccine antigen N %fHbp 20 12.7NHBA 21 13.4fHpb+NHBA 40 25.5fHpb+PorA 3 1.9fHbp+NadA 1 0.6NHBA+NadA 1 0.6PorA+ fHbp+NHBA 18 11.5Antigen not sufficient for coverage or not presentb 53 33.8a Strains were defined as covered by 4CMenB if they possessed PorA P1.4 or hada RP above the PBT for fHbp, NHBA or NadA.b Included PorA alone, NadA alone, NHBA+PorA, fHbp+NHBA+NadA andPorA+ fHbp+NHBA+NadA.P1.19-1,15-P1.18-7,9,3and P1.5,2,MenB isolaA total ooccurring o46 (29.3%) wIsolates froin their fHbfHbp varianexpressed vprevalencein childrenfHbp 1.1 (vaof those froTable 3Potential coverage of 4CMenB vaccine in Canada, 2006–2009 (IMPACT surveillance) (n=157).Characteristic Predicted covered according tNumber PAge group0–4 years (n=79) 48 65+ years (n=78) 56 7Male (n=80) 50 6Female (n=77) 54 7EthnicityWhite (n=99) 64 6Other (n=19) 13 6Unknown (n=39) 27 6ProvinceBritish Columbia (n=14) 6 4Alberta (n=13) 9 6Central Canada (Sasktchewan and Manitoba (n=8) 8 10Ontario (n=38) 23 6Québec (n=72) 48 6Atlantic (Nova Scotia and Newfoundland) (n=12) 10 8a Strains were defined as covered by 4CMenB if they possessed PorA P1.4 or had a RP above the PBT f8, ST2678, ST2820, ST2989, ST3752, ST41, ST43, ST46, ST5553, ST6465,, ST7813.11,36 (n=34); P1.7-2,4,37 (n=21); P1.22,14,36 (n=16);5-1 (n=16); P1.22-1,14,38 (n=12); P1.7,16,35 (n=6);36-2 (n=5). Together these represented 70.1% of thetes.f 39 different fHbp peptides were identified, with 26nly once. The majority (n=100) were from variant 1;ere from variant 2; and 11 (7.0%) were from variant 3.m infants <1 year of age showed the greatest variabilityp antigens: 34% (n=14) of isolates in infants expressedt 1; 56% (n=23) expressed variant 2; and 10% (n=4)ariant 3. In the remaining age groups fHbp variant 1ranged from a low of 60% in adults to a high of 92%5–14 years of age. All of the strains (n=5) containingriant 1, peptide 1, included in 4CMenB) and 81% (n=77)m variant 1 but with a different peptide (e.g. 4, 110,o MATSaercent 95% CI P-value0.8 44.3–79.70.141.8 47.4–76.92.5 47.5–76.30.310.1 44.2–80.54.6 47.5–80.80.868.4 42.1–78.99.2 43.6–71.82.9 28.6–57.10.089.2 61.5–76.90 75–1000.5 47.4–63.26.7 38.9–84.73.3 66.7–100or fHbp, NHBA or NadA.J.A. Bettinger et al. / Vaccine 32 (2014) 124–130 127Fig. 1. Predictdicted to be coPBT for fHbp, NBstrains, 2006that were assisigned represe(N=21).413, etc.) wthe fHbp vand wouldPorA, NHBAfHbp peptidspecificallymostly assoeither covercovered (0%Canada (e.gonly foundTable 5the relativegen. Thirty-occurring o(n=23) 112tributed acfrom infantprimarily inwhile peptifound every(n=36) of pthe NHBA Pvaccine whpredicted twithin 4CM41% (23/51)coverage oftwo differendifferent NHtively, P<0expressionThe nadAing NadA ato be coverwhich accowas not preGeograpbinations wwere foundotypeinCanada,2006–2009(IMPACTsurveillance).cc35(n=11)cc32(n=8)cc60(n=6)Othercc/unassigned(n=30)Overall(N=157)TotalCoveredTotalCoveredTotalCoveredTotalCoveredTotalCovered––44(100%)––––55(100%)––––62(33%)32(67%)124(33%)––––––––3933(85%)––––––32(67%)2019(95%)60(0%)––––––60(0%)––––––10(0%)240(0%)10(0%)––––10(0%)50(0%)43(75%)41(25%)––227(32%)4621(46%)ssedaRPabovethePBTforfHbp.ludedthefollowing:1.8,1.14,1.54,1.65,1.89,1.108,1.110,1.144,1.226,1.252,1.407,1.410,1.413,1.414,1.415,1.416,2.23,2.25,2.101,2.106,2.118,ed 4CMenB vaccine antigen coverage (Strains were defined as pre-vered by 4CMenB if they possessed PorA P1.4 or had a RP above theHBA or NadA.) by serogroup B clonal complex in Canadian serogroup–2009 (IMPACTsurveillance).Note:Other includes7clonal complexesgned only once and 1 clonal complex that was assigned twice. Unas-nts isolates for which a clonal complex was unable to be determinedere predicted to be covered by the vaccine. None ofariant 2 or 3 strains had RPs above the PBT for fHbprequire expression of a different vaccine antigen (i.e., NadA) to be covered. Table 4 shows the distribution ofes by cc, and the relative coverage predicted by MATSfor this antigen. Themost prevalent fHbppeptideswereciated with one cc and the fHbp-MATS phenotype wased (85% and 100% for 1.15 and 1.4, respectively) or not-for 2.19). Of note, fHbp 1.15 occurred in isolates across.Quebec,Ontario, BritishColumbia andAlberta) butwasin cc269.shows the distribution of NHBA peptides by cc, andcoverage predicted by MATS specifically for this anti-three different NHBA peptides were identified with 18nce. The most frequent peptides were 21 (n=51), 2(n=14) and 6 (n=14). Peptides 21, 2 and 6 were dis-ross all age groups, while peptide 112 was primarilys and young children. Peptides 21 and 112 were foundQuébec (peptide 21, n=40 and peptide 112, n=12)de 6was concentrated in Ontario (n=13). Peptide 2waswhere exceptQuébec. Of these 4 commonpeptides 71%eptide 21, and 96% (n=22) of peptide 2 had RPs overBT thus were predicted to be covered by the 4CMenBilst only 7% of peptides 112 (n=1) and 6 (n=1) wereo be covered. NHBA peptide 2, the peptide containedenB, was only found in cc41/44 where it constitutedof the NHBA peptides in cc41/44 with MATS predicting96% (22/23) (Table 5), whereas peptide 21was found int ccs (cc269 n=40 and cc35 n=11) with a significantlyBA-MATS coverage phenotype (85% and 18%, respec-.0001), suggesting a consistently lower level of NHBAin cc35 compared to cc269.gene was found in 12 isolates but only 2 isolates, bear-lleles 2 and 3, expressed NadA with a RP over the PBTed by the 4CMenB vaccine. The subvariant NadA-1.1,unted for half (n=6) of the isolates with a nadA gene,dicted to be covered.hically, the prevalence of fHbp and NHBA antigen com-ere diverse except for two antigen combinations thatprimarily in Québec: NHBA 112 fHbp 2.19 in 15.3% Table4Relationshipamongclonalcomplex,fHbpantigengenotypeandMATSphenfHbppeptideaPredictedCoveredaccordingtofHbp-MATScc269(n=51)cc41/44(n=51)TotalCoveredTotalCovered1.1––11(100%)1.1330(0%)––1.153933(85%)––1.4––1717(100%)2.16––––2.1920(0%)210(0%)2.24––30(0%)Othersb74(57%)96(67%)aStrainsweredefinedaspredictedtobecoveredby4CMenBiftheypossebOtherfHbpvariantsandpeptidesoccurringinfewerthan5isolatesinc2.138,2.411,3.30,3.31,3.45,3.47,3.94,3.406,3.408,3.409,3.412.128 J.A. Bettinger et al. / Vaccine 32 (2014) 124–130Table5Relationshipamongclonalcomplex,NHBAantigengenotypeandMATSphenotypeinCanada,2006–2009(IMPACTsurveillance).NHBApeptideaPredictedcoveredaccordingtoNHBA-MATScc269(n=51)cc41/44(n=51)cc35(n=11)cc32(n=8)cc60(n=6)Othercc/unassigned(n=30)Overall(N=157)TotalCoveredTotalCoveredTotalCoveredTotalCoveredTotalCoveredTotalCoveredTotalCovered214034(85%)––112(18%)––––––5136(71%)2––2322(96%)––––––––2322(96%)630––––––––111(9%)141(7%)112––141(7%)––––––––141(7%)24––––––––63(50%)––63(50%)20––––––10––42(50%)52(40%)Othersb82(25%)147(50%)––74(57%)––152(13%)4415(34%)aStrainsweredefinedaspredictedtobecoveredby4CMenBiftheypossessedaRPabovethePBTforNHBA.bOtherNHBApeptidesoccurringinfewerthan5isolatesincludedthefollowing:1,3,5,9,10,17,18,19,29,43,44,47,122,145,197,276,277,278,279,280,281,282,283,284,285,286,287.(n=11) of strains from Québec (and 1 from Ontario) and occurredprimarily in infants (n=9); and NHBA 21 fHbp 1.15 was found in49.0% (n=35) of Québec strains (and 2 Vancouver strains) acrossall age groups. Of these two common antigen combination 8.3%(n=1) of N95% (n=35)fHbp 1.15 s4. DiscussiThis stuCanadian MUsing a conprovide goofor the mo154 predictgroups, the4CMenB vaacross a widtecting agacovered bycontributinare also fouother serognot immunof preventiwere potenOur resuwhere thein 2007–20withMATS[26]. The ovlower (40%[26], thus tuse could dThe last1994 to 199PorA serosuP1.7 (7.0%),clones werin our currin Québeclent clones2006–2009for about 33ral changesof commonby the findthe provincAtlantic proranged fromeach regionlate. 4CMenand ST-154than otherdeterminefHbp and Nple were ascc being cca similar ping to diffethat was sigesting a bigenetic divecific combinHBA 112 fHbp 2.19 were predicted to be covered andof NHBA 21 fHbp 1.15 were covered. The two NHBA 21trains not predicted to be covered were from Québec.ondy provides the first data on the potential coverage ofenB isolates by the investigational 4CMenB vaccine.servative predictor for coverage, 4CMenB appears tod strain coverage (65% for cc41/44 and 82% for cc269)st prevalent recent ccs, which include ST-269 and ST-ed covered at 95% and 100%, respectively. Across all agemajority of isolates are predicted to be covered by theccine. Of note the vaccine appears to provide coveragee diversity of endemic strains and is not limited to pro-inst one or two subtypes. At least 40% of isolates weretwo or more vaccine antigens, with fHbp and NHBAg the most to vaccine coverage. The 4CMenB antigensnd in non-MenB isolates thus protection against theseroupsmaybeanaddedbonus,particularly in individualsized with meningococcal conjugate vaccines. In termson, over two-thirds of the recent cases caused by MenBtially preventable with this vaccine.lts are similar to those found in England and Walesoverall proportion of strains estimated to be covered08 was 73% (57–87%) and the combinations of antigensRP above the PBTwas similar to that observed in Canadaerall frequency of coverage by at least two antigenswasvs. 50%) in Canadian than in English and Welsh isolateshe chance for escape mutants to emerge with vaccineiffer between the two countries.national characterization of MenB isolates was from6. In this earlier study the most commonly expressedbtypes were P1.14 (13.3%), P1.16 (11.3%), P1.5 (7.9%),P1.13 (7.0%), andP1.2 (4.3%); and theonlyhypervirulente cc32 and cc11 [27]. The most noticeable differencesent study were the emergence of the ST-269 cloneand a change in the prevalence of other hyperviru-. CC32 decreased from 12.0% in 1994–1996 to 5.1% inand cc41/44 became a predominant clone, accounting% ofMenB isolates in 2006–2009. Besides these tempo-, we noted geographical differences in the distributionhypervirulent clones from 2006 to 2009 as exemplifieding of ST-269 (cc269) and ST-571 (cc41/44) mainly ine of Québec, and ST-154 (cc41/44) from Ontario and thevinces. By province, the predicted coverage of 4CMenB43% to100%and reflected the strains circulatingwithinand the level of antigen expression within each iso-B coverage of Canadian hyper-endemic strains (ST-269, 95% and 100%, respectively) was significantly higherSTs in the same cc, indicating that cc cannot be used toif an isolate is potentially covered by 4CMenB. For bothHBA, antigen peptides with high frequency in the sam-sociated mostly with one or two ccs, the most diverse41/44 for both antigens. In general each peptide hadroportion of coverage when found in strains belong-rent ccs, with the exception of the NHBA peptide 21gnificantly more covered in cc269 than in cc35, sug-as in the level of antigen expression associated with thersity between the two ccs. Albeit strains harboring spe-ations ofMLST and antigen genotypewere consistentlyJ.A. Bettinger et al. / Vaccine 32 (2014) 124–130 129covered (e.g. cc32 and fHbp1.1; cc41/44 and fHbp1.4; cc41/44 andNHBA2) the majority of genetic profiles had both strains coveredand not covered, confirming that antigen genotyping, neither alonenor in combination with MLST, would be sufficient to predict vac-cine strain cWhile oprovide theseveral limany given adetect diffestrain covertically signiwere confirAdditionallCanada andThe MATSwhich maygene was fexpressed Nis repressedestimate Na5. ConclusOur studology andof 4CMenBpost-implemdetermineinto accounany herd prAcknowledWe gratthe IMPACTmonitors anZhang, ShuLaboratoryUK (Jay Lucour public hDirectors alaboratoriesAuthor cfirst authorMeningocotion and deand the stulyzed and inmanuscriptCo-PI for IMHe was invcal surveillaacquisitionthe submittIMPACT surand designreported hethe submittfor the IMPception andstudy reporthe submittizing the serandNadAatthe submitted manuscript. R. Borrow was responsible for charac-terizing the serogroup B isolates by MATS and sequencing fHbp,NHBA and NadA at the Health Protection Agency and was involvedwith interpretation of the data. He revised and approved the sub-manaboraboraandor thion ar thsandprovAdvria (ry Bothefor Nard, Nalf oovartancit froedforPasteteme(IMPan PaatricveillanalpporuppFoundix Asiblo 200ert M, St., Cac Citonts, Mternspiteg Cal MUnivy Chin’s Hettinncesdate ojugatemuntingere burdct Dislmanne J, Lts andpathpuolioverage for all isolates.ur active population-based sentinel surveillance datamost comprehensive measurement of IMD in Canada,itations apply. MenB IMD is rare and the numbers inge group or province are small; therefore our ability torences among subgroups is limited, and differences inage among age or geographic groups were not statis-ficant. Approximately 20% of MenB cases in our datamed by PCR only with no isolate available for testing.y, IMPACTsurveillance includesprimarilyurbanareasofmay not be representative of remote or rural regions.provides a conservative estimate of vaccine coverage,be an underestimate [15,28]. Finally, although the nadAound in 12 isolates (7%) in our study, only two (1%)adA with a RP above the PBT. Since expression of NadAin vitro, but not in vivo, conditions, MATS may under-dA’s contribution to vaccine strain coverage [29,30].ionsy characterizes the current MenB molecular epidemi-provides a good estimate of the potential coverage. Accurate post-implementation surveillance and/orentation effectiveness studies will be necessary tothe true effectiveness of this new vaccine [31], takingt the level of vaccine coverage in the population andotection.gementsefully acknowledge the expert assistance provided byMonitor Liaison (Heather Samson), the IMPACT nursed staff of the IMPACT data center (Kim Marty, WenliYu Fan and Debbe Heayn), the National Microbiology(Averil Henderson), the HPA laboratory Manchester,idarme, Stefanie Gilchrist and Danielle Thompson) andealth and infectious disease colleagues. We thank thend staff of the provincial and territorial public healthfor providing the isolates for this study.ontributions: J.A. Bettinger is the PI for the study andon the manuscript. She is Co-PI for IMPACT’s Invasiveccal Surveillanceproject. Shewas involvedwith concep-sign of the invasive meningococcal surveillance projectdy reported here as well as data acquisition. She ana-terpreted thedata andwrote and revised the submitted. D.W. Scheifele is the IMPACT Data Center Director andPACT’s Invasive Meningococcal Surveillance project.olved with conception and design of the meningococ-nce project and the study reported here as well as dataand interpretation of the data. He revised and approvededmanuscript. S.A. Halperin is one of two Co-PIs for theveillance network. He was involved with conceptionof themeningococcal surveillance project and the studyre as well as data acquisition. He revised and approveded manuscript. W. Vaudry is the second of two Co-PIsACT surveillance network. She was involved with con-design of the meningococcal surveillance project, theted here and data acquisition. She revised and approvededmanuscript. J. Findlowwas responsible for character-ogroup B isolates byMATS and sequencing fHbp, NHBAtheHealth ProtectionAgency.He revised andapprovedmittedof the linter-lrevisedsible fcollectsible foisolateand apad-hochonoraAdvisoraria inBoarding Boon behGSK, NconsulsupporperformAgencySanofiing staActiveCanadiof pedical suradditiowas suJAB is sSmithAppenrespon2006 tRobCentreHalifaxQuébepital, Menfantof EasThe HoWinnipNationRoyalStollerChildreJulie BRefere[1] UpconCom[2] BeteasInfe[3] Ede[4] Finnenand[5] Rapuscript. D. Medini provided access to and explanationatory and statistical methods used in the Plikaytis et al.tory study and theDonnelly et al.MATSmanuscript. Heapproved the submittedmanuscript. R. Tsang is respon-e maintenance of the IMPACT N. meningitidis isolatet the National Microbiology Laboratory. He was respon-e serogroup and sequencing typing of the serogroup Bwas involvedwith interpretationof thedata.He reviseded the submitted manuscript. Conflicts of interest: JAB:isory Boards (Novartis Vaccines, Canada) and speakerNovartis Vaccines, Pfizer Inc., Baxter Inc.). SAH: ad-hocard for Novartis Vaccines, Canada and speaker hono-past year (Novartis Vaccines). DWS: ad hoc Advisoryovartis Vaccines, Canada.WV: Data Safety andMonitor-ovartis Vaccines. RB has performed contract researchf the Health Protection Agency for Baxter Biosciences,tis, Merck, Pfizer and Sanofi Pasteur. JF has performedes for Baxter, GSK, Novartis and Pfizer, received travelm Baxter Biosciences, GSK, Novartis and Pfizer andcontract research on behalf of the Health ProtectionBaxter Biosciences, GSK, Novartis, Merck, Pfizer andur. DM: employee (Novartis Vaccines). RT: None. Fund-nt: The Canadian Immunization Monitoring Program,ACT) is a national surveillance initiativemanagedby theediatric Society and conducted by the IMPACT networkinvestigators. From2002 to2011, IMPACTmeningococ-nce was supported by a grant from Sanofi-Pasteur. Thetyping and laboratory testing performed in this studyted by a grant from Novartis Vaccines & Diagnostics.orted by a Career Investigator Award from the Michaeldation for Health Research.. IMPACT co-investigators who weree for data and isolate collection at each site from9 include the followingorris, Janeway Children’s Health and RehabilitationJohn’s, Canada. Scott Halperin, IWK Health Centrenada. Pierre Déry, Centre Mère-Enfant de Québec,y, Canada. Dorothy Moore, Montreal Children’s Hos-real, Canada. Marc Lebel, Hôpital Ste-Justine pour lesontreal, Canada. Nicole Le Saux, Children’s HospitalOntario, Ottawa, Canada. Dat Tran, Lee Ford-Jones,al for Sick Children, Toronto, Canada. Joanne Embree,hildren’s Hospital Winnipeg, Canada. Raymond Tsang,icrobiology Laboratory, Winnipeg, Canada. Ben Tan,ersity Hospital, Saskatoon, Canada. Wendy Vaudry,ldren’s Hospital, Edmonton, Canada. Taj Jadavji, Albertaospital, Calgary, Canada. David Scheifele, Laura Sauvé,ger, BC Children’s Hospital, Vancouver, Canada.n the invasive meningococcal disease and meningococcal vaccinerecommendations. An Advisory Committee Statement (ACS). CanDis Rep 2009;36:1–40.JA, Scheifele DW, Le Saux N, Halperin SA, Vaudry W, Tsang R. The dis-en of invasive meningococcal serogroup B disease in Canada. PediatrJ 2013;32:e20–5.GM. Cell adhesion molecules. Science 1983;219:450–7.einonen M, Makela PH. Antigenic similarities between brain compo-bacteria causing meningitis. Implications for vaccine developmentogenesis. Lancet 1983;2:355–7.R. Reverse vaccinology. Curr Opin Microbiol 2000;3:445–50.130 J.A. Bettinger et al. / Vaccine 32 (2014) 124–130[6] Feavers IM, Pizza M. Meningococcal protein antigens and vaccines. Vaccine2009;27:B42–50.[7] Feavers IM, Pizza M. Choosing isolates for the evaluation of meningococcalprotein vaccines. Expert Rev Vaccines 2009;8:1461–3.[8] Serruto D, Bottomley MJ, Ram S, Giuliani MM, Rappuoli R. The newmulticomponent vaccine against meningococcal serogroup B, 4CMenB:immunological, functional and structural characterization of the antigens. Vac-cine 2012;30(Suppl. 2):B87–97.[9] Gregory A. Biggest advance against meningitis in 30 years: new jab approvedwhich could save thousands of lives. online ed. London: Mirror; 2013.[10] Pillai S, Howell A, Alexander K, Bentley BE, Jiang HQ, Ambrose K, et al. Outermembrane protein (OMP) based vaccine for Neisseria meningitidis serogroup B.Vaccine 2005;23:2206–9.[11] Caron F, du Chatelet IP, Leroy JP, Ruckly C, Blanchard M, Bohic N, et al. Fromtailor-made to ready-to-wear meningococcal B vaccines: longitudinal study ofa clonal meningococcal B outbreak. 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