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Meningococcal Vaccines The Journey Continues. Canadian Public Health Association Conference June 19, 2011. Bryna Warshawsky, Associate Medical Officer of Health 519-663-5317 ext. 2427; bryna.warshawsky@mlhu.on.ca. Outline. Background Epidemiology Journey Polysaccharide vaccines - PowerPoint PPT Presentation

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  • *Meningococcal VaccinesThe Journey ContinuesBryna Warshawsky, Associate Medical Officer of Health519-663-5317 ext. 2427; bryna.warshawsky@mlhu.on.ca

    Canadian Public Health Association ConferenceJune 19, 2011

  • *OutlineBackground EpidemiologyJourneyPolysaccharide vaccinesConjugate C vaccinesConjugate quadrivalent vaccinesMeningococcal A vaccineMeningococcal B vaccines

  • *Background

  • *Meningococcal DiseaseNeisseria meningitidisGram negative diplococciThirteen different serogroups, classified by their polysaccharide (sugar) capsule Most common A, B, C, Y, W135 and X

  • *Meningococcal DiseaseCauses:meningitis - inflammation of the lining brainmeningococcemia - in the bloodDisseminated intravascular coagulation (DIC)Presents as fever, headache, vomiting, stiff neck, photophobia and petechial rashFatal in approximately 10%Long term sequelae 10 - 20% such as hearing loss, amputation or neurologic

  • *ImmunogenicityVaccines authorized based on immunogenicity, not efficacyCorrelate of protectionSerum bactericidal antibody (SBA) titreDilution of serum able to kill meningococcal bacteria in vitro; requires the addition of complementUsing human complement correlate is 1:4Measure: Percent achieving titreGeometric mean titre

  • *Protection Circulating antibody titre

    Immune memoryMay be too slow for post-exposure protection

    Herd immunity

  • *Epidemiology

  • Meningococcal by Year and SerogroupSource: NACI Statement, August 2009

  • *Meningococcal Epidemiology2006:210 cases in CanadaSerogroup C 43 cases0.13/100,000Serogroup B 113 cases0.34/100,000Serogroup Y27 cases0.08/100,000Serogroup W135 6 cases 0.02/100,000Serogroup A2 cases0.01/100,000Other 19 casesNACI Statement, CCDR, Volume 35 ACS-3 April 2009

  • *The Journey

  • 1960 - 1980200120062010PolysaccharideA, C A, C, Y, W135Conjugate C Quadrivalent conjugate A, C, Y and W135

    Meningococcal B

    Meningococcal A

  • *Polysaccharide Vaccines

  • *Polysaccharide VaccinesMenomune sanofi pasteur Provides protection against A, C, Y, W135T-cell independentNot effective in less than 2 years of ageOnly 40% effective in 2-9 years of age~ 85% effective in teenagersProtection decreases rapidly and likely gone by 3-5 years of ageDoes not reliably decrease carriageMay induce hyporesponsiveness

  • Chart1

    20

    20

    19

    16

    10

    8

    8

    30

    30

    29

    28

    Booster dose

    First dose

    Time

    GMT

    Boosting effect

    Chart2

    2020

    2020

    1919

    1616

    1010

    88

    88

    3015

    3015

    2914

    2812

    First dose

    Booster dose

    Boosting

    Hyporesponsive

    Time

    GMT

    Hyporesponsiveness-Polysaccharide Vaccines

    Sheet1

    BoostingHyporesponsive

    12020

    22020

    31919

    41616

    51010

    688

    788

    83015

    93015

    102914

    112812

    Sheet2

    Sheet3

  • *NACI Recommendation Polysaccharide Vaccineasplenic patients, sickle cell diseasecomplement deficient, properdin or factor D deficiencytravellers e.g. Hajj, Mecca, Saudi Arabialaboratory workers who handle meningococcal specimensmilitaryclose contacts of serogroups A, C, Y, W135outbreaks of serogroups A, C, Y, W135

  • *Conjugate C Vaccines

  • *Conjugate Vaccines

    Sugar linked to a proteindiphtheria toxoiddiphtheria toxoid mutant CRM 197 tetanus toxoidT cell dependentWorks in young childrenDecreases carriage leading to herd immunityBoostable response

  • *Meningococcal C Conjugate VaccinesThree conjugate C vaccines on the market:

    Menjugate (Novartis Vaccines) CRM197 carrier

    MeningitecTM (Pfizer) - CRM197 carrier

    Neisvac-CTM (GlaxoSmithKline) tetanus toxoid carrier

  • *NACI RecommendationsMeningococcal C conjugate

    Routine program:2 months to 4 year oldsadolescentsyoung adultsconsider for 5-10 year olds

    Post exposure for serogroup C Outbreaks serogroup CNACI; CCDR, 2001; 27:2-36

  • Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3

  • Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3

  • *Effectiveness By Age - UK

    Trotter CL et al. Lancet, July 24, 2004;364:365-367.

  • *Effectiveness By Age - Quebec

    De Wals et al. Pediatric Infectious Disease, July 2011;30(7):566-569.

  • *Infant VaccinationBased on decreasing effectiveness and immunogenicity, NACI recommended:

    If vaccinated as infant (< 1 year) need a dose in second year of life (12 to 23 months)NACI, CCDR, November 2007;33(ACS-11):1-12

  • *Quadrivalent ConjugateA, C, Y, W135

  • *Conjugate A, C, Y, W135MenactraTM (sanofi pasteur) diphtheria toxoidAuthorized for use May 2006Authorized for ages 2 55 years Not very immunogenic in infantsMenveoTM (Novartis ) - mutant diphtheria toxoid CRM197Authorized for use May 2010Mix lyophilized A with liquid C, Y, W135Authorized for ages 11-55 yearsHas been shown to be immunogenic in infants

  • *NACI Recommendationasplenic patients, sickle cell diseasecomplement deficient, properdin or factor D deficiencytravellers e.g. Hajj, Mecca, Saudi Arabialaboratory workers who handle meningococcal specimensmilitaryclose contacts of serogroups A, Y, W135outbreaks of serogroups A, Y, W135primary antibody deficienciesHIV positive - consider

  • *NACI RecommendationAdolescent Vaccination

    Meningococcal C conjugate or quadrivalent conjugate vaccines can be used depending on epidemiology and other considerations

    Give an adolescent doses even if vaccinated at young age

    NACI, CCDR, May 2007;33(ACS-3):1-23 NACI, CCDR, April 2009;36(ACS-3):1-40.

  • Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10C non-inferior; others Menveo superior

  • Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10All Menveo superior

  • *Effectiveness Data from US MenactraTM14 vaccine failures in the US 8 serogroup C; 6 serogroup YMedian age at vaccination 18 years (12-20 years)Mean time from vaccination to disease 395 days (43-1021 day)3 underlying conditions3 fatal (21% case fatality)Vaccine effectiveness estimated at 80-85% within 2 3 years after vaccination

    MacNeil et al. Pediatric Infectious Disease Journal, June 2011;30(6):451-455

  • *Effectiveness Data from US MenactraTMCase control study 108 cases; 158 controls

    78% effectiveness over 5 years of vaccination (95% CI: 29-93%)

    Vaccinated < 1 year ago 95% (95% CI:10-100%)Vaccinated 1 year ago 91% (95% CI:10-101% ??)Vaccinated 2-5 years ago 58% (95% CI: -72% - 89%)

    Waning protection over time

    ACIP; MMWR; January 8, 2011;60(3):72-76.

  • *US Vaccination RecommendationAdolescents 11-12 year of age and booster at 16 years High risk conditions 2-dose primary schedule 2 months apartBooster every five yearExposure risk (microbiologist, travelers to endemic countries) 1-dose primary scheduleBooster 3 years later (2-6 years of age)Booster 5 years later (7 years of age or older)ACIP; MMWR; January 8, 2011;60(3):72-76.

  • *Canada Different than United StatesIn the United States:No conjugate C meningococcal vaccine for infants / toddlersUsing quadrivalent conjugate vaccine for routine immunizations for 11 - 19 year olds just over 50% coverageLimited herd immunity

    Also more serogroup Y disease

  • *Guillain Barr Syndrome (GBS)Passive surveillance suggested a possible association between GBS and MenactraTMTwo large studies in US using managed care organization data have not found any associationPast GBS no longer needs to be considered a precaution for MenactraTMPresentations by Velentgas and Weintraub to ACIP; June 2010.

  • Provincial Schedules

    ProvinceInfant / ToddlerMen C ConjugateAdolescent TimingAdolescent ProductBC2, 12 monthsGrade 6Men CAlberta2, 4, 12 monthsGrade 9QuadrivalentSK12 months, 4-6 yearsGrade 6Men C QuadrivalentManitoba12 monthsGrade 4 Men COntario12 months Grade 7 QuadrivalentQuebec12 months Catch-up < 18 yearsMen CNB12 monthsGrade 9Quadrivalent

  • Provincial SchedulesCanadian Nursing Coalition on Immunization (CNCI) as of April 19, 2011 http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php

    ProvinceInfant / ToddlerMen C ConjugateAdolescent TimingAdolescent ProductNS12 monthsGrade 7Men CPEI12 monthsGrade 9QuadrivalentNF12 monthsGrade 4QuadrivalentNWT2, 12 months; < 5 yearsGrade 9Men CQuadrivalent if going to school outsideYukon2, 12 monthsGrade 6University students if not previously vaccinatedMen CNunavut12 monthsGrade 9Men C

  • *Meningococcal A

  • *MenAfriVacTMConjugate meningococcal A vaccine for Sub-Saharan Africa meningitis beltMeningitis Vaccine ProjectIntroduced into Burkina Faso, Mali and Niger in December 2010 with dramatic effects Plans for Cameroon, Chad and Nigeria, then other countriesGiven to 1-29 year oldsCost less than 50 cents per doseEstimated to prevent 1 million cases and save $300 million over the next decadehttp://www.meningvax.org/

  • *Meningococcal B

  • *Difficulties with DevelopmentCapsule structurally identical to fetal brain cell adhesion moleculesInduce a weak immune responseCould involve production of autoantibodiesOuter-membrane-vesicle vaccineStrain specific PorA, highly variable across strainsEach outbreak needs its own vaccineVaccines incorporate multiple PorAs

  • *Reverse VaccinologyTake the genetic composition of the bacteriaLook for genes that may represent surface exposed proteinsPut into Escherichia coli expression system to make proteinsMi

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