Meningococcal Vaccines The Journey Continues

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Meningococcal VaccinesThe Journey Continues
Canadian Public Health Association
Conference June 19, 2011

• Bryna Warshawsky, Associate Medical Officer of
  Health
• 519-663-5317 ext. 2427 bryna.warshawsky_at_mlhu.on.c
  a

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Outline

• Background
• Epidemiology
• Journey
• Polysaccharide vaccines
• Conjugate C vaccines
• Conjugate quadrivalent vaccines
• Meningococcal A vaccine
• Meningococcal B vaccines

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Background
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Meningococcal Disease

• Neisseria meningitidis
• Gram negative diplococci
• Thirteen different serogroups, classified by
  their polysaccharide (sugar) capsule
• Most common A, B, C, Y, W135 and X

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Meningococcal Disease

• Causes
• meningitis - inflammation of the lining brain
• meningococcemia - in the blood
• Disseminated intravascular coagulation (DIC)
• Presents as fever, headache, vomiting, stiff
  neck, photophobia and petechial rash
• Fatal in approximately 10
• Long term sequelae 10 - 20 such as hearing loss,
  amputation or neurologic

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Immunogenicity

• Vaccines authorized based on immunogenicity, not
  efficacy
• Correlate of protection
• Serum bactericidal antibody (SBA) titre
• Dilution of serum able to kill meningococcal
  bacteria in vitro requires the addition of
  complement
• Using human complement correlate is 14
• Measure
• Percent achieving titre
• Geometric mean titre

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Protection

• Circulating antibody titre
• Immune memory
• May be too slow for post-exposure protection
• Herd immunity

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Epidemiology
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Meningococcal by Year and SerogroupSource NACI
Statement, August 2009
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Meningococcal Epidemiology

• 2006
• 210 cases in Canada
• Serogroup C 43 cases 0.13/100,000
• Serogroup B 113 cases 0.34/100,000
• Serogroup Y 27 cases 0.08/100,000
• Serogroup W135 6 cases 0.02/100,000
• Serogroup A 2 cases 0.01/100,000
• Other 19 cases

NACI Statement, CCDR, Volume 35 ACS-3 April
2009
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The Journey
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Meningococcal A
Quadrivalent conjugate A, C, Y and W135
Meningococcal B
Conjugate C
Polysaccharide A, C A, C, Y, W135
2001
1960 - 1980
2006 2010
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Polysaccharide Vaccines
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Polysaccharide Vaccines

• Menomune sanofi pasteur
• Provides protection against A, C, Y, W135
• T-cell independent
• Not effective in less than 2 years of age
• Only 40 effective in 2-9 years of age
• 85 effective in teenagers
• Protection decreases rapidly and likely gone by
  3-5 years of age
• Does not reliably decrease carriage
• May induce hyporesponsiveness

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NACI Recommendation Polysaccharide Vaccine

• asplenic patients, sickle cell disease
• complement deficient, properdin or factor D
  deficiency
• travellers e.g. Hajj, Mecca, Saudi Arabia
• laboratory workers who handle meningococcal
  specimens
• military
• close contacts of serogroups A, C, Y, W135
• outbreaks of serogroups A, C, Y, W135

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Conjugate C Vaccines
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Conjugate Vaccines

• Sugar linked to a protein
• diphtheria toxoid
• diphtheria toxoid mutant CRM 197
• tetanus toxoid
• T cell dependent
• Works in young children
• Decreases carriage leading to herd immunity
• Boostable response

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Meningococcal C Conjugate Vaccines

• Three conjugate C vaccines on the market
• Menjugate (Novartis Vaccines) CRM197 carrier
• MeningitecTM (Pfizer) - CRM197 carrier
• Neisvac-CTM (GlaxoSmithKline) tetanus toxoid
  carrier

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NACI RecommendationsMeningococcal C conjugate

• Routine program
• 2 months to 4 year olds
• adolescents
• young adults
• consider for 5-10 year olds
• Post exposure for serogroup C
• Outbreaks serogroup C

NACI CCDR, 2001 272-36
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Richmond P et al. The Journal of Infectious
Disease 2001 183160-3
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Richmond P et al. The Journal of Infectious
Disease 2001 183160-3
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Effectiveness By Age - UK
 
Trotter CL et al. Lancet, July 24,
2004364365-367.
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Effectiveness By Age - Quebec
 
De Wals et al. Pediatric Infectious Disease,
July 201130(7)566-569.
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Infant Vaccination

• Based on decreasing effectiveness and
  immunogenicity, NACI recommended
• If vaccinated as infant (lt 1 year) need a dose
  in second year of life (12 to 23 months)

NACI, CCDR, November 200733(ACS-11)1-12
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Quadrivalent ConjugateA, C, Y, W135
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Conjugate A, C, Y, W135

• MenactraTM (sanofi pasteur) diphtheria toxoid
• Authorized for use May 2006
• Authorized for ages 2 55 years
• Not very immunogenic in infants
• MenveoTM (Novartis ) - mutant diphtheria toxoid
  CRM197
• Authorized for use May 2010
• Mix lyophilized A with liquid C, Y, W135
• Authorized for ages 11-55 years
• Has been shown to be immunogenic in infants

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NACI Recommendation

• asplenic patients, sickle cell disease
• complement deficient, properdin or factor D
  deficiency
• travellers e.g. Hajj, Mecca, Saudi Arabia
• laboratory workers who handle meningococcal
  specimens
• military
• close contacts of serogroups A, Y, W135
• outbreaks of serogroups A, Y, W135
• primary antibody deficiencies
• HIV positive - consider

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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 200733(ACS-3)1-23
NACI, CCDR, April 200936(ACS-3)1-40.
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Jackson LA et al. Clinical Infectious Diseases
200949e1-10
C non-inferior others Menveo superior
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All Menveo superior
Jackson LA et al. Clinical Infectious Diseases
200949e1-10
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Effectiveness Data from US MenactraTM

• 14 vaccine failures in the US
• 8 serogroup C 6 serogroup Y
• Median age at vaccination 18 years (12-20 years)
• Mean time from vaccination to disease 395 days
  (43-1021 day)
• 3 underlying conditions
• 3 fatal (21 case fatality)
• Vaccine effectiveness estimated at 80-85 within
  2 3 years after vaccination

MacNeil et al. Pediatric Infectious Disease
Journal, June 201130(6)451-455
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Effectiveness Data from US MenactraTM

• Case control study 108 cases 158 controls
• 78 effectiveness over 5 years of vaccination
• (95 CI 29-93)
• Vaccinated lt 1 year ago 95 (95 CI10-100)
• Vaccinated 1 year ago 91 (95 CI10-101 ??)
• Vaccinated 2-5 years ago 58 (95 CI -72 -
  89)
• Waning protection over time

ACIP MMWR January 8, 201160(3)72-76.
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US Vaccination Recommendation

• Adolescents
• 11-12 year of age and booster at 16 years
• High risk conditions
• 2-dose primary schedule 2 months apart
• Booster every five year
• Exposure risk (microbiologist, travelers to
  endemic countries)
• 1-dose primary schedule
• Booster 3 years later (2-6 years of age)
• Booster 5 years later (7 years of age or older)

ACIP MMWR January 8, 201160(3)72-76.
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Canada Different than United States

• In the United States
• No conjugate C meningococcal vaccine for infants
  / toddlers
• Using quadrivalent conjugate vaccine for routine
  immunizations for 11 - 19 year olds just over
  50 coverage
• Limited herd immunity
• Also more serogroup Y disease

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Guillain Barré Syndrome (GBS)

• Passive surveillance suggested a possible
  association between GBS and MenactraTM
• Two large studies in US using managed care
  organization data have not found any association
• Past GBS no longer needs to be considered a
  precaution for MenactraTM

Presentations by Velentgas and Weintraub to ACIP
June 2010.
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Provincial Schedules
Province Infant / Toddler Men C Conjugate Adolescent Timing Adolescent Product
BC 2, 12 months Grade 6 Men C
Alberta 2, 4, 12 months Grade 9 Quadrivalent
SK 12 months, 4-6 years Grade 6 Men C ? Quadrivalent
Manitoba 12 months Grade 4 Men C
Ontario 12 months Grade 7 Quadrivalent
Quebec 12 months Catch-up lt 18 years Men C
NB 12 months Grade 9 Quadrivalent
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Provincial Schedules
Province Infant / Toddler Men C Conjugate Adolescent Timing Adolescent Product
NS 12 months Grade 7 Men C
PEI 12 months Grade 9 Quadrivalent
NF 12 months Grade 4 Quadrivalent
NWT 2, 12 months lt 5 years Grade 9 Men C Quadrivalent if going to school outside
Yukon 2, 12 months Grade 6 University students if not previously vaccinated Men C
Nunavut 12 months Grade 9 Men C
Canadian Nursing Coalition on Immunization (CNCI)
as of April 19, 2011 http//www.phac-aspc.gc.ca/i
m/ptimprog-progimpt/table-1-eng.php
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Meningococcal A
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MenAfriVacTM

• Conjugate meningococcal A vaccine for Sub-Saharan
  Africa meningitis belt
• Meningitis Vaccine Project
• Introduced into Burkina Faso, Mali and Niger in
  December 2010 with dramatic effects
• Plans for Cameroon, Chad and Nigeria, then other
  countries
• Given to 1-29 year olds
• Cost less than 50 cents per dose
• Estimated to prevent 1 million cases and save
  300 million over the next decade

http//www.meningvax.org/
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Meningococcal B
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Difficulties with Development

• Capsule structurally identical to fetal brain
  cell adhesion molecules
• Induce a weak immune response
• Could involve production of autoantibodies
• Outer-membrane-vesicle vaccine
• Strain specific PorA, highly variable across
  strains
• Each outbreak needs its own vaccine
• Vaccines incorporate multiple PorAs

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Reverse Vaccinology

• Take the genetic composition of the bacteria
• Look for genes that may represent surface exposed
  proteins
• Put into Escherichia coli expression system to
  make proteins
• Mice immunized and antibodies assessed by serum
  bactericidal antibody (SBA) assay
• Best candidate antigens made into vaccine

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Novartis Vaccine Bexsero

• Factor H binding protein (fHbp) fusion protein
• Neisserial heparin-binding antigen (NHBA) -
  fusion protein
• Neisserial adhesin A (NadA)
• Outer-membrane-vesicle New Zealand (OMVnz)
• Aluminum adjuvant

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Immunogenicity

• Needs to be assessed using serum bactericidal
  antibody (SBA) assays against various strains
  that express the target antigens
• Evidence showing it is immunogenic at various
  ages and has an acceptable safety profile

Bai et al. Expert Opin Biol Ther 2011
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Coverage of Strains

• Because of the antigenic variation and different
  levels of expression of the proteins, need to
  assess how well the vaccine will protect against
  circulating strains
• Meningococcal antigen typing assay (MATS)
• ELISA measures cross-reactivity and quantity of
  the antigen
• Correlates with serum bactericidal antibody (SBA)
  assay

Donnelly J et al. PNAS Early Edition
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Coverage of Strains

• Strains exceeded the threshold value for any of
  the three antigens had a 80 chance of being
  killed by SBA
• MATS will allow for assessing expected strain
  coverage in various countries

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Pfizer Vaccine

• Contains two factor H binding proteins, to cover
  various strains
• In Phase II trials

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The Journey Continues

• ?? Questions ??
• Thank You