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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; [email protected] Outline. Background Epidemiology Journey Polysaccharide vaccines

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meningococcal vaccines the journey continues

Meningococcal VaccinesThe Journey Continues

Canadian Public Health

Association Conference

June 19, 2011

Bryna Warshawsky, Associate Medical Officer of Health

519-663-5317 ext. 2427; [email protected]

outline
Outline
  • Background
  • Epidemiology
  • Journey
    • Polysaccharide vaccines
    • Conjugate C vaccines
    • Conjugate quadrivalent vaccines
    • Meningococcal A vaccine
    • Meningococcal B vaccines
meningococcal disease
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
meningococcal disease1
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
immunogenicity
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 ≥1:4
    • Measure:
      • Percent achieving titre
      • Geometric mean titre
protection
Protection
  • Circulating antibody titre
  • Immune memory
    • May be too slow for post-exposure protection
  • Herd immunity
meningococcal epidemiology
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

slide17

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

naci recommendation polysaccharide vaccine
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
conjugate vaccines
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
naci recommendations meningococcal c conjugate
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; 27:2-36

conjugate a c y w135
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
naci recommendation
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
naci recommendation adolescent vaccination
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.

slide31

All Menveo superior

Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10

effectiveness data from us menactra tm
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 2011;30(6):451-455

effectiveness data from us menactra tm1
Effectiveness Data from US MenactraTM
  • Case 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 recommendation
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, 2011;60(3):72-76.

guillain barr syndrome gbs
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.

provincial schedules1
Provincial Schedules

Canadian Nursing Coalition on Immunization (CNCI) as of April 19, 2011

http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php

menafrivac tm
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/

difficulties with development
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
reverse vaccinology
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
novartis vaccine bexsero
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
immunogenicity1
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

coverage of strains
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

coverage of strains1
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
pfizer vaccine
Pfizer Vaccine
  • Contains two factor H binding proteins, to cover various strains
  • In Phase II trials
the journey continues

The Journey Continues

?? Questions ??

Thank You

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