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Meningococcal Vaccines The Journey Continues

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

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Meningococcal Vaccines The Journey Continues

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  1. 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@mlhu.on.ca

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

  3. Background

  4. 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

  5. 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

  6. 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

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

  8. Epidemiology

  9. Meningococcal by Year and SerogroupSource: NACI Statement, August 2009

  10. 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

  11. The Journey

  12. 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

  13. Polysaccharide Vaccines

  14. 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

  15. Conjugate C Vaccines

  16. 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

  17. 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

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

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

  20. Quadrivalent ConjugateA, C, Y, W135

  21. 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

  22. 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

  23. 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.

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

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

  26. 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

  27. 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.

  28. 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.

  29. 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.

  30. Provincial Schedules

  31. 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

  32. Meningococcal A

  33. 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/

  34. Meningococcal B

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

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

  42. The Journey Continues ?? Questions ?? Thank You

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