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2. 2 Meningococcal Vaccines The Journey Continues Bryna Warshawsky, Associate Medical Officer of Health 519-663-5317 ext. 2427; bryna.warshawsky@mlhu.on.ca Canadian Public Health Association Conference June 19, 2011

3. 3 Outline Background Epidemiology Journey –Polysaccharide vaccines –Conjugate C vaccines –Conjugate quadrivalent vaccines –Meningococcal A vaccine –Meningococcal B vaccines

4. 4 Background

5. 5 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

6. 6 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

7. 7 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

8. 8 Protection Circulating antibody titre Immune memory –May be too slow for post-exposure protection Herd immunity

9. 9 Epidemiology

10. Meningococcal by Year and Serogroup Source: NACI Statement, August 2009

11. 11 Meningococcal Epidemiology 2006: –210 cases in Canada –Serogroup C 43 cases0.13/100,000 –Serogroup B 113 cases0.34/100,000 –Serogroup Y27 cases0.08/100,000 –Serogroup W135 6 cases 0.02/100,000 –Serogroup A2 cases0.01/100,000 –Other 19 cases NACI Statement, CCDR, Volume 35 ACS-3 April 2009

16. 16 The Journey

17. 1960 - 1980 2001 2006 2010 Polysaccharide A, C A, C, Y, W135 Conjugate C Quadrivalent conjugate A, C, Y and W135 Meningococcal B Meningococcal A

18. 18 Polysaccharide Vaccines

19. 19 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

21. 21 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

22. 22 Conjugate C Vaccines

23. 23 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

24. 24 Meningococcal C Conjugate Vaccines Three conjugate C vaccines on the market: –Menjugate ® (Novartis Vaccines) – CRM 197 carrier –Meningitec TM (Pfizer) - CRM 197 carrier –Neisvac-C TM (GlaxoSmithKline) – tetanus toxoid carrier

25. 25 NACI Recommendations Meningococcal 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

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

28. 28 Effectiveness By Age - UK Age of vaccinationWithin 1 yearMore than 1 year 2, 3, 4 months (3 doses) 93% (67 to 99) -81% (-7430 to 71) 5 to 11 months (2 doses) 87% (11 to 99) 82% (-8 to 97) 1 to 2 years (1 dose) 88% (65 to 96) 61% (-327 to 94) 3 to 4 years (1 dose) 98% (90 to 100) 93% (78 to 98) 11 to 16 years (1 dose) 96% (89 to 99) 90% (77 to 96) Trotter CL et al. Lancet, July 24, 2004;364:365-367.

29. 29 Effectiveness By Age - Quebec Age of vaccinationWithin 2 yearMore than 2 year < 1 year (2-3 doses) 83% (4 to 97) 34% (-168 to 83) 1 year (1 dose) 92% (60 to 98) 67% (-38 to 92) ≥ 2 years (1 dose) 97% (88 to 99) 88% (67 to 95) All ages 96% (84 to 99) 81% (62 to 93) De Wals et al. Pediatric Infectious Disease, July 2011;30(7):566-569.

30. 30 Infant Vaccination Based 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

31. 31 Quadrivalent Conjugate A, C, Y, W135

32. 32 Conjugate A, C, Y, W135 Menactra TM (sanofi pasteur) – diphtheria toxoid –Authorized for use May 2006 –Authorized for ages 2 – 55 years –Not very immunogenic in infants Menveo TM (Novartis ) - mutant diphtheria toxoid CRM 197 –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

33. 33 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

34. 34 NACI Recommendation Adolescent 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.

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

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

37. 37 Effectiveness Data from US Menactra TM 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

38. 38 Effectiveness Data from US Menactra TM 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.

39. 39 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.

40. 40 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

41. 41 Guillain Barré Syndrome (GBS) Passive surveillance suggested a possible association between GBS and Menactra TM 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 Menactra TM Presentations by Velentgas and Weintraub to ACIP; June 2010.

42. Provincial Schedules ProvinceInfant / Toddler Men C Conjugate Adolescent Timing Adolescent Product BC2, 12 monthsGrade 6Men C Alberta2, 4, 12 monthsGrade 9Quadrivalent SK12 months, 4-6 years Grade 6Men C  Quadrivalent Manitoba12 monthsGrade 4Men C Ontario12 monthsGrade 7Quadrivalent Quebec12 monthsCatch-up < 18 years Men C NB12 monthsGrade 9Quadrivalent

43. Provincial Schedules ProvinceInfant / Toddler Men C Conjugate Adolescent Timing Adolescent Product NS12 monthsGrade 7Men C PEI12 monthsGrade 9Quadrivalent NF12 monthsGrade 4Quadrivalent NWT2, 12 months; < 5 years Grade 9Men C Quadrivalent if going to school outside Yukon2, 12 monthsGrade 6 University students if not previously vaccinated Men C Nunavut12 monthsGrade 9Men C Canadian Nursing Coalition on Immunization (CNCI) as of April 19, 2011 http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php

44. 44 Meningococcal A

45. 45 MenAfriVac TM 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/

46. 46 Meningococcal B

47. 47 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

48. 48 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

49. 49 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

50. 50 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

51. 51 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

52. 52 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

53. 53 Pfizer Vaccine Contains two factor H binding proteins, to cover various strains In Phase II trials

54. 54 The Journey Continues ?? Questions ?? Thank You