MenB vaccines: pre and post implementation issues by Dr Matthew Snape

4,009 views

Published on

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
4,009
On SlideShare
0
From Embeds
0
Number of Embeds
2,075
Actions
Shares
0
Downloads
40
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

MenB vaccines: pre and post implementation issues by Dr Matthew Snape

  1. 1. MenB vaccines: pre and post implementation issuesDr Matthew SnapeConsultant in Paediatrics and VaccinologyHonorary Senior Clinical LecturerOxford Radcliffe Hospitals NHS TrustOxford Vaccine Group, University of Oxford Department of Paediatrics
  2. 2. Disclosures• Principal investigator or co-investigator for clinical trials conducted on behalf of University of Oxford with manufacturers of vaccines, including Novartis Vaccine and Diagnostics and Pfizer• Fees from consultancy work and presentations from vaccine manufacturers paid to seminar fund administered by University of Oxford Department of Paediatrics• Travel and accommodation expenses for attendance at immunisation conferences paid by vaccine manufacturers to University of Oxford Department of Paediatrics
  3. 3. Bivalent rLP2086/fHbp based vaccine• Produced by Pfizer• Contains lipidated, recombinant, versions of – rLP2086/fHbp subfamily A (A05) – rLP2086/fHbp subfamily B (B01) Marshall et al PIDJ 2012
  4. 4. Investigational MenB vaccine: 4CMenB N NHBA GNA1030 C N GNA2091 fHbp C + N NadA CKey antigens• 50µg Factor H Binding Protein (fHbp)• 50µg Neisserial adhesin A (NadA)• 50µg Neisseria Heparin Binding Antigen (NHBA)• 25µg OMV (New Zealand strain) • PorA 1.7-2,4 (1.4) Submitted for licensure in EU in 2010
  5. 5. MenB vaccines: what do we need to know?• Are the vaccine components immunogenic?• Can this vaccine be incorporated into routine immunisation schedules?• How well tolerated is the vaccine?• What is the likely breadth of protection against serogroup B meningococcal disease?• If introduced, how will we tell if the vaccines are: – Safe? – Working?
  6. 6. MenB vaccines: what do we need to know?• Are the vaccine components immunogenic?
  7. 7. Testing immunogenicity of MenB vaccines Serum bactericidal assay (SBA) Add human complement X SBA ≥ 1:4 used as correlate of protection• For MenB, need to test against a range of meningococcal strains to assess breadth of coverage• Lack of serum (especially in paediatric studies) limits numbers of strains that can be tested• MenB test strains used aim to show immunogenicity of vaccine antigens
  8. 8. Bivalent rLP2086/fHbp based vaccine• Produced by Pfizer• Contains lipidated, recombinant, versions of – rLP2086/fHbp subfamily A (A05) – rLP2086/fHbp subfamily B (B01) Marshall et al PIDJ 2012
  9. 9. Testing immunogenicty of fHbp proteins in bivalent fHbp MenB vaccinePhase II study of ninety 18 to 36 month olds Marshall et al PIDJ 2012
  10. 10. Investigational MenB vaccine: 4CMenB N NHBA GNA1030 C N GNA2091 fHbp C + N NadA CKey antigens• 50µg Factor H Binding Protein (FHbp)• 50µg Neisserial adhesin A (NadA)• 50µg Neisseria Heparin Binding Antigen (NHBA)• 25µg OMV (New Zealand strain) • PorA 1.7-2,4 (1.4) Submitted for licensure in EU in 2010
  11. 11. Are these proteins immunogenic?• Need to assess response against SBA strains that: – contain the target antigen being assessed – are ‘mis-matched’ for the other target antigens Strain ST fHBP NadA NHBA PorA 4CMenB contains 44/76-SL 32 1.1 - (3) P1.16 fHBP 1.1 NadA 2 5/99 8 2.8 2 20 P1.2 NHBA PorA P1.4 M10713 136 2.9 - 10 P1.3 (OMV) NZ 98/254 41/44 1.14 - 2 P1.4
  12. 12. Immunisation with 4CMenB at 2, 4, 6 and 12 months: % Participants with hSBA Titres ≥1:4 44/76-SL NZ98/254 5/99 UKP1.4 GB101 GB355 GB364 fHbp PorA (OMV) NadA Assessing the bactericidal activity of post-immunisation serum against strains with differing antigen sub-variants or levels of expression n = 30 - 45 Baseline Post 3rd dose Pre 12 month dose Post 12 month dose Adapted from Findlow, Borrow et al CID 2010
  13. 13. MenB vaccines: what do we need to know?• Are the vaccine components immunogenic?• Can this vaccine be incorporated into routine immunisation schedules?
  14. 14. Incorporating 2 month 3 month 4 month 5 month 6 month 7 month 4CMenB into Group of age of age of age of age of age of age immunisation Blood draw Blood draw schedule B+R246 4CMenB 4CMenB 4CMenB (n= 622) Routine Routine Routine MenCPhase IIb study Blood draw Blood draw B246_R357 4CMenB Routine 4CMenB Routine 4CMenB Routine (n=632)• 1885 enrolled MenC Blood draw Blood draw B+R234 4CMenB 4CMenB 4CMenB (n=317) Routine Routine Routine MenC Blood draw Blood draw R234 (n=314) Routine Routine Routine Men C *Routine vaccines: Infanrix-Hexa and Prevenar Gossger, Snape et al JAMA 2012
  15. 15. Immunogenicity of 4CMenB Minimal reduction in immunogenicity with concomitant routine immunisation administration (fHbp) (NadA 2) (PorA P1.4)Adapted from Gossger, Snape et al JAMA 2012
  16. 16. 2 month 3 month 4 month 5 month 6 month 7 monthPhase IIb study Group of age of age of age of age of age of age• 1885 enrolled Blood draw Blood draw B+R246 4CMenB 4CMenB 4CMenB (n= 622) Routine Routine Routine MenC Blood draw Blood draw B246_R357 4CMenB Routine 4CMenB Routine 4CMenB Routine (n=632) MenC Blood draw Blood draw B+R234 4CMenB 4CMenB 4CMenB (n=317) Routine Routine Routine MenC Blood draw Blood draw R234 (n=314) Routine Routine Routine Men C *Routine vaccines: Infanrix-Hexa and Prevenar
  17. 17. Immunogenicity of 4CMenB No reduction in immunogenicity with an accelerated (2, 3, 4, month) schedule (fHbp) (NadA 2) (PorA P1.4)Adapted from Gossger, Snape et al JAMA 2012
  18. 18. 2 month 3 month 4 month 5 month 6 month 7 monthPhase IIb study Group of age of age of age of age of age of age• 1885 enrolled Blood draw Blood draw B+R246 4CMenB 4CMenB 4CMenB (n= 622) Routine Routine Routine MenC Blood draw Blood draw B246_R357 4CMenB Routine 4CMenB Routine 4CMenB Routine (n=632) MenC Blood draw Blood draw B+R234 4CMenB 4CMenB 4CMenB (n=317) Routine Routine Routine MenC Blood draw Blood draw R234 (n=314) Routine Routine Routine Men C *Routine vaccines: Infanrix-Hexa and Prevenar
  19. 19. Minimal interference with routine vaccinesAdapted from Gossger, Snape et al JAMA 2012
  20. 20. MenB vaccines in adolescents Lancet 2012 Lancet 2012
  21. 21. MenB vaccines: what do we need to know?• Are the vaccine components immunogenic?• Can this vaccine be incorporated into routine immunisation schedules?• How well tolerated is the vaccine?
  22. 22. Reactogenicity of bivalent fHbp vaccine: 18 to 36 month olds100 90 Fever 100 Irritability 80 90 70 80 60 70 50 60 Dose 1 50 40 Dose 1 30 Dose 2 40 30 Dose 2 20 Dose 3 20 Dose 3 10 0 10 0 20µg 60µg 200µg Hep A Vaccine/ 20µg 60µg 200µg Hep A Placebo Vaccine/ Placebo 100 Local Tenderness 90 80 n = 19 - 32 70 60 50 Dose 1 40 30 Dose 2 20 Dose 3 10 0 20µg 60µg 200µg Hep A Vaccine/ Placebo Marshall et al PIDJ 2012
  23. 23. Reactogenicity 2 month 3 month 4 month 5 month 6 month 7 month of 4CMenB Group of age of age of age of age of age of age Blood draw Blood draw B+R246 4CMenB 4CMenB 4CMenB (n= 622) Routine Routine Routine MenC Blood draw Blood draw B246_R357 4CMenB Routine 4CMenB Routine 4CMenB Routine (n=632) MenC Blood draw Blood draw B+R234 4CMenB 4CMenB 4CMenB (n=317) Routine Routine Routine MenC Blood draw Blood draw R234 (n=314) Routine Routine Routine Men C *Routine vaccines: Infanrix-Hexa and Prevenar
  24. 24. Safety Profile of 4CMenB Vaccine in Infants Fever Rates After First, Second and Third Doses Study V72P12 ≥40°C 100 100 100 39-<40°C 90 90 90 38-<39°C 80 80 80 % of Subjects 70 70 70 60 60 60 50 50 50 40 40 40 30 30 30 20 20 20 10 10 10 0 0 0 Dose 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 4CMenB + Routine 4CMenB Alone Routine Routine 4CMenB + Routine 2-4-6 mo 2-4-6 mo 3-5-7 mo 2-3-4 mo 2-3-4 mo N = 605-624 N = 592-612 N = 602-627 N = 304-311 N = 310-317Routine vaccines: Infanrix-hexa, Prevenar Adapted from Gossger, Snape et al JAMA 2012
  25. 25. Local Reactions to 4CMenB and Routine Vaccines R357 R357 R357 R357 R357B+R246: 4CMenB + routine infant vaccines at 2, 4, 6 months R357B246_R357: 4CMenB at 2, 4, 6 months, routine infant vaccines at 3, 5, 7 monthsB+R234: 4CMenB+ routine infant vaccines at 2, 3, 4 months Adapted from Gossger, Snape et al JAMA 2012R234: routine infant vaccines at 2, 3, 4 months
  26. 26. Safety: 4CMenB• 1882 participants immunised – 1570 received 4CMenB +/- routine immunisations – 312 received routine immunisations alone• 7365 immunisation episodes – 2787 4CMenB + routine – 1838 4CMenB alone • 4625 4CMenB episodes – 2740 routine imms alone• 20 serious adverse events possibly related to immunisationGossger, Snape et al JAMA 2012
  27. 27. Safety: 4CMenB• 20 SAEs possibly related to • 6 hospitalisations for fever within imms… 2 days of 4CMenB receipt +/- routine vaccines• 3 hypotonic +/- • 1 hospitalisation for fever after hyporesponsiveness: routine imms alone. – 2 days following 4CMenB and routine immunisation • 2 episodes of reported Kawasaki – Same day as 4CMenB and disease, reviewed by routine immunisation independent expert panel – Same day as routine – 1 ‘unlikely’ Kawasaki’s disease, immunisations symptom onset prior to 4CMenB – 1 ‘complete’ Kawasaki disease, onset 23 days after 4CMenB: ‘possibly related’Gossger, Snape et al JAMA 2012
  28. 28. Convulsions in Phase IIb study of 4CMenB Participants With Febrile Seizures Days 1-2+ Days 3-14 Days >14 Total 4CMenB +/- routine 0 1 1 2 Control* 0 0 2 2 Participants With Afebrile Seizures Days 1-2+ Days 3-14 Days >14 Total 4CMenB +/- routine 2 0 1 3 Control* 2 0 1 3*Routine vaccines: Infanrix-Hexa and Prevenar Gossger, Snape et al JAMA 2012
  29. 29. MenB vaccines: what do we need to know?• Are the vaccine components immunogenic?• Can this vaccine be incorporated into routine immunisation schedules?• How well tolerated is the vaccine?• What is the likely breadth of protection against serogroup B meningococcal disease?
  30. 30. • Through the looking glass……..
  31. 31. Testing immunogenicty of fHbp proteins in bivalent fHbp MenB vaccinePhase II study of ninety 18 to 36 month olds Marshall et al PIDJ 2012
  32. 32. Immunisation with 4CMenB at 2, 4, 6 and 12 months: % Participants with hSBA Titres ≥1:4 44/76-SL NZ98/254 5/99 UKP1.4 GB101 GB355 GB364 fHbp PorA (OMV) NadA Assessing the bactericidal activity of post-immunisation serum against strains with differing antigen sub-variants or levels of expression n = 30 - 45 Baseline Post 3rd dose Pre 12 month dose Post 12 month dose Adapted from Findlow, Borrow et al CID 2010
  33. 33. Investigational MenB vaccine: 4CMenB N NHBA GNA1030 C N GNA2091 fHBP C + N NadA CKey antigens• 50µg Factor H Binding Protein (FHbp)• 50µg Neisserial adhesin A (NadA)• 50µg Neisseria Heparin Binding Antigen (NHBA)• PorA 1.7-2,4 (1.4)
  34. 34. Predicting susceptibility of 4CMenB induced bactericidal antibodiesVaccine
  35. 35. Predicting susceptibility of 4CMenB induced bactericidal antibodiesVaccine
  36. 36. Predicting susceptibility of 4CMenB induced bactericidal antibodiesVaccine
  37. 37. Predicting susceptibility of 4CMenB induced bactericidal antibodiesVaccine ?
  38. 38. Susceptibility of meningococcal strains to serum obtained in recipients of 4CMenB can be predicted by: 3. Whether the antibodies induced by the vaccine antigens ‘cross-react’ with the relevant antigen on the target strainVaccine • PorA • fHbp variant 1.1 and fHbp 1.2, 1.3, 1.4….? ? • NHBA peptides …….
  39. 39. Predicting breadth of coverage of 4CMenB• Need to estimate what % of strains will have at least one ‘target’ antigen that is: – Expressed at sufficient quantities – Sufficiently ‘cross-reactive’ with the vaccine antigens Susceptible to killing by vaccine induced antibodies
  40. 40. Predicting breadth of coverage of 4CMenBVaccine X X X X
  41. 41. Predicting breadth of coverage of 4CMenBVaccine X X X X X X X X Would predict 16/24 strains X X likely to be killed by vaccine induced antibodies X X X X
  42. 42. Meningococcal Antigen Typing System: MATS• Developed by Novartis Vaccines to create a – reproducible system for assessing panels of region specific meningococcal strains – assess for presence of at least one expressed antigen sufficiently matched to allow killing by vaccine induced antibodies
  43. 43. Predicting breadth of coverage of 4CMenB: MATSBinding of target proteins in MenB strains underassessment to assay antibodies compared tothat of ‘reference strains’• Assessing both expression and cross- protection• Expressed as a proportion (‘relative potency’)• Threshold for proportion that predicts killing by pooled post-immunisation infant sera SBA determined for each antigen• Representative panel of strains assessed to assess proportion of strains with at least one antigen above this threshold Y Y Y Y
  44. 44. MATS methodology: – Transferred across 8 reference laboratories • Health Protection Agency, Institut Pasteur, Norwegian Institute of Public Health, University of Würzburg, Istituto Superiore di Sanità, National Center for Microbiology-Institute of Health Carlos III, Centers for Disease Control, Queensland Paediatric Infectious Disease Laboratory – Ongoing in several more Slide provided by Novartis Vaccines
  45. 45. ‘Coverage’ of 4CMenB in 5 European countries as predicted by MATS 4CMenB European coverage estimates† Norway: 85% [95% CI: 76%, 98%] n=41 England & Wales: 73% [59%, 88%] n=535 Germany: 82% [69%, 92%] n=222 France: 85% [70%, 93%] n=200 Italy: 87% [70%, 93%] n=54 Based on MATS, 4CMenB is predicted to cover 78% of strains isolated during 2007 - 2008 Slide provided by Novartis Vaccines Boccadifuoco G, et al. Presented at: Meningitis and Septicaemia in Children and Adults 2011 (Organized by Meningitis Research Foundation); 8–9 November 2011; London, UK. Poster V36.
  46. 46. Half of All European Strains Tested Were Covered by More Than One Antigen Contained in 4CMenB Percent of strains predicted covered by number of 4CMenB antigens above Positive Bactericidal Threshold Percent (%) 4CMenB coverage estimates† 28% 5 European Countries: 1Ag>Threshold 78% [66%, 92%] 22% 34% 2Ag>Threshold • 4CMenB may still be effective 0Ag>Threshold if one antigen is down 16% regulated or mutated 3Ag>Threshold0.1%4Ag>Threshold Slide provided by Novartis Vaccines Boccadifuoco G, et al. Presented at: Meningitis and Septicaemia in Children and Adults 2011 (Organized by Meningitis Research Foundation); 8–9 November 2011; London, UK. Poster V36.
  47. 47. Bivalent fHbp vaccine• Meningococcal Antigen Surface Expression (MEASURE) Assay• FACS based analysis to determine expression of fHBP, to predict killing on SBA
  48. 48. MenB vaccines: potential for herd immunity• Impact of either vaccine on oro- pharyngeal carriage unknown• Potential for herd immunity therefore unknown• Would require deployment of vaccine in adolescence/ young adulthood Christensen et al Lancet ID 2010
  49. 49. MenB vaccines: what do we need to know?• Are the vaccine components immunogenic?• Can this vaccine be incorporated into routine immunisation schedules?• How well tolerated is the vaccine?• What is the likely breadth of protection against serogroup B meningococcal disease?• If introduced, how will we tell if the vaccines are: – Safe? – Working?
  50. 50. MenB vaccines: post implementation surveillance Safety/Reactogenicity • Potential need for active surveillance for – Kawasaki disease – Febrile convulsions following immunisation – Numbers and management of infants < 3 months presenting to hospital with fever following immunisation • Ideally conducted before and after implementation, to determine if any change from baseline • Precedent of using BPSU (e.g. GBS post H1N1 immunisation) • Requires agreement of disease definitions (Brighton colloboration)
  51. 51. MenB vaccines: post implementation surveillanceDetermining vaccine effectiveness requires – Accurate data on vaccine uptake – Robust system of disease notificationVaccine effectiveness determined by comparing – Rates of immunised/unimmunised in • child with disease • general population
  52. 52. What would constitute a ‘MenB’ vaccine failure?• If a child develops serogroup B meningococcal disease due to strain not bearing vaccine targets – is this a failure?• If a child develops serogroup Y meningococcal disease due to a strain bearing vaccine targets – is this a vaccine failure?
  53. 53. Determining vaccine effectiveness• Expression of vaccine target antigens (e.g. by MATS) can only be determined on meningococcal isolates (not PCR)• Represents a challenge, especially given widespread use of antibiotics prior to hospital
  54. 54. Will we see ‘strain replacement’? Oropharyngeal carriage strains• If the MenB vaccines can in a population influence oropharyngeal carriage of meningococcus….• Potential for ‘selection’ for strains either – Lacking the genes for the target antigens – Low expressors of the target antigens
  55. 55. Will we see ‘strain replacement’?• If the MenB vaccines can Oropharyngeal carriage strains in a population influence oropharyngeal carriage of meningococcus….• Potential for ‘selection’ for strains either – Lacking the genes for the target antigens – Low expressors of the target antigens
  56. 56. Will we see ‘strain replacement’?• If the MenB vaccines can Oropharyngeal carriage strains in a population influence oropharyngeal carriage of meningococcus….• Potential for ‘selection’ for strains either – Lacking the genes for the target antigens – Low expressors of the target antigens
  57. 57. Strain replacement?• Can only be determined by large scale oropharyngeal carriage studies evaluating strains for vaccine target phenotype – e.g. by MATS
  58. 58. Summary: 4CMenB• Vaccine prevention of serogroup B meningococcal disease closer than ever before• Clinical trials have shown immunogenicity of vaccine components• Immunogenicity demonstrated across a range of immunisation schedules and with routine immunisations• Implementation of new vaccines will ultimately depend on cost-effectiveness analyses, and local epidemiology• True effectiveness unlikely to be known until vaccines have been introduced
  59. 59. Acknowledgments• Jamie Findlow (HPA) for provision of vaccine failure definitions• Novartis Vaccines for provision of MATS data• Professor Andrew Pollard and staff of the Oxford Vaccine Group

×