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Leonard Mayer, Ph.D. Chief, Meningitis Laboratory MVPDB, DBD, CDC

Leonard Mayer, Ph.D. Chief, Meningitis Laboratory MVPDB, DBD, CDC. Characterization of candidate vaccine antigens among invasive Neisseria meningitidis isolates in the United States. National Center for Immunization & Respiratory Diseases.

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Leonard Mayer, Ph.D. Chief, Meningitis Laboratory MVPDB, DBD, CDC

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  1. Leonard Mayer, Ph.D. Chief, Meningitis Laboratory MVPDB, DBD, CDC Characterization of candidate vaccine antigens among invasive Neisseria meningitidis isolates in the United States National Center for Immunization & Respiratory Diseases Meningitis and Vaccine Preventable Diseases Branch

  2. Introduction Active Bacterial Core surveillance and the meningococcal strain collection in the US Prevalence and genetic diversity of vaccine antigen FHbp, NadA and NhbA in the US Epidemiological features of the three vaccine antigens in the US Molecular epidemiological features of the US meningococcal isolates Relationship between clonal complex and vaccine antigens Summary Outline

  3. Serogroup B cause of 1/3 of disease >60% of disease in infants age <1 year Proportion will increase with MenACWY vaccine program Overall meningococcal disease incidence low Vaccines would have to cover large proportion of disease causing strains to have impact Only adolescents receive MenACWY at this time Benefits of serogroup B vaccination program increases if vaccine provides protection against other serogroups Duration of protection important as cases do occur throughout life Importance of Serogroup B Vaccines in the US

  4. Bivalent vaccine FHbp (factor H binding protein) -subfamily B (variant 1) -subfamily A (variant 2 & 3) Multi-component vaccine FHbp variant 1 (subfamily B) NadA (Neisserial adhesin A ) NhbA (Neisserial heparin binding antigen ) (5 gene products with fusions 2 + 2 + 1 => 3 peptides) OMV NZ (Outer membrane vesicles of the New Zealand epidemic strain) Candidate Serogroup B Vaccines

  5. Active Bacterial Core surveillance (ABCs) Sites* ABCs *Represents approximately 13% of US population (40 million population size)

  6. Meningococcal Disease Incidence, United States, 1999-2008 Active Bacterial Core surveillance system, incidence excluding Oregon estimated to U.S. population of 49 states and Oregon incidence added in for 50 state estimate

  7. Annual Average Serogroup B Incidence, by Age, 1999-2008 Active Bacterial Core surveillance system, incidence excluding Oregon estimated to U.S. population of 49 states and Oregon incidence added in for 50 state estimate

  8. Meningococcal Disease Incidence ABCs*, 2000-2008 *Analysis excludes New Mexico which joined ABCs in 2004

  9. Serogroup B Isolates Collected, ABCs, 2000-2008 *Joined ABCs 7/1/2000

  10. Weighted Isolates, ABCs, Serogroup B, 2000-2008 *Joined ABCs 7/1/2000

  11. Prevalence and genetic diversity of FHbp, NadA, and NhbA

  12. Isolates Characterized for Vaccine Antigens, ABCs *Random sample of serogroup B isolates from 1989-1999 also tested, data not presented **650 NmB isolates, 2000-8 (with weighting for Oregon)

  13. FHbp Subfamily/Variant by Serogroup *650 NmB isolates, 2000-8 (with weighting for Oregon) **11 serogroup C isolates contain a single nucleotide deletion creating a frame-shift

  14. Proportion of nadA PCR+ and nhbA+ Isolates by Serogroup *650 NmB isolates, 2000-8 (with weighting for Oregon); 514 isolates not tested for nhbA

  15. NadA Presence Among Nm Isolates by FHbp Subfamily/Variant *650 NmB isolates, 2000-8 (with weighting for Oregon)

  16. FHbp Subvariant by Serogroup 650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in >5 isolates of any serogroup (B, C, or Y) are shown. Other includes subvariants present in ≤5 isolates of any serogroup (B, C, or Y).

  17. NadA Subvariant by Serogroup Not weighted for Oregon; all subvariants that were present in any serogroup (B, C, or Y) are shown. 

  18. NhbA Subvariant by Serogroup 650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in >5 isolates of any serogroup (B, C, or Y) are shown.  Other includes subvariants present in ≤5 isolates of any serogroup (B, C, or Y).

  19. Epidemiological features of the three vaccine antigens in NmB isolates

  20. FHbp Subfamily/Variant Distribution Among NmB Isolates by Year 650 NmB isolates, 2000-8 (with weighting for Oregon)

  21. Distribution of Most Frequent FHbp Subvariants Among NmB Isolates by Year 650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in ≥25 NmB isolates are shown.  Other includes subvariants present in <25 NmB isolates.

  22. FHbp Subfamily/Variant Distribution Among NmB Isolates by Age-Group 650 NmB isolates, 2000-8 (with weighting for Oregon)

  23. FHbp Subfamily/Variant Distribution Among NmB Isolates by Syndrome 650 NmB isolates, 2000-8 (with weighting for Oregon)

  24. FHbp Subfamily/Variant Distribution Among NmB Isolates by State Not weighted for Oregon

  25. Molecular epidemiological features of the U.S. meningococcal isolates

  26. Most Frequent Clonal Complexes and the Serogroup Typically Associated With It

  27. Most Frequent NmB Clonal Complexes by Syndrome 650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  28. Most Frequent NmB Clonal Complexes by Age-Group 650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  29. Most Frequent NmB Clonal Complexes by State Not weighted for Oregon; *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  30. Most Frequent NmB Clonal Complexes by Year 650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  31. Most Frequent PorA Types by Serogroup 650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥18 isolates in any serogroup (B, C, or Y) are shown.  Other includes PorA types present in <18 isolates in any serogroup (B, C, or Y) .

  32. Most Frequent PorA Types by Syndrome Among NmB Isolates 650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

  33. Most Frequent PorA Types by Age-Group Among NmB Isolates 650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

  34. Most Frequent PorA Types by State Among NmB Isolates Not weighted for Oregon; *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

  35. Most Frequent PorA Types by Year Among NmB Isolates 650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

  36. Relationships between clonal complex and vaccine antigens

  37. FHbpSubvariant by Clonal Complex Among NmB Isolates 650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in ≥25 NmB isolates are shown.  Other includes subvariants present in <25 NmB isolates; **CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  38. Proportion of NmB Isolates with NadA Presence by Clonal Complex 650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  39. NhbA Subvariant by Clonal Complex in NmB Isolates Not weighted for Oregon; 514 isolates not tested for nhbA; *Subvariants that were present in ≥10 NmB isolates are shown.  Other includes subvariants present in <10 NmB isolates; **CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

  40. Summary • FHbp and NhbA are widely distributed among NmB and non-B Nm isolates. All isolates contain one of these two antigens. • NadA is only present in a small subset of Nm isolates. • Proportion of strains with FHbp B/v1 vary by geographic area and age group • Oregon with high B/v1 rates because of the outbreak clone • Young children and elderly more likely to have an A/2-3 strain

  41. Summary • Distribution of the major clonal complexes among the US isolates is relatively stable over time. • PorA in the US isolates is considerably diverse, but composition of the major PorA types did not show significant variation over time • Some association was observed between clonal complex and these vaccine antigens but clonal complex cannot be used to predict vaccine antigen type.

  42. Implications for a serogroup B vaccination program in the U.S. Potential for broad protection against serogroup B and non-B strains Data needed regarding antigen expression and their ability to induce sufficient serum bactericidal activity against the US isolates.

  43. Acknowledgements The MVPDB Epidemiology Team The Meningitis Laboratory Novartis Vaccines Pfizer Vaccine Research University of Pittsburg ABCs Team

  44. Thank you National Center for Immunization & Respiratory Diseases Meningitis and Vaccine Preventable Diseases Branch

  45. NmB Weighting for Oregon • To better estimate the prevalence of vaccine antigens on NmB strains circulating in the US, analyses of NmB isolates are weighted to account for the increased incidence of NmB in Oregon • A weight of 0.10 was assigned to isolates from Oregon • A weight of 0.90 (1-0.10) was assigned to isolates from other ABCs sites • All results presented for NmB will be weighted for Oregon, unless specified

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