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VRBPAC April 7, 2011

Effectiveness of Sub-capsular Meningococcal Vaccines An Approach to Evaluate Vaccines for the Prevention of Invasive Group B Meningococcal Disease. VRBPAC April 7, 2011. Vaccine Effectiveness. Requirement for evidence of safety and effectiveness

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VRBPAC April 7, 2011

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  1. Effectiveness of Sub-capsular Meningococcal VaccinesAn Approach to Evaluate Vaccines for the Prevention of Invasive Group B Meningococcal Disease VRBPAC April 7, 2011

  2. Vaccine Effectiveness • Requirement for evidence of safety and effectiveness • Demonstration of effectiveness of a new vaccine: • Clinical end-point efficacy studies • Alternative methods using a serologic marker to infer effectiveness may be acceptable

  3. Evaluation of Effectiveness • Evaluation of Sub-capsular Vaccines for Prevention of Group B Meningococcal Disease • Step 1: Immunogenicity – hSBA based on vaccine antigens • Are bactericidal antibodies to protein antigens protective? • Historical support for using hSBA as an appropriate serologic marker in the context of protein vaccines for prevention of Group B disease • Age-specific; dose-specific; strain-specific immunogenicity • Step 2: Microbiologic Bridge - Determine the proportion of disease isolates susceptible to vaccine induced bactericidal antibodies • Are antibodies that are bactericidal to one strain protective against other strains? • Correlate antigen specific hSBA killing to antigen variant and expression levels

  4. ? Clinical Endpoint Efficacy hSBA Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Immunogenicity Microbiologic Characterization Vaccine Effectiveness

  5. hSBA as a Serologic Marker of Protection from Group B Disease • Antibody-dependent complement mediated bactericidal activity is the predominant mechanism of protection from invasive meningococcal disease • Bactericidal antibody measured in hSBA assays predicts protection • Applies to group B meningococcal disease • Applies to anti-outer membrane protein (OMP) antibody

  6. Invasive Disease Occurred in Recruits that Lacked Bactericidal Antibody • Prospectively bled 14,744 recruits; processed and stored active C’ sera at -70oC • Baseline sera from cases and platoon matched controls tested for intrinsic SBA against disease isolate. Baseline sera were bactericidal against the disease strain in 5.6% of cases vs. 82.2% of controls Goldschneider et al., J Exp Med 1969;129:1307-1326

  7. Normal Complement Function in Cases • Anti-strain C-11 IgG hSBA titer using baseline sera from cases as the complement source. Eight baseline non-bactericidal sera from cases were able to support bactericidal activity in the presence of specific antibody Goldschneider et al., J Exp Med 1969;129:1307-1326

  8. hSBA is Antibody Dependent • Convalescent sera from cases were bactericidal • Strain specific IgG, IgM and IgA were absent in baseline sera and present in convalescent sera Goldschneider et al., J Exp Med 1969;129:1307-1326

  9. Susceptibility to Disease is Strain Specific • 11 recruits that lacked baseline hSBA to the circulating group C disease isolate did have baseline hSBA to the group C isolate they were exposed to • These were sulfonamide resistant encapsulated group C strains • Non-capsular bactericidal antibody was protective or strains were not pathogenic Goldschneider et al., J Exp Med 1969;129:1307-1326

  10. Naturally Acquired Group B Bactericidal Antibodies • Meningococcal disease (-Δ-) is inversely related to the prevalence of bactericidal activity (-●-) Goldschneider et al., J Exp Med 1969;129:1307-1326

  11. Group B Vaccine Efficacy and Immunogenicity

  12. OMV Immunogenicity by Age and Dose Tappero et al., JAMA 1999;281(16):1520–7.

  13. New Zealand Group B Epidemic VaccineEffectiveness Experience • Based on the previous efficacy and immunogenicity studies, an OMV vaccine was developed to address a persistent group B meningococcal epidemic • Three doses (4th booster dose added for infants) • Approval in New Zealand based on safety and immunogenicity • Estimates of effectiveness during and following public health scale immunization

  14. hSBA and Effectiveness – New Zealand • New Zealand OMV vaccine • hSBA sero-response defined as 4-fold rise • Infants (6-10 weeks, 4 doses): 69% (54, 80) • 6-8 months, 16-24 months, 8-12 years (3 doses): 74-75% (67, 80) • Estimated efficacy • 73% (52, 85) in individuals <20 years using statistical model • No age dependent differences in effectiveness estimates • 80% (52.5, 91.6) in 6 month to <5 year olds using an observational cohort study • Lennon et al., CID 2009; 49:597 • Kelly et al., Am J Epi 2007; 166;817 • Galloway et al., Int J Epi 2009; 38:413

  15. Group B hSBA and OMV VaccinesSummary • Bactericidal antibody measured by hSBA is a meaningful serologic marker of protection in the context of non-capsular vaccines and group B meningococcal disease • Duration of protection mirrored hSBA antibody persistence (Norwegian OMV vaccine) • Age-related efficacy consistent with hSBA but not ELISA (Chile, Brazil studies) • Breadth of immune response increases with age and number of doses (Tappero et al.) • Infant immune response was effective against the epidemic strain following 3 or 4 immunizations (New Zealand OMV vaccine)

  16. Vaccines for Prevention of Endemic Group B Meningococcal Disease • How does hSBA serology from clinical vaccine studies relate to effectiveness against endemic group B meningococcal disease? • Optimally, sera from clinical studies would be tested for bactericidal activity against strains causing invasive group B meningococcal disease in the population • Technically not feasible if: • hSBA assays for 150 to 200 strains are needed • Using fully validated assays and separate complement sources

  17. Bridging from hSBA Test Strains to Endemic Disease Isolates • CBER advice • If the number and diversity of strains tested by hSBA are limited then a link between test strains and disease isolates must be established • Approach to bridging should: • Provide strong experimental evidence of a correlation between antigen characterization and susceptibility to bactericidal antibody • Address age related differences in breadth of coverage • Directly link clinical immunogenicity to inferred effectiveness against relevant disease isolates

  18. Y ? Y Y Y Y Y Clinical Endpoint Efficacy hSBA Y Y Y Y Y Y Y Y Y Y Y Y Immunogenicity Microbiologic Characterization Vaccine Effectiveness

  19. Y ? Y Y Y Y Y Y Y Y Y Y Clinical Endpoint Efficacy Y Y Y X X X X X X X X X X X Y Y Antigen similarity and expression Can susceptibility to antibody be predictably related to antigen variant and expression level? Y Y Immunogenicity Microbiologic Characterization Vaccine Effectiveness

  20. Example Antigen Characterization as a Marker of Strain Susceptibility Post- • Identify a method to characterize the vaccine antigen in isolates • Antigen marker that is sensitive to degree of homology and expression • Characterize isolates with a range of antigen variants and expression levels • Test for correlation between antigen marker and susceptibility to specific complement-dependent killing Pre- Example

  21. Y ? Y Y Y Y Y Y Y Y Y Y Clinical Endpoint Efficacy Y Y Y X X X X X X X X X X X Y Y Susceptibility to antibody is related to antigen variant and expression level Y Y Immunogenicity Microbiologic Characterization Vaccine Effectiveness Bridge Immunogenicity to Effectiveness

  22. Antigen Marker of Strain Susceptibility Bridges hSBA Test Strain to Endemic Isolates • Characterize marker in hSBA test strain • From the subset of strains tested in correlation studies, determine the proportion of strains with antigen marker ≥ hSBA test strain that are susceptible to killing • Use this microbiologic marker and the associated proportion of strains predicted to be susceptible to bridge from clinical immunogenicity to estimated effectiveness hSBA test strain

  23. Microbiologic Bridge to Estimate EffectivenessAn Example for Vaccine Component Protein “P” Microbiologic Bridge – Established Prior to Pivotal Study • Protein P variant and expression diversity measured by marker “P-m” • Susceptibility to anti-P bactericidal antibodies correlate with “P-m” • 90% of isolates with “P-m” at or above the hSBA test strain (P-mtest) are susceptible Clinical Immunogenicity • Bactericidal anti-P hSBA sero-response occurs in 85% of vaccinees Inferred Effectiveness • P is antigenically similar and expressed at equal or higher levels than the hSBA test strain in 50% of disease isolates

  24. X X X X X X X X X X X Microbiologic Bridge – An Example • Contribution to effectiveness from “P” 0.85 (proportion of vaccinees that responded) x 0.50 (proportion of endemic isolates expressing “P” ≥ P-mtest) x 0.90 (proportion of strains susceptible if they express “P” ≥ P-mtest) = 38% for the one vaccine component “P” • Multiple antigens may have additive effects = 38% + 38% + 10% = 86% • No measure for synergistic effect of cooperative killing by antibodies to several antigens

  25. An Approach to Evaluating the Effectiveness of Vaccines for Group B Meningococcal Disease • Evidence supports that: • Bactericidal antibodies to protein antigens are protective, and • hSBA is a serologic marker of strain-specific protection against group B invasive disease • Endemic group B disease is caused by antigenically diverse strains • Effectiveness will depend on both the immune response to vaccine antigens AND the proportion of disease isolates that are susceptible • Thus, hSBA titer determinations in sera from vaccinees combined with microbiologic bridging from hSBA strains to disease isolates may be an approach for estimating effectiveness • Estimating effectiveness using microbiologic characterization will depend on a strong correlation between the target antigen and strain susceptibility.

  26. Benefits Based on historical evidence of hSBA and OMV vaccine efficacy Provides a pathway to facilitate vaccine development and evaluation Provides a description of the limitations of a vaccine given disease isolate diversity Once established, microbiologic marker may be a useful tool in evaluating vaccine relevance over time Limitations Experimental correlation cannot sample all isolates or all sera – estimate of effectiveness will have some inherent uncertainty Correlation between microbiologic marker and strain susceptibility is likely dependent on age of vaccinees Less breadth of coverage in infants Limited sera from infants Disease burden is relatively low which affects risk-benefit assessment Benefits and Limitations

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