1. Effectiveness of Sub-capsular Meningococcal Vaccines An 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. Vaccine EffectivenessY ?
Clinical Endpoint
Efficacy
Immunogenicity
Microbiologic Characterization
hSBA

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:

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:

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:

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:

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:

11. Group B Vaccine Efficacy and Immunogenicity
Location
Study
Design
Age
Group
Efficacy or
Effectiveness
Immunogenicity
Iquique, Chile
Purified OMP
+ C PS, 2 doses
‘87–’89
Vaccine 1995;13(9):821
Prospective,
randomized,
double-blind
(ACWY)
1-21 yr
5 to 21 yr
1-4 yr
All 95% CI included 0
80% for 6 months
51% for 20 months
70% for 20 months
No efficacy
ELISA
IgG greatest in 1-4 yr olds
hSBA (alt. strain)
35% (78%) 4-fold rise
12% (59%) 4-fold rise
Cuba
dOMV, 2 doses
NIPH Ann 1991;14(2):195
(Placebo)
10-14 yr
83% for 16 months
São Paulo, Brazil
‘89–’90
Lancet
1992;340(8827):1074
Retrospective
Case-control
3 mo-6 yr
Age dependent
-37% (<-100, 73) <2 yr
47% (-72, 84) 2-4 yr
74% (16, 92) 4-6 yr
ELISA % 2-fold
81%; 85%; 87% (by age)
hSBA % 4-fold
22% <2 yr
45% 2-4 yr
52% 4-6 yr
Norway
‘88–’91
1991;338(8775):1093
13-21 yr
Time dependent
57.2% (21, 87) for 29 months
(87% at 10 months)
hSBA
97% ≥1:4
80% 4-fold rise
CI wide because of # cases
All 2 doses

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

13. New Zealand Group B Epidemic Vaccine Effectiveness 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
Add about based on OMV AND Tappero Immunogenicity

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, 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
CI look for it

15. Group B hSBA and OMV Vaccines Summary
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. Vaccine EffectivenessY ?
Clinical Endpoint
Efficacy Y
Immunogenicity
Microbiologic Characterization
hSBA

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

20. Antigen Characterization as a Marker of Strain Susceptibility
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. Vaccine EffectivenessY ?
Clinical Endpoint
Efficacy
Immunogenicity
Microbiologic Characterization X
Susceptibility to antibody is
related to antigen variant
and expression level
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 Effectiveness An 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. 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 X
Overlap may decrease breadth
Overlap may also increase with synergy

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 and 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
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