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 Demonstration of effectiveness of a new vaccine: Clinical end-point efficacy studies Alternative methods using a serologic marker to infer effectiveness may be acceptable

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

Vaccine Effectiveness Y ? Clinical Endpoint Efficacy Immunogenicity Microbiologic Characterization hSBA

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

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

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

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

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

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

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

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

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

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 CI look for it

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)

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

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

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

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

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

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

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

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

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

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.

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