0 H1N1 Vaccines VRBPAC Meeting Robin Robinson, Ph.D. HHS/ASPR/BARDA Director July 23, 2009.
VRBPAC April 7, 2011
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Transcript of VRBPAC April 7, 2011
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Effectiveness of Sub-capsular Meningococcal Vaccines
An Approach to Evaluate Vaccines for the Prevention of Invasive Group B Meningococcal Disease
VRBPAC April 7, 2011
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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
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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
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Vaccine Effectiveness
?
Clinical EndpointEfficacy
Immunogenicity Microbiologic Characterization
hSBA
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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
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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
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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
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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
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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 pathogenicGoldschneider et al., J Exp Med 1969;129:1307-1326
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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
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Group B Vaccine Efficacy and ImmunogenicityLocation Study
Design Age
Group Efficacy or
Effectiveness Immunogenicity
Iquique, Chile Purified OMP + C PS, 2 doses ‘87–’89Vaccine 1995;13(9):821
Prospective, randomized, double-blind (ACWY)
1-21 yr1-21 yr
5 to 21 yr1-4 yr
All 95% CI included 080% for 6 months51% for 20 months
70% for 20 monthsNo efficacy
ELISAIgG greatest in 1-4 yr olds
hSBA (alt. strain)35% (78%) 4-fold rise12% (59%) 4-fold rise
Cuba dOMV, 2 doses ‘87–’89NIPH Ann 1991;14(2):195
Prospective, randomized, double-blind(Placebo)
10-14 yr 83% for 16 months
São Paulo, Brazil dOMV, 2 doses‘89–’90 Lancet 1992;340(8827):1074
RetrospectiveCase-control
3 mo-6 yr
Age dependent-37% (<-100, 73) <2 yr47% (-72, 84) 2-4 yr74% (16, 92) 4-6 yr
ELISA % 2-fold81%; 85%; 87% (by age)
hSBA % 4-fold22% <2 yr45% 2-4 yr52% 4-6 yr
Norway dOMV, 2 doses ‘88–’91 Lancet 1991;338(8775):1093
Prospective, randomized, double-blind (Placebo)
13-21 yr
Time dependent57.2% (21, 87) for 29
months(87% at 10 months)
hSBA97% ≥1:480% 4-fold rise
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OMV Immunogenicity by Age and Dose
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% 4
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2 doseInfant
3 dose 2 doseChild
3 dose 2 doseAdult
3 dose
hSBA SeroresponseFindlay Vaccine (Cu385 strain)
CH539 CU385 44/76
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% 4
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3 dose 2 doseChild
3 dose 2 doseAdult
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hSBA SeroresponseNorwegian Vaccine (44/76 strain)
CH539 CU385 44/76
Tappero et al., JAMA 1999;281(16):1520–7.
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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
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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
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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)
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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
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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
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Vaccine Effectiveness
?
Clinical EndpointEfficacy
Immunogenicity Microbiologic Characterization
hSBA
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Vaccine Effectiveness
?
Clinical EndpointEfficacy
Immunogenicity Microbiologic Characterization
X X X X X X X X X X X
Can susceptibility to antibody bepredictably related to antigen variant
and expression level?
Antigen similarity and expression
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• 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
hSBA titers of Pre- and Post-immunization Sera by Antigen Marker
1
10
100
1000
0.1 1 10
Antigen Marker Value of N. meningitidis Strains
hS
BA
tit
er
0.1 0.1 0.1 0.3 0.35 0.4 0.6 2 2 5 5.5 6 7.5 8
pre-1
post-1
pre-2
post-2
pre-3
post-3
pre-4
post-4
Antigen Marker Value of Strains
hSBA of Pre- and Post-immunization Sera
Example
Example
Pre-
Post-
Antigen Characterization as a Marker of Strain Susceptibility
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Vaccine Effectiveness
Bridge Immunogenicityto Effectiveness
?
Clinical EndpointEfficacy
Immunogenicity Microbiologic Characterization
X X X X X X X X X X X
Susceptibility to antibody isrelated to antigen variant
and expression level
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• 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
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% S
trai
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Kill
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Antigen marker (units)
Strain Susceptibility vs. Antigen Marker
hSBAteststrain
Antigen Marker of Strain Susceptibility Bridges hSBA Test Strain to Endemic Isolates
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Microbiologic Bridge to Estimate Effectiveness An Example for Vaccine Component Protein “P”
0
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% a
bo
ve
T
hre
sh
old
Tit
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Pre- Post
hSBA Immunogenicity .
hSBA-1
hSBA-2
hSBA-3
Endemic Disease Isolates
0
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100
1 2 3 4 5 6 7 8 9 10 11 12P-m units
% o
f is
ola
tes
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
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• 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%10% = 86%
• No measure for synergistic effect of cooperative killing by antibodies to several antigens
Microbiologic Bridge – An Example
X X
X
X
XX
X
X
XX
X
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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.
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Benefits and Limitations
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