Effectiveness of Sub-capsular Meningococcal Vaccines An Approach to Evaluate Vaccines for the...

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

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

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

-Fo

ld R

ise

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

-Fo

ld R

ise

2 doseInfant

3 dose 2 doseChild

3 dose 2 doseAdult

3 dose

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

Vaccine Effectiveness

?

Clinical EndpointEfficacy

Immunogenicity Microbiologic Characterization

hSBA

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

Vaccine Effectiveness

Bridge Immunogenicityto Effectiveness

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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

0

1020

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% S

trai

ns

Kill

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1 2 3 4 5 6 7 8 9 10

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”

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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

20

40

60

80

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