Use of Use of Immunogenicity Immunogenicity Data to AssessData to Assess

Vaccine EffectivenessVaccine EffectivenessCara R. Fiore, Ph D

Microbiologist, Master ReviewerOffice of Vaccines Research and Review

Center for Biologics Evaluation and ResearchU. S. Food and Drug Administration

Phacilitate Washington Vaccine Forum, 2013

National Center for Toxicological Research

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and TobaccoOffice of Global Regulatory

Operations and Policy

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CBER OverviewCBER Overview

OVRR Regulates:OVRR Regulates: Vaccines for Infectious Disease IndicationsVaccines for Infectious Disease Indications

Live attenuated preparations of bacteria or viruses Inactivated or killed whole organisms Polysaccharides (+/- protein conjugates) Purified proteins, inactivated toxins VLPs DNA vaccines Vectored vaccines

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Phase 1 Phase 2 Phase 3 Phase 4

Safety Safety, Effectiveness

Safety, Immunogenicity

Pre IND

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Development Development of Preventive Vaccinesof Preventive Vaccines

Initial product characterizationPreclinical Safety & Immunogenicity

Optimization of Manufacturing Process Process Validation

Assay Development & Assay Validation Assay Development & Assay Validation (EOP2)(EOP2)

Final Product Specifications Final Formulation/Dosage

Clinical Serologic Assay DataClinical Serologic Assay Data

CMC – Immunogenicity Bridging manufacturing changes

• New facility • Continued/additional product development

Lot consistency

Clinical – Immunogenicity and Effectiveness (inferred efficacy) Demonstration of non-inferiority of relevant immune response

• Comparison to current standard of care • Comparison to sera from an efficacy trial with a clinical

endpoint Non-interference with concomitant vaccines

Immunogenicity data to evaluate effectiveness

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Use of Immunogenicity Data to Use of Immunogenicity Data to Evaluate Vaccine EffectivenessEvaluate Vaccine Effectiveness

Clinical end-point efficacy studies are the Gold Standard

Why/When to use serologic data to evaluate vaccine effectiveness?

Clinical efficacy study not possible• Burden of disease too low • Biodefense products (Animal Rule)

New population (age group) for which there is no comparator

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Clinical Assay ConsiderationsClinical Assay Considerations New population where there is no comparator

Assay selection Functional antibody assays vs. ELISA Scientific rationale and practical advantages Is it an acceptable correlate of protection?

Assay validation should demonstrate that it is suitable for its intended purpose

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Example 1: Example 1: Meningococcal Conjugate VaccinesMeningococcal Conjugate Vaccines

Neisseria meningitidis

Using data from serologic assays to evaluate vaccine effectiveness

Anti-polysaccharide IgG antibody assay Serum bactericidal activity (SBA) assay

Meningococcal anti-PS antibody measured by ELISA does not always correlate with

functional antibody measured by complement-mediated SBA

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Serum Bactericidal Activity Serum Bactericidal Activity (SBA)(SBA)

Measures the antibody dependent complement mediated killing of the specific meningococcal strain in vitro

Critical factors - defined and adequately controlled: Complement –

• Human (h) vs. rabbit (r) • individual vs. pooled source

Choice of target strain Assay conditions Meningococci + Complement + Sera: Incubate: survival of

meningococci. Antibody titer = highest dilution that results in killing of ≥ 50% cfu of target strain

Data support the use of SBA as an immunologic correlate of meningococcal conjugate vaccine effectiveness

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VRBPAC 1999VRBPAC 1999Vaccines and Related Biological Products Advisory

Committee Meeting

VRBPAC agreed that new meningococcal vaccines could be evaluated using immunologic assays

Serum bactericidal activity was an appropriate parameter to evaluate immunogenicity of a new vaccine in age groups for which the current meningococcal vaccine is licensed for use

FDA implementation: SBA has been used to evaluate the immunogenicity of new meningococcal vaccines in comparison

to the currently licensed vaccine (Mn ps)

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U.S. Licensed Meningococcal U.S. Licensed Meningococcal VaccinesVaccines

Menomune 1981 (>2 yo). (A, C, Y, W-135) PSPS vaccine, licensed based on efficacy data for A and C only. Not enough disease in W-135 and Y. W-135 and Y were based on 4 fold rise of SBA in 90% of vaccinees.

Menactra - Quadravalent (A, C, Y, W-135) PS PS conjugateconjugate 2005: 11-55 yo

4-fold rise rSBA non-inferiority to Menomune 2007: 2-10 yo

% ≥ 1:8 hSBA non-inferiority to Menomune 2011, 9-23mo

% ≥ 1:8 hSBA (no comparator)Menveo - Quadravalent (A, C, Y, W-135) PS conjugate 2010: 11-55 yo

% ≥ 1:8 hSBA non-inferiority to Menactra 2011: 2-10 yo

% ≥ 1:8 hSBA non-inferiority to MenactraMenHibrix – (C and Y) and Hib Conjugate Vaccine 2012: 6 wks – 18 mo

% ≥ 1:8 hSBA (no comparator); Hib: non-inferiority to US-licensed monovalent Hib 13

VRBPAC April 6, 2011VRBPAC April 6, 2011 VRBPAC was asked to “comment on the use of hSBA as

an immune measure to infer effectiveness of meningococcal conjugate vaccine for children younger than two years old.”

The Advisory Committee agreed that data supported the role of functional antibody in protection from meningococcal disease and that vaccine effectiveness can be inferred from serum bactericidal activity measurements in children less than 2 years of age. 

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U.S. Licensed Meningococcal U.S. Licensed Meningococcal VaccinesVaccines

Menomune 1981 (>2 yo). (A, C, Y, W-135) PS vaccine, licensed based on efficacy data for A and C only. Not enough disease in W-135 and Y. W-135 and Y were based on 4 fold rise of SBA in 90% of vaccinees.

Menactra - Quadravalent (A, C, Y, W-135) PS conjugate 2005: 11-55 yo

4-fold rise rSBA non-inferiority to Menomune 2007: 2-10 yo

% ≥ 1:8 hSBA non-inferiority to Menomune 2011, 9-23mo

% ≥ 1:8 hSBA (no comparator)Menveo - Quadravalent (A, C, Y, W-135) PS conjugate 2010: 11-55 yo

% ≥ 1:8 hSBA non-inferiority to Menactra 2011: 2-10 yo

% ≥ 1:8 hSBA non-inferiority to MenactraMenHibrix – (C and Y) and Hib Conjugate Vaccine 2012: 6 wks – 18 mo

% ≥ 1:8 hSBA (no comparator); Hib: non-inferiority to US-licensed monovalent Hib 15

Example 2: Example 2: Pneumococcal Conjugate Vaccines Pneumococcal Conjugate Vaccines

Streptococcus pneumoniae

Using data from serologic assays to evaluate vaccine effectiveness

ELISA – Serotype specific IgG Infants

• IgG antibody levels are associated with protection from invasive pneumococcal disease

• Good correlation between IgG and pediatric serum OPA titers Older children and adults

• Not considered to be an appropriate endpoint.

Opsonophagocytic Antibody (OPA) Assay OPA measures functional antibodies which play a critical role in

protection against pneumococcus; directed at capsular antigens 16

Opsonophagocytic Antibody Opsonophagocytic Antibody Assay (OPA)Assay (OPA)

The OPA measures the ability of functional antibody to bind and opsonize the target bacteria in the presence of a complement source, engulfment by phagocytic human cells (HL-60 cells.)

Polysaccharide bound human antibodies activate the complement mediated opsonization through the classical

pathway.4 components

Human Sera + pneumococcus + complement + HL-60 cellsOPA titer = reciprocal of the lowest serum dilution that

results in complement-dependent killing of 50% of the bacteria in vitro.

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US Licensed Pneumococcal US Licensed Pneumococcal VaccinesVaccines

Pneumovax 23 (1983) Multivalent (23) polysaccharide vaccine. 50 years of age or older, and persons aged ≥2 years who are at

increased risk for pneumococcal disease. Efficacy of PS vaccines evaluated in several clinical trials

Prevnar - 7 valent polysaccharide conjugate vaccine Clinical endpoint efficacy trials:

2000: infants and toddlers against invasive disease caused by S. pneumoniae vaccine serotypes

2002: infants and toddlers against otitis media caused by S. pneumoniae vaccine serotypes

VRBPAC 2001 - advised that for new pneumococcal vaccines effectiveness could be inferred from non-inferiority studies using ELISA to measure GMT. Immunologic endpoint trial.

Prevnar 13 18

US Licensed Pneumococcal US Licensed Pneumococcal Vaccines, con’tVaccines, con’t

Prevnar 13 – 13 valent polysaccharide conjugate vaccine 2010: Licensed in 6 weeks through 5 years of age.

Prevention of invasive disease caused by S. pneumoniae vaccine specific serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F).

Prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.

The efficacy was inferred from comparisons to Prevnar 7 using IgG (ELISA) to measured the production of vaccine type (VT) functional antibody.

VRBPAC 2005 – emphasized the need for clinical endpoint studies while acknowledging challenges, accelerated approval reasonable path

VRBPAC 2011 IgG does not correlate with functional antibody for older children and

adults. Therefore, IgG measurement was not considered to be an appropriate endpoint in these age groups. OPA - used as the “surrogate endpoint that is reasonably likely… to predict clinical benefit” of Prevnar 13 in adults.

2012: Licensed for ≥ 50 years of age for active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F using the OPA as a surrogate endpoint (confirmatory trial). 19

Example 3Example 3Meningococcal Protein Vaccines Meningococcal Protein Vaccines

for Serogroup Bfor Serogroup B No US licensed vaccine available.

Broad range of endemic serogroup B isolates, i.e., many antigenically diverse strains.

Experimental and epidemiologic data support complement-mediated bactericidal activity as the predominant mechanism of human protection from invasive meningococcal disease.

Performing hSBA assays against all disease causing strains is not possible. Therefore methods to assess how hSBA measured against a subset of strains can predict protection against other strains are being investigated. 20

VRBPAC April 7, 2011VRBPAC April 7, 2011 Advisory committee was asked to consider regulatory pathways to

evaluate the effectiveness of meningococcal vaccines for prevention of serogroup B disease

Specifically, they were requested to discuss the evaluation of effectiveness of vaccines for prevention of serogroup B meningococcal disease based on:

Bactericidal antibodies to OMP antigens tested in hSBA assays

Bridging test strain specific hSBA to endemic disease isolates using microbiologic characterization that predicts strain susceptibility

Committee considered that bactericidal antibodies to OMP antigens of test strains measured in hSBA assays was appropriate for evaluation of effectiveness of group B vaccines

Committee discussed that bridging of test strain-specific hSBA to endemic disease isolates using microbiologic characterization requires more data to predict susceptibility of disease strains

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Summary: Summary: Demonstration of EffectivenessDemonstration of Effectiveness

Gold Standard: Clinical endpoint efficacy study

The clinical serologic assay should measure directly, or correlate with, the biological function that is associated with protective immunity.

Immunogenicity Assessment: Serologic endpoint

Non inferiority: Licensure on the basis of a comparison to licensed product.

In populations where no direct comparison is possible:

• Accepted immune marker of protection Menactra® in children 9 month to 23 mo MenHibrix ® in children 6 wks to 18 mo Prevnar 13 ® in adults ≥ 50 years of age (Accelerated

Approval)22

Take Home MessageTake Home Message

Using serologic endpoints to infer vaccine efficacy:

Ideally, we understand the immunologic basis for protection

Ideally, there is a well established measurable correlate of protection

Need to develop an assay that can be well validated and conducted to provide accurate results reliably

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Thanks!Thanks!

Margaret Bash, MD, MPHMargaret Bash, MD, MPH

Elizabeth Sutkowski, Ph DElizabeth Sutkowski, Ph D

Wellington Sun, MDWellington Sun, MD

cara.fiore@fda.hhs.gov

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ReferencesReferences

VRBPAC transcripts and briefing VRBPAC transcripts and briefing packages:packages:

http://www.fda.gov/AdvisoryCommittees/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdVaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm241549.htmvisoryCommittee/ucm241549.htm

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