1. Use of Immunogenicity Data to Assess Vaccine Effectiveness Cara R. Fiore, Ph D Microbiologist, Master Reviewer Office of Vaccines Research and Review Center for Biologics Evaluation and Research U. S. Food and Drug Administration Phacilitate Washington Vaccine Forum, 2013

2. National Center for Toxicological Research 2 Office of the Commissioner Center for Drug Evaluation and Research Center for Biologics Evaluation and Research Center for Tobacco Products Center for Food Safety And Applied Nutrition Center for Veterinary Medicine Center for Devices and Radiological Health Office of Regulatory Affairs Office of Foods Office of Medical Products and Tobacco Office of Global Regulatory Operations and Policy FDA Overview

3. Office of Management Office of the Director Office of Vaccines Research and Review Office of Biostatistics and Epidemiology Office of Blood Research and Review Office of Cellular, Tissue and Gene Therapies Office of Compliance and Biologics Quality Office of Communication, Outreach and Development 3 CBER Overview

4. OVRR Regulates: Vaccines 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 4

5. Phase 1 Phase 2 Phase 3 Phase 4 Safety Safety, Effectiveness Safety, Immunogenicity Pre IND 7 Development of Preventive Vaccines Initial product characterization Preclinical Safety & Immunogenicity Optimization of Manufacturing Process Process Validation Assay Development & Assay Validation (EOP2) Final Product Specifications Final Formulation/Dosage

6. Clinical 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 6

7. Use of Immunogenicity Data to Evaluate 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 7

8. Clinical Assay Considerations Clinical 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 8

9. Example 1: Meningococcal Conjugate Vaccines Example 1: Meningococcal 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 9

10. Serum Bactericidal Activity (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 10

11. VRBPAC 1999 Vaccines 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) 12

12. U.S. Licensed Meningococcal Vaccines PS 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. PS conjugate 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 Menactra MenHibrix – (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

13. VRBPAC 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. 14

14. U.S. Licensed Meningococcal Vaccines 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 Menactra MenHibrix – (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

15. Example 2: Pneumococcal Conjugate Vaccines Example 2: 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

16. Opsonophagocytic Antibody 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 cells   OPA titer = reciprocal of the lowest serum dilution that results in complement-dependent killing of 50% of the bacteria in vitro. 17

17. US Licensed Pneumococcal Vaccines 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

18. US Licensed Pneumococcal Vaccines, 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

19. Example 3 Meningococcal Protein Vaccines for 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

20. VRBPAC 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 21

21. Summary: Demonstration 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

22. Take 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 23

23. Thanks! Margaret Bash, MD, MPH Elizabeth Sutkowski, Ph D Wellington Sun, MD cara.fiore@fda.hhs.gov 24

24. References  VRBPAC transcripts and briefing packages: http://www.fda.gov/AdvisoryCommittees/C ommitteesMeetingMaterials/BloodVaccine sandOtherBiologics/VaccinesandRelatedB iologicalProductsAdvisoryCommittee/ucm2 41549.htm 25