1. 1 Approaches to Demonstrate Effectiveness of Vaccines for Prevention of Group B Meningococcal Disease Introduction Vaccines and Related Biological Products Advisory Committee April 7, 2011

2. 2 Purpose Consider a pathway for demonstration of effectiveness of sub-capsular meningococcal vaccines intended for the prevention of invasive group B meningococcal disease

3. 3 Meningococcal Vaccines Surface structures - Capsule - Major OMPs  PorA, PorB, RMP, Opa - Minor OMPs  many are lipoproteins - LOS – endotoxin Vaccines - Polysaccharide  A, C, ACYW-135  B PS poorly immunogenic - PS-conjugates  ACYW-135  B PS poorly immunogenic - Detoxified outer membrane vesicles (OMV)

4. 4 N. meningitidis Genetic Diversity Mechanisms - Naturally transformable - Extensive mechanisms for DNA uptake and incorporation Impact on Disease Epidemiology - Capsule type, MLST type, OMP types - Epidemics and outbreaks - clonal - Endemic group B disease - diverse

5. 5 Vaccine Effectiveness Measured in what way? - Disease incidence in US is low - Inference from a serologic marker is a possible alternative Against what? - Endemic US group B disease - Antigen sequence and expression diversity among disease strains

6. 6 hSBA as a Measure of Vaccine Effectiveness Evidence supports the use of bactericidal antibody, measured in hSBA assays, as a relevant serologic marker of protection - Studies of military recruits - Efficacy studies of OMP and OMV vaccines  Chile, Cuba, Norway, - Effectiveness  Brazil, New Zealand However, hSBA correlation to effectiveness has been strain specific especially in pediatric populations Clinically relevant indication is for prevention of invasive disease caused by group B N. meningitidis - Broadly protective, not strain specific

7. 7 Demonstration of Effectiveness Therefore, CBER has advised that demonstration of effectiveness will depend on both the immune response to vaccine antigens AND the proportion of disease isolates that are susceptible. - hSBA as a relevant measure of immunogenicity  Bactericidal antibodies to outer membrane protein antigens - Inference of effectiveness for prevention of group B meningococcal disease from immunogenicity  Added complexity due the diversity of strains causing endemic disease - Additional evaluation of effectiveness post marketing  Future product specific discussions

8. 8 Demonstration of Effectiveness (cont.) If hSBA testing of a large representative panel of disease strains is not feasible, then CBER will consider bridging from immunogenicity in clinical studies using strain specific hSBA to diverse disease isolates using microbiologic markers as an alternative - Requires evidence that the marker is:  Predictive of strain susceptibility to antibody mediated killing  Sensitive to the impact of both antigen variant and expression diversity

9. Vaccine Effectiveness ? Clinical Endpoint Efficacy Immunogenicity Microbiologic Characterization

10. Vaccine Effectiveness

11. 11 Presentations Epidemiology of Group B Invasive Meningococcal Disease in the US and Worldwide - Thomas Clark, MD, MPH Molecular Epidemiology and Antigen Diversity of Candidate Vaccine Targets - Leonard Mayer, Ph.D. Effectiveness of Sub-capsular Meningococcal Vaccines - Margaret Bash, MD, MPH Novartis Approaches - Rino Rappuoli, Ph.D. - John Donnelly, Ph.D. Pfizer Approaches - Kathrin Jansen, Ph.D.

12. 12 VRBPAC Discussion Please discuss the evaluation of effectiveness of vaccines for prevention of group 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